RESUMO
Unresectable, metastatic, advanced urothelial carcinoma (aUC) is an aggressive disease and is treated with platinum-containing first-line chemotherapy, followed by immune checkpoint inhibitors and antibody-drug conjugates. Response to first-line chemotherapy is a vital priority in sequential treatment strategies because a better response to first-line chemotherapy is associated with a better response to subsequent therapies. Gemcitabine plus carboplatin chemotherapy is conventionally recommended for cisplatin-ineligible patients. This multicenter, single-arm prospective trial will investigate whether dose-dense methotrexate, vinblastine, doxorubicin, and carboplatin (DD-MVACarbo) chemotherapy is superior to gemcitabine plus carboplatin chemotherapy in terms of efficacy in platinum-naïve, cisplatin-ineligible patients with aUC. After screening and registration, a total of 46 patients will be treated with this novel chemotherapy regimen. The primary endpoint is the objective response rate. The secondary endpoints include disease control rate, patient-reported outcomes, and adverse events. No evidence of this novel intervention is available as of July 2024. The results are expected to change the standard of care and improve the management of patients with aUC.
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The tight junction (TJ) protein claudin-4 (CLDN4) is overexpressed in bladder urothelial carcinoma (BUC) and correlates with cancer progression. However, the mechanism of CLDN4 upregulation and promotion of malignant phenotype is not clear. Here, we analyzed 157 cases of BUC and investigated the hypomethylation of CpG island in the CLDN4 promoter DNA and its correlation with cancer progression. In hypomethylated cases, CLDN4 expression, cell proliferation, stemness, and epithelial-mesenchymal transition were increased. Treatment of three human BUC cell lines with the demethylating agent aza-2'-deoxycytidine (AZA) led to excessive CLDN4 expression, and, specifically, to an increase in CLDN4 monomer that is not integrated into the TJ. The TJ-unintegrated CLDN4 was found to bind integrin ß1 and increase stemness, drug resistance, and metastatic ability of the cells as well as show an anti-apoptosis effect likely via FAK phosphorylation, which reduces upon knockdown of CLDN4. Thus, CLDN4 is overexpressed in BUC by an epigenetic mechanism and the high expression enhances the malignant phenotype of BUC via increased levels of TJ-unintegrated CLDN4. CLDN4 promoter DNA methylation is expected to be a novel indicator of BUC malignant phenotype and a new therapeutic target.
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Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Carcinoma de Células de Transição/genética , Linhagem Celular Tumoral , Claudina-4/genética , Claudina-4/metabolismo , Metilação de DNA , Humanos , Fenótipo , Neoplasias da Bexiga Urinária/genéticaRESUMO
BACKGROUND: The naturally occurring amino acid 5-aminolevulinic acid (5-ALA) is a precursor of protoporphyrin IX (PpIX) biosynthesised in the mitochondria. When accumulated PpIX is excited by light (wavelength of 625-635 nm), reactive oxygen species (ROS) are generated. Here, we investigated whether 5-ALA may increase the sensitisation of prostate cancer (PCA) cells to radiotherapy through the generation of ROS via its metabolite, PpIX. METHODS: Effect of 5-ALA on PC-3 and DU-145 PCA cell lines treated with ionising radiation (IR) was examined in vitro and in vivo with assessment by clonogenic assay, mitochondrial function and ROS production under normoxia or hypoxia condition. RESULTS: 5-ALA enhanced intra-mitochondrial ROS production immediately after exposure to IR and decreased mitochondrial membrane potential via increase of intra-cellular PpIX. IR with 5-ALA induced mitochondrial dysfunction and increased ATP production, switching energy metabolism to the quiescence. Under hypoxic condition, ROS burst and mitochondrial dysfunction were induced by IR with 5-ALA resulting reducing cancer stemness and radiation resistance. CONCLUSION: These results suggest that combined therapy with 5-ALA and radiation therapy is a novel strategy to improve the anti-cancer effects of radiation therapy for PCA.
