RESUMO

Transitional carcinoma (TC) is the most common neoplasm of the bladder (80%). The immune checkpoint (IC) Human leukocyte antigen G (HLA-G) expression has been demonstrated within numerous types of cancer and correlates with the degree of malignancy. This study aims for HLA-G expression in the bladder TC in a public hospital in Argentina linking its malignancy grade with the survival of the patients. We study thirty TC samples, in which we determine the invasion level and the HLA-G expression by immunohistochemistry. From all analyzed cases, 23 correspond to high-grade TC, of whom 91% presented HLA-G immunostaining and 83% compromised the muscularis propria layer of the bladder. Four patients in this group have not exceeded 5 years of survival. This data confirms that HLA-G expression in the bladder TC is associated with greater aggressiveness. Therefore, adding this immunostaining to the immunohistochemical panel used in the routine diagnosis of this neoplasm would be very useful.

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We present the case of a female patient with a history of high-grade urothelial carcinoma of the bladder with secondary lymph node and bone involvement, who presented with hematochezia, tenesmus and rectal pain one year after her oncological surgery. The abdomen and pelvis magnetic resonance image showed a 5 cm solid rectal lesion that stenosed the lumen and crossed the peritoneum, 6 cm away from the anal margin. The histology of this lesion reported an urothelial metastasis at the level of the lower rectum according to the patient's history. This case identifies an atypical evolution of urothelial carcinomas (UC), highlighting an unusual route of distant metastasis. UC can, on rare occasions, metastasize to the rectum, usually in advanced or recurrent cases of the disease. As the literature available on this topic is scarce, it is crucial to highlight the importance of maintaining high suspicion in patients with a history of urothelial carcinoma and urinary/rectal symptoms (rectal pain and urgency, suprapubic pain, urinary and fecal incontinence).

Se presenta el caso de una paciente con antecedentes de carcinoma urotelial de vejiga de alto grado con compromiso secundario ganglionar y óseo, la cual presentó cuadro de hematoquecia, tenesmo y dolor rectal un año después de su cirugía oncológica. La resonancia magnética de abdomen y pelvis, demostró una lesión sólida rectal de 5 cm de longitud que estenosaba la luz y atravesaba el peritoneo, a 6 cm del margen anal. La anatomía patológica de dicha lesión, informó una metástasis urotelial a nivel del recto inferior en concordancia con el antecedente de la paciente. Este caso identifica una evolución atípica de carcinomas uroteliales (CU), destacando una ruta inusual de metástasis a distancia. Los CU pueden, en raras ocasiones, hacer metástasis rectales, generalmente en casos avanzados o recurrentes de la enfermedad. Al ser escasa la bibliografía disponible sobre dicho tema, cabe destacar la importancia de mantener un alto índice de sospecha en pacientes con antecedentes de carcinoma urotelial y síntomas urinarios/rectales (dolor y tenesmo rectal, dolor suprapúbico, incontinencia urinaria y fecal).

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Numerous studies have attempted to restore the function of the tumour suppressor p53 as an anti-cancer strategy through gene delivery. However, most studies employed non-bacterial vectors to deliver p53. Various facultative and obligate anaerobic bacteria have been proposed as vectors because of their intrinsic tumour targeting ability and anti-tumour activity. Salmonella enterica Typhimurium is the most studied bacterial vector in anti-cancer therapy. We used the previously designed χ11218 strain of S. enterica Typhimurium, displaying regulated delayed lysis, as a vector for delivering p53 to human bladder carcinoma cells, restoring wild-type p53 protein function. We cloned p53 into pYA4545 (containing a eukaryotic expression system) to generate the χ11218 pYA4545p53 strain. Cloning of p53 did not affect the growth or interfere with the invasive and replicative capacity of χ11218 bacteria in tumour cells. Human bladder carcinoma cells (expressing mutated p53) transfected with pYA4545p53 showed a significant increase in the expression of p53 protein. We demonstrated that p53 supplied by χ11218 significantly decreased the viability of human bladder cancer cells in a dose-dependent manner. This study demonstrates the applicability of the attenuated χ11218 strain as a vector for DNA plasmids expressing tumour suppressor genes.

