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1.
Life Sci ; 283: 119855, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34314734

RESUMO

AIMS: Aging is an obvious risk factor for detrusor underactivity. We investigated the effects of aging on bladder function in spontaneously hypertensive rats. MAIN METHODS: Male spontaneously hypertensive rats and Wistar Kyoto rats (used as normotensive controls) at the ages of 18, 36, 54, or 72 weeks were used. Bladder weight, blood pressure, bladder blood flow, and urodynamic and renal parameters were measured. Additionally, detrusor thickness and renal histology were evaluated. KEY FINDINGS: In spontaneously hypertensive rats, significant increases were observed in bladder weight/body weight ratio, blood pressure, detrusor thickness, intercontraction interval, urine output, serum creatinine, and renal glomerular and tubular scores, and decreases in bladder blood flow and urine osmolality at 72 weeks as compared to those at 18 weeks. In spontaneously hypertensive rats, significant increases were observed in single voided volume, post voiding residual urine volume, and bladder capacity, with decrease in voiding efficiency were observed at 54 or 72 weeks than at 18 weeks. However, there were no significant differences in blood pressure, urodynamic and renal parameters, detrusor thickness and renal histology among Wistar Kyoto rats of different ages. SIGNIFICANCE: In spontaneously hypertensive rats, aging induces significant increases in blood pressure, single voided volume, post voiding residual urine volume, intercontraction intervals and urine output, and decreases in voiding efficiency and bladder blood flow indicative of detrusor underactivity. Aging-related severe hypertension could induce voiding dysfunction such as detrusor underactivity via severe bladder ischemia and polyuria. Aged spontaneously hypertensive rats may be useful animal models for detrusor underactivity.


Assuntos
Envelhecimento/metabolismo , Hipertensão , Bexiga Inativa , Bexiga Urinária , Envelhecimento/patologia , Animais , Hipertensão/complicações , Hipertensão/metabolismo , Hipertensão/patologia , Hipertensão/fisiopatologia , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Índice de Gravidade de Doença , Bexiga Urinária/metabolismo , Bexiga Urinária/patologia , Bexiga Urinária/fisiopatologia , Bexiga Inativa/etiologia , Bexiga Inativa/metabolismo , Bexiga Inativa/patologia , Bexiga Inativa/fisiopatologia
2.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199527

RESUMO

Overactive bladder (OAB) syndrome, including frequency, urgency, nocturia and urgency incontinence, has a significantly negative impact on the quality-of-life scale (QoL) and can cause sufferer withdrawal from social activities. The occurrence of OAB can result from an imbalance between the production of pro-oxidants, such as free radicals and reactive species, and their elimination through protective mechanisms of antioxidant-induced oxidative stress. Several animal models, such as bladder ischemia/reperfusion (I/R), partial bladder outlet obstruction (PBOO) and ovarian hormone deficiency (OHD), have suggested that cyclic I/R during the micturition cycle induces oxidative stress, leading to bladder denervation, bladder afferent pathway sensitization and overexpression of bladder-damaging molecules, and finally resulting in bladder hyperactivity. Based on the results of previous animal experiments, the present review specifically focuses on four issues: (1) oxidative stress and antioxidant defense system; (2) oxidative stress in OAB and biomarkers of OAB; (3) OAB animal model; (4) potential nature/plant antioxidant treatment strategies for urinary dysfunction with OAB. Moreover, we organized the relationships between urinary dysfunction and oxidative stress biomarkers in urine, blood and bladder tissue. Reviewed information also revealed the summary of research findings for the effects of various antioxidants for treatment strategies for OAB.


Assuntos
Antioxidantes/uso terapêutico , Isquemia/tratamento farmacológico , Bexiga Urinária Hiperativa/tratamento farmacológico , Incontinência Urinária/tratamento farmacológico , Humanos , Isquemia/patologia , Estresse Oxidativo/genética , Estresse Oxidativo/fisiologia , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/patologia , Incontinência Urinária/patologia
3.
Int J Mol Sci ; 22(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199232

RESUMO

Non-muscle-invasive bladder cancer is the most common form of bladder cancer. The main problem in managing bladder tumors is the high recurrence after the transurethral resection of bladder tumors (TURBT). Our study aimed to examine the fate of intravesically applied cancer cells as the implantation of cancer cells after TURBT is thought to be a cause of tumor recurrence. We established an orthotopic mouse bladder tumor model with MB49-GFP cancer cells and traced them during the first three days to define their location and contacts with normal urothelial cells. Data were obtained by Western blot, immunolabeling, and light and electron microscopy. We showed that within the first two hours, applied cancer cells adhered to the traumatized epithelium by cell projections containing α3ß1 integrin on their tips. Cancer cells then migrated through the epithelium and on day 3, they reached the basal lamina or even penetrated it. In established bladder tumors, E-cadherin and desmoplakin 1/2 were shown as feasible immunohistochemical markers of tumor margins based on the immunolabeling of various junctional proteins. Altogether, these results for the first time illustrate cancer cell implantation in vivo mimicking cellular events of tumor recurrence in bladder cancer patients.


