RESUMO
PURPOSE: PD-L1 is expressed on tumor cells and tumor immune cell infiltrates. In metastatic bladder cancer increased tumor immune cell infiltrate PD-L1 positivity correlated with better overall survival. However, to our knowledge in high grade T1 bladder tumors positivity on tumor cells and tumor immune cell infiltrates, and correlation with outcomes or pathological features remain unknown. MATERIALS AND METHODS: Formalin fixed, paraffin embedded tumor samples from 140 patients with clinically annotated, high grade T1 bladder tumors were retrieved. All patients were initially diagnosed with high grade T1 bladder tumors by transurethral resection, subsequently received bacillus Calmette-Guérin and had a median followup of 7.4 years. PD-L1 positivity on initial transurethral resection was evaluated by immunohistochemistry using a mouse monoclonal antiPD-L1 antibody (405.9A11). Tumor cell PD-L1 positivity was defined as staining of 5% of the tumor cell membrane. Tumor immune cell infiltrate PD-L1 positivity was scored based on the extent of infiltrate and the percent of positive cells. The Fisher exact test was used to assess associations of PD-L1 positivity with disease outcomes, carcinoma in situ presence and the difference between high grade T1 bladder tumors and muscle invasive bladder cancer. RESULTS: Among 140 patients with high grade T1 bladder tumors tumor cells and tumor immune cell infiltrate PD-L1 positivity was seen in 6 (4%) and 48 (34.3%), respectively. In a subset of 106 patients with adequate followup PD-L1 positivity did not correlate with disease outcomes on tumor cells (p = 0.3) or on tumor immune cell infiltrates (p = 0.47). PD-L1 positivity also did not correlate with the presence of carcinoma in situ. Tumor cell PD-L1 positivity was significantly less in high grade T1 bladder tumors than in muscle invasive bladder cancer (p <0.001). CONCLUSIONS: PD-L1 is widely expressed on tumor immune cell infiltrates but not on tumor cells in high grade T1 bladder tumors. We did not find a correlation between PD-L1 positivity and outcomes or carcinoma in situ presence. Tumor cell PD-L1 positivity is significantly lower in high grade T1 bladder tumors than in muscle invasive bladder cancer.
Assuntos
Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma in Situ/patologia , Carcinoma de Células de Transição/patologia , Neoplasias da Bexiga Urinária/patologia , Administração Intravesical , Adulto , Antígeno B7-H1/imunologia , Vacina BCG/uso terapêutico , Biomarcadores Tumorais/imunologia , Carcinoma in Situ/imunologia , Carcinoma in Situ/mortalidade , Carcinoma in Situ/terapia , Carcinoma de Células de Transição/imunologia , Carcinoma de Células de Transição/mortalidade , Carcinoma de Células de Transição/terapia , Criança , Cistectomia , Progressão da Doença , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Gradação de Tumores , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Análise de Sobrevida , Bexiga Urinária/imunologia , Bexiga Urinária/patologia , Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/terapiaRESUMO
BACKGROUND: Tumour expression of selected microRNAs (miRs) correlates with cisplatin efficacy in multiple cancers. We investigated the role of selected miRs in patients receiving cisplatin-based therapy for advanced urothelial carcinoma (UC). METHODS: RNA was extracted from formalin-fixed paraffin-embedded tumour from 83 advanced UC patients who received cisplatin. A miR panel based on relevance for platinum sensitivity and UC was studied by quantitative reverse transcription quantitative PCR (RT-qPCR). Association of progression-free survival (PFS) with miR expression was analysed using cox regression. Selected TFs were chosen by association with the panel of miRs using the Transcription Regulation algorithm (GeneGo MetaCore+MetaDrug version 6.23 build 67496). Bladder cancer (BC) cell lines were used to investigate the previously described role of miR-21 mediating cisplatin sensitivity. RESULTS: The 83 patients had a median PFS of 8 months. In multivariate analysis, higher levels of E2F1 (P=0.01, HR: 1.95 (1.14, 3.33)), miR-21 (P=0.01, HR: 2.01 (1.17, 3.45)) and miR-372 (P=0.05, HR: 1.70 (1.00, 2.89)) were associated with a shorter PFS. In the 8 BC cell lines, miR-21 was not shown to be necessary nor sufficient for modulating cisplatin sensitivity. CONCLUSIONS: In metastatic UC patients treated with cisplatin-based therapy, high primary tumour levels of E2F1, miR-21 and miR-372 are associated with poor PFS independent of clinical prognostic factors. The in vitro study could not confirm miR-21 levels role in modulating platinum sensitivity.