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Fotoquimioterapia , Neoplasias da Próstata , Ácido Aminolevulínico/farmacologia , Ácido Aminolevulínico/uso terapêutico , Linhagem Celular Tumoral , Humanos , Hipóxia , Masculino , Mitocôndrias/metabolismo , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêutico , Neoplasias da Próstata/metabolismo , Protoporfirinas/metabolismo , Protoporfirinas/farmacologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
PURPOSE: The treatment landscape for advanced, unresectable, or metastatic urothelial carcinoma (aUC) has shifted substantially since the advent of immune checkpoint inhibitors (ICIs). We investigated the extent to which pembrolizumab therapy is superior to conventional chemotherapy as a second-line treatment. PATIENTS AND METHODS: A multicenter-derived database registered 454 patients diagnosed with aUC between 2008 and 2020. Of these, 94 patients (21%) who received second-line pembrolizumab and 75 (17%) who received second-line chemotherapy but never received third-line or later ICI therapy were included. We compared overall survival (OS) from the initial date of first-line chemotherapy between two groups by adjusting for prognostic factors through propensity score matching (PSM) and inverse probability of treatment weighting (IPTW). The IPTW-adjusted hazard ratio and 95% confidence interval were estimated using a multivariate Cox regression analysis. To identify patients who were more likely to benefit from second-line pembrolizumab than from chemotherapy, we performed a subgroup analysis for OS with an IPTW-adjusted model. RESULTS: The PSM-adjusted comparison showed a significant improvement in the prognosis with second-line pembrolizumab use (P = 0.01). The OS benefit with the advent of pembrolizumab was 8 months (18 months vs 26 months). Multivariable analyses using IPTW adjustment demonstrated that lymph node metastasis (P = 0.001), lung metastasis (P = 0.013), and bone metastasis (P = 0.003) were poor independent prognostic factors, and pembrolizumab use (P = 0.021) was a favorable independent prognostic factor. Subgroup analyses revealed that pembrolizumab was associated with survival benefits over chemotherapy in all subgroups, including young patients (age <70 years), those who received radical surgery, and those without visceral metastasis. CONCLUSION: We demonstrated a significant improvement in prognosis after the advent of pembrolizumab for patients with aUC. ICIs should not be restricted based on patient characteristics.
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A 76-year-old male patient developed right hydronephrosis due to peritoneal and retroperitoneal dissemination after surgery for gastric cancer. A ureteral stent was inserted, and systemic chemotherapy was introduced for metastatic gastric cancer. Disease progression was observed, and paclitaxel/ramucirumab combination therapy was started as the second-line treatment. After seven courses, severe gross hematuria appeared intermittently, and refractory epistaxis was observed concurrently. No hemorrhagic lesion was found in the imaging test and urethrocystoscopy. The patient received conservative treatment, such as blood transfusion, and further examination was planned. However, hematuria and epistaxis resolved spontaneously during the course of treatment. From the clinical course, it was thought to be a hemorrhagic adverse event due to ramucirumab, and the patient's treatment was therefore changed to another drug. The patient recovered without recurrence of gross hematuria.
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Neoplasias Gástricas , Idoso , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Hematúria/induzido quimicamente , Humanos , Masculino , Paclitaxel/efeitos adversos , Neoplasias Gástricas/tratamento farmacológico , RamucirumabRESUMO
OBJECTIVE: We previously developed genitourinary (GU) cancer-specific scoring system for prediction of survival in patients with bone metastasis (the Bone-Fujimoto-Owari-Miyake [B-FOM] scoring model) based on five prognostic factors: the type of primary tumor (prostate cancer (PCa) vs renal cell carcinoma (RCC) and PCa vs urothelial carcinoma (UC)), poor performance status (PS), visceral metastasis, high Glasgow-prognostic score (GPS), elevated neutrophil-to-lymphocyte ratio (NLR). The aim of this study was to externally validate and further improve the performance of the B-FOM score. METHODS: The external validation cohort comprised 309 patients with GU cancer with bone metastasis from multiple institutions. Clinical factors were analyzed using Kaplan-Meier method and COX regression hazard model. Performance of a modified B-FOM score was compared to that of other scoring models by the Kaplan-Meier method and the area under the curve (AUC) of receiver operating characteristic curves. RESULTS: The median follow-up period of development and validation cohort were 25 and 17 months, respectively. Kaplan-Meier curve demonstrated that the type of primary tumor (RCC and UC vs PCa), poor PS, presence of visceral metastasis, high GPS, elevated NLR were significantly associated with shorter cancer-specific survival. Risk groups were successfully stratified by the modified B-FOM score classification. Moreover, the AUC of the modified B-FOM scoring model for predicting mortality at 6, 12, and 24 months were 0.895, 0.856, and 0.815, respectively, which were the highest among evaluated models. CONCLUSIONS: The B-FOM scoring model is a simple and accurate prediction tool. By using this scoring model at the time of the diagnosis of bone metastasis in patients with GU cancers, an individualized optimal treatment strategy can be selected.