Assuntos
Epitélio/patologia , Recidiva Local de Neoplasia/patologia , Neoplasias da Bexiga Urinária/patologia , Bexiga Urinária/patologia , Animais , Caderinas/metabolismo , Adesão Celular , Linhagem Celular Tumoral , Movimento Celular , Modelos Animais de Doenças , Feminino , Integrina alfa3beta1/metabolismo , Junções Intercelulares/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Invasividade Neoplásica , Bexiga Urinária/ultraestrutura , Neoplasias da Bexiga Urinária/ultraestrutura , Urotélio/patologia , Urotélio/ultraestrutura
4.
Biomed Pharmacother ; 138: 111522, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34311526

RESUMO

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a disorder with complex pathogenesis and lacks effective treatment. Chronic inflammation is the main pathogenesis of Hunner-type IC/BPS. The NLR family pyrin domain-containing 3 (NLRP3) inflammasome-related transforming growth factor-ß (TGF-ß)/Smad signaling pathway plays a crucial role in inflammation-related tissue fibrosis. Lipopolysaccharide (LPS) and protamine sulfate (LPS/PS) were instilled into the mouse bladder twice a week for 5 consecutive weeks to establish a chronic inflammation-induced IC/BPS model (LPS/PS model). Following LPS/PS treatment, curcumin (oral, 100 mg/kg; a potent NLRP3 modulator) was administered for 2 weeks in the curcumin treatment group, and normal saline was used for the sham group. Bladder function was evaluated by performing the voiding spot assay and examining the status of urothelial denudation and fibrosis in bladder tissues. The expression of NLRP3 inflammasome, interleukin-1ß, TGF-ß, Smad, vimentin, and E-cadherin in bladder tissues was evaluated through immunohistochemistry staining. Results revealed that the repeated instillation of LPS/PS leads to voiding dysfunction, bladder urothelium denudation, and detrusor muscle fibrosis through the upregulation of the NLRP3 inflammasome/IL-1ß-related TGF-ß/Smad pathway and the increased epithelial-mesenchymal transition process in bladder tissues. The downregulation of the NLRP3 inflammasome/IL-1ß-related TGF-ß/Smad pathway in bladder tissues through curcumin effectively mitigated bladder injury in the LPS/PS model. In conclusion, the NLRP3 inflammasome/IL-1ß-related TGF-ß/Smad pathway plays a crucial role in bladder injury in the LPS/PS model, and modulation of this pathway, such as by using curcumin, can effectively mitigate the sequelae of chronic inflammation-induced IC/BPS.


Assuntos
Anti-Inflamatórios/farmacologia , Curcumina/farmacologia , Cistite Intersticial/tratamento farmacológico , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Bexiga Urinária/efeitos dos fármacos , Urodinâmica/efeitos dos fármacos , Animais , Cistite Intersticial/metabolismo , Cistite Intersticial/patologia , Cistite Intersticial/fisiopatologia , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Fibrose , Camundongos Endogâmicos BALB C , Transdução de Sinais , Bexiga Urinária/metabolismo , Bexiga Urinária/patologia , Bexiga Urinária/fisiopatologia , Micção/efeitos dos fármacos
5.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34210091

RESUMO

(1) Background: We established a new bladder ischemia rat model through bilateral partial iliac arterial occlusion (BPAO) and investigated the therapeutic effect of adipose-derived stem cells (ADSCs) and ADSC-derived microvesicles (MVs); (2) Methods: The study included four groups: (1) sham, (2) BPAO, (3) BPAO + ADSCs, and (4) BPAO + ADSC-derived MVs. Female Wistar rats with BPAO were injected with ADSCs or ADSC-derived MVs through the femoral artery. Doppler flowmetry and real-time laser speckle contrast imaging were performed to quantify blood flow in the common iliac arteries and bladder microcirculation. A 24-h behavior study and transcystometrogram were conducted after 2 weeks. Bladder histology, immunostaining, and lipid peroxidation assay were performed. The expressions of P2X2, P2X3, M2, and M3 receptors and nerve growth factor (NGF) were evaluated; (3) Results: BPAO significantly reduced bladder microcirculation, intercontraction interval (ICI), and bladder volume and increased the amplitude of nonvoiding contraction, neutrophil infiltration, and malondialdehyde and NGF levels. ADSCs and ADSC-derived MVs significantly ameliorated these effects. The results of Western blot showed that the BPAO group exhibited the highest expression of M3 and P2X2 receptors. ADSCs significantly attenuated the expressions of M2 and P2X2 receptors. ADSC-derived MVs significantly attenuated the expressions of M3 and P2X2 receptors; (4) Conclusions: ADSCs and ADSC-derived MVs ameliorated the adverse effects of BPAO including bladder overactivity, bladder ischemia, and oxidative stress. Inflammation, muscarinic signaling, purinergic signaling, and NGF might be involved in the therapeutic mechanism.


