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1.
BJU Int ; 2024 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-38717014

RESUMEN

OBJECTIVE: To investigate and compare the performance of urinary cytology and the Xpert BC Monitor test in the detection of bladder cancer in various clinically significant patient cohorts, including patients with carcinoma in situ (CIS), in a prospective multicentre setting, aiming to identify potential applications in clinical practice. PATIENTS AND METHODS: A total of 756 patients scheduled for transurethral resection of bladder tumour (TURBT) were prospectively screened between July 2018 and December 2020 at six German University Centres. Central urinary cytology and Xpert BC Monitor tests were performed prior to TURBT. The diagnostic performance of urinary cytology and the Xpert BC Monitor was evaluated according to sensitivity (SN), specificity (SC), negative predictive value (NPV) and positive predictive value (PPV). Statistical comparison of urinary cytology and the Xpert BC Monitor was conducted using the McNemar test. RESULTS: Of 756 screened patients, 733 (568 male [78%]; median [interquartile range] age 72 [62-79] years) were included. Bladder cancer was present in 482 patients (65.8%) with 258 (53.5%) high-grade tumours. Overall SN, SC, NPV and PPV were 39%, 93%, 44% and 92% for urinary cytology, and 75%, 69%, 59% and 82% for the Xpert BC Monitor. In patients with CIS (concomitant or solitary), SN, SC, NPV and PPV were 59%, 93%, 87% and 50% for urinary cytology, and 90%, 69%, 95% and 50% for the Xpert BC Monitor. The Xpert BC Monitor missed four tumours (NPV = 98%) in patients with solitary CIS, while potentially avoiding 63.3% of TURBTs in inconclusive or negative cystoscopy and a negative Xpert result. CONCLUSION: Positive urinary cytology may indicate bladder cancer and should be taken seriously. The Xpert BC Monitor may represent a useful diagnostic tool for correctly identifying patients with solitary CIS and unsuspicious or inconclusive cystoscopy.

2.
Cell Mol Biol Lett ; 29(1): 94, 2024 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-38956497

RESUMEN

BACKGROUND: We have previously identified an unsuspected role for GJB3 showing that the deficiency of this connexin protein induces aneuploidy in human and murine cells and accelerates cell transformation as well as tumor formation in xenograft models. The molecular mechanisms by which loss of GJB3 leads to aneuploidy and cancer initiation and progression remain unsolved. METHODS: GJB3 expression levels were determined by RT-qPCR and Western blot. The consequences of GJB3 knockdown on genome instability were assessed by metaphase chromosome counting, multinucleation of cells, by micronuclei formation and by the determination of spindle orientation. Interactions of GJB3 with α-tubulin and F-actin was analyzed by immunoprecipitation and immunocytochemistry. Consequences of GJB3 deficiency on microtubule and actin dynamics were measured by live cell imaging and fluorescence recovery after photobleaching experiments, respectively. Immunohistochemistry was used to determine GJB3 levels on human and murine bladder cancer tissue sections. Bladder cancer in mice was chemically induced by BBN-treatment. RESULTS: We find that GJB3 is highly expressed in the ureter and bladder epithelium, but it is downregulated in invasive bladder cancer cell lines and during tumor progression in both human and mouse bladder cancer. Downregulation of GJB3 expression leads to aneuploidy and genomic instability in karyotypically stable urothelial cells and experimental modulation of GJB3 levels alters the migration and invasive capacity of bladder cancer cell lines. Importantly, GJB3 interacts both with α-tubulin and F-actin. The impairment of these interactions alters the dynamics of these cytoskeletal components and leads to defective spindle orientation. CONCLUSION: We conclude that deregulated microtubule and actin dynamics have an impact on proper chromosome separation and tumor cell invasion and migration. Consequently, these observations indicate a possible role for GJB3 in the onset and spreading of bladder cancer and demonstrate a molecular link between enhanced aneuploidy and invasive capacity cancer cells during tumor cell dissemination.


Asunto(s)
Actinas , Aneuploidia , Invasividad Neoplásica , Tubulina (Proteína) , Neoplasias de la Vejiga Urinaria , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/metabolismo , Humanos , Animales , Tubulina (Proteína)/metabolismo , Tubulina (Proteína)/genética , Línea Celular Tumoral , Ratones , Actinas/metabolismo , Actinas/genética , Urotelio/patología , Urotelio/metabolismo , Movimiento Celular/genética , Microtúbulos/metabolismo , Inestabilidad Genómica , Unión Proteica
3.
Cell Mol Life Sci ; 80(10): 299, 2023 Sep 22.
Artículo en Inglés | MEDLINE | ID: mdl-37740130

RESUMEN

We have recently shown that loss of ORP3 leads to aneuploidy induction and promotes tumor formation. However, the specific mechanisms by which ORP3 contributes to ploidy-control and cancer initiation and progression is still unknown. Here, we report that ORP3 is highly expressed in ureter and bladder epithelium while its expression is downregulated in invasive bladder cancer cell lines and during tumor progression, both in human and in mouse bladder cancer. Moreover, we observed an increase in the incidence of N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-induced invasive bladder carcinoma in the tissue-specific Orp3 knockout mice. Experimental data demonstrate that ORP3 protein interacts with γ-tubulin at the centrosomes and with components of actin cytoskeleton. Altering the expression of ORP3 induces aneuploidy and genomic instability in telomerase-immortalized urothelial cells with a stable karyotype and influences the migration and invasive capacity of bladder cancer cell lines. These findings demonstrate a crucial role of ORP3 in ploidy-control and indicate that ORP3 is a bona fide tumor suppressor protein. Of note, the presented data indicate that ORP3 affects both cell invasion and migration as well as genome stability through interactions with cytoskeletal components, providing a molecular link between aneuploidy and cell invasion and migration, two crucial characteristics of metastatic cells.