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OBJECTIVES: To evaluate the clinical benefit of bone-modifying agents and identify the risk factors of skeletal-related events in patients with genitourinary cancer with newly diagnosed bone metastasis. METHODS: This was a multicenter retrospective study including a total of 650 patients with bone metastasis of the following cancer types: hormone-sensitive prostate cancer (n = 443), castration-resistant prostate cancer (n = 50), renal cell carcinoma (n = 80) and urothelial carcinoma (n = 77). Clinical factors at the time of diagnosis of bone metastasis were analyzed. Early treatment with bone-modifying agents was defined as follows: administration of bone-modifying agents before the development of skeletal-related events and within 6 months from the diagnosis of bone metastasis. RESULTS: During the follow-up period (median 19.0 months, interquartile range 6.0-43.8 months), skeletal-related events were reported in 88 (20%) patients with hormone-sensitive prostate cancer, 17 (34%) patients with castration-resistant prostate cancer, 58 (73%) patients with renal cell carcinoma and 34 (44%) patients with urothelial carcinoma. Early treatment with bone-modifying agents significantly prolonged the time to the first skeletal-related event in castration-resistant prostate cancer, renal cell carcinoma and urothelial carcinoma, but not in hormone-sensitive prostate cancer. Bone pain and elevated alkaline phosphatase levels were independent predictive risk factors of the first skeletal-related event. The subgroup analysis showed that early treatment with bone-modifying agents was associated with prolonged time to the first skeletal-related events in patients with bone pain or elevated alkaline phosphatase levels. CONCLUSIONS: Early treatment with bone-modifying agents should be considered, especially for patients with bone pain and elevated alkaline phosphatase levels, to prevent skeletal-related events in patients with genitourinary cancer with bone metastasis.
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Conservadores da Densidade Óssea/uso terapêutico , Neoplasias Ósseas/prevenção & controle , Neoplasias Ósseas/secundário , Neoplasias Urogenitais/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/patologia , Humanos , Japão , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Neoplasias da Próstata/patologia , Estudos Retrospectivos , Medição de Risco , Fatores de RiscoRESUMO
BACKGROUND: The aim of this study is to investigate the prognostic relevance of the best objective response of metastatic target lesions during sunitinib treatment in patients with metastatic renal cell carcinoma. METHODS: Radiographic analysis of the best objective response according to the Response Evaluation Criteria in Solid Tumors was assessed in 50 patients. Clinicopathological characteristics including the Heng risk classification and sunitinib-related adverse reactions were compared among four patient subgroups [complete response or partial response (CR/PR), stable disease (SD), progressive disease (PD), and those without treatment evaluation (NE)]. Kaplan-Meier and Cox proportional regression analyses of progression-free survival and overall survival were performed to identify prognostic variables. RESULTS: The best objective response was CR/PR in 12 (24 %) patients, SD in 22 (44 %), PD in 6 (12 %), and NE in 10 (20 %). The incidence of hypertension and hypothyroidism was associated with a better objective response. Progression-free survival was 15.0, 9.2, 6.8, and 2.2 months in the CR/PR, SD, PD, and NE groups, respectively (P = 0.0004, log-rank test), while the corresponding median overall survival was 59.7, 24.2, 17.1, and 18.1 months, respectively (P = 0.007). Multivariate analysis revealed that hazard ratios for risk of death of the SD, PD, and NE groups were 4.51 (P = 0.06), 7.93 (P = 0.02), and 4.88 (P = 0.04), respectively, as compared to the CR/PR group. CONCLUSIONS: Our findings suggested that the best objective response of target lesions was a prognostic marker for both progression-free survival and overall survival in sunitinib treatment. Furthermore, the incidence of sunitinib-induced hypertension was associated with a longer progression-free survival.