Assuntos
Tecido Adiposo/citologia , Células-Tronco Adultas/transplante , Micropartículas Derivadas de Células/transplante , Bexiga Urinária Hiperativa/terapia , Células-Tronco Adultas/citologia , Animais , Arteriopatias Oclusivas/complicações , Arteriopatias Oclusivas/terapia , Micropartículas Derivadas de Células/fisiologia , Modelos Animais de Doenças , Feminino , Artéria Ilíaca/patologia , Isquemia/etiologia , Isquemia/terapia , Ratos , Ratos Wistar , Bexiga Urinária/patologia , Bexiga Urinária Hiperativa/etiologia
6.
Life Sci ; 279: 119690, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34111460

RESUMO

AIMS: We examined age-associated changes in bladder and urethral coordination involving the nitric oxide (NO)/soluble guanylyl cyclase (sGC) system, which induces urethral smooth muscle relaxation, and urethral ischemic/oxidative stress changes in rats. MAIN METHODS: Sixteen female Sprague-Dawley rats were divided into young (3 months old) and middle-aged (12-15 months old) groups. Urethral activity was evaluated by simultaneously recording intravesical pressure under isovolumetric conditions and urethral perfusion pressure (UPP) under urethane anesthesia. Sodium nitroprusside (SNP, 0.1 mg/kg), an NO donor, and BAY 41-2272, a novel NO-independent stimulator of sGC (0.1 mg/kg), were administered intravenously to both groups. N-nitro-l-arginine methyl ester hydrochloride (l-NAME, 100 mg/kg) was also injected intravenously, to inhibit NO synthase activity in both groups. Staining for the ischemic marker, hypoxia-inducible factor-1α (HIF-1α), and the oxidative stress markers, 8-hydroxy-2'-deoxyguanosine (8-OHdG) and malondialdehyde (MDA), was performed on tissue sections of the urethra, in both groups. KEY FINDINGS: Baseline UPP and UPP changes were significantly lower in middle-aged rats than in young rats. After administration of SNP and BAY 41-2272, baseline UPP and UPP nadir were significantly decreased in both groups. After administration of l-NAME, UPP change/bladder contraction amplitude in young rats was still lower than at baseline but was completely restored to control levels in middle-aged rats. Immunoreactivity of HIF-1α, 8-OHdG, and MDA was higher in middle-aged rats than in young rats. SIGNIFICANCE: Age-associated ischemic and oxidative stress in the urethra might be correlated with impairment of the NO/sGC system and with coordination of the bladder and urethra.


Assuntos
Ataxia/patologia , Óxido Nítrico/metabolismo , Estresse Oxidativo , Guanilil Ciclase Solúvel/metabolismo , Uretra/patologia , Bexiga Urinária/patologia , Fatores Etários , Animais , Ataxia/metabolismo , Feminino , Relaxamento Muscular , Ratos , Ratos Sprague-Dawley , Uretra/metabolismo , Bexiga Urinária/metabolismo
7.
Ann R Coll Surg Engl ; 103(7): e227-e230, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34192502

RESUMO

Adenocarcinoma of the bladder is a rare form of malignancy accounting for fewer than 2% of bladder tumours. It is most commonly a result of direct invasion from prostatic, rectal or gynaecological primaries and less commonly presents from distant haematological or lymphatic metastasis. We report a rare case of oesophageal carcinoma metastasising to the bladder. It involves a 71-year-old man with progressive dysphagia and diagnostic computerised tomography findings of thickening in the oesophagus, bladder and common bile duct. Subsequent endoscopic biopsies of the oesophageal and bladder abnormalities showed immunohistochemical features consistent with upper gastrointestinal malignancy. This report aims to add to current clinical evidence of this route of metastasis and also highlight some of the key markers used by pathologists in interpretation of specimens. It also emphasises the essential role of a multidisciplinary approach for the diagnosis of such rare conditions.


Assuntos
Adenocarcinoma/patologia , Transtornos de Deglutição/etiologia , Neoplasias Esofágicas/patologia , Hidronefrose/diagnóstico , Neoplasias da Bexiga Urinária/diagnóstico , Adenocarcinoma/complicações , Adenocarcinoma/diagnóstico , Adenocarcinoma/terapia , Idoso , Biópsia , Cistoscopia , Neoplasias Esofágicas/complicações , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/terapia , Esôfago/diagnóstico por imagem , Esôfago/patologia , Humanos , Hidronefrose/etiologia , Masculino , Cuidados Paliativos , Assistência Terminal , Bexiga Urinária/diagnóstico por imagem , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/secundário , Neoplasias da Bexiga Urinária/terapia , Perda de Peso
8.
FASEB J ; 35(7): e21703, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34105799