Asunto(s)
Actinas , Neoplasias de la Vejiga Urinaria , Animales , Humanos , Ratones , Aneuploidia , Inestabilidad Genómica , Microtúbulos , Invasividad Neoplásica , Vejiga Urinaria , Neoplasias de la Vejiga Urinaria/genética
4.
Urol Int ; 108(3): 183-189, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38246156

RESUMEN

INTRODUCTION: The aim of the study was to determine the adaption of neoadjuvant chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC) in Germany, Austria, and Switzerland and especially underlying reasons for potential low adherence to guidelines. METHODS: We conducted a non-validated survey among 336 urologic departments in Germany, Austria, and Switzerland. RedCap questionnaires were electronically distributed and included 23 items concerning the general NAC administration standards and guideline compliance in patient counseling regarding the actual treatment. RESULTS: The return rate of the questionnaire was 19.1% (63/336). Although 45 departments (71.4%) claim to perform NAC as the standard of care, only 49% of eligible patients actually receive NAC. An advanced disease stage (≥cT3) and a high tumor volume were mentioned to support the application of NAC, whereas 35% of responders worry about deterioration of patients' preoperative status due to NAC. Furthermore, 26.7% of respondents are concerned about the low extent of survival benefit. CONCLUSION: Application of NAC in eligible MIBC patients in Germany, Austria, and Switzerland remains low. Although the majority of urologic departments discuss NAC and acknowledge the need for intensified treatment in advanced disease stages, not all eligible patients will actually receive NAC before radical cystectomy.


Asunto(s)
Terapia Neoadyuvante , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Quimioterapia Adyuvante , Suiza , Alemania , Austria , Adhesión a Directriz , Encuestas y Cuestionarios , Cistectomía , Pautas de la Práctica en Medicina , Encuestas de Atención de la Salud
5.
BMC Biol ; 21(1): 55, 2023 03 20.
Artículo en Inglés | MEDLINE | ID: mdl-36941669

RESUMEN

BACKGROUND: The reactivation of genetic programs from early development is a common mechanism for injury-induced organ regeneration. T-box 3 (TBX3) is a member of the T-box family of transcription factors previously shown to regulate pluripotency and subsequent lineage commitment in a number of tissues, including limb and lung. TBX3 is also involved in lung and heart organogenesis. Here, we provide a comprehensive and thorough characterization of TBX3 and its role during pancreatic organogenesis and regeneration. RESULTS: We interrogated the level and cell specificity of TBX3 in the developing and adult pancreas at mRNA and protein levels at multiple developmental stages in mouse and human pancreas. We employed conditional mutagenesis to determine its role in murine pancreatic development and in regeneration after the induction of acute pancreatitis. We found that Tbx3 is dynamically expressed in the pancreatic mesenchyme and epithelium. While Tbx3 is expressed in the developing pancreas, its absence is likely compensated by other factors after ablation from either the mesenchymal or epithelial compartments. In an adult model of acute pancreatitis, we found that a lack of Tbx3 resulted in increased proliferation and fibrosis as well as an enhanced inflammatory gene programs, indicating that Tbx3 has a role in tissue homeostasis and regeneration. CONCLUSIONS: TBX3 demonstrates dynamic expression patterns in the pancreas. Although TBX3 is dispensable for proper pancreatic development, its absence leads to altered organ regeneration after induction of acute pancreatitis.


Asunto(s)
Pancreatitis , Adulto , Humanos , Animales , Ratones , Enfermedad Aguda , Pancreatitis/genética , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/metabolismo , Páncreas/metabolismo , Organogénesis/genética
6.
Lancet Oncol ; 24(4): 347-359, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36868252