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Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/secundário , Hipertensão/induzido quimicamente , Hipertensão/epidemiologia , Indóis/efeitos adversos , Indóis/uso terapêutico , Estimativa de Kaplan-Meier , Pirróis/efeitos adversos , Pirróis/uso terapêutico , Idoso , Demografia , Intervalo Livre de Doença , Feminino , Humanos , Incidência , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Sunitinibe , Resultado do TratamentoRESUMO
BACKGROUND: The mechanism underlying the increased levels of protoporphyrin IX in bladder cancer remains unclear. Here, we focus on proteins associated with protoporphyrin IX accumulation in bladder cancer cells and investigate the protein that plays a key role in increased protoporphyrin IX accumulation in bladder cancer cells. METHODS: Western blotting was used to determine the expression of peptide transporter 1, hydroxymethylbilane synthase, ferrochelatase, ATP-binding cassette 2, and heme oxygenase-1 in bladder cancer cell line cells. We evaluated the correlation between the expression of each protein and accumulated protoporphyrin IX in these cells using Pearson's correlation analysis. Immunohistochemistry was used to estimate the expression of the same five proteins in samples from 75 patients who underwent transurethral resection of bladder tumors. The correlation between the expression of each protein in cells from resected bladder specimens and accumulated protoporphyrin IX in bladder cancer cells in voided urine was evaluated using Pearson's correlation analysis. RESULTS: The expression of ferrochelatase showed a significant negative correlation with protoporphyrin IX accumulation in vitro (p=0.04). The expression of peptide transporter 1 (p<0.01, R=0.39), heme oxygenase-1 (p<0.01, R=0.33), and ferrochelatase (p<0.01, R=0.75) in resected bladder specimens by immunohistochemistry was correlated with protoporphyrin IX accumulation in bladder cancer cells in voided urine. On multivariate analysis, the expression of ferrochelatase (p=0.03) was significant factors to predict positive 5-aminolevulinic acid-induced fluorescent cytology. CONCLUSION: The expression of ferrochelatase has a strong correlation in protoporphyrin IX accumulation with photodynamic detection of bladder cancer.
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Ácido Aminolevulínico/farmacocinética , Cistoscopia/métodos , Ferroquelatase/metabolismo , Protoporfirinas/farmacocinética , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Ácido Aminolevulínico/administração & dosagem , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Humanos , Microscopia de Fluorescência/métodos , Imagem Molecular/métodos , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/farmacocinética , Protoporfirinas/administração & dosagemRESUMO
A 68-year-old man underwent radical nephrectomy for renal cell carcinoma of the right kidney 12 years ago. He was diagnosed as having a recurrent tumor of the contralateral kidney and a single metastatic pulmonary lesion by diagnostic imaging on the annual checkup. He visited us in order to receive nephron sparing surgery. Since the preoperative abdominal computed tomography showed tumor thrombus invading into the intrarenal vein, ex vivo partial nephrectomy and auto-transplantation was performed. Although he received transit hemodialysis during the postoperative 10 days, his renal function, thereafter became stable without hemodialysis. Eighty-seven days later he underwent right lower lobectomy. At postoperative 6 months he has no local recurrence or distant metastasis and maintains well-preserved renal function.