RESUMO

Ketamine cystitis (KC) is a chronic bladder inflammation leading to urinary urgency, frequency, and pain. The pathogenesis of KC is complicated and involves multiple tissue injuries in the bladder. Recent studies indicated that urothelium disruption, lamina propria fibrosis and inflammation, microvascular injury, neuropathological alterations, and bladder smooth muscle (BSM) abnormalities all contribute to the pathogenesis of KC. Ketamine has been shown to induce these tissue injuries by regulating different signaling pathways. Ketamine can stimulate antiproliferative factor, adenosine triphosphate, and oxidative stress to disrupt urothelium. Lamina propria fibrosis and inflammation are associated with the activation of cyclooxygenase-2, nitric oxide synthase, immunoglobulin E, and transforming growth factor ß1. Ketamine contributes to microvascular injury via the N-methyl-D aspartic receptor (NMDAR), and multiple inflammatory and angiogenic factors such as tumor necrosis factor α and vascular endothelial growth factor. For BSM abnormalities, ketamine can depress the protein kinase B, extracellular signal-regulated kinase, Cav1.2, and muscarinic receptor signaling. Elevated purinergic signaling also plays a role in BSM abnormalities. In addition, ketamine affects neuropathological alterations in the bladder by regulating NMDAR- and brain-derived neurotrophic factor-dependent signaling. Inflammatory cells also contribute to neuropathological changes via the secretion of chemical mediators. Clarifying the role and function of these signaling underlying tissue injuries in the bladder with KC can contribute to a better understanding of the pathophysiology of this disease and to the design of effective treatments for KC.


Assuntos
Cistite/patologia , Regulação da Expressão Gênica , Ketamina/efeitos adversos , Transdução de Sinais , Bexiga Urinária/patologia , Cistite/induzido quimicamente , Cistite/genética , Cistite/metabolismo , Humanos , Bexiga Urinária/lesões , Bexiga Urinária/metabolismo
9.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070317

RESUMO

Urinary bladder cancer is often multifocal; however, the intraluminal dissemination of the urothelial cancer cells is poorly understood. The involvement of N-cadherin in the adhesion of the cancer urothelial cells to the urothelium had not previously been studied. Therefore, we herein explore the possibility of the intraluminal dissemination of the urothelial cancer cells by evaluating the role of classical cadherins in the adhesion of urothelial cancer cells to the urothelium. We used E-cadherin negative T24 cells and established a T24 Ncadlow cell line with an additionally decreased expression of N-cadherin in the plasma membrane and a decreased secretion of proform of metalloproteinase 2. The labelled T24 and T24 Ncadlow cells were seeded onto urothelial in vitro models. After 24 h in co-culture, unattached cancer cells were rinsed and urothelia with attached cancer urothelial cells were processed for fluorescence and electron microscopy. Both the T24 and T24 Ncadlow cells attached to the urothelium, yet only to the uroplakin-negative urothelial cells. The ultrastructural analysis showed that T24 and T24 Ncadlow cells adhere to poorly differentiated urothelial cells by desmosomes. To achieve this, they first disrupt tight junctions of superficial urothelial cells. This study indicates that the lack of E-cadherin expression and decreased expression of N-cadherin in the plasma membrane of T24 cells does not interfere with their adhesion to the urothelium; therefore, our results suggest that intraluminal dissemination of cancer urothelial cells along the urothelium occurs on uroplakin-negative cells and is desmosome-mediated.


Assuntos
Proteínas de Neoplasias/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Bexiga Urinária/imunologia , Uroplaquinas/metabolismo , Urotélio/metabolismo , Adesão Celular , Linhagem Celular Tumoral , Técnicas de Cocultura , Humanos , Junções Íntimas/metabolismo , Junções Íntimas/patologia , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/patologia , Urotélio/patologia
10.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070905

RESUMO

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.


Assuntos
Movimento Celular/genética , Células Epiteliais/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-1alfa/genética , Interleucina-1beta/genética , Neoplasias da Bexiga Urinária/genética , Animais , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Proliferação de Células , Células Epiteliais/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-1alfa/metabolismo , Interleucina-1beta/metabolismo , Invasividade Neoplásica , Transdução de Sinais , Suínos , Bexiga Urinária/metabolismo , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia
12.
J Urol ; 206(3): 577-585, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33872050