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Resumen Se presenta el caso de una paciente con antecedentes de carcinoma urotelial de vejiga de alto grado con compromiso secundario ganglionar y óseo, la cual presentó cuadro de hematoquecia, tenesmo y dolor rectal un año después de su cirugía oncológica. La resonancia magnética de abdomen y pelvis, demos tró una lesión sólida rectal de 5 cm de longitud que estenosaba la luz y atravesaba el peritoneo, a 6 cm del margen anal. La anatomía patológica de dicha lesión, informó una metástasis urotelial a nivel del recto inferior en concordancia con el antecedente de la paciente. Este caso identifica una evolución atípica de carcinomas uroteliales (CU), destacando una ruta inusual de metástasis a distancia. Los CU pueden, en raras ocasiones, hacer metástasis rectales, generalmente en casos avanzados o recurrentes de la enfermedad. Al ser escasa la bibliografía disponible sobre dicho tema, cabe destacar la importancia de mantener un alto índice de sospecha en pacientes con antecedentes de carcinoma urotelial y síntomas urinarios/rectales (dolor y tenesmo rectal, dolor suprapúbico, incontinencia urinaria y fecal).

Abstract We present the case of a female patient with a history of high-grade urothelial carcinoma of the bladder with secondary lymph node and bone involvement, who presented with hematochezia, tenesmus and rectal pain one year after her oncological surgery. The abdomen and pelvis magnetic resonance image showed a 5 cm solid rectal lesion that stenosed the lumen and crossed the peritoneum, 6 cm away from the anal margin. The histology of this lesion reported an urothelial metastasis at the level of the lower rectum according to the patient's history. This case identifies an atypical evolution of urothelial carcinomas (UC), highlighting an unusual route of distant metastasis. UC can, on rare occasions, metastasize to the rectum, usually in advanced or recurrent cases of the disease. As the literature available on this topic is scarce, it is crucial to highlight the importance of maintaining high suspicion in patients with a history of urothelial carcinoma and urinary/rectal symptoms (rectal pain and urgency, suprapubic pain, urinary and fecal incontinence).

RESUMO

Numerous studies have attempted to restore the function of the tumour suppressor p53 as an anticancer strategy through gene delivery. However, most studies employed non-bacterial vectors to deliver p53. Various facultative and obligate anaerobic bacteria have been proposed as vectors because of their intrinsic tumour targeting ability and antitumour activity. Salmonella enterica Typhimurium is the most studied bacterial vector in anticancer therapy. We used the previously designed χ11218 strain of S. enterica Typhimurium, displaying regulated delayed lysis, as a vector for delivering p53 to human bladder carcinoma cells, restoring wild-type p53 protein function. We cloned p53 into pYA4545 (containing a eukaryotic expression system) to generate the χ11218 pYA4545p53 strain. Cloning of p53 did not affect the growth or interfere with the invasive and replicative capacity of χ11218 bacteria in tumour cells. Human bladder carcinoma cells (expressing mutated p53) transfected with pYA4545p53 showed a significant increase in the expression of p53 protein. We demonstrated that p53 supplied by χ11218 significantly decreased the viability of human bladder cancer cells in a dose-dependent manner. This study demonstrates the applicability of the attenuated χ11218 strain as a vector for DNA plasmids expressing tumour suppressor genes.

RESUMO

Appendiceal carcinoma is a rare disorder. Although imaging exams can suggest carcinoma of the appendix simulating as a primary bladder cancer a transurethral biopsy is essential for diagnosis. We reported a case of a 27-year-old man, presented with hypogastric pain associated with recurrent gross hematuria and dysuria but without any intestinal symptoms such as pain, obstruction or melena. MRI revealed an enlarged appendix contiguous with the bladder. An en-bloc resection was performed and revealed appendiceal mucinous adenocarcinoma. Carcinoma of the appendix is an important differential diagnosis to other lesions and allow a good chance of cure by en bloc resection.