Assuntos
Carcinoma/tratamento farmacológico , Carcinoma/genética , MicroRNAs/genética , Compostos Organoplatínicos/uso terapêutico , Neoplasias Urológicas/tratamento farmacológico , Neoplasias Urológicas/genética , Linhagem Celular , Linhagem Celular Tumoral , Cisplatino/uso terapêutico , Intervalo Livre de Doença , Células HEK293 , Humanos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genéticaRESUMO
PURPOSE OF REVIEW: Neoadjuvant chemotherapy followed by cystectomy improves survival compared with surgery alone. To prevent overtreatment is of outmost importance to define molecular predictors of response for patient selection. We present the currently available data outlining a variety of potential markers to aid for a personalized decision-making process. RECENT FINDINGS: Apart from p53, other markers of cell cycle regulation and apoptosis such as p21WAF1/CIP1 (p21) gene, Bcl-2, mouse double minute-2 and pRB have also been related to survival. The clinical relevance of epidermal growth factor receptor and HER2 expression has also been investigated with no success. Regarding Ki67, overexpressing tumors may potentially benefit from neoadjuvant therapy and conversely overexpression of vascular endothelial growth factor and bFGF have been linked to resistance to cisplatin-induced apoptosis. The role of multidrug resistance gene 1 and excision repair cross-complementing rodent repair deficiency complementation group 1 supports that enhanced DNA repair in the tumor decreases the benefit of platinum-based treatment. A 20-gene expression model has shown to predict lymph node involvement, helping on decision-making. A gene expression profiling has been proposed as predictive for response to neoadjuvant chemotherapy. SUMMARY: Predictive markers will eventually aid in the selection of patients that most likely benefit from preoperative treatment. In the coming years, a panel of markers will become available to achieve the predicted goal.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Cistectomia , Terapia Neoadjuvante , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Biomarcadores Tumorais/genética , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Humanos , Seleção de Pacientes , Medicina de Precisão , Valor Preditivo dos Testes , Resultado do Tratamento , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/cirurgiaRESUMO
Variant forms of bladder cancer are non-urothelial neoplasms or urothelial carcinomas mixed with other histologies. Compared to pure urothelial carcinoma, they all present with a high stage and grade. Prognosis is variable and there is a lack of evidence regarding the ideal treatment approach, because of their relative infrequency and the noninclusion in bladder cancer randomized trials. Despite this, basic recommendations can be extracted from case series. In the present report, existent literature about variant forms of bladder cancer is reviewed with focus on the most frequent: squamous cell, adenocarcinoma, small cell, micropapillary, sarcomatoid, and lymphoepithelioma-like.