RESUMEN

BACKGROUND: Nivolumab is used after platinum-based chemotherapy in patients with metastatic urothelial carcinoma. Studies suggest improved outcomes for dual checkpoint inhibition with high ipilimumab doses. We aimed to examine the safety and activity of nivolumab induction and high-dose ipilimumab as an immunotherapeutic boost as a second-line treatment for patients with metastatic urothelial carcinoma. METHODS: TITAN-TCC is a multicentre, single-arm, phase 2 trial done at 19 hospitals and cancer centres in Germany and Austria. Adults aged 18 years or older with histologically confirmed metastatic or surgically unresectable urothelial cancer of the bladder, urethra, ureter, or renal pelvis were eligible. Patients had to have progression during or after first-line platinum-based chemotherapy and up to one more second-line or third-line treatment, a Karnofsky Performance Score of 70 or higher, and measurable disease as per Response Evaluation Criteria in Solid Tumors version 1.1. After four doses of intravenous nivolumab 240 mg induction monotherapy every 2 weeks, patients with a partial or complete response at week 8 continued maintenance nivolumab, whereas those with stable or progressive disease (non-responders) at week 8 received a boost of two or four doses of intravenous nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks. Patients who subsequently had progressive disease during nivolumab maintenance also received a boost, using this schedule. The primary endpoint was the confirmed investigator-assessed objective response rate in the intention-to-treat population and had to exceed 20% for the null hypothesis to be rejected (based on the objective response rate with nivolumab monotherapy in the CheckMate-275 phase 2 trial). This study is registered with ClinicalTrials.gov, NCT03219775, and is ongoing. FINDINGS: Between April 8, 2019, and Feb 15, 2021, 83 patients with metastatic urothelial carcinoma were enrolled and all received nivolumab induction treatment (intention-to-treat population). The median age of enrolled patients was 68 years (IQR 61-76), and 57 (69%) were male and 26 (31%) were female. 50 (60%) patients received at least one boost dose. A confirmed investigator-assessed objective response was recorded in 27 (33%) of 83 patients in the intention-to-treat population, including six (7%) patients who had a complete response. This objective response rate was significantly higher than the prespecified threshold of 20% or less (33% [90% CI 24-42]; p=0·0049). The most common grade 3-4 treatment-related adverse events were immune-mediated enterocolitis (nine [11%] patients) and diarrhoea (five [6%] patients). Two (2%) treatment-related deaths were reported, both due to immune-mediated enterocolitis. INTERPRETATION: Treatment with nivolumab and nivolumab plus ipilimumab boosts in early non-responders and patients who progress late significantly improved objective response rate after previous platinum-based chemotherapy compared with the rate reported with nivolumab in the CheckMate-275 trial. Our study provides evidence for the added value of high-dose ipilimumab 3 mg/kg and suggests a potential role for the combination as a rescue strategy in platinum-pretreated patients with metastatic urothelial carcinoma. FUNDING: Bristol Myers Squibb.


Asunto(s)
Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Adulto , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Nivolumab/efectos adversos , Ipilimumab/efectos adversos , Carcinoma de Células Transicionales/tratamiento farmacológico , Platino (Metal) , Inmunoterapia/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos
7.
Urol Int ; 107(5): 480-488, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36630942

RESUMEN

PURPOSE: Precision oncology requires biomarker testing from tumor tissue for clinical decision-making and selection of targeted therapies. We systematically evaluated the role of tissue biomarker testing within interventional clinical trials for locally advanced and metastatic urothelial carcinoma (UC). METHODS: A systematic search within the publicly available ClinicalTrials.gov database was performed for the period 1995 to January 2020. We searched for all interventional studies on systemic treatments for advanced UC. Two investigators independently screened the records and extracted the data for statistical analyses. RESULTS: We included 356 studies out of 827 initial records in the final analysis. The overall number of interventional trials in UC patients significantly increased during the past 25 years. Forty-three studies (12.1%) required specific biomarker testing as a prerequisite for inclusion. Of the remaining 313 trials, explorative biomarkers of interest were studied in 83 studies (23.3%). In trials with obligate biomarker testing as a precondition for study inclusion, only 3 studies (7%) required an actual fresh pretreatment biopsy, while the majority of studies did not state any tissue requirements (55.8%) or accepted archival tissue samples (37.3%). Among studies without biomarker prerequisites, freshly obtained tissue samples were required in 16.3% of studies evaluating immune checkpoint inhibition and 5.7% evaluating targeted therapy. The collection of archival tissue was allowed in 67.4% and 20% of studies evaluating immune checkpoint inhibitors and targeted therapies, respectively. CONCLUSION: There has been an increase in the number of studies using biomarker-guided interventions for the treatment of advanced UC over the past 25 years. Studies investigating druggable targets in actual UC biopsies immediately before treatment are still rare. Standardized criteria for tissue-based biomarker testing may further accelerate personalized treatment of patients with advanced UC.


Asunto(s)
Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/patología , Carcinoma de Células Transicionales/patología , Medicina de Precisión , Biomarcadores
8.
World J Urol ; 40(2): 307-315, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-34779884

RESUMEN

PURPOSE: One of the main issues in testicular germ cell tumors (TGCTs) management is to reduce the necessary amount of treatment to achieve cure. Excess treatment burden may arise from late diagnosis of the primary as well as from false positive or negative staging results. Correct imaging is of paramount importance for successful management of TGCT. The aim of this review is to point out the current state of the art as well as innovative developments in TGCT imaging on the basis of three common challenging clinical situations. METHODS: A selective literature search was performed in PubMed, Medline as well as in recent conference proceedings. RESULTS: Regarding small testicular lesions, recent studies using elastography, contrast-enhanced ultrasound or magnetic resonance imaging (MRI) showed promising data for differentiation between benign and malignant histology. For borderline enlarged lymph nodes FDG-PET-CT performance is unsatisfactory, promising new techniques as lymphotropic nanoparticle-enhanced MRI is the subject of research in this field. Regarding the assessment of postchemotherapeutic residual masses, the use of conventional computerized tomography (CT) together with serum tumor markers is still the standard of care. To avoid overtreatment in this setting, new imaging modalities like diffusion-weighted MRI and radiomics are currently under investigation. For follow-up of clinical stage I TGCTs, the use of MRI is non-inferior to CT while omitting radiation exposure. CONCLUSION: Further efforts should be made to refine imaging for TGCT patients, which is of high relevance for the guidance of treatment decisions as well as the associated treatment burdens and oncological outcomes.