RESUMO

PURPOSE: According to the American Urological Association/American Society of Clinical Oncology/American Society for Radiation Oncology/Society of Urologic Oncology Guideline on treatment of nonmetastatic muscle invasive bladder cancer (MIBC), females requiring radical cystectomy (RC) should undergo concomitant anterior pelvic exenteration despite low rates of malignant involvement of gynecologic organs. We present the clinicopathological characteristics of patients with MIBC treated with neoadjuvant chemotherapy (NAC) and evaluate the impact of NAC on gynecologic organ involvement. MATERIALS AND METHODS: An institutional review board approved review of patients with cT2-T3 MIBC treated with RC at our institution between 2005 and 2018 was performed. Patients were stratified by receipt of NAC. RESULTS: A total of 186 females with cT2-T3 MIBC underwent RC during the study period, of whom 67.7% received NAC prior to RC. Patients who received NAC were more likely to have cT3 disease, preoperative hydronephrosis, and variant histology on transurethral resection (p <0.001, p=0.004, p=0.029, respectively). Rates of recurrence or metastasis were similar between groups (27.0% vs 26.7%, p=0.964). No patients had isolated genitourinary organ recurrence (median followup 32.1 months). Nine patients (5.7%) had gynecologic organ involvement (6 NAC vs 3 no NAC, p=0.978). Among those who underwent hysterectomy, 2 patients (3.1%) who received NAC had uterine involvement compared to none in the no NAC cohort (p=0.551). Rates of vaginal involvement were similar between the groups (4 NAC vs 3 no NAC, p=0.402). Additionally, 1 patient who received NAC had incidentally diagnosed localized endometrial cancer. No women had fallopian tube or ovarian involvement. CONCLUSIONS: Even among high risk patients with MIBC, gynecologic organ involvement of MIBC is rare, and organ preservation, especially of the ovaries, is likely safe.


Assuntos
Cistectomia , Neoplasias dos Genitais Femininos/epidemiologia , Terapia Neoadjuvante , Recidiva Local de Neoplasia/epidemiologia , Neoplasias da Bexiga Urinária/patologia , Idoso , Quimioterapia Adjuvante , Feminino , Seguimentos , Neoplasias dos Genitais Femininos/secundário , Humanos , Histerectomia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/prevenção & controle , Estudos Retrospectivos , Bexiga Urinária/patologia , Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/terapia , Útero/patologia , Útero/cirurgia , Vagina/patologia , Vagina/cirurgia
13.
J Urol ; 206(3): 548-557, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33881933

RESUMO

PURPOSE: We compared upper tract urothelial carcinoma (UTUC) and bladder urothelial carcinoma (BUC) in same-patient metachronous UTUC and synchronous UTUC and BUC using next-generation sequencing. MATERIALS AND METHODS: Consecutive untreated same-patient samples of UTUC and BUC were macrodissected from unstained formalin-fixed, paraffin-embedded slides after quality control. Samples were divided into 4 groups: 1) UTUC-metachronous BUC, 2) BUC-metachronous UTUC, 3) synchronous UTUC-BUC, 4) UTUC without BUC. Exclusions were inadequate clinical data or histological tumor purity <30%. Whole transcriptome RNA sequencing was performed. After quality assessment, gene expression clusters using unsupervised hierarchical consensus clustering and correlation with pertinent clinicopathologic variables, a prior RNASeq data set and other published data were performed. RESULTS: RNAseq was performed on 95 samples (UTUC=61, BUC=34) from 40 untreated patients. Unsupervised consensus clustering segregated the tumors into 2 clusters that were enriched with BASE47 basal-like or luminal-like gene expression. Almost two-thirds (61.9%) of Group 2 tumors were basal-like, while the majority of Groups 1, 3, 4 (80.6%, 70.0% and 69.6%, respectively) were luminal-like (p=0.017). Further analyses revealed that the differences in basal-like and luminal-like gene expression were associated with differential fibroblast and immune cell gene expression signatures. In all, 87.5% of metachronous tumors maintained subtype membership. CONCLUSIONS: Gene expression analysis of same-patient metachronous UTUC-BUC suggests that the majority of mUTUC developing after BUC appear more basal-like, while synchronous and initial UTUC tumors appear luminal-like. Metachronous tumors largely maintain molecular subtype membership of the initial tumor regardless of chronologic development or anatomical origin.


Assuntos
Carcinoma de Células de Transição/diagnóstico , Neoplasias Renais/diagnóstico , Neoplasias Primárias Múltiplas/diagnóstico , Segunda Neoplasia Primária/diagnóstico , Neoplasias Ureterais/diagnóstico , Neoplasias da Bexiga Urinária/diagnóstico , Idoso , Biomarcadores Tumorais/genética , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/imunologia , Carcinoma de Células de Transição/cirurgia , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Rim/imunologia , Rim/patologia , Rim/cirurgia , Neoplasias Renais/genética , Neoplasias Renais/imunologia , Neoplasias Renais/cirurgia , Masculino , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/imunologia , Neoplasias Primárias Múltiplas/cirurgia , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/imunologia , Segunda Neoplasia Primária/cirurgia , RNA-Seq , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Ureter/imunologia , Ureter/patologia , Ureter/cirurgia , Neoplasias Ureterais/genética , Neoplasias Ureterais/imunologia , Neoplasias Ureterais/cirurgia , Bexiga Urinária/imunologia , Bexiga Urinária/patologia , Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/cirurgia
14.
J Urol ; 206(3): 568-576, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33881931