Assuntos
Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/terapia , Urotélio/patologia , Feminino , Humanos , Masculino , Estadiamento de Neoplasias , PrognósticoRESUMO
OBJECTIVE: To determine factors predictive of positive findings at the 3-month follow-up evaluation (after transurethral resection of bladder tumour [TUR] and bacille Calmette-Guérin [BCG] therapy) in patients with initial high-grade (HG)T1 bladder cancer, and to assess the depth of lamina propria (LP) invasion and effectiveness of BCG therapy. PATIENTS AND METHODS: In all, 138 patients with initial HGT1-transitional cell carcinoma (TCC) were prospectively assigned, after TUR + BCG and according to depth of LP invasion, to a postBCG-TUR (T1b) or cystoscopy/cytology (T1a) at 3 months. Any finding at 3 months was considered positive. The predictive value of 11 clinical and pathological variables was assessed by chi-squared, Mann-Whitney U and multivariate logistic regression. RESULTS: Of the 138 patients (14 women, mean age 69 years), 42% had T1a and 58% T1b TCC. Tumour size and carcinoma in situ (CIS) were significantly associated with positive findings and present in 26% (36/138) of the patients. The postBCG-TUR (T1b cases), was positive in 31% (25/80), including seven infiltrating tumours. On multivariate analysis, again a tumour size of >3 cm (odds ratio, OR, 7.02) and associated CIS (OR 5.4) were significantly related to a positive postBCG-TUR. A secondary finding was that at 20.3 months; patients with T1a TCC, who did not undergo a repeat TUR, did not have increased progression; only 3% (two of 58) had progressed compared with 21% (17/80) of those with T1b/c TCC (P < 0.002). CONCLUSIONS: In initial HGT1-TCC, tumour size and CIS were predictive factors of positive findings at 3 months after the initial TUR + BCG therapy. Patients with HGT1-TCC invading the LP (T1b TCC) had a seven times higher risk of a positive repeat TUR if the initial tumour was >3 cm and a five-fold increased risk if associated with CIS. The repeat TUR after BCG therapy allowed confirmation of complete resection and pathological evaluation of the BCG response. Although data are still preliminary, the strategy of performing a repeat TUR only in cases with LP involvement, i.e. T1b TCC, did not increase the risk of progression in cases with T1a TCC.
Assuntos
Antineoplásicos/uso terapêutico , Vacina BCG/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/cirurgia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/cirurgia , Administração Intravesical , Idoso , Carcinoma de Células de Transição/patologia , Terapia Combinada , Cistoscopia/métodos , Métodos Epidemiológicos , Feminino , Humanos , Masculino , Metástase Neoplásica , Prognóstico , Reoperação , Fatores de Risco , Resultado do Tratamento , Neoplasias da Bexiga Urinária/patologiaRESUMO
INTRODUCTION: To determine clinical and biopsy features with predictive capacity to identify pathologically insignificant prostate cancer (pIPCa). MATERIAL AND METHODS: pIPCa was defined as cancer volume <0.5 cm(3) and a Gleason score (GS) of
Assuntos
Biópsia/métodos , Próstata/cirurgia , Prostatectomia/métodos , Neoplasias da Próstata/diagnóstico , Adulto , Idoso , Reações Falso-Positivas , Humanos , Masculino , Oncologia/métodos , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Neoplasias da Próstata/cirurgia , Análise de Regressão , RiscoRESUMO
No consensus currently exist on the optimal treatment of patients with high-risk nonmuscle invasive (HGT1) micropapillary variant of bladder cancer (MPBC). Transcripsome analysis may allow stratification of MPBC-HGT1 enabling prediction of recurrence and guide therapeutic management for individual patients. Whole transcriptome RNA-Sequencing of tumors from 23 patients with MPBC-HGT1 and 64 conventional urothelial carcinomas (cUC) (reference set) was performed. Differentially expressed genes between MPBC-HGT1 and cUC-HGT1 were explored. Cox proportional hazard models and Kapplan-Meier methods were used to assess the relation between time to progression (TTP) and individual gene expression adjusting for clinical covariates. Over 3000 genes were differentially expressed in MPBC-HGT1 as compared with cUC-HGT1 and a 26-gene signature is characteristic of MPBC within HGT1. A set of three genes; CD36, FAPB3 and RAETE1; were significantly associated with TTP. High expression of FABP3 and CD36 were associated with shorter TTP (p = 0.045 and p = 0.08) as was low expression of RAET1E (p = 0.01). Our study suggest that a 26-gene signature can define MPBC-HGT1 within conventional urothelial carcinomas. A prognostic risk index of three genes (FABP3, CD36 and RAET1E) was found to be associated with shorter TTP and may help classify a group of patients with MPBC-HGT1 with high-risk of early progression. These observations might have implications in terms of radical cystectomy recommendation in MPBC patients.
