RESUMEN
PURPOSE: To develop a risk score based on a prognostic model and a nomogram integrating baseline clinicopathological variables to predict bladder cancer-specific survival (BCSS) to neoadjuvant chemotherapy (NAC) in muscle-invasive bladder cancer (MIBC) patients. METHODS: We retrospectively identified a consecutive sample of 247 MIBC patients treated with cisplatin-based NAC-plus-cystectomy in two Spanish hospitals between 2000 and 2019. Age at MIBC diagnosis, sex, histology, lymphovascular invasion, previous non-MIBC, hydronephrosis, and clinical TNM were included in the initial Cox regression model. A risk score was computed based on the final prognostic model and a nomogram was used to estimate BCSS at 2 and 5 years. RESULTS: Median age was 66 years; 89% were males; 83% had pure urothelial carcinoma; 16.2% had previous non-MIBC. Clinical stage was T2N0, T3-4aN0, and Tx-4N + in 24%, 57%, and 19% of patients, respectively. Complete pathological response was seen in 29.4% and downstaging to non-MIBC (ypT1, ypTa, ypTis) in 12.5% of patients. Overall 5-year BCSS was 59%. Four prognostic factors were identified: variant histology, previous non-MIBC, female sex and hydronephrosis. By adding the points attributed to each of these factors, we categorized patients in three groups: low-risk (0 points); intermediate-risk (1-9 points); high-risk (≥ 10 points). Five-year BCSS was 72%, 53%, and 15%, respectively (p < 0.0001). CONCLUSION: We developed a nomogram and risk score based on four baseline clinicopathological characteristics to predict BCSS to NAC-plus-cystectomy in MIBC patients. If validated in prospective studies, this nomogram can be useful for selecting patients likely to benefit from NAC.
Asunto(s)
Carcinoma de Células Transicionales , Hidronefrosis , Neoplasias de la Vejiga Urinaria , Masculino , Humanos , Femenino , Anciano , Neoplasias de la Vejiga Urinaria/patología , Terapia Neoadyuvante , Carcinoma de Células Transicionales/patología , Nomogramas , Estudios Prospectivos , Estudios Retrospectivos , Invasividad Neoplásica , Cistectomía , MúsculosRESUMEN
Since 2010, several treatment options have been available for men with metastatic castration-resistant prostate cancer (mCRPC), including immunotherapeutic agents, although the clinical benefit of these agents remains inconclusive in unselected mCRPC patients. In recent years, however, immunotherapy has re-emerged as a promising therapeutic option to stimulate antitumor immunity, particularly with the use of immune checkpoint inhibitors (ICIs), such as PD-1/PD-L1 and CTLA-4 inhibitors. There is increasing evidence that ICIs may be especially beneficial in specific subgroups of patients with high PD-L1 tumor expression, high tumor mutational burden, or tumors with high microsatellite instability/mismatch repair deficiency. If we are to improve the efficacy of ICIs, it is crucial to have a better understanding of the mechanisms of resistance to ICIs and to identify predictive biomarkers to determine which patients are most likely to benefit. This review focuses on the current status of ICIs for the treatment of mCRPC (either as monotherapy or in combination with other drugs), mechanisms of resistance, potential predictive biomarkers, and future challenges in the management of mCRPC.
Asunto(s)
Adenocarcinoma/secundario , Antineoplásicos Inmunológicos/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia/métodos , Neoplasias de la Próstata Resistentes a la Castración/terapia , Adenocarcinoma/terapia , Antineoplásicos Inmunológicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores , Ensayos Clínicos como Asunto , Reparación del ADN/genética , Resistencia a Antineoplásicos , Predicción , Humanos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Masculino , Proteínas de Transporte de Membrana/efectos de los fármacos , Estudios Multicéntricos como Asunto , Proteínas de Neoplasias/antagonistas & inhibidores , Compuestos Organoplatinos/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Medicina de Precisión/métodos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Taxoides/administración & dosificaciónRESUMEN
In this article, we propose a Wright-Fisher model with two types of individuals: the inefficient individuals, those who need more resources to reproduce and can have a higher growth rate, and the efficient individuals. In this model, the total amount of resource N is fixed, and the population size varies randomly depending on the number of efficient individuals. We show that, as N increases, the frequency process of efficient individuals converges to a diffusion which is a generalization of the Wright-Fisher diffusion with selection. The genealogy of this model is given by a branching-coalescing process that we call the Ancestral Selection/Efficiency Graph, and that is an extension of the Ancestral Selection Graph (Krone and Neuhauser, 1997a,b). The main contribution of this paper is that, in evolving populations, inefficiency can arise as a promoter of selective advantage and not necessarily as a trade-off.