RESUMO

PURPOSE: Trimodal therapy is a reasonable bladder-preserving option to radical cystectomy. However, many tumors are radioresistive. In this sense, the identification of new prognostic and predictive biomarkers that allow the selection of patients with better responses to radiation therapy would improve outcomes. With the aim of using ecto-5'-nucleotidase/CD73 as a predictive biomarker, the role of this enzyme in the context of radiotherapy in T24 human bladder cancer cell line was investigated. METHODS: T24 cell line was exposure to a single dose of radiation (4 Gray) and trypan blue assay (pharmacological assays of viability/cumulative population doubling), flow cytometry (cell cycle/cell death/active caspase-3/ecto-5'-nucleotidase/CD73 protein staining), DAPI staining (nuclear morphometric assay), RT-PCR and real-time PCR, malachite green method (ectonucleotidase enzymatic assay), and HPLC (analysis of AMP metabolism) were carried out. T24 cell line in which ecto-5'-nucleotidase/CD73 has been completely silenced (5'KO) was also used. RESULTS: The exposure of T24 cell line to a single dose (4 Gray) of radiation-induced cell death and triggered a transitory increase in ecto-5'-nucleotidase/CD73 expression, increased ectonucleotidase activity, and led to adenosine and inosine accumulation in the extracellular medium. Pharmacological inhibition or knocking out ecto-5'-nucleotidase/CD73 rescued cells' proliferative capacity, reducing their sensitivity to radiation. CONCLUSION: Our findings show that the induction of ecto-5'-nucleotidase/CD73 by radiation contributes to the radiosensitivity of T24 cell line.

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Angiogenesis is an essential process for the establishment, development, and dissemination of several malignant tumors including bladder cancer. The hypoxic condition promotes the stabilization of hypoxia-inducible factor 1 alpha (HIF-1α), which translocates to the nucleus to mediate angiogenic factors including the vascular endothelial growth factor A (VEGF-A). AnaeroGen system was developed for microbiology area to create a low oxygen tension required to the growth of anaerobic bacteria. Here, we hypothesized the use of AnaeroGen system to induce hypoxia in T24 human bladder carcinoma cells, in order to promote the overexpression of VEGF-A. T24 cells were cultured in six-well plates containing McCoy medium. Exposures of T24 cells to hypoxia for 1, 8, 24, and 48 h were performed using the Oxoid AnaeroGen system, while T24 cells under normoxia were used as control. The expression of VEGF-A and HIF-1α was analyzed by real-time PCR. ELISA for HIF-1α was carried out. The VEGF-A expression increased significantly by Oxoid AnaeroGen-induced hypoxia in a time-depending manner, reaching the peak in 48 h of hypoxia. Although HIF-1α mRNA was not changed, HIF-1α protein was increased in the presence of hypoxia, reaching a peak at 8 h. These results demonstrated that the Oxoid AnaeroGen system is a simple method to expose T24 cells to hypoxia and efficiently to upregulate VEGF expression in T24 cells.

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Crude brazilin extract from Sappan wood has demonstrated strong anti tumor activity in the mouse model of human bladder carcinoma and clinical trial for intravesical therapy. Purified brazilin was confirmed the most active molecule in inhibition of bladder carcinoma T24 cells. Brazilin decreased proliferation and viability of T24 cells in a dose- and time-dependent manner, with a calculated LC50 of 32 µg/mL. More than 1,000 of genes were found upregulated and down regulated by brazilin treatment in digital gene expression profiling. Gene ontology analysis indicated that stress response, apoptosis, and cell cycle regulatory pathways were highly enriched. Among the regulated genes, c-Fos was the most and specifically upregulated. Overexpression of c-Fos in T24 cells resulted in tumor cell specific changes in cell morphology and viability. Over expression of stress-responsive gene, HSP70, and other highly upregulated genes did not have any effect on cell growth. Brazilin may inhibit T24 cell growth and trigger cell death through a c-Fos-mediated and tumor cell specific signaling pathway. Further studies of its down stream mediators may help to identify better tumor cell type specific drug targets.