Assuntos
Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Antígenos CD36/genética , Proteínas de Transporte/genética , Proteína 3 Ligante de Ácido Graxo/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Estimativa de Kaplan-Meier , Masculino , Proteínas de Membrana/genética , Estadiamento de Neoplasias , Análise de Sequência de RNA , Neoplasias da Bexiga Urinária/mortalidadeRESUMO
High-grade T1 (HGT1) bladder cancer is the highest risk subtype of non-muscle-invasive bladder cancer with unpredictable outcome and poorly understood risk factors. Here, we examined the association of somatic mutation profiles with nonrecurrent disease (GO, good outcome), recurrence (R), or progression (PD) in a cohort of HGT1 patients. Exome sequencing was performed on 62 HGT1 and 15 matched normal tissue samples. Both tumor only (TO) and paired analyses were performed, focusing on 95 genes known to be mutated in bladder cancer. Somatic mutations, copy-number alterations, mutation load, and mutation signatures were studied. Thirty-three GO, 10 R, 18 PD, and 1 unknown outcome patients were analyzed. Tumor mutational burden (TMB) was similar to muscle-invasive disease and was highest in GO, intermediate in PD, and lowest in R patients (P = 0.017). DNA damage response gene mutations were associated with higher TMB (P < 0.0001) and GO (P = 0.003). ERCC2 and BRCA2 mutations were associated with GO. TP53, ATM, ARID1A, AHR, and SMARCB1 mutations were more frequent in PD. Focal copy-number gain in CCNE1 and CDKN2A deletion was enriched in PD or R (P = 0.047; P = 0.06). APOBEC (46%) and COSMIC5 (34%) signatures were most frequent. APOBEC-A and ERCC2 mutant tumors (COSMIC5) were associated with GO (P = 0.047; P = 0.0002). pT1b microstaging was associated with a genomic cluster (P = 0.05) with focal amplifications of E2F3/SOX4, PVRL4, CCNE1, and TP53 mutations. Findings were validated using external public datasets. These findings require confirmation but suggest that management of HGT1 bladder cancer may be improved via molecular characterization to predict outcome. SIGNIFICANCE: Detailed genetic analyses of HGT1 bladder tumors identify features that correlate with outcome, e.g., high mutational burden, ERCC2 mutations, and high APOBEC-A/ERCC2 mutation signatures were associated with good outcome.
Assuntos
Mutação , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Ciclina E/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Feminino , Seguimentos , Dosagem de Genes , Humanos , Masculino , Músculos/patologia , Recidiva Local de Neoplasia/patologia , Proteínas Oncogênicas/genética , Proteína Supressora de Tumor p53/genética , Neoplasias da Bexiga Urinária/mortalidade , Proteína Grupo D do Xeroderma Pigmentoso/genéticaRESUMO
OBJECTIVE: To evaluate changes in bone mass and fracture risk in patients with prostate cancer on androgen-deprivation therapy (ADT) and with a basal T-score of >-2.0, who were treated with an oral bisphosphonate, as such patients treated with ADT are at increased risk of bone loss and bone fracture. PATIENTS AND METHODS: We selected 61 patients with prostate cancer treated with ADT; 31 were treated with oral alendronate 70 mg once-weekly and a control group of 30 were not. At baseline and 12 months we measured bone mineral density (BMD) of the lumbar spine, femoral neck and total hip by dual-energy X-ray absorptiometry. All patients had severe osteopenia or osteoporosis at baseline. The risk of femoral neck fracture was calculated at baseline and 12 months (Z-score 2.7). RESULTS: Patients treated with alendronate had a significant increase in BMD at the lumbar spine and femoral neck after 1 year of follow-up, with mean (sd) values of 1.06 (0.26) vs 1.01 (0.21) g/cm(2) at baseline (P < 0.001), and 0.75 (0.07) vs 0.73 (0.07) g/cm(2) (P = 0.03), respectively, while the control group had a significant loss of BMD at the total hip of 0.79 (0.14) vs 0.81 (0.13) g/cm(2) (P = 0.03). BMD was significantly improved at the three locations in patients treated with alendronate compared with the control group, with differences at the lumbar spine, femoral neck and total hip of 0.05 (0.07) vs 0.01 (0.10) (P = 0.001), 0.01 (0.04) vs -0.002 (0.03) (P = 0.04) and 0.01 (0.04) vs -0.01 (0.02) g/cm(2), respectively (P = 0.001). Patients treated with alendronate had a significant decrease in the fracture risk at the femoral neck, by -0.54 (1.29) (P = 0.04) after 1 year of follow-up. CONCLUSIONS: Treatment with once-weekly 70 mg alendronate significantly improved the BMD at the lumbar spine and femoral neck in patients with prostate cancer with severe osteopenia or osteoporosis and on ADT, and significantly decreased the risk of femoral neck fracture.