Asunto(s)
Genética de Población , Modelos Genéticos , Humanos , Densidad de Población , Selección GenéticaRESUMEN
Neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy is the recommended treatment, with the highest level of evidence, for patients with muscle-invasive bladder cancer (MIBC). However, only a minority of patients receive this treatment, mainly due to patient comorbidities, the relatively small survival benefit, and the lack of predictive biomarkers to select those patients most likely to benefit from this multimodal approach. In addition, adjuvant chemotherapy has been recommended for patients with high-risk MIBC, although randomized trials have not provided conclusive evidence on the impact of this approach. At present, however, this situation is changing, largely due to our improved knowledge of the molecular biology of bladder cancer, which has enabled us to identify new prognostic and predictive biomarkers that can be used to select the most appropriate treatment for each patient. Moreover, new active treatments, especially immunotherapy, have shown promising results in the neoadjuvant setting. In addition, the gene expression profile of bladder tumors can be used to classify them into different subtypes, which correlate with specific clinical-pathological characteristics and with treatment response or resistance. Therefore, the main objective for the near future is to introduce these translational breakthroughs into routine clinical practice in order to personalize treatment for each patient.
Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma de Células Transicionales/terapia , Cisplatino/uso terapéutico , Cistectomía/métodos , Neoplasias de la Vejiga Urinaria/terapia , Carcinoma de Células Transicionales/genética , Quimioterapia Adyuvante , Terapia Combinada , Comorbilidad , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Medicina de Precisión , Nivel de Atención , Análisis de Supervivencia , Neoplasias de la Vejiga Urinaria/genéticaRESUMEN
Homologous recombination (HR) is a DNA repair pathway that is deficient in 50% of high-grade serous ovarian carcinomas (HGSOC). Deficient HR (DHR) constitutes a therapeutic opportunity for these patients, thanks to poly (ADP-ribose) polymerases (PARP) inhibitors (PARPi; olaparib, niraparib, and rucaparib are already commercialized). Although initially, PARPi were developed for patients with BRCA1/2 mutations, robust clinical data have shown their benefit in a broader population without DHR. This breakthrough in daily practice has raised several questions that necessitate further research: How can populations that will most benefit from PARPi be selected? At which stage of ovarian cancer should PARPi be used? Which strategies are reasonable to overcome PARPi resistance? In this paper, we present a summary of the literature and discuss the present clinical research involving PARPi (after reviewing ClinicalTrials.gov) from a translational perspective. Research into the functional biomarkers of DHR and clinical trials testing PARPi benefits as first-line setting or rechallenge are currently ongoing. Additionally, in the clinical setting, only secondary restoring mutations of BRCA1/2 have been identified as events inducing resistance to PARPi. The clinical frequency of this and other mechanisms that have been described in preclinics is unknown. It is of great importance to study mechanisms of resistance to PARPi to guide the clinical development of drug combinations.
Asunto(s)
Recombinación Homóloga , Neoplasias Ováricas/genética , Investigación Biomédica Traslacional , Animales , Antineoplásicos/uso terapéutico , Ensayos Clínicos como Asunto , Femenino , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéuticoRESUMEN
Pediatric glioma recurrence can cause morbidity and mortality; however, recurrence pattern and severity are heterogeneous and challenging to predict with established clinical and genomic markers. Resultingly, almost all children undergo frequent, long-term, magnetic resonance (MR) brain surveillance regardless of individual recurrence risk. Deep learning analysis of longitudinal MR may be an effective approach for improving individualized recurrence prediction in gliomas and other cancers but has thus far been infeasible with current frameworks. Here, we propose a self-supervised, deep learning approach to longitudinal medical imaging analysis, temporal learning, that models the spatiotemporal information from a patient's current and prior brain MRs to predict future recurrence. We apply temporal learning to pediatric glioma surveillance imaging for 715 patients (3,994 scans) from four distinct clinical settings. We find that longitudinal imaging analysis with temporal learning improves recurrence prediction performance by up to 41% compared to traditional approaches, with improvements in performance in both low- and high-grade glioma. We find that recurrence prediction accuracy increases incrementally with the number of historical scans available per patient. Temporal deep learning may enable point-of-care decision-support for pediatric brain tumors and be adaptable more broadly to patients with other cancers and chronic diseases undergoing surveillance imaging.