Asunto(s)
Neoplasias de Células Germinales y Embrionarias , Neoplasias Testiculares , Humanos , Masculino , Estadificación de Neoplasias , Neoplasias de Células Germinales y Embrionarias/diagnóstico por imagen , Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias de Células Germinales y Embrionarias/terapia , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Tomografía de Emisión de Positrones , Neoplasias Testiculares/diagnóstico por imagen , Neoplasias Testiculares/terapia , Ultrasonografía
9.
Int J Mol Sci ; 23(22)2022 Nov 18.
Artículo en Inglés | MEDLINE | ID: mdl-36430759

RESUMEN

TKS5 promotes invasion and migration through the formation of invadopodia in some tumour cells, and it also has an important physiological function in cell migration through podosome formation in various nontumour cells. To date, the role of TKS5 in urothelial cells, and its potential role in BC initiation and progression, has not yet been addressed. Moreover, the contribution of TKS5 to ploidy control and chromosome stability has not been reported in previous studies. Therefore, in the present study, we wished to address the following questions: (i) Is TKS5 involved in the ploidy control of urothelial cells? (ii) What is the mechanism that leads to aneuploidy in response to TKS5 knockdown? (iii) Is TKS5 an oncogene or tumour-suppressor gene in the context of BC? (iv) Does TKS5 affect the proliferation, migration and invasion of BC cells? We assessed the gene and protein expressions via qPCR and Western blot analyses in a set of nontumour cell strains (Y235T, HBLAK and UROtsa) and a set of BC cell lines (RT4, T24, UMUC3 and J82). Following the shRNA knockdown in the TKS5-proficient cells and the ectopic TKS5 expression in the cell lines with low/absent TKS5 expression, we performed functional experiments, such as metaphase, invadopodia and gelatine degradation assays. Moreover, we determined the invasion and migration abilities of these genetically modified cells by using the Boyden chamber and wound-healing assays. The TKS5 expression was lower in the bladder cancer cell lines with higher invasive capacities (T24, UMUC3 and J82) compared to the nontumour cell lines from human ureter (Y235T, HBLAK and UROtsa) and the noninvasive BC cell line RT4. The reduced TKS5 expression in the Y235T cells resulted in augmented aneuploidy and impaired cell division. According to the Boyden chamber and wound-healing assays, TKS5 promotes the invasion and migration of bladder cancer cells. According to the present study, TKS5 regulates the migration and invasion processes of bladder cancer (BC) cell lines and plays an important role in genome stability.


Asunto(s)
Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/genética , Vejiga Urinaria , Aneuploidia , Inestabilidad Cromosómica , Proteínas Adaptadoras del Transporte Vesicular
10.
BJU Int ; 127(1): 64-70, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32564459

RESUMEN

OBJECTIVE: To compare the incidence of postoperative flank bulges between patients with multiple-layer closure and single superficial-layer closure after retroperitoneal surgery via open flank incision in the SIngle versus MUltiple-LAyer wound Closure for flank incision (SIMULAC) trial. PATIENTS AND METHODS: The study was a randomised controlled, patient- and assessor-blinded, multicentre trial. Between May 2015 and February 2017, 225 patients undergoing flank incisions were randomised 1:1 to a multiple-layer closure (SIMULAC-I) or a single superficial-layer closure (SIMULAC-II) group. The primary outcome was the occurrence of a flank bulge 6 months after surgery. RESULTS: Overall, 177 patients (90 in SIMULAC-I, 87 in SIMULAC-II) were eligible for final assessment. The cumulative incidence of a flank bulge was significantly higher in the SIMULAC-II group (51.7%) compared to the SIMULAC-I group [34.4%; odds ratio (OR) 2.04, 95% confidence interval (CI) 1.11-3.73; P = 0.02]. Rate of severe postoperative complications (4.4% SIMULAC-I vs 10.3% SIMULAC-II; P = 0.21) or hernia (6.7% SIMULAC-I vs 10.3% SIMULAC-II; P = 0.59) was similar between the groups. There was no difference in pain (visual analogue scale) and the requirement for pain medication at 6 months postoperatively. Quality of life assessed with the European Quality of Life 5 Dimensions Questionnaire was higher in the SIMULAC-I group compared to the SIMULAC-II group at 6 months postoperatively, with a (median range) score of 80 (30-100) vs 75 (5-100) (P = 0.012). CONCLUSION: The overall risk of a flank bulge after flank incision is high. Multiple-layer closure after flank incision should be performed as a standard procedure.