RESUMO

PURPOSE: Intravesical recurrence (IVR) after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) has an incidence of approximately 20%-50%. Studies to date have been composed of mixed treatment cohorts-open, laparoscopic and robotic. The objective of this study is to assess clinicopathological risk factors for intravesical recurrence after RNU for UTUC in a completely minimally invasive cohort. MATERIALS AND METHODS: We performed a multicenter, retrospective analysis of 485 patients with UTUC without prior or concurrent bladder cancer who underwent robotic or laparoscopic RNU. Patients were selected from an international cohort of 17 institutions across the United States, Europe and Asia. Univariate and multiple Cox regression models were used to identify risk factors for bladder recurrence. RESULTS: A total of 485 (396 robotic, 89 laparoscopic) patients were included in analysis. Overall, 110 (22.7%) of patients developed IVR. The average time to recurrence was 15.2 months (SD 15.5 months). Hypertension was a significant risk factor on multiple regression (HR 1.99, CI 1.06; 3.71, p=0.030). Diagnostic ureteroscopic biopsy incurred a 50% higher chance of developing IVR (HR 1.49, CI 1.00; 2.20, p=0.048). Treatment specific risk factors included positive surgical margins (HR 3.36, CI 1.36; 8.33, p=0.009) and transurethral resection for bladder cuff management (HR 2.73, CI 1.10; 6.76, p=0.031). CONCLUSIONS: IVR after minimally invasive RNU for UTUC is a relatively common event. Risk factors include a ureteroscopic biopsy, transurethral resection of the bladder cuff, and positive surgical margins. When possible, avoidance of transurethral resection of the bladder cuff and alternative strategies for obtaining biopsy tissue sample should be considered.


Assuntos
Carcinoma de Células de Transição/epidemiologia , Neoplasias Renais/cirurgia , Nefroureterectomia/efeitos adversos , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Neoplasias Ureterais/cirurgia , Neoplasias da Bexiga Urinária/epidemiologia , Idoso , Biópsia/efeitos adversos , Biópsia/métodos , Carcinoma de Células de Transição/diagnóstico , Carcinoma de Células de Transição/secundário , Carcinoma de Células de Transição/cirurgia , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Rim/patologia , Rim/cirurgia , Neoplasias Renais/diagnóstico , Neoplasias Renais/mortalidade , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Inoculação de Neoplasia , Nefroureterectomia/métodos , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Ureter/patologia , Ureter/cirurgia , Neoplasias Ureterais/diagnóstico , Neoplasias Ureterais/mortalidade , Ureteroscopia/efeitos adversos , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/secundário
15.
J Urol ; 206(3): 669-678, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33890486

RESUMO

PURPOSE: We aimed to investigate the impact of various bladder lesions on the clinical symptoms and recurrence of interstitial cystitis (IC). MATERIALS AND METHODS: Patients with IC who underwent transurethral resection and cauterization for Hunner lesions (HLs) were enrolled. Features of HLs-noninflamed, inflamed, and gradually inflamed-and associated cystoscopic findings, including waterfall bleeding (none, focal or extensive), submucosal hemorrhage, and mucosal streak, were analyzed to investigate their association with preoperative symptoms and recurrence. RESULTS: We included 272 procedures from 141 patients (male:female ratio 37:104) with a mean±SD age of 61.4±10.5 years. Recurrence was observed in 160 procedures after a mean of 15.6 months (range 0.7-91.7); repeat transurethral resection and cauterization was performed in 131 cases. The number of HLs observed at each procedure was variable, and sufficient bladder filling revealed hidden lesions in 10.7% of cases. Waterfall bleeding was frequently accompanied with inflamed/gradually inflamed HLs. Inflammatory HLs were associated with smaller functional bladder capacity and preoperative urgency (p=0.007). Extensive waterfall bleeding was associated with smaller functional bladder capacity (p=0.006). On multivariate analysis, initially inflamed HLs (HR: 1.675, 95% CI: 1.022-2.746, p=0.041) and gradual inflammatory changes in HLs (HR: 1.893, 95% CI: 1.050-3.410, p=0.034) were found to be risk factors for recurrence. CONCLUSIONS: Sufficient bladder filling revealed hidden HLs. The features of HLs were not associated with subjective symptoms; inflamed changes were a predictive factor for IC recurrence, and associated with frequent urgency episodes and smaller bladder capacity.