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Carcinoma de Células Renais/cirurgia , Neoplasias Renais/cirurgia , Transplante de Rim/métodos , Recidiva Local de Neoplasia/cirurgia , Nefrectomia/métodos , Idoso , Humanos , Masculino , Transplante Autólogo , Resultado do TratamentoRESUMO
Bladder cancer displays an aggressive phenotype in the muscle-invasive phase, and is associated with a high mortality rate. Therefore, novel molecular therapeutic targets are needed to improve patient survival. A monoclonal antibody against the extracellular domain of the claudin-4 (CLDN4) tight junction protein was established by immunizing rats with a plasmid vector encoding human CLDN4. A hybridoma clone, producing a rat monoclonal antibody recognizing CLDN4 (clone 4D3), was obtained. Immunohistochemistry by using the 4D3 antibody showed that CLDN4 expression was associated with local invasion, nodal metastasis, distant metastasis, and advanced stage in 86 cases of bladder cancer. The 4D3 antibody inhibited growth, invasion, and survival, associated with abrogation of the intratumoral microenvironment; lowered concentrations of epidermal growth factor and vascular endothelial growth factor were found in three-dimensional cultures of T24 and RT4 cells. In combination with cisplatin therapy, 4D3 enhanced cisplatin cytotoxicity by increasing cellular permeability, leading to increased intracellular cisplatin concentrations. In mouse models of subcutaneous tumors and lung metastasis, 4D3 enhanced tumor growth inhibition, alone and with concurrent cisplatin treatment. The anti-tumor activity of the newly established 4D3 antibody suggests that it may be a powerful tool in CLDN4-targeting therapy, and in combination with chemotherapy.
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Anticorpos Monoclonais/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Claudina-4/imunologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , Sinergismo Farmacológico , Feminino , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Ratos Wistar , Neoplasias da Bexiga Urinária/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Past attempts at detecting prostate cancer (PCa) cells in voided urine by traditional cytology have been impeded by undesirably low sensitivities but high specificities. To improve the sensitivities, we evaluate the feasibility and clinical utility of photodynamic diagnosis (PDD) of prostate cancer by using 5-aminolevulinic acid (5-ALA) to examine shed prostate cancer cells in voided urine samples. METHODS: One hundred thirty-eight patients with an abnormal digital rectal exam (DRE) and/or abnormal prostate-specific antigen (PSA) levels were recruited between April 2009 and December 2010. Voided urine specimens were collected before prostate biopsy. Urine specimens were treated with 5-ALA and imaged by fluorescence microscopy and reported as protoporphyrin IX (PPIX) positive (presence of cells demonstrating simultaneous PPIX fluorescence) or PPIX negative (lack of cells demonstrating fluorescence). RESULTS: Of the 138 patients, PCa was detected on needle biopsy in 81 patients (58.7%); of these 81 patients with PCa, 60 were PPIX-positive (sensitivity: 74.1%). Although 57 patients did not harbor PCa by conventional diagnostic procedures, 17 of these at-risk patients were found to be PPIX-positive (specificity: 70.2%). PPIX-PDD was more sensitive compared with DRE and transrectal ultrasound and more specific compared with PSA and PSA density. The incidence of PPIX-PDD positivity did not increase with increasing total PSA levels, tumor stage or Gleason score. CONCLUSIONS: To our knowledge, this is the first successful demonstration of PPIX in urine sediments treated with 5-ALA used to detect PCa in a noninvasive yet highly sensitive manner. However, further studies are warranted to determine the role of PPIX-PPD for PCa detection.