Assuntos
Alendronato/uso terapêutico , Antagonistas de Androgênios/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Doenças Ósseas Metabólicas/tratamento farmacológico , Fraturas do Colo Femoral/prevenção & controle , Neoplasias da Próstata/tratamento farmacológico , Absorciometria de Fóton , Idoso , Densidade Óssea , Doenças Ósseas Metabólicas/induzido quimicamente , Métodos Epidemiológicos , Humanos , Masculino , Osteoporose/prevenção & controle , Neoplasias da Próstata/complicaçõesRESUMO
OBJECTIVES: To present recent data on the epidemiology of urinary incontinence in prostate cancer (PCa). To review the incidence of urinary incontinence, its impact on quality of life and related pharmacoeconomic features. METHODS: We performed a bibliographic review about the complications of the various therapeutic options for PCa including radical prostatectomy (RP) (open, laparoscopic and robotic), external beam radiotherapy, brachytherapy, cryotherapy, and high intensity focused ultrasound (HIFU). RESULTS: The lack of uniformity for urinary incontinence definition, for its evaluation, and for the way to report it makes the interpretation of functional results and impact on quality of life after any treatment option difficult and uneven. Generally, we documented that urinary incontinence after treatment appears more often in patients undergoing radical surgery. Nevertheless, we stated that neurovascular bundle preservation, performance of the procedure in high volume centers, by high volume surgeons, and development of robotic surgery may positively influence the global outcomes of this technique. Moderate incontinence is less frequent after external beam radiotherapy, but the association of rectal pain and diarrhea, in up to 40%of the patients, worsens voiding symptoms. Irritative and obstructive voiding symptoms after perineal brachytherapy are especially associated with long term erectile dysfunction as well as rectal morbidity. In the case of cryotherapy and HIFU the available studies are case series and there are not randomized studies comparing them with the primary treatment of localized PCa. CONCLUSIONS: Each treatment modality for PCa is associated with a different pattern of changes in the urinary, sexual, intestinal and hormonal related quality of life domains. Two key factors when evaluating incontinence are information about continence before the procedure and the use of validated, self-administered evaluation means. Although technical improvements in all procedures should contribute to diminish the impact of complications, we should not forget the trend to the association of therapies- multimodal therapy- has a higher complication profile. Therefore, they should be reserved for patients in whom a benefit has been proved.
Assuntos
Neoplasias da Próstata/terapia , Qualidade de Vida , Incontinência Urinária/epidemiologia , Crioterapia/efeitos adversos , Farmacoeconomia , Humanos , Incidência , Masculino , Prostatectomia/efeitos adversos , Radioterapia/efeitos adversos , Robótica , Incontinência Urinária/etiologiaRESUMO
OBJECTIVES: To review the relationship between the Gleason grade and prostate volume in biopsy and radical prostatectomy (RP) specimens, and thus assess the hypothesis that smaller prostates have a greater incidence of high-grade tumours. PATIENTS AND METHODS: We selected 390 patients who had RP at our institution, with a prostate-specific antigen (PSA) level of < 10 ng/mL and who had not had hormonal therapy. We retrospectively reviewed the data for transrectal ultrasonography (TRUS)-guided prostate biopsies from these patients and the RP specimens. Indications for biopsy included a PSA level of > or = 4 ng/mL or an abnormal digital rectal examination. High-grade tumours were defined as having a Gleason score of > or = 7. RESULTS: The TRUS volume was statistically related to the rate of high-grade tumours at biopsy and RP. On multivariate analyses, TRUS volume was a significant predictor of high-grade tumour for biopsy and RP specimens, with an inverse relationship between high-grade tumours and prostate volume for biopsy and RP specimens. CONCLUSIONS: Our data suggest that there is a relationship between the rate of high-grade tumours and prostate volume even in biopsy and RP specimens and it is not an artefact related to the biopsy.