Assuntos
Cistite Intersticial/cirurgia , Dor/diagnóstico , Reoperação/estatística & dados numéricos , Bexiga Urinária/patologia , Idoso , Cauterização/estatística & dados numéricos , Cistite Intersticial/complicações , Cistite Intersticial/diagnóstico , Cistite Intersticial/epidemiologia , Cistoscopia/estatística & dados numéricos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Dor/etiologia , Medição da Dor/estatística & dados numéricos , Período Pós-Operatório , Período Pré-Operatório , Prognóstico , Recidiva , Fatores de Risco , Índice de Gravidade de Doença , Resultado do Tratamento , Bexiga Urinária/cirurgia
16.
J Urol ; 206(3): 558-567, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33908802

RESUMO

PURPOSE: Diagnostic ureteroscopic biopsy for upper tract urothelial carcinoma (UTUC) has been hypothesized to increase intravesical recurrence of urothelial carcinoma after radical nephroureterectomy (RNU). Moreover, the impact of ureteroscopy without biopsy or percutaneous biopsy on intravesical recurrence remains unknown. Herein, we compared post-RNU intravesical recurrences across UTUC diagnostic modalities. MATERIALS AND METHODS: Patients undergoing RNU at our institution between 1995 and 2019 were categorized by UTUC diagnostic modality: 1) no ureteroscopy or percutaneous biopsy; 2) percutaneous biopsy; 3) ureteroscopy without biopsy; 4) ureteroscopic biopsy. Intravesical recurrences were compared using Kaplan-Meier analyses and Cox-proportional hazard models. Results of group 4 vs 1 were pooled with the literature using a fixed effects meta-analysis. RESULTS: In a cohort of 834 RNU patients, 210 (25.2%) had undergone no ureteroscopy, 57 (6.6%) percutaneous biopsy, 125 (15.0%) ureteroscopy without biopsy, and 442 (53.0%) ureteroscopic biopsy. Two-year intravesical recurrence rates were 15.0%, 12.7%, 18.4%, and 21.9% for groups 1 through 4, respectively (p=0.09). Multivariable analysis found that group 4 had increased intravesical recurrences (HR 1.40, p=0.04) relative to group 1 while group 2 (HR 1.07, p=0.87) and group 3 (HR 1.15, p=0.54) did not. Group 4 remained associated with intravesical recurrence on subset analyses accounting for post-RNU surveillance cystoscopy frequency. On meta-analysis including 11 other series, ureteroscopic biopsy was associated with intravesical recurrence (HR 1.47, p <0.01). CONCLUSIONS: Ureteroscopic biopsy before RNU, but not percutaneous biopsy or ureteroscopy without biopsy, was associated with increased intravesical recurrence. Clinical trials of intravesical chemotherapy after ureteroscopic biopsy are warranted to reduce intravesical recurrences.


Assuntos
Carcinoma de Células de Transição/epidemiologia , Neoplasias Renais/cirurgia , Nefroureterectomia/efeitos adversos , Neoplasias Ureterais/cirurgia , Neoplasias da Bexiga Urinária/epidemiologia , Idoso , Biópsia/efeitos adversos , Biópsia/métodos , Biópsia/estatística & dados numéricos , Carcinoma de Células de Transição/diagnóstico , Carcinoma de Células de Transição/secundário , Carcinoma de Células de Transição/cirurgia , Feminino , Seguimentos , Humanos , Neoplasias Renais/diagnóstico , Neoplasias Renais/patologia , Masculino , Inoculação de Neoplasia , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Neoplasias Ureterais/diagnóstico , Neoplasias Ureterais/patologia , Ureteroscopia/efeitos adversos , Ureteroscopia/estatística & dados numéricos , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/secundário
17.
Aging (Albany NY) ; 13(8): 12099-12112, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33888644

RESUMO

BACKGROUND: Bladder cancer (BLCA) is one of the most common urinary tract malignant tumors. It is associated with poor outcomes, and its etiology and pathogenesis are not fully understood. There is great hope for immunotherapy in treating many malignant tumors; therefore, it is worthwhile to explore the use of immunotherapy for BLCA. METHODS: Gene expression profiles and clinical information were obtained from The Cancer Genome Atlas (TCGA), and immune-related genes (IRGs) were downloaded from the Immunology Database and Analysis Portal. Differentially-expressed and survival-associated IRGs in patients with BLCA were identified using computational algorithms and Cox regression analysis. We also performed functional enrichment analysis. Based on IRGs, we employed multivariate Cox analysis to develop a new prognostic index. RESULTS: We identified 261 IRGs that were differentially expressed between BLCA tissue and adjacent tissue, 30 of which were significantly associated with the overall survival (all P<0.01). According to multivariate Cox analysis, nine survival-related IRGs (MMP9, PDGFRA, AHNAK, OAS1, OLR1, RAC3, IGF1, PGF, and SH3BP2) were high-risk genes. We developed a prognostic index based on these IRGs and found it accurately predicted BLCA outcomes associated with the TNM stage. Intriguingly, the IRG-based prognostic index reflected infiltration of macrophages. CONCLUSIONS: An independent IRG-based prognostic index provides a practical approach for assessing patients' immune status and prognosis with BLCA. This index independently predicted outcomes of BLCA.