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Ácido Aminolevulínico , Biomarcadores Tumorais/urina , Microscopia de Fluorescência/métodos , Fármacos Fotossensibilizantes , Neoplasias da Próstata/patologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Viabilidade , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Neoplasias da Próstata/urina , Protoporfirinas/urina , Sensibilidade e Especificidade , Urina/citologiaRESUMO
BACKGROUND: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare tumor predisposition syndrome characterized by cutaneous and uterine leiomyomas and papillary type 2 renal cell cancer. Germline mutation of the fumarate hydratase (FH) gene is known to be associated with HLRCC. CASE PRESENTATION: We describe a 64-year-old father and his 39-year-old son with HLRCC who developed papillary type 2 RCCs lacking cutaneous leiomyomas at any site. A common missense mutation in the FH gene, (c.1021G > A, p.D341N) in exon 7, was detected in the 2 cases. Functional prediction with the bioinformatics programs, SIFT and Polyphen-2, reported "damaging (SIFT score 0.00)" and "probably damaging (PSIC score 1.621)" values, respectively. In 162 healthy individuals, there were no cases of a G transition to any base. Finally, (c.1021G > A) in exon 7, was identified as a point mutation. CONCLUSION: We report a family with HLRCC in which a novel missense mutation was detected. A familial papillary type 2 renal cancer should be considered HLRCC unless typical cutaneous leiomyomas do not occur.
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Carcinoma de Células Renais/genética , Fumarato Hidratase/genética , Neoplasias Renais/genética , Leiomiomatose/genética , Mutação de Sentido Incorreto , Neoplasias Cutâneas/genética , Neoplasias Uterinas/genética , Adulto , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/patologia , Éxons , Humanos , Neoplasias Renais/diagnóstico , Neoplasias Renais/patologia , Leiomiomatose/diagnóstico , Leiomiomatose/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Neoplásicas Hereditárias , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/patologiaRESUMO
Bladder urothelial carcinoma is diagnosed and followed up after transurethral resection using a combination of cystoscopy, urine cytology and urine biomarkers at regular intervals. However, cystoscopy can overlook flat lesions like carcinoma in situ, and the sensitivity of urinary tests is poor in low-grade tumors. There is an emergent need for an objective and easy urinary diagnostic test for the management of bladder cancer. In this study, three different modalities for 5-aminolevulinic acid (ALA)-based photodynamic diagnostic tests were used. We developed a compact-size, desktop-type device quantifying red fluorescence in cell suspensions, named "Cellular Fluorescence Analysis Unit" (CFAU). Urine samples from 58 patients with bladder cancer were centrifuged, and urine sediments were then treated with ALA. ALA-treated sediments were subjected to three fluorescence detection assays, including the CFAU assay. The overall sensitivities of conventional cytology, BTA, NMP22, fluorescence cytology, fluorescent spectrophotometric assay and CFAU assay were 48%, 33%, 40%, 86%, 86% and 87%, respectively. Three different ALA-based assays showed high sensitivity and specificity. The ALA-based assay detected low-grade and low-stage bladder urothelial cells at shigher rate (68-80% sensitivity) than conventional urine cytology, BTA and NMP22 (8-20% sensitivity). Our findings demonstrate that the ALA-based fluorescence detection assay is promising tool for the management of bladder cancer. Development of a rapid and automated device for ALA-based photodynamic assay is necessary to avoid the variability induced by troublesome steps and low stability of specimens.
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Ácido Aminolevulínico/química , Microscopia de Fluorescência/métodos , Espectrometria de Fluorescência/métodos , Urinálise/métodos , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/urina , Urina/citologia , Urotélio/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma in Situ/patologia , Carcinoma in Situ/urina , Linhagem Celular Tumoral , Técnicas Citológicas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Sensibilidade e Especificidade , Espectrometria de Fluorescência/instrumentação , Urinálise/instrumentação , Neoplasias da Bexiga Urinária/cirurgiaRESUMO
The role of the high mobility group box 1 (HMGB1) protein in chemotherapy-induced cell death was examined. CT26 mouse colon cancer cells were treated with trichostatin A (TSA; apoptosis inducer) or doxorubicin (DXR; necrosis inducer). DXR increased HMGB1 concentration in CT26 cell culture medium, whereas TSA did not. In a CT26 bilateral subcutaneous tumour model, DXR or TSA was injected in a single tumour. After injection, serum HMGB1 concentration in DXR-treated mice was 10 times higher than that in TSA-treated mice. After DXR treatment, the contralateral and remnant tumours showed more pronounced growth than did those treated with TSA. In mouse models, lung and liver metastasis was enhanced by DXR but not by TSA. DXR-enhanced metastasis was abrogated by anti-HMGB1 antibody treatment. In a cancer dormancy model, DXR induced regrowth of quiescent CT26 cells. HMGB1 induced tumour necrosis factor-α secretion via Toll-like receptor (TLR)4 in U937 monocytes; however, HMGB1 decreased the number of U937 cells, resulting in restriction of immune activation via receptor for advanced glycation endproducts (RAGE). RAGE showed a more pronounced effect on nuclear factor kappa B activation than did TLR4 in CT26 cells. These findings suggest that HMGB1 released from necrotic cancer cells treated with a necrosis inducer enhances regrowth and metastasis of remnant cancer cells via RAGE activation.