Asunto(s)
Hernia Abdominal/etiología , Hernia Incisional/etiología , Complicaciones Posoperatorias/etiología , Técnicas de Cierre de Heridas/efectos adversos , Adulto , Anciano , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/etiología , Estudios Prospectivos , Calidad de Vida , Procedimientos Quirúrgicos Urológicos/efectos adversos
11.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33803949

RESUMEN

Invasive urothelial carcinomas of the bladder (UCB) characteristically show a loss of differentiation markers. The transcription factor Grainyhead-like 3 (GRHL3) plays an important role in the development and differentiation of normal urothelium. The contribution to UCB progression is still elusive. Differential expression of GRHL3 was assessed in normal human urothelium and in non-invasive and invasive bladder cancer cell lines. The contribution of GRHL3 to cell proliferation, viability and invasion in UCB cell lines was determined by gain- and loss-of-function assays in vitro and in an organ culture model using de-epithelialized porcine bladders. GRHL3 expression was detectable in normal human urothelial cells and showed significantly higher mRNA and protein levels in well-differentiated, non-invasive RT4 urothelial carcinoma cells compared to moderately differentiated RT112 cells. GRHL3 expression was absent in anaplastic and invasive T24 cells. Ectopic de novo expression of GRHL3 in T24 cells significantly impaired their migration and invasion properties in vitro and in organ culture. Its downregulation improved the invasive capacity of RT4 cells. The results indicate that GRHL3 may play a role in progression and metastasis in UCB. In addition, this work demonstrates that de-epithelialized porcine bladder organ culture can be a useful, standardized tool to assess the invasive capacity of cancer cells.


Asunto(s)
Carcinoma/genética , Proteínas de Unión al ADN/genética , Factores de Transcripción/genética , Neoplasias de la Vejiga Urinaria/genética , Urotelio/metabolismo , Animales , Carcinoma/patología , Carcinoma de Células Transicionales , Diferenciación Celular/genética , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Metástasis de la Neoplasia , Técnicas de Cultivo de Órganos , Porcinos , Neoplasias de la Vejiga Urinaria/patología , Urotelio/patología
12.
Int J Mol Sci ; 22(11)2021 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-34070905

RESUMEN

BACKGROUND: The interleukin-1-receptor antagonist IL1RA (encoded by the IL1RN gene) is a potent competitive antagonist to interleukin-1 (IL1) and thereby is mainly involved in the regulation of inflammation. Previous data indicated a role of IL1RA in muscle-invasive urothelial carcinoma of the bladder (UCB) as well as an IL1-dependent decrease in tissue barrier function, potentially contributing to cancer cell invasion. OBJECTIVE: Based on these observations, here we investigated the potential roles of IL1RA, IL1A, and IL1B in bladder cancer cell invasion in vitro. METHODS: Cell culture, real-time impedance sensing, invasion assays (Boyden chamber, pig bladder model), qPCR, Western blot, ELISA, gene overexpression. RESULTS: We observed a loss of IL1RA expression in invasive, high-grade bladder cancer cell lines T24, UMUC-3, and HT1197 while IL1RA expression was readily detectable in the immortalized UROtsa cells, the non-invasive bladder cancer cell line RT4, and in benign patient urothelium. Thus, we modified the invasive human bladder cancer cell line T24 to ectopically express IL1RA, and measured changes in cell migration/invasion using the xCELLigence Real-Time-Cell-Analysis (RTCA) system and the Boyden chamber assay. The real-time observation data showed a significant decrease of cell migration and invasion in T24 cells overexpressing IL1RA (T24-IL1RA), compared to cells harboring an empty vector (T24-EV). Concurrently, tumor cytokines, e.g., IL1B, attenuated the vascular endothelial barrier, which resulted in a reduction of the Cell Index (CI), an impedance-based dimensionless unit. This reduction could be reverted by the simultaneous incubation with IL1RA. Moreover, we used an ex vivo porcine organ culture system to evaluate cell invasion capacity and showed that T24-IL1RA cells showed significantly less invasive capacity compared to parental T24 cells or T24-EV. CONCLUSIONS: Taken together, our results indicate an inverse correlation between IL1RA expression and tumor cell invasive capacity and migration, suggesting that IL1RA plays a role in bladder carcinogenesis, while the exact mechanisms by which IL1RA influences tumor cells migration/invasion remain to be clarified in future studies. Furthermore, we confirmed that real-time impedance sensing and the porcine ex vivo organ culture methods are powerful tools to discover differences in cancer cell migration and invasion.


Asunto(s)
Movimiento Celular/genética , Células Epiteliales/metabolismo , Proteína Antagonista del Receptor de Interleucina 1/genética , Interleucina-1alfa/genética , Interleucina-1beta/genética , Neoplasias de la Vejiga Urinaria/genética , Animales , Carcinogénesis/genética , Carcinogénesis/metabolismo , Carcinogénesis/patología , Línea Celular Tumoral , Proliferación Celular , Células Epiteliales/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Proteína Antagonista del Receptor de Interleucina 1/metabolismo , Interleucina-1alfa/metabolismo , Interleucina-1beta/metabolismo , Invasividad Neoplásica , Transducción de Señal , Porcinos , Vejiga Urinaria/metabolismo , Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patología
13.
Eur J Nucl Med Mol Imaging ; 47(10): 2339-2347, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32157427