Assuntos
Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Neoplasias da Bexiga Urinária/mortalidade , Idoso , Biologia Computacional , Feminino , Redes Reguladoras de Genes/imunologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , RNA-Seq , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/imunologia , Bexiga Urinária/imunologia , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/imunologia
18.
Nat Commun ; 12(1): 2301, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33863885

RESUMO

The molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we perform an integrative multi-omics analysis of patients diagnosed with NMIBC (n = 834). Transcriptomic analysis identifies four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provide independent prognostic value beyond established prognostic clinicopathological parameters. High chromosomal instability, p53-pathway disruption and APOBEC-related mutations are significantly associated with transcriptomic class 2a and poor outcome. RNA-derived immune cell infiltration is associated with chromosomally unstable tumors and enriched in class 2b. Spatial proteomics analysis confirms the higher infiltration of class 2b tumors and demonstrates an association between higher immune cell infiltration and lower recurrence rates. Finally, the independent prognostic value of the transcriptomic classes is documented in 1228 validation samples using a single sample classification tool. The classifier provides a framework for biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células de Transição/genética , Recidiva Local de Neoplasia/epidemiologia , Neoplasias da Bexiga Urinária/genética , Idoso , Vacina BCG/administração & dosagem , Carcinoma de Células de Transição/imunologia , Carcinoma de Células de Transição/mortalidade , Carcinoma de Células de Transição/terapia , Instabilidade Cromossômica , Cistectomia/métodos , Dinamarca/epidemiologia , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Genômica , Humanos , Estimativa de Kaplan-Meier , Masculino , Mutação , Recidiva Local de Neoplasia/genética , Prognóstico , Intervalo Livre de Progressão , RNA-Seq , Bexiga Urinária/imunologia , Bexiga Urinária/patologia , Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/terapia
19.
Int J Mol Sci ; 22(6)2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33802033

RESUMO

In high-risk non-muscle invasive bladder cancer (HR-NMIBC), patient outcome is negatively affected by lack of response to Bacillus-Calmette Guérin (BCG) treatment. Lack of response to cisplatin-based neoadjuvant chemotherapy and cisplatin ineligibility reduces successful treatment outcomes in muscle-invasive bladder cancer (MIBC) patients. The effectiveness of PD-1/PD-L1 immune checkpoint inhibitors (ICI) in metastatic disease has stimulated its evaluation as a treatment option in HR-NMIBC and MIBC patients. However, the observed responses, immune-related adverse events and high costs associated with ICI have provided impetus for the development of methods to improve patient stratification, enhance anti-tumorigenic effects and reduce toxicity. Here, we review the challenges and opportunities offered by PD-1/PD-L1 inhibition in HR-NMIBC and MIBC. We highlight the gaps in the field that need to be addressed to improve patient outcome including biomarkers for response stratification and potentially synergistic combination therapy regimens with PD-1/PD-L1 blockade.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias da Bexiga Urinária/tratamento farmacológico , Bexiga Urinária/efeitos dos fármacos , Anticorpos Monoclonais Humanizados/imunologia , Antígeno B7-H1/imunologia , Sinergismo Farmacológico , Humanos , Inibidores de Checkpoint Imunológico/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Receptor de Morte Celular Programada 1/imunologia , Fatores de Risco , Bexiga Urinária/imunologia , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/imunologia
20.
Arch Esp Urol ; 74(3): 359-362, 2021 Apr.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-33818434

RESUMO

OBJECTIVES: We present a unique case with a ureteral fibroepithelial tumor originating from the ureter, which could be confused with a bladder tumor on ultrasound examination due to its movement in and out of the bladder. METHODS: In cystoscopy, a papillary tumor lesion emerging from the right ureteral orifice was seen. After scanning the other quadrants, however, the tumor was not observed at the right ureteral orifice. It was then protruded back into the bladder. The tumor was seen several times to protrude into the bladder and return to the ureter, possibly due to ureteral peristalsis. Then, a semi-rigid ureteroscope was introduced through the right ureteric orifice, and the tumor was excised in one piece using Holmium laser fiber with 365µm of diameter. The size of the removed tumor was approximately 8 cm long. A double-j stent of 4.8 Fr was placed in the ureter. RESULTS: The patient was discharged on the first day without complications. The fibroepithelial polyps of the ureter, which consist of the stroma of mesoderm origin, covered with histologically normal or hyperplastic urothelial epithelial cells, are extremely rare tumors. It is important to distinguish these polyps from urothelial cancers, since these two entities are different in treatment and prognosis, although similar in symptoms and imaging procedures. CONCLUSIONS: Minimally invasive treatment techniques can be safely applied in the treatment of such exceedingly rare tumors.


Assuntos
Pólipos , Ureter , Neoplasias Ureterais , Humanos , Pólipos/diagnóstico por imagem , Pólipos/patologia , Pólipos/cirurgia , Ureter/patologia , Neoplasias Ureterais/diagnóstico por imagem , Neoplasias Ureterais/patologia , Neoplasias Ureterais/cirurgia , Ureteroscopia , Bexiga Urinária/diagnóstico por imagem , Bexiga Urinária/patologia , Bexiga Urinária/cirurgia
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