Assuntos
Próstata/patologia , Neoplasias da Próstata/patologia , Adulto , Idoso , Biópsia por Agulha/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias/métodos , Tamanho do Órgão , Antígeno Prostático Específico/sangue , Prostatectomia/métodos , Estudos Retrospectivos , Ultrassonografia de Intervenção/métodosRESUMO
PURPOSE: The pretreatment neutrophil-to-lymphocyte ratio (NLR) has been associated with cancer prognosis, influencing progression and chemosensitivity. We aimed to define the role of the NLR in predicting the outcomes to neoadjuvant chemotherapy (NAC) in patients with muscle invasive bladder cancer (MIBC). PATIENTS AND METHODS: The data from patients treated with NAC and radical cystectomy for MIBC from 2007 to 2015 at a tertiary care center were reviewed. The clinicopathologic pretreatment, including the NLR, and post-treatment predictors were documented. The NLR was evaluated as a continuous variable on uni- and multivariate analysis and dichotomized in Kaplan-Meier curves. The relationships with outcomes (progression-free survival [PFS], cancer-specific survival [CSS], and overall survival [OS]) were analyzed using Cox regression analysis and log-rank tests. The pathologic response (PR) included any downstaging from the baseline clinical stage to the final pathologic stage. RESULTS: Of 205 patients with MIBC, 75 underwent NAC (median follow-up, 31 months) with a 5-year PFS, CSS, and OS rate of 56%, 60%, and 52%, respectively, and a PR of 38.6%. On multivariate analysis, the PR, PFS, CSS, and OS were predicted by the NLR (hazard ratio > 0.8, 1.25, 1.27, and 1.12, respectively; P < .05 for all). The NLR with age and clinical stage predicted the PR. A NLR threshold of 2.26 better predicted CSS (P < .05) and OS (P = .055). The limitations included the retrospective design and modest number of cases. CONCLUSION: We have provided initial evidence that a low NLR helps understand the value of the underlying immune system in predicting a good outcome to NAC. The NLR is a simple and accessible biomarker that is easy to implement in clinical practice. In addition to established prognosticators and newer genomic predictors, the NLR could improve therapeutic algorithms and help in decision-making regarding the need for NAC, which is currently underused, in MIBC patients.
Assuntos
Antineoplásicos/uso terapêutico , Neutrófilos/citologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/cirurgia , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante , Cistectomia , Intervalo Livre de Doença , Feminino , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Análise de Sobrevida , Resultado do Tratamento , Neoplasias da Bexiga Urinária/sangueRESUMO
BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) might reflect an increased neutrophilic inflammatory response, and urothelial tumors with squamous-cell features (SqD) have been linked to inflammation. We hypothesized that NLR could be prognostic in these patients. PATIENTS AND METHODS: In patients with SqD muscle-invasive bladder cancer treated with curative intent, NLR and relationships with outcomes were analyzed by Cox regression, log-rank, and Kaplan-Meier analysis. RESULTS: Fifty patients presented SqD (median follow-up, 29 months). The ideal NLR cutoff (by receiver operating characteristic curves) was 5. Thirty-seven patients had NLR < 5 and 13 had NLR ≥ 5. The 5-year progression-free survival, cancer-specific survival (CSS), and overall survival were 46.8%, 48.4%, and 45% for NLR < 5 cases, and 10.3%, 10.3%, and 11.7% for NLR ≥ 5 cases (all P < .05). On multivariate analysis, NLR was prognostic (hazard ratio = 4.26, 6.21, and 4.08 for progression-free survival, CSS, and overall survival). Neoadjuvant chemotherapy (NAC) was of significant benefit in NLR < 5 patients, with a CSS of 91.2 months (n = 3) versus 38.1 months (n = 24) for those treated with up-front radical cystectomy (P = .009); Kaplan-Meier curves were also significantly different. These differences did not reach statistical significance for patients with NLR ≥ 5. For the 19 patients treated with NAC, NLR was also predictive of response to NAC. CONCLUSION: Inflammation, measured by NLR, is potentially prognostic in the perioperative management of SqD. NLR identifies 2 risk groups. Patients displaying low NLR had a 4-fold survival improvement and were highly responsive to NAC. NLR might be a good prognostic tool. Its role as a predictor of response to NAC deserves future study, along with its role as a selection criterion for therapies other than chemotherapy.
Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/imunologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Neutrófilos , Período Perioperatório , Prognóstico , Curva ROC , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Please also verify that the expansion of HGT1 is OK as set: The risk of progression for high-grade T1 (HGT1) cancer has been recently established at 21% using updated information on large series and a meta-analysis. These outcomes are better than those classically expected supporting the rule of thirds for HGT1. The main limitation of this subgroup is that most studies are retrospective observational studies, which, compared with randomized controlled trials, are subject to various selection biases, carrying a higher risk of uncontrolled confounding factors, with potential preferential reporting of positive findings.
Assuntos
Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/terapia , Gerenciamento Clínico , Humanos , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Risco , Neoplasias da Bexiga Urinária/mortalidadeRESUMO
Therapy for urothelial carcinoma appears poised for a breakthrough on the basis of information regarding molecular subtypes and promising activity of PD-1/PD-L1 inhibitors. Precision medicine may be possible using rational marker-driven trial designs with enriched information from tumor genotyping and extreme responders.
Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Terapia de Alvo Molecular , Medicina de Precisão/métodos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Urotélio/efeitos dos fármacos , Animais , Biomarcadores Tumorais/genética , Difusão de Inovações , Predisposição Genética para Doença , Genômica , Humanos , Terapia de Alvo Molecular/tendências , Seleção de Pacientes , Fenótipo , Medicina de Precisão/tendências , Valor Preditivo dos Testes , Fatores de Risco , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Urotélio/metabolismo , Urotélio/patologiaRESUMO
BACKGROUND: Upper tract urothelial carcinoma (UTUC) accounts for <5% of all urothelial cancers. Although the main treatment is radical nephroureterectomy (NU), oncologic outcomes are not comparable to lower tract urothelial cancers. Identifying prognostic factors can help guide management and potentially improve outcomes. This article systematically reviews current literature on prognostic factors and management options for UTUC. METHODS: A comprehensive literature search was performed to identify all studies examining prognostic factors and management options for UTUC. The search included the Medline, Embase, Cochrane Central Register of Controlled Trials databases, and abstracts from the American Society of Clinical Oncology meetings up to November 2014. An updated systematic review was performed. RESULTS: Preoperative prognostic factors for UTUC patients include age, race, performance status, obesity, smoking status, elevated fibrinogen levels, hydronephrosis, tumor size, multi-focality, location, clinical grade and previous/synchronous bladder cancer. Postoperative variables include tumor stage/grade, multifocality, nodal involvement, lympho-vascular invasion, initial ureteral location, necrosis, sessile architecture, variant histologies and presence of tissue ALDH1 and SOX2. Curative treatment of choice is NU, with lymphadenectomy conferring survival benefits. Minimally invasive surgery has equivalent oncologic and better peri-operative outcomes compared to open surgery. Conservative therapy includes adjuvant BCG and intravesical mitomycin C. Two randomized trials investigating postoperative instillation of mitomycin C suggest bladder recurrence benefits. Adjuvant chemo-radiotherapy may be useful for patients with advanced T3/4 and/or N+ disease. CONCLUSION: Gold-standard treatment for UTUC remains NU, increasingly performed using minimally invasive surgery. Nomograms including pre- and post-operative variables can aid prognostication and guide further therapy.
Assuntos
Neoplasias Renais/diagnóstico , Neoplasias Renais/terapia , Neoplasias Ureterais/diagnóstico , Neoplasias Ureterais/terapia , Quimioterapia Adjuvante , Gerenciamento