RESUMEN

PURPOSE: 68Ga-PSMA-11-PET/CT is increasingly used in early-stage biochemical recurrence of prostate cancer to detect potential lesions for an individualized radiotherapy concept. However, subtle findings especially concerning small local recurrences can still be challenging to interpret and are prone to variability between different readers. Thus, we analyzed interobserver variability, detection rate, and lesion patterns systematically in a homogeneous patient population with low-level biochemical recurrence. METHODS: We analyzed 68Ga-PSMA-11-PET/CTs in 116 patients with status post-prostatectomy and PSA levels up to 0.6 ng/ml. None of them received ADT or radiotherapy beforehand. Images were interpreted and blinded by two nuclear medicine physicians (R1 and R2). Findings were rated using a 5-point scale concerning local recurrence, lymph nodes, bone lesions, and other findings (1: definitely benign, 2: probably benign, 3: equivocal, 4: probably malignant, 5: definitely malignant). In findings with substantial discrepancies of 2 or more categories and/or potentially leading to differences in further patient management, a consensus reading was done with a third reader (R3). Interobserver agreement was measured by Cohens Kappa analysis after sub-categorizing our classification system to benign (1 + 2), equivocal (3), and malignant (4 + 5). Time course of PSA levels after salvage treatment of patients rated as positive (4 + 5) was analyzed. RESULTS: The overall detection rate (categories 4 and 5) was 50% (R1/R2, 49%/51%) and in the PSA subgroups 0-0.2 ng/ml, 0.21-0.3 ng/ml, and 0.31-0.6 ng/ml 24%/27%, 57%/57%, and 65%/68%, respectively. Local recurrence was the most common lesion manifestation followed by lymphatic and bone metastases. The overall agreement in the Cohens Kappa analysis was 0.74 between R1 and R2. For local, lymphatic, and bone sites, the agreement was 0.76, 0.73, and 0.58, respectively. PSA levels of PSMA PET/CT-positive patients after salvage treatment decreased in 75% (27/36) and increased in 25% (9/36). A decrease of PSA, although more frequent in patients with imaging suggesting only local tumor recurrence (86%, 18/21), was also observed in 67% (10/15) of patients with findings of metastatic disease. CONCLUSIONS: In a highly homogeneous group of prostate cancer patients with early-stage biochemical recurrence after radical prostatectomy, we could show that 68Ga-PSMA-11-PET/CT has a good detection rate of 50% which is in accordance with literature, with clinically relevant findings even in patients with PSA < 0.21 ng/ml. The interobserver variability is low, particularly concerning assessment of local recurrences and lymph nodes. Therefore, PSMA-PET/CT is a robust diagnostic modality in this patient group for therapy planning.


Asunto(s)
Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias de la Próstata , Ácido Edético/análogos & derivados , Isótopos de Galio , Radioisótopos de Galio , Humanos , Masculino , Recurrencia Local de Neoplasia/diagnóstico por imagen , Variaciones Dependientes del Observador , Oligopéptidos , Antígeno Prostático Específico , Prostatectomía , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/cirugía , Recurrencia
14.
Urol Int ; 104(1-2): 10-15, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31563906

RESUMEN

PURPOSE: To investigate prevalence and variables associated with early oncologic mortality (EOM; within ≥30 to ≤90 days) of open radical cystectomy (RC) for bladder cancer. The unexpected rapidity of tumour recurrence and the huge metastatic burden of these patients drew us to analyse this cohort. METHODS: We reviewed our RC database. All 1,487 patients were treated with curative intent between January 1986 and December 2008. Imaging for staging was done by CT (chest) and CT or MRI (abdomen). Clinical and histopathological variables were recorded until death to determine whether disease- or treatment-related factors were associated with mortality. RESULTS: There were 93 deaths within 90 days of surgery. Twenty-four patients died from early progression to high volume disseminated metastatic disease. Group 1: unresectable tumours, which were never free of disease. Group 2: resectable tumours, considered tumour-free after RC. Group 1 is characterized by local tumour spread and a low distant failure rate. Group 2 has a low local and a high distant failure rate. CONCLUSIONS: Disease related (advanced tumour stage, positive soft tissue surgical margins (+STSM), non urothelial histology, unresectable tumours, atypical occult metastasis), rather than technical factors, had the leading role in EOM. Understaging was universal.


Asunto(s)
Cistectomía/efectos adversos , Cistectomía/mortalidad , Neoplasias de la Vejiga Urinaria/mortalidad , Neoplasias de la Vejiga Urinaria/cirugía , Progresión de la Enfermedad , Estudios de Seguimiento , Humanos , Imagen por Resonancia Magnética , Clasificación del Tumor , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Prevalencia , Estudios Prospectivos , Estudios Retrospectivos , Factores de Riesgo , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/diagnóstico por imagen
15.
Int J Mol Sci ; 21(9)2020 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-32397303

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) has still a dismal prognosis. Different factors such as mutational landscape, intra- and intertumoral heterogeneity, stroma, and immune cells impact carcinogenesis of PDAC associated with an immunosuppressive microenvironment. Different cell types with partly opposing roles contribute to this milieu. In recent years, immunotherapeutic approaches, including checkpoint inhibitors, were favored to treat cancers, albeit not every cancer entity exhibited benefits in a similar way. Indeed, immunotherapies rendered little success in pancreatic cancer. In this review, we describe the communication between the immune system and pancreatic cancer cells and propose some rationale why immunotherapies may fail in the context of pancreatic cancer. Moreover, we delineate putative strategies to sensitize PDAC towards immunological therapeutics and highlight the potential of targeting neoantigens.