RESUMEN
Background: Docetaxel remains the standard treatment for metastatic castration-resistant prostate cancer (mCRPC). However, resistance frequently emerges as a result of hyperactivation of the PI3K/AKT and the MEK/ERK pathways. Therefore, the inhibition of these pathways presents a potential therapeutic approach. In this study, we evaluated the efficacy of simultaneous inhibition of the PI3K/AKT and MEK/ERK pathways in docetaxel-resistant mCRPC, both in vitro and in vivo. Methods: Docetaxel-sensitive and docetaxel-resistant mCRPC cells were treated with selumetinib (MEK1/2 inhibitor), AZD8186 (PI3Kß/δ inhibitor) and capivasertib (pan-AKT inhibitor) alone and in combination. Efficacy and toxicity of selumetinib+AZD8186 were tested in docetaxel-resistant xenograft mice. CRISPR-Cas9 generated a PTEN-knockdown docetaxel-resistant cell model. Changes in phosphorylation of AKT, ERK and downstream targets were analyzed by Western blot. Antiapoptotic adaptations after treatments were detected by dynamic BH3 profiling. Results: PI3K/AKT and MEK/ERK pathways were hyperactivated in PTEN-wild-type (wt) docetaxel-resistant cells. Selumetinib+AZD8186 decreased cell proliferation and increased apoptosis in PTEN-wt docetaxel-resistant cells. This observation was further confirmed in vivo, where docetaxel-resistant xenograft mice treated with selumetinib+AZD8186 exhibited reduced tumor growth without additional toxicity. Conclusion: Our findings on the activity of selumetinib+AZD8186 in PTEN-wt cells and in docetaxel-resistant xenograft mice provide an excellent rationale for a novel therapeutic strategy for PTEN-wt mCRPC patients resistant to docetaxel, in whom, unlike PTEN-loss patients, a clinical benefit of treatment with single-agent PI3K and AKT inhibitors has not been demonstrated. A phase I-II trial of this promising combination is warranted.
RESUMEN
BACKGROUND: Cutaneous melanoma is the skin cancer with the highest mutational burden and metastatic rate. Early genetic alterations and biomarkers of distant progression are a point of interest. In addition to germline-susceptibility loci, almost 30% of melanomas arise from precursor benign nevi lesions, providing a source for malignant transformation. CASE PRESENTATION: Patient#009 developed a cutaneous melanoma over a nevus, followed by progression to regional and distant metastases in months, unresponsive to targeted therapy. To search for the genetic contribution to this rapid progression, a longitudinal analysis was performed through WES of germline, nevi, primary tumor, and a metastatic lymph node. Differential SNP/INDEL and CNV gene alterations, with functional impact on key pathways and cancer hallmarks in each step of evolution, were discerned. Tumor-associated nevus was, for the first time, split into two sections, distant and adjacent to the primary tumor, to study its heterogeneity. Shared SNP alterations, with stable allele fraction from germline to metastasis were detected, mainly affecting DNA repair genes and promoting genome instability. Early somatic alterations, shared by nevi and primary and metastatic tumors, included BRAFV600E and focal copy-loss of several genes, acquiring additional cancer hallmarks. Phylogenetic analyses revealed that these common somatic alterations would provide a "bridge", allowing progression from a benign to a malignant state. Distant and adjacent nevi were rich in alterations, presenting differential SNP and CNV alterations. Upon tumor transformation, a marked increase in CNV over SNP alterations was determined. Both the number of SNP and CNV-affected genes, including known driver genes, increased throughout progression, although TMB levels remained lower than expected for melanoma. Typical alterations in BRAFV600E tumors related to intrinsic resistance to targeted therapy were found, including BRAF amplification and loss of PTEN, CDKN2A/B, and TP53 surveillance genes. Finally, numerous metastatic alterations were detected, further promoting tumor progression. CONCLUSIONS: In this patient, longitudinal WES analysis revealed a sequential and cumulative pattern of genetic alterations, where germline and nevi somatic events contributed early to its rapid clinical progression. In this case report, we found tumor-associated nevi as genetically heterogeneous precursor entities, in which potential prognostic biomarkers should be studied prospectively.
Asunto(s)
Melanoma , Nevo , Neoplasias Cutáneas , Humanos , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Melanoma/genética , Melanoma/patología , Proteínas Proto-Oncogénicas B-raf/genética , Filogenia , Transformación Celular Neoplásica , Melanoma Cutáneo MalignoRESUMEN
INTRODUCTION: Tuberculosis (TB) is among the deadliest diseases worldwide, and its impact is mainly due to the continuous emergence of resistant isolates during treatment due to the laborious process of resistance diagnosis, nonadherence to treatment and circulation of previously resistant isolates of Mycobacterium tuberculosis. In this study, we evaluated the performance and functionalities of web-based tools, including Mykrobe, TB-profiler, PhyResSE, KvarQ, and SAM-TB, for detecting resistance in 88 Ecuadorian isolates of Mycobacterium tuberculosis drug susceptibility tested previously. Statistical analysis was used to determine the correlation between genomic and phenotypic analysis. Our results showed that with the exception of KvarQ, all tools had the highest correlation with the conventional drug susceptibility test (DST) for global resistance detection (98% agreement and 0.941 Cohen's kappa), while SAM-TB, PhyResSE, TB-profiler and Mykrobe had better correlations with DST for first-line drug analysis individually. We also identified that in our study, only 50% of mutations characterized by the web-based tools in the rpoB, katG, embB, pncA, gyrA and rrs regions were canonical and included in the World Health Organization (WHO) catalogue. Our findings suggest that SAM-TB, PhyResSE, TB-profiler and Mykrobe were efficient in determining canonical resistance-related mutations, but more analysis is needed to improve second-line detection. Improving surveillance programs using whole-genome sequencing tools for first-line drugs, MDR-TB and XDR-TB is essential to understand the molecular epidemiology of TB in Ecuador. IMPORTANCE: Tuberculosis, an infectious disease caused by Mycobacterium tuberculosis, most commonly affects the lungs and is often spread through the air when infected people cough, sneeze, or spit. However, despite the existence of effective drug treatment, patient adherence, long duration of treatment, and late diagnosis have reduced the effectiveness of therapy and increased drug resistance. The increase in resistant cases, added to the impact of the COVID-19 pandemic, has highlighted the importance of implementing efficient and timely diagnostic methodologies worldwide. The significance of our research is in evaluating and identifying a more efficient and user-friendly web-based tool to characterize resistance in Mycobacterium tuberculosis by whole-genome sequencing, which will allow more routine application to improve TB strain surveillance programs locally.
Asunto(s)
Mycobacterium tuberculosis , Tuberculosis Resistente a Múltiples Medicamentos , Humanos , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Ecuador/epidemiología , Pandemias , Tuberculosis Resistente a Múltiples Medicamentos/diagnóstico , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/epidemiología , Biología Computacional , Genómica , Mutación , Pruebas de Sensibilidad Microbiana , Internet , Farmacorresistencia Bacteriana Múltiple/genéticaRESUMEN
Electric, magnetic, and electromagnetic fields are ubiquitous in our society, and concerns have been expressed regarding possible adverse effects of these exposures. Research on Extremely Low-Frequency (ELF) magnetic fields has been performed for more than two decades, and the methodology and quality of studies have improved over time. Studies have consistently shown increased risk for childhood leukemia associated with ELF magnetic fields. There are still inadequate data for other outcomes. More recently, focus has shifted toward Radio Frequencies (RF) exposures from mobile telephony. There are no persuasive data suggesting a health risk, but this research field is still immature with regard to the quantity and quality of available data. This technology is constantly changing and there is a need for continued research on this issue. To investigate whether exposure to high-frequency electromagnetic fields (EMF) could induce adverse health effects, we cultured acute T-lymphoblastoid leukemia cells (CCRF-CEM) in the presence of 900 MHz MW-EMF generated by a transverse electromagnetic (TEM) cell at short and long exposure times. We evaluated the effect of high-frequency EMF on gene expression and we identified functional pathways influenced by 900 MHz MW-EMF exposure.