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El carcinoma neuroendocrino primario de vejiga es una neoplasia infrecuente que representa el 0,5por ciento de todos los tumores vesicales. La asociación de carcinoma neuroendocrino de vejiga en un paciente con infección por VIH nunca hasta hoy había sido descrita. Presentamos el primer caso clínico español y mundial de esta desconocida y nunca descrita asociación. MATERIAL Y MÉTODOS: Se presenta el caso clínico de una paciente de 46 años con infección por VIH que desarrolló un carcinoma neuroendocrino de vejiga urinaria de evolución fatal. Se describe su clínica de presentación, métodos de diagnóstico utilizados y su tratamiento. La paciente debutó con retención urinaria aguda que rápidamente progresó a la instauración de una uropatía obstructiva alta con deterioro de la función renal. El diagnóstico se efectuó mediante TAC, resección transuretral y estudio histopatológico donde la clave del diagnóstico fue el estudio inmunohistoquímico intensamente positivo para la cromogranina A. El tratamiento adyuvante con quimioterapia le ocasionó una aplasia medular severa, falleciendo por fallo multiórganico a los 26 días de su diagnóstico. A propósito de este caso, se revisa la literatura inglesa en PubMed sobre carcinoma neuroendocrino de vejiga y sobre tumores vesicales en pacientes con infección VIH, no existiendo ningún caso publicado de carcinoma neuroendocrino de vejiga en un paciente con infección por VIH. CONCLUSIONES: El carcinoma neuroendocrino de vejiga es un tumor infrecuente y muy agresivo. Es un tumor que suele presentarse clínicamente en estadios avanzados o metastásicos donde ninguna terapia es eficaz. El tratamiento incluye resección trans-uretral (RTU), cistectomía parcial, cistectomía radical y quimioterapia. El estudio inmunohistoquímico (IHQ) y la tinción con cromogranina A dan la clave para su diagnóstico. Su presentación en pacientes VIH implica muy mal pronóstico. Éste caso es el primer caso mundial publicado de carcinoma neuroendocrino...

The primary neuroendocrine carcinome of the bladder is an infrequent neoplasm which represents 0.5 percent of all vesical tumors. The association of neuroendocrine carcinome of the bladder in a patient with HIV infection has never been described before today. We present the first clinical case in the Spanish-speaking world and worldwide, of this unknown and never written about association. MATERIAL AND METHODS: The clinical case of a 46-yearoldpatient with HIV infection who developed a neuroendocrine carcinoma of the urinary bladder with a fatal evolution, its clinical presentation, the diagnosis methods used and its treatment, are described. The patient started with a severe urinary retention which rapidly progressed to the establishment of a high obstructive uropathy with deterioration in the renal function. The diagnosis was done using TAC, transurethral resection and histopathological study where the key to diagnosis was the intensely positive immunohistochemical study for the chromogranin A. The adjuvant treatment with chemotherapy led to a severe medular aplasia, with the patient dying due to a multi-organ failure, 26 days after her diagnosis. As a result of this case, English literature on the matter in PubMed about neuroendocrine carcinome of the bladder and about vesical tumors in patients with HIV infection was revised, with no published case existing about neuroendocrine carcinome in a patient with HIV. CONCLUSIONS: The neuroendocrine carcinome of the bladder is an infrequent and very aggressive tumor. It is a tumor that tends to be clinically present in advanced or metastasic states, where no therapy is efficient. The treatment includes transurethral resection (TUR), partial cystectomy, radical cystectomy and chemotherapy. The immunohistochemical study (IHC), and the stain with chromogranin A are key for its diagnosis. Its presentation in HIV patients implies a very bad prognosis. This case is the first published case worldwide of neuroendocrine...

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Bladder carcinoma, which has the ninth highest incidence among malignant tumors in the world, is a complex, multifactorial disease. The malignant transformation of bladder cells results from DNA mutations and alterations in gene expression levels. In this work, we used a bioinformatics approach to investigate the molecular mechanisms of bladder carcinoma. Biochips downloaded from the Gene Expression Omnibus (GEO) were used to analyze the gene expression profile in urinary bladder cells from individuals with carcinoma. The gene expression profile of normal genomes was used as a control. The analysis of gene expression revealed important alterations in genes involved in biological processes and metabolic pathways. We also identified some small molecules capable of reversing the altered gene expression in bladder carcinoma; these molecules could provide a basis for future therapies for the treatment of this disease.