Asunto(s)
Carcinoma Ductal Pancreático/inmunología , Inmunoterapia/métodos , Neoplasias Pancreáticas/inmunología , Microambiente Tumoral/inmunología , Animales , Linfocitos B/inmunología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/terapia , Humanos , Células Asesinas Naturales/inmunología , Macrófagos/inmunología , Mastocitos/inmunología , Neutrófilos/inmunología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/terapia , Pronóstico
16.
World J Urol ; 37(11): 2419-2427, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-30759271

RESUMEN

PURPOSE: To evaluate the prognostic value of BRCA1-associated protein-1 (BAP1) expression in upper tract urothelial carcinoma (UTUC), as BAP1 mutations have been associated with prognostic implications in urologic and non-urologic malignancies. METHODS: We reviewed a multi-institutional cohort of patients who underwent radical nephroureterectomy (RNU) for high-grade UTUC from 1990-2008. Immunohistochemistry (IHC) for BAP1 was performed on tissue microarrays. Staining intensity was graded from 0-3, with BAP1 loss defined as an average intensity of < 1. Clinicopathologic characteristics and oncologic outcomes [recurrencefree (RFS), cancer-specific (CSS), and overall survival (OS)] were stratified by BAP1 status. The prognostic role of BAP1 was assessed using Kaplan-Meier (KM) and Cox regression analysis. Significance was defined as p < 0.05. RESULTS: 348 patients were included for analysis and 173 (49.7%) showed BAP1 loss. Median follow-up was 36.0 months. BAP1 loss was associated with papillary architecture and absence of tumor necrosis or CIS. On univariable analysis, BAP1 loss was associated with improved RFS (HR 0.60, p = 0.013) and CSS (HR 0.55, p = 0.007), although significance was lost on multivariable analysis (HR 0.71, p = 0.115 and HR 0.65, p = 0.071; respectively) after adjusting for other significant parameters. BAP1 expression was not significantly associated with OS. CONCLUSIONS: BAP1 loss was associated with favorable pathologic features and better oncologic outcomes in univariate but not multivariate analysis in patients with high-grade UTUC. In contrast to renal cell carcinoma, loss of BAP1 expression appears to confer a better prognosis in high-grade UTUC. The role of the BAP1 pathway in UTUC pathogenesis remains to be further elucidated.


Asunto(s)
Carcinoma de Células Transicionales/metabolismo , Carcinoma de Células Transicionales/mortalidad , Neoplasias Renales/metabolismo , Neoplasias Renales/mortalidad , Proteínas Supresoras de Tumor/biosíntesis , Ubiquitina Tiolesterasa/biosíntesis , Neoplasias Ureterales/metabolismo , Neoplasias Ureterales/mortalidad , Anciano , Carcinoma de Células Transicionales/química , Carcinoma de Células Transicionales/patología , Femenino , Humanos , Neoplasias Renales/química , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Proteínas Supresoras de Tumor/análisis , Ubiquitina Tiolesterasa/análisis , Neoplasias Ureterales/química , Neoplasias Ureterales/patología
17.
Int J Mol Sci ; 21(1)2019 Dec 20.
Artículo en Inglés | MEDLINE | ID: mdl-31877678

RESUMEN

In this study, we describe the identification of a novel splice variant of TERF1/PIN2, one of the main components of the telomeric shelterin complex. This new splice variant is identical to TERF1, apart from a 30 amino acid internal insertion near to the C-terminus of TERF1. Based on genome comparison analyses and RNA expression data, we show that this splice variant is conserved among hominidae but absent from all other species. RNA expression and histological analyses show specific expression in human spermatogonial and hematopoietic stem cells (HSCs), while all other analyzed tissues lack the expression of this TERF1-isoform, hence the name TERF1-tsi (TERF1-tissue-specific-isoform). In addition, we could not detect any expression in primary human cells and established cancer cell lines. Immunohistochemistry results involving two new rabbit polyclonal antibodies, generated against TERF1-tsi specific peptides, indicate nuclear localization of TERF1-tsi in a subset of spermatogonial stem cells. In line with this observation, immunofluorescence analyzes in various cell lines consistently revealed that ectopic TERF1-tsi localizes to the cell nucleus, mainly but not exclusively at telomeres. In a first attempt to evaluate the impact of TERF1-tsi in the testis, we have tested its expression in normal testis samples versus matched tumor samples from the same patients. Both RT-PCR and IHC show a specific downregulation of TERF1-tsi in tumor samples while the expression of TERF1 and PIN2 remains unchanged.