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Neoplasias do Colo/tratamento farmacológico , Proteína HMGB1/fisiologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias do Colo/patologia , Doxorrubicina/uso terapêutico , Humanos , Ácidos Hidroxâmicos/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Necrose , Metástase Neoplásica , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/fisiologia , Células U937RESUMO
Persistent mullerian duct syndrome describes a group of patients with a 46 XY karyotype and normal male external genitalia, but internal mullerian structures. A 7-month-old boy presented with a left inguinal hernia, a left undescended testis and a right impalpable testis. Inguinal herniorrhaphy was performed and laparoscopy was done for search of a right impalpable testis and internal genitalia simultaneously. Laparoscopic examination revealed the structure like a mullerian duct remnant along the left spermatic duct in rectovesical fossa and right intra-abdominal testis. The structure like a mullerian duct remnant was not removed to preserve the left spermatic duct. Left orchiopexy and right laparoscopic staged Fowler- Stephens orchiopexy were performed. Chromosomal analysis was 46 XY karyotype and we diagnosed this case as persistent mullerian duct syndrome.
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Criptorquidismo/diagnóstico , Laparoscopia , Ductos Paramesonéfricos/anormalidades , Humanos , Lactente , Masculino , OrquidopexiaRESUMO
Sorafenib and sunitinib are multi-kinase inhibitors with antitumor activity in patients with advanced renal cell carcinoma (RCC). Several studies have evaluated the effect of sorafenib/sunitinib in combination with chemotherapeutic agents in different types of tumor. However, few studies have addressed the activity of fluorinated pyrimidine in combination with sorafenib/sunitinib. In this study, we examined the potential of combination therapy with 5FU and sorafenib/sunitinib in human RCC cell lines. Three human RCC cell lines, ACHN, Caki-1 and Caki-2, were used to assess sensitivity to 5-fluorouracil (5FU), sorafenib and sunitinib alone or in combination using an in vitro cell survival assay. Caki-2 cells demonstrated significantly higher resistance to 5FU and sorafenib as compared to ACHN and Caki-1. Additive antitumor effects of the combination therapy were observed in the in vitro study. There was a tendency for a positive correlation between the sensitivity to sunitinib and platelet-derived growth factor ß (PDGFR-ß) expression levels, which were examined by reverse transcription polymerase chain reaction. Caki-1 xenograft models were prepared by inoculating cells subcutaneously into nude mice, which were divided randomly into six groups: control, 5FU (8 mg/kg/day, intraperitoneally), sorafenib (15 mg/kg/day, orally), sunitinib (20 mg/kg/day, orally), and 5FU with sorafenib or sunitinib. The treatments were administered on 5 days each week, and tumor growth was monitored for 42 days following inoculation of cells. Synergistic antitumor effects of the combination therapy were observed in an in vivo study. The resected tumors were evaluated using the Ki-67 labeling index and microvessel density. Both the Ki-67 labeling index and microvessel density were decreased in tumors treated with the combination therapy compared to those treated with sorafenib/sunitinib alone. These findings suggest that the combination therapy of 5FU with sorafenib/sunitinib may be an effective therapeutic modality for advanced RCC patients.
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Transverse testicular ectopia (TTE) is a rare congenital anomaly. Although TTE often coexists with abnormalities such as inguinal hernia and persistent Mullerian duct syndrome, disorders of sex development (DSD) in combination with TTE is extremely rare. We report a case of DSD with sex chromosomal abnormality in combination with TTE. To our knowledge, this case report is a first presentation of such anomaly.