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The species Drimys angustifolia Miers and D. brasiliensis Miers, commonly known as "casca-de-anta", have in their leaves essential oils that can confer cytotoxic effects. In this study, we evaluated the citotoxic effects of the volatile oils from these two species. We also proposed a nanoemulsion formulation for each of the species and assessed the in vitro cytotoxicity on U-138 MG (human glioblastoma) and T24 (human bladder carcinoma) cell lines. The plant chemical composition was evaluated by gas chromatography coupled to mass spectrometer. Furthermore, the nanoemulsions were prepared and characterized. Our results showed that; bicyclogermacrene (19.6%) and cyclocolorenone (18.2%) were the most abundant for the D angustifolia oil and D brasiliensis oil, respectively. Both nanoemulsions, D angustifolia and D brasiliensis appeared macroscopically homogeneous and opalescent bluish liquids, with nanometric mean diameters of 168 nm for D brasiliensis and 181 nm for D angustifolia. The polydispersity indices were below 0.10, with an acid pH of 4.7-6.3, and negative zeta potentials about -34 mV. The results of transmission electron microscopy showed that droplets are present in the nanometer range. Only the D brasiliensis oil was efficient in reducing the cell viability of both U-138 MG (42.5%±7.0 and 67.8%±7.8) and T24 (33.2%±2.8, 60.3%±1.6 and 80.5%±8.8) cell lines, as assessed by MTT assay. Noteworthy, similar results were obtained with cell counting. Finally, D brasiliensis oil incubation caused an increase of annexin-V and propidium iodite population, according to evaluation by cytometry analysis, what is characteristic of late apoptosis. The results presented herein lead us to consider the potential therapeutic effects of the essential oils and nanoformulations as novel strategies to inhibit tumor growth.

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Two exemplary case reports of respiratory granulomatous infection caused by bacillus of Calmette-Guérin (BCG) in patients who were repeatedly treated with local, intravesical adjuvant BCG therapy for a relapsing transitional bladder carcinoma, are outlined and discussed, on the ground of the cumbersome diagnostic and differential diagnostic process (especially when a prior tuberculosis and a concurrent chronic obstructive pulmonary disease are of concern), and an updated literature revision. Only four cases of respiratory BCG-itis (pulmonary tuberculosis-like forms), have been reported until now to the best of our knowledge (two of them following bladder instillation of BCG). One episode of ours represents the first described case with a dual, concomitant granulomatous localization of BCG-itis, also involving the genitourinary tract

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OBJECTIVE: To investigate the immunoexpression of p53 protein as a risk factor in transitional cell carcinoma of the bladder (TCC). METHODS: We analyzed retrospectively 90 patients with TCC and mean age of 71 years: G1 - 45, G1 - 29, G3 - 16, pTa-1 - 62 and pT2-4 - 28. The superficial TCC were treated TUR plus intravesical BCG (>G1), and the invasives by radical cystectomy and urinary diversion. The mean time of followup was 55 months and 25 patients died of the disease. The rate or reccurence in superficial tumors was 55.5%. The p53 immunoexpression was determined in formalin fixed paraffin embedded tumors sections by the avidin-biotin-immunoperoxidase method (DO - 7, Dako). We considered p53 positive TCC when the labeling nuclear index was >10%. RESULTS: P53 immunoexpression exhibited a positive association with tumor grade and stage (p=0.01), but not with the size of primary lesion (p=0.25) or rate of reccurence of pTa-1 tumors (p=0.81). A strong correlation was seen with metastases (p=0.002) and survival (p=0.003). CONCLUSION: A positive reaction for p53 showed correlation with tumor grade, T stage, metastases rate and parient survival, but had no predictive value for local reccurence rate of superficial tumors.