Asunto(s)
Regulación hacia Abajo , Seminoma/genética , Proteínas de Unión a Telómeros/genética , Neoplasias Testiculares/genética , Animales , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Humanos , Masculino , Ratones , Isoformas de Proteínas/análisis , Isoformas de Proteínas/genética , Seminoma/patología , Complejo Shelterina , Telómero/genética , Telómero/patología , Proteínas de Unión a Telómeros/análisis , Neoplasias Testiculares/patología , Testículo/metabolismo , Testículo/patología
18.
J Cancer Educ ; 34(2): 381-387, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-29313299

RESUMEN

A growing number of patients search for health information online. An early investigation of websites about bladder cancer (BCa) revealed mostly incomplete and particularly inaccurate information. We analyzed the quality, readability, and popularity of the most frequented websites on BCa. An Internet search on www.google.com was performed for the term "bladder cancer." After selecting the most frequented websites for patient information, HONcode quality certification, Alexa popularity rank, and readability scores (according to US grade levels) were investigated. A 36-point checklist was used to assess the content according to the EAU guidelines on BCa, which was categorized into seven topics. The popularity of the 49 websites analyzed was average, with a median Alexa popularity rank of 41,698 (interquartile range [IQR] 7-4,671,246). The readability was rated difficult with 11 years of school education needed to understand the information. Thirteen (27%) websites were HONcode certified. Out of 343 topics (seven EAU guideline topics each on 49 websites), 79% were mentioned on the websites. Of these, 10% contained incorrect information, mostly outdated or biased, and 34% contained incomplete information. Publically provided websites mentioned more topics per website (median [IQR] 7 [5.5-7] vs. 5.5 [3.3-7]; p = 0.022) and showed less incorrect information (median [IQR] 0 [0-1] vs. 1 [0-1]; p = 0.039) than physician-provided websites. Our study revealed mostly correct but partially incomplete information on BCa websites for patients. Physicians and public organizations should strive to keep their website information up-to-date and unbiased to optimize patients' health literacy.


Asunto(s)
Comprensión , Información de Salud al Consumidor , Alfabetización en Salud , Internet , Neoplasias de la Vejiga Urinaria , Humanos
19.
Health Qual Life Outcomes ; 16(1): 21, 2018 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-29357874

RESUMEN

BACKGROUND: Patient-reported health-related quality of life (HRQOL) differs between treatment options for prostate carcinoma. Long-term HRQOL data in brachytherapy series are scarce. Therefore, we analyzed prostate-specific and general HRQOL in patients treated with brachytherapy for prostate carcinoma after long-term follow-up. METHODS: Two hundred ninety-six patients with prostate carcinoma were treated with brachytherapy (01/1998-11/2003). General and prostate-specific HRQOL were measured using EORTC-QLQ-C30 and EORTC-QLQ-PR25, respectively. Patients were asked to complete the questionnaires after a median follow-up of 141 (119-181) months. QLQ-C30 results were compared to the German reference population. QLQ-PR25 results were compared to an earlier follow-up after a median of 51 months (no published QLQ-PR25 reference population for comparison). Additionally, a literature review on HRQOL data in brachytherapy series was performed. RESULTS: One hundred six (35.8%) patients were lost to follow-up, 70 (23.6%) had died. 120 (40.5%) patients were contacted. 80 questionnaires were returned (27% of the original cohort; 91% of alive patients were ≥70 years). Sexual activity declined over time (mean scores: 40.5 vs. 45.5; p = 0.006), hormonal treatment-related symptoms, problems associated with incontinence aids, and burden of obstructive urinary symptoms did not differ significantly compared to the 51-month follow-up. General HRQOL was numerically better in our cohort as compared to the German reference population (> 16% relative difference for both age strata; < 70 and ≥70 years). CONCLUSIONS: Our results indicate that symptom-burden after long-term follow-up and associated prostate-specific HRQOL remains relatively stable from 51 to 141 months. General HRQOL in surviving patients was numerically better compared to the reference population.


Asunto(s)
Braquiterapia , Neoplasias de la Próstata/radioterapia , Calidad de Vida , Anciano , Anciano de 80 o más Años , Braquiterapia/efectos adversos , Braquiterapia/métodos , Disfunción Eréctil/psicología , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Medición de Resultados Informados por el Paciente , Dosificación Radioterapéutica , Estadísticas no Paramétricas , Encuestas y Cuestionarios , Factores de Tiempo , Incontinencia Urinaria/psicología
20.
Urol Int ; 100(1): 122-125, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-26780095

RESUMEN

Urothelial carcinoma (UC) is one of the most common cancers and survival rates are low in metastatic disease with currently established first-line platinum-based chemotherapies. Unlike in many other cancers, no clinically established molecular targeted therapies exist for the treatment of this malignancy. Here we present a case of complete tumor remission following third-line treatment with trastuzumab and gemcitabine in a patient with human epidermal growth factor receptor 2 (HER2)-positive UC after progression under cisplatin and vinflunine chemotherapies. This case shows the potential significance of anti-HER2 therapy in selected patients with molecularly characterized UC. Clinical trials so far show inconclusive outcomes of anti-HER2 therapies in UC, indicating further need for both basic research and clinical studies for the identification of resistance factors and improved patient selection.


Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/secundario , Desoxicitidina/análogos & derivados , Trastuzumab/uso terapéutico , Carcinoma de Células Transicionales/química , Desoxicitidina/uso terapéutico , Humanos , Receptor ErbB-2/análisis , Inducción de Remisión , Gemcitabina
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