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OBJECTIVE: According to several guidelines, it is acceptable to spare a bone scan in the patients who are newly diagnosed with low-risk prostate cancer. Our aim is to clarify a suitable group whereby a bone scan could be spared at the initial staging of prostate cancer. METHODS: Consecutive 857 patients who were newly diagnosed from 2004 through 2009 and received bone scans using technetium 99m methylene diphosphonate at the initial staging were enrolled. The proportion of positive bone metastases by age distribution, prostate-specific antigen level at diagnosis, Gleason score and clinical T stage were evaluated. Univariate and multivariate logistic regression analyses were performed to identify the predictors of positive bone metastases. RESULTS: Of all 857 patients, 40 patients (4.7%) showed bone metastases. Patients with higher age, prostate-specific antigen level, clinical stage and Gleason score showed significantly higher rate of bone metastases (P < 0.001). In univariate logistic regression analyses, age, prostate-specific antigen level, clinical stage and Gleason score were independent predictors of bone metastasis. The multivariate analysis showed that both the prostate-specific antigen level >50 ng/ml and the Gleason score ≥4 + 3 were independent predictors of bone metastases. CONCLUSIONS: The incidences of bone metastases in patients with a prostate-specific antigen level of ≤20 ng/ml and Gleason score of ≤6 were reasonably low. Collectively, a bone scan is not necessary as a routine examination for these patients at their initial staging of prostate cancer.
Assuntos
Neoplasias Ósseas/diagnóstico por imagem , Neoplasias da Próstata/patologia , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/prevenção & controle , Neoplasias Ósseas/secundário , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Antígeno Prostático Específico/sangue , CintilografiaRESUMO
Angiogenesis is necessary for the growth, invasion, and metastasis of solid tumors. Previous studies have shown that heme oxygenase-1 (HO-1) plays an important role in angiogenesis in both normal and cancerous cells, such as vascular endothelial cells and pancreatic cancer cells, respectively. In this study, we analyzed the role of HO-1 and other angiogenic factors in urothelial carcinoma of the bladder. Specifically, we used real-time reverse transcription polymerase chain reaction (PCR) and Western blotting to investigate the upregulation of 7 angiogenic factors, namely, HO-1, vascular endothelial growth factor (VEGF), hypoxia-inducible factor (HIF)-1α, HIF-2α, cyclooxygenase-2 (COX-2), interleukin-8 (IL-8), and basic fibroblast growth factor (bFGF) under hypoxic conditions in the T24 urothelial carcinoma cell line. We also used enzyme-linked immunosorbent assay (ELISA) to measure the amount of VEGF secreted into the growth media. In addition, we administered an HO-1 inhibitor, zinc protoporphyrin IX, to mice with subcutaneous T24 tumors to assess the modulation of angiogenesis in solid tumors in vivo. We also performed immunohistochemical analyses of 23 primary bladder cancer specimens with high-grade tumors infiltrating into the stroma (pT1) for expression of HO-1, VEGF, HIF-1α, HIF-2α, COX-2, and CD31. Image analysis of CD31 staining was performed to estimate microvessel density (MVD), a measure of angiogenesis. Hypoxic conditions induced upregulation of HO-1, VEGF, HIF-1α, HIF-2α, and COX-2 in T24 cells and increased VEGF secretion, which could be suppressed by zinc protoporphyrin IX. In vivo, inhibition of HO-1 decreased tumor growth and MVD by suppressing angiogenic factors, particularly VEGF and HIF-1α. In clinical specimens of bladder cancer, high expression of HO-1 was correlated with high expression of HIF-1α (P=0.027) and high MVD (P=0.005), but not with VEGF expression (P=0.19). In conclusion, since overexpression of HO-1 promotes angiogenesis in urothelial carcinoma cells, HO-1 inhibitors could be used as novel therapeutics for urothelial carcinoma of the urinary bladder.