OBJETIVO: Investigar a expressão imuno-histoquímica da p53 com fator de risco em carcinoma de células transicionais da bexiga (CCT). MÉTODOS: Foram estudados restrospectivamente 90 pacientes com CCT com idade média de 71 anos: G1 - 45, G2 - 29, G3 - 16, pTa-1 - 62 e pT2-4 - 28. Entre os pacientes com tumores não invasivos houve recidiva vesical em 35 casos (55,5%). Os tumores superficiais foram tratados por ressecção trans-uretral associados ao BCG (>G1), e os invasivos por cistectomia radical. O tempo médio de seguimento dos pacientes foi de 55 meses e 25 deles faleceram da doença. A expressão imuno-histoquímica foi estudada em peças preservadas em formol 10% e blocos de parafina pelo método da avidina-biotina-imunoperoxidase. Considerou-se p53 positivo o tumor com índice de marcação nuclear superior a 10%. RESULTADOS: A expressão da p53 mostrou associação com o grau do tumor e com o estádio da lesão primária (p=0,01), mas não com o tamanho do tumor vesical (p=0,25) ou com a taxa de recidiva dos tumores superficiais (p=0,81). Houve forte correlação entre o padrão de marcação da p53 com metástases (p=0,002) e com a sobrevida dos pacientes (p=0,003). CONCLUSÃO: A expressão da p53 mostrou valor preditivo para grau tumoral, estádio, incidência de metástases e sobrevida dos pacientes, mas não para recidiva vesical dos tumores superficiais.

RESUMO

OBJECTIVE: To investigate the immunoexpression of p53 protein as a risk factor in transitional cell carcinoma of the bladder (TCC). METHODS: We analyzed retrospectively 90 patients with TCC and mean age of 71 years: G1 - 45, G1 - 29, G3 - 16, pTa-1 - 62 and pT2-4 - 28. The superficial TCC were treated TUR plus intravesical BCG (>G1), and the invasives by radical cystectomy and urinary diversion. The mean time of followup was 55 months and 25 patients died of the disease. The rate or reccurence in superficial tumors was 55.5%. The p53 immunoexpression was determined in formalin fixed paraffin embedded tumors sections by the avidin-biotin-immunoperoxidase method (DO - 7, Dako). We considered p53 positive TCC when the labeling nuclear index was >10%. RESULTS: P53 immunoexpression exhibited a positive association with tumor grade and stage (p=0.01), but not with the size of primary lesion (p=0.25) or rate of reccurence of pTa-1 tumors (p=0.81). A strong correlation was seen with metastases (p=0.002) and survival (p=0.003). CONCLUSION: A positive reaction for p53 showed correlation with tumor grade, T stage, metastases rate and parient survival, but had no predictive value for local reccurence rate of superficial tumors.

OBJETIVO: Investigar a expressão imuno-histoquímica da p53 com fator de risco em carcinoma de células transicionais da bexiga (CCT). MÉTODOS: Foram estudados restrospectivamente 90 pacientes com CCT com idade média de 71 anos: G1 - 45, G2 - 29, G3 - 16, pTa-1 - 62 e pT2-4 - 28. Entre os pacientes com tumores não invasivos houve recidiva vesical em 35 casos (55,5%). Os tumores superficiais foram tratados por ressecção trans-uretral associados ao BCG (>G1), e os invasivos por cistectomia radical. O tempo médio de seguimento dos pacientes foi de 55 meses e 25 deles faleceram da doença. A expressão imuno-histoquímica foi estudada em peças preservadas em formol 10% e blocos de parafina pelo método da avidina-biotina-imunoperoxidase. Considerou-se p53 positivo o tumor com índice de marcação nuclear superior a 10%. RESULTADOS: A expressão da p53 mostrou associação com o grau do tumor e com o estádio da lesão primária (p=0,01), mas não com o tamanho do tumor vesical (p=0,25) ou com a taxa de recidiva dos tumores superficiais (p=0,81). Houve forte correlação entre o padrão de marcação da p53 com metástases (p=0,002) e com a sobrevida dos pacientes (p=0,003). CONCLUSÃO: A expressão da p53 mostrou valor preditivo para grau tumoral, estádio, incidência de metástases e sobrevida dos pacientes, mas não para recidiva vesical dos tumores superficiais.