Asunto(s)
Campos Electromagnéticos/efectos adversos , Microondas/efectos adversos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Transcriptoma/efectos de la radiación , Apoptosis/genética , Apoptosis/efectos de la radiación , Puntos de Control del Ciclo Celular/genética , Puntos de Control del Ciclo Celular/efectos de la radiación , Línea Celular Tumoral , Supervivencia Celular/genética , Supervivencia Celular/efectos de la radiación , Cromosomas/genética , Cromosomas/efectos de la radiación , Daño del ADN/genética , Reparación del ADN/genética , Reparación del ADN/efectos de la radiación , Humanos , Neovascularización Fisiológica/genética , Neovascularización Fisiológica/efectos de la radiación , Análisis de Secuencia por Matrices de Oligonucleótidos , Factores de TiempoRESUMEN
Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy is the standard treatment for patients with muscle-invasive bladder cancer (MIBC). However, the implementation of NAC is lower than desirable mainly due to its limited impact on overall survival, patients' comorbidities and the lack of predictive biomarkers to select those patients most likely to benefit from NAC. In the last decade, improved molecular MIBC characterisation, the identification of potential predictive and prognostic biomarkers as well as the incorporation of new effective therapies with a better toxicity profile, such as immunotherapy, has changed the treatment paradigm for MIBC. Therefore, the main goal for the near future is to introduce these clinical and translational advances into routine clinical practice to personalise treatment for each patient and increase the opportunity to implement bladder preservation strategies. The present review focuses on the current status of NAC in MIBC, unsolved questions and future therapeutic approaches.
Asunto(s)
Neoplasias de la Vejiga Urinaria , Quimioterapia Adyuvante , Cisplatino , Cistectomía , Humanos , Músculos , Terapia Neoadyuvante , Invasividad Neoplásica , Neoplasias de la Vejiga Urinaria/tratamiento farmacológicoRESUMEN
Prostate cancer (PC) is the most common malignancy and the fifth cause of cancer death in men. The treatment for localized or locally advanced stages offers a high probability of cure. Even though the therapeutic landscape has significantly improved over the last decade, metastatic PC (mPC) still has a poor prognosis mainly due to the development of therapy resistance. In this context, the use of immunotherapy alone or in combination with other drugs has been explored in recent years. However, T-cell directed immune checkpoint inhibitors (ICIs) have shown limited activity with inconclusive results in mPC patients, most likely due to the highly immunosuppressive PC tumor microenvironment (TME). In this scenario, targeting macrophages, a highly abundant immunosuppressive cell type in the TME, could offer a new therapeutic strategy to improve immunotherapy efficacy. In this review, we summarize the growing field of macrophage-directed immunotherapies and discuss how these could be applied in the treatment of mPC, focusing on their combination with ICIs.
RESUMEN
The CSF-470 vaccine (VACCIMEL) plus BCG and GM-CSF as adjuvants has been assayed in cutaneous melanoma patients. In the adjuvant randomized Phase II study CASVAC-0401, vaccinated patients had longer distant metastasis-free survival (DMFS) than those treated with IFNα2b. Five years after locking the data, an actualization was performed. The benefit in DMFS was maintained in the vaccinated group versus the IFNα2b-treated group (p = 0.035), with a median DMFS of 96 months for VACCIMEL and 13 months for IFNα2b. The favorable risk-benefit ratio was maintained. DMFS was also analyzed as a single cohort in all the IIB, IIC, and III patients (n = 30) who had been treated with VACCIMEL. The median DMFS was 169 months, and at 48 months follow-up, it was 71.4%, which was not statistically different from DMFS of previously published results obtained in adjuvancy with ipilimumab, pembrolizumab, nivolumab, or dabrafenib/trametinib. The possible toxicity of combining VACCIMEL with anti-immune checkpoint inhibitors (ICKi) was analyzed, especially since VACCIMEL was co-adjuvated with BCG in every vaccination. A patient with in-transit metastases was studied to produce a proof of concept. During treatment with VACCIMEL, the patient developed T-cell clones reactive towards tumor-associated antigens. Three years after ending the VACCIMEL study, the patient progressed and was treated with ICKi. During ICKi treatment, the patient did not reveal any toxicity due to previous BCG treatment. When she recurred after a 4-year treatment with nivolumab, a biopsy was obtained and immunohistochemistry and RNA-seq were performed. The tumor maintained expression of tumor-associated antigens and HLA-I and immune infiltration, with immunoreactive and immunosuppressive features. VACCIMEL plus BCG and GM-CSF is an effective treatment in adjuvancy for stages IIB, IIC, and III cutaneous melanoma patients, and it is compatible with subsequent treatments with ICKi.
Asunto(s)
Vacunas contra el Cáncer , Trasplante de Células Madre Hematopoyéticas , Melanoma , Neoplasias Cutáneas , Adyuvantes Inmunológicos , Antígenos de Neoplasias , Vacuna BCG , Vacunas contra el Cáncer/efectos adversos , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos , Humanos , Nivolumab/uso terapéutico , Melanoma Cutáneo MalignoRESUMEN
Neoadjuvant chemotherapy followed by a cystectomy is the standard treatment in muscle-invasive bladder cancer (MIBC). However, the role of chemotherapy in the adjuvant setting remains controversial, and therefore new prognostic and predictive biomarkers are needed to improve the selection of MIBC patients. While lipid metabolism has been related to several biological processes in many tumours, including bladder cancer, no metabolic biomarkers have been identified as prognostic in routine clinical practice. In this multicentre, retrospective study of 198 patients treated with cystectomy followed by platinum-based adjuvant chemotherapy, we analysed the immunohistochemical expression of CD36 and correlated our findings with clinicopathological characteristics and survival. CD36 immunostaining was positive in 30 patients (15%) and associated with more advanced pathologic stages (pT3b-T4; p = 0.015). Moreover, a trend toward lymph node involvement in CD36-positive tumours, especially in earlier disease stages (pT1-T3; p = 0.101), was also observed. Among patients with tumour progression during the first 12 months after cystectomy, disease-free survival was shorter in CD36-positive tumours than in those CD36-negative (6.51 months (95% CI 5.05-7.96) vs. 8.74 months (95% CI 8.16-9.32); p = 0.049). Our results suggest an association between CD36 immunopositivity and more aggressive features of MIBC and lead us to suggest that CD36 could well be a useful prognostic marker in MIBC.
RESUMEN
BACKGROUND: Taxanes are the most active chemotherapy agents in metastatic castration-resistant prostate cancer (mCRPC) patients; yet, resistance occurs almost invariably, representing an important clinical challenge. Taxane-platinum combinations have shown clinical benefit in a subset of patients, but the mechanistic basis and biomarkers remain elusive. OBJECTIVE: To identify mechanisms and response indicators for the antitumor efficacy of taxane-platinum combinations in mCRPC. DESIGN, SETTING, AND PARTICIPANTS: Transcriptomic data from a publicly available mCRPC dataset of taxane-exposed and taxane-naïve patients were analyzed to identify response indicators and emerging vulnerabilities. Functional and preclinical validation was performed in taxane-resistant mCRPC cell lines and genetically engineered mouse models (GEMMs). INTERVENTION: Metastatic CRPC cells were treated with docetaxel, cisplatin, carboplatin, the CXCR2 antagonist SB265610, and the BCL-2 inhibitor venetoclax. Gain and loss of function in culture of CXCR2 and BCL-2 were achieved by overexpression or siRNA silencing. Preclinical assays in GEMM mice tested the antitumor efficacy of taxane-platinum combinations. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Proliferation, apoptosis, and colony assays measured drug activity in vitro. Preclinical endpoints in mice included growth, survival, and histopathology. Changes in CXCR2, BCL-2, and chemokines were analyzed by reverse transcriptase quantitative polymerase chain reaction and Western blot. Human expression data were analyzed using Gene Set Enrichment Analysis, hierarchical clustering, and correlation studies. GraphPad Prism software and R-studio were used for statistical and data analyses. RESULTS AND LIMITATIONS: Transcriptomic data from taxane-exposed human mCRPC tumors correlate with a marked negative enrichment of apoptosis and inflammatory response pathways accompanied by a marked downregulation of CXCR2 and BCL-2. Mechanistically, we show that docetaxel inhibits CXCR2 and that BCL-2 downregulation occurs as a downstream effect. Further, we demonstrated in experimental models that the sensitivity to cisplatin is dependent on CXCR2 and BCL-2, and that targeting them sensitizes prostate cancer (PC) cells to cisplatin. In vivo taxane-platinum combinations are highly synergistic, and previous exposure to taxanes sensitizes mCRPC tumors to second-line cisplatin treatment. CONCLUSIONS: The hitherto unappreciated attenuation of the CXCR2/BCL-2 axis in taxane-treated mCRPC patients is an acquired vulnerability with potential predictive activity for platinum-based treatments. PATIENT SUMMARY: A subset of patients with aggressive and therapy-resistant prostate cancer benefits from taxane-platinum combination chemotherapy; however, we lack the mechanistic understanding of how that synergistic effect occurs. Here, using patient data and preclinical models, we found that taxanes reduce cancer cell escape mechanisms to chemotherapy-induced cell death, hence making these cells more vulnerable to additional platinum treatment.
Asunto(s)
Antineoplásicos , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración , Taxoides/uso terapéutico , Animales , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cisplatino/uso terapéutico , Docetaxel/uso terapéutico , Humanos , Masculino , Ratones , Platino (Metal)/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Proteínas Proto-Oncogénicas c-bcl-2/uso terapéuticoRESUMEN
BACKGROUND: Abiraterone acetate (AA) is widely used in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). However, a significant percentage of patients will still progress, highlighting the need to identify patients more likely to benefit from AA. Parameters linked to prostate-specific antigen (PSA) kinetics are promising prognostic markers. We have examined clinical and PSA-related factors potentially associated with overall survival (OS) in patients treated with AA. METHODS: Between 2011 and 2014, 104 patients with mCRPC treated with AA after progression to docetaxel at centers of the Catalan Institute of Oncology were included in this retrospective study. Patients were assessed monthly. Baseline characteristics and variables related to PSA kinetics were included in univariate and multivariate analyses of OS. RESULTS: Median OS was 16.4 months (range 12.4-20.6) for all patients. The univariate analysis identified the following baseline characteristics as significantly associated with OS: ECOG PS, location of metastases, time between starting androgen deprivation therapy and starting AA, time between stopping docetaxel treatment and starting AA, neutrophil-lymphocyte ratio (NLR), alkaline phosphatase levels, and PSA levels. Factors related to PSA kinetics associated with longer OS were PSA response >50%, early PSA response (>30% decline at four weeks), PSA decline >50% at week 12, PSA nadir <2.4ng/mL, time to PSA nadir >140 days, the combination of PSA nadir and time to PSA nadir, and low end-of-treatment PSA levels. The multivariate analysis identified ECOG PS (HR 37.46; p<0.001), NLR (HR 3.7; p<0.001), early PSA response (HR 1.22; p=0.002), and time to PSA nadir (HR 0.39; p=0.002) as independent prognostic markers. CONCLUSION: Our results indicate an association between PSA kinetics, especially early PSA response, and outcome to AA after progression to docetaxel. Taken together with other factors, lack of an early PSA response could identify patients who are unlikely to benefit from AA and who could be closely monitored with a view to offering alternative therapies.
RESUMEN
Tuberculosis (TB) is a significant public health problem in Ecuador with an incidence of 43 per 100,000 inhabitants and an estimated multidrug-resistant-TB prevalence in all TB cases of 9%. Genotyping of Mycobacterium tuberculosis (MTBC) is important to understand regional transmission dynamics. This study aims to describe the main MTBC lineages and sublineages circulating in the country. A representative sample of 373 MTBC strains from 22 provinces of Ecuador, with data comprising geographic origin and drug susceptibility, were genotyped using 24 loci-MIRU-VNTR. For strains with an ambiguous sublineage designation, the lineage was confirmed by Regions of Difference analysis or by Whole Genome Sequencing. We show that lineage 4 is predominant in Ecuador (98.3% of the strains). Only 4 strains belong to lineages 2-sublineage Beijing and two strains to lineage 3-sublineage Delhi. Lineage 4 strains included sublineages LAM (45.7%), Haarlem (31.8%), S (13.1%), X (4.6%), Ghana (0.6%) and NEW (0.3%). The LAM sublineage showed the strongest association with antibiotic resistance. The X and S sublineages were found predominantly in the Coastal and the Andean regions respectively and the reason for the high prevalence of these strains in Ecuador should be addressed in future studies. Our database constitutes a tool for MIRU-VNTR pattern comparison of M. tuberculosis isolates for national and international epidemiologic studies and phylogenetic purposes.
Asunto(s)
Antituberculosos/farmacología , Farmacorresistencia Microbiana/genética , Mycobacterium tuberculosis/genética , Tuberculosis/epidemiología , Antituberculosos/uso terapéutico , ADN Bacteriano/genética , ADN Bacteriano/aislamiento & purificación , Ecuador/epidemiología , Variación Genética , Humanos , Repeticiones de Minisatélite/genética , Epidemiología Molecular , Tipificación de Secuencias Multilocus , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/aislamiento & purificación , Filogenia , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiología , Secuenciación Completa del GenomaRESUMEN
T-DM1 is an antibody drug conjugate that combines trastuzumab with emtansine via a stable thioether linker. In two phase III clinical trials, EMILIA and TH3RESA, T-DM1 was shown to be effective in HER2-positive metastatic breast cancer patients who had progressed to taxanes and trastuzumab. We have performed a real-world study to complement the findings of the clinical trials. From 2012 to 2016, 15 patients with HER2-positive breast cancer who had progressed to prior treatment received T-DM1 at our center. We have retrospectively analyzed outcomes in these patients and compared our findings with those of the two clinical trials. Progression-free survival (PFS) was 10 months compared with the 9.6 months of the EMILIA trial and the 6.2 months of the TH3RESA trial, overall survival was 34 months compared with the 29.9 months of the EMILIA trial and the 22.7 months of the TH3RESA trial. PFS was ≥12 months in five patients, three of whom attained a PFS of ≥23 months. Among five patients with metastases of the central nervous system, PFS was six months, OS was not reached, and the objective response rate was 80%. Our findings are in line with those of the EMILIA study and slightly superior to those of the TH3RESA study. In our series of patients, T-DM1 has demonstrated efficacy in the treatment of HER2-positive metastatic breast cancer. Our real-world data thus confirm and support the findings of the two major phase III trials and indicate the usefulness of T-DM1 in routine clinical practice.
Asunto(s)
Neoplasias de la Mama , Maitansina/administración & dosificación , Receptor ErbB-2/metabolismo , Trastuzumab/administración & dosificación , Adulto , Anciano , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
The Beijing family, the most successful Mycobacterium tuberculosis lineage, is considered hypervirulent, associated with clustering and has a strong association with multidrug-resistant tuberculosis. The Beijing strains have spread worldwide and also to Latin America. Genotyping of a countrywide collection of 380 M. tuberculosis strains from Ecuador, with 24-loci mycobacterial interspersed repetitive units-variable number tandem repeats (MIRU-VNTR), revealed only six Beijing strains, but four of these were MDR-TB. There was no clustering as all six strains had very distinct MIRU-VNTR profiles that have not been reported in the rest of Latin America. Although active transmission for Beijing has been described for the neighboring countries Peru and Colombia, there is no evidence that Beijing strains in Ecuador are more frequently transmitted than other strains. Moreover, the low prevalence (1.6%) of the Beijing sublineage in Ecuador challenges the concept of hyperadaptability and transmissibility of the Beijing strains in our country.
Asunto(s)
Variación Genética/genética , Mycobacterium tuberculosis/genética , Tuberculosis Resistente a Múltiples Medicamentos/genética , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , Antibacterianos/uso terapéutico , Beijing , Colombia , ADN Bacteriano/genética , Ecuador/epidemiología , Genotipo , Humanos , Repeticiones de Minisatélite/genética , Mycobacterium tuberculosis/efectos de los fármacos , Perú , Prevalencia , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/epidemiologíaRESUMEN
Background: Strains of the Beijing sublineage of Mycobacterium tuberculosis have caused large outbreaks of tuberculosis, often involving multidrug resistance strains and this genetically highly conserved family of strains predominates in some geographic areas. For most of the countries of Latin America, no country-wide studies about the prevalence of the Beijing lineage are available. Methods: In this study, we determine the prevalence of the Beijing sublineage in Ecuador, using a large nation-wide sample of 991 isolates from the years 2014-2016 and with the strains, in case-related-proportional representation, emerging from most of the provinces of the country. The isolates were genotyped with asinglenucleotidespecific polymorphism (SNP) polymerase chain reaction for the Beijing sublineage. SNPpositive strains were confirmed as belonging to this lineage with 24 mycobacterial interspersed repetitive unitvariable number of tandem repeat and DNA sequencing. Results: We identified only four Beijing isolates in this collection of 991 strains and calculated a prevalence rate of 0.43%. Conclusions: Our study shows a limited dissemination of the Beijing strains in the Ecuadorian population. This in contrast with the neighbor countries of Peru and Colombia were locally a prevalence of up to 16% has been reported.