ABSTRACT
Bladder cancer (BC) is the second most frequent cancer of the genitourinary system. The most successful therapy since the 1970s has consisted of intravesical instillations of Bacillus Calmette-Guérin (BCG) in which the tumor microenvironment (TME), including macrophages, plays an important role. However, some patients cannot be treated with this therapy due to comorbidities and severe inflammatory side effects. The overexpression of histone deacetylases (HDACs) in BC has been correlated with macrophage polarization together with higher tumor grades and poor prognosis. Herein we demonstrated that phenylbutyrate acid (PBA), a HDAC inhibitor, acts as an antitumoral compound and immunomodulator. In BC cell lines, PBA induced significant cell cycle arrest in G1, reduced stemness markers and increased PD-L1 expression with a corresponding reduction in histone 3 and 4 acetylation patterns. Concerning its role as an immunomodulator, we found that PBA reduced macrophage IL-6 and IL-10 production as well as CD14 downregulation and the upregulation of both PD-L1 and IL-1ß. Along this line, PBA showed a reduction in IL-4-induced M2 polarization in human macrophages. In co-cultures of BC cell lines with human macrophages, a double-positive myeloid-tumoral hybrid population (CD11b+EPCAM+) was detected after 48 h, which indicates BC cell-macrophage fusions known as tumor hybrid cells (THC). These THC were characterized by high PD-L1 and stemness markers (SOX2, NANOG, miR-302) as compared with non-fused (CD11b-EPCAM+) cancer cells. Eventually, PBA reduced stemness markers along with BMP4 and IL-10. Our data indicate that PBA could have beneficial properties for BC management, affecting not only tumor cells but also the TME.
ABSTRACT
BACKGROUND AND AIMS: Metastatic urothelial carcinoma (mUC) remains an incurable disease with limited treatment options after platinum-based chemotherapy and immune checkpoint blockade (ICB). Vinflunine has shown a modest increase in overall survival and remains a therapeutic option for chemo- and immunotherapy refractory tumours. However, biomarkers that could identify responding patients to vinflunine and possible alternative therapies after failure to treatment are still missing. In this study, we aimed to identify potential genomic biomarkers of vinflunine response in mUC patient samples and potential management alternatives. METHODS: Formalin-fixed paraffin-embedded samples of mUC patients (n = 23) from three university hospitals in Spain were used for genomic targeted-sequencing and transcriptome (using the Immune Profile panel by NanoString) analyses. Patients who received vinflunine after platinum-based chemotherapy failure were classified in non-responders (NR: progressive disease ≤ 3 months; n= 11) or responders (R: response ≥ 6 months; n = 12). RESULTS: Genomic characterization revealed that the most common alteration, TP53 mutations, had comparable frequency in R (6/12; 50%) and NR (4/11; 36%). Non-synonymous mutations in KTM2C (4/12; 33.3%), PIK3CA (3/12; 25%) and ARID2 (3/12; 25%) were predominantly associated with response. No significant difference was observed in tumour mutational burden (TMB) between R and NR patients. The NR tumours showed increased expression of diverse immune-related genes and pathways, including various interferon gamma-related genes. We also identified increased MAGEA4 expression as a potential biomarker of non-responding tumours to vinflunine treatment. CONCLUSIONS: Our data may help to identify potential genomic biomarkers of response to vinflunine. Moreover, tumours refractory to vinflunine showed immune signatures potentially associated with response to ICB. Extensive validation studies, including longitudinal series, are needed to corroborate these findings.
ABSTRACT
PURPOSE: The usefulness and mechanisms of antiarrhythmic drug (AAD) pre-treatment as a facilitator of the acute success of electrical cardioversion (ECV) in atrial fibrillation (AF) remain controversial. We sought to analyze the role of AAD treatment with this purpose, differentiating its possible utility either facilitating the restoration of sinus rhythm (SR) or reducing immediate AF recurrences (IAFR). METHODS: We analyzed 2962 consecutive patients with persistent AF undergoing ECV prospectively included in 3 national registries. The acute success of ECV was indicated by the reversion to SR without presenting an IAFR (< 2 h). RESULTS: A total of 1410 patients (48%) received AAD treatment prior to ECV (80% amiodarone, 15% class Ic AAD, 2% other AAD). The rate of restoration of SR was similar between the patients treated with amiodarone (92%), class Ic AAD (91%) and who did not receive AAD pre-treatment (91%) (p = 0.92). However, those treated with amiodarone had fewer IAFR than those in the other two groups (amiodarone 3% vs class Ic 7% vs without treatment 6%; p = 0.002), so the ECV success rate was higher in the amiodarone group than in the other groups (amiodarone 89% vs Ic 84% vs without treatment 86%; p = 0.04). After adjusting for multiple variables, amiodarone remained as an independent predictor of a lower occurrence of IAFR (OR = 0.57; p = 0.01) and of a successful ECV (OR 1.37; p = 0.01). CONCLUSIONS: For patients with persistent AF undergoing ECV, AAD has a neutral effect on the restoration of SR but amiodarone increases its effectiveness due to a lower incidence of IAFR.
Subject(s)
Amiodarone/therapeutic use , Anti-Arrhythmia Agents/therapeutic use , Atrial Fibrillation/therapy , Electric Countershock , Heart Rate/drug effects , Aged , Atrial Fibrillation/diagnosis , Atrial Fibrillation/physiopathology , Electric Countershock/adverse effects , Female , Humans , Male , Middle Aged , Recurrence , Registries , Retrospective Studies , Risk Factors , Spain , Time Factors , Treatment OutcomeABSTRACT
OBJECTIVE: The purpose of this study was to analyze the association between the dilatation of the aortic root and the diameters of the rest of the aorta and to identify some related factors that could be used to identify patients at higher risk of presenting with an aortic aneurysm. METHODS: In 71 consecutive patients with a dilated aortic root identified by transthoracic echocardiography, prospective helical computed tomography was performed. Aortic diameters were measured perpendicular to the flow at seven levels in the thoracic and abdominal aorta. RESULTS: Ascending aorta diameter showed a moderate correlation with aortic indexed diameters at the thoracic and abdominal level in tricuspid aortic valve patients (r ranging from 0.37-0.56), whereas in patients with a bicuspid aortic valve, a moderate correlation between the ascending aorta diameters and the thoracic descending aorta diameters was observed (r 0.51-0.53). In a multivariate analysis, age was independently related to indexed diameter at all aortic sites (ß ranging from 0.06-0.12 per year), whereas aortic regurgitation was independently related only to thoracic aorta diameter (ß ranging from 1.17-1.84). Age (P < .0001), body surface area (P < .0001), and grade of aortic valve regurgitation (P = .001) independently predicted aortic volume. CONCLUSION: Different patterns of aortic diameters were observed in patients with dilated aortic root, depending on age, aortic valve morphology, and function. When a dilated aortic root is detected in older patients with a tricuspid aortic valve, an accurate cardiovascular survey that includes the entire aorta is needed. These results provide further evidence about the systemic nature of aortic dilatation.
Subject(s)
Aorta, Abdominal/pathology , Aorta, Thoracic/pathology , Aortic Aneurysm/etiology , Aortic Valve Insufficiency/complications , Aortic Valve/abnormalities , Age Factors , Aged , Aorta, Abdominal/diagnostic imaging , Aorta, Thoracic/diagnostic imaging , Aortic Aneurysm/pathology , Aortic Valve/diagnostic imaging , Aortic Valve Insufficiency/diagnostic imaging , Aortography/methods , Body Surface Area , Chi-Square Distribution , Dilatation, Pathologic , Echocardiography , Female , Humans , Linear Models , Male , Middle Aged , Prospective Studies , Risk Assessment , Risk Factors , Severity of Illness Index , Spain , Tomography, Spiral ComputedABSTRACT
Aortic regurgitation was the commonest functional anomaly among younger patients in a group of 63 individuals with a diagnosis of bicuspid aortic valve. With increasing age, a rise in the number with combined aortic valve disease and aortic stenosis was observed. Aortic dilatation was found in 65% of cases. Dilatation was independently associated with age and transvalvular aortic gradient.
Subject(s)
Aortic Diseases/etiology , Aortic Valve/abnormalities , Aortic Valve/physiopathology , Adult , Age Factors , Aortic Diseases/epidemiology , Dilatation, Pathologic , Female , Humans , Male , Middle AgedABSTRACT
En 63 pacientes diagnosticados de válvula aórtica bicúspide, la insuficiencia aórtica fue la alteración funcional más frecuente en los pacientes más jóvenes, mientras que con el envejecimiento se observó un aumento de casos con doble lesión y estenosis aórtica. Se detectó una dilatación aórtica en el 65% de los casos. La edad y el gradiente transvalvular aórtico eran factores independientes relacionados con la dilatación (AU)
Aortic regurgitation was the commonest functional anomaly among younger patients in a group of 63 individuals with a diagnosis of bicuspid aortic valve. With increasing age, a rise in the number with combined aortic valve disease and aortic stenosis was observed. Aortic dilatation was found in 65% of cases. Dilatation was independently associated with age and transvalvular aortic gradient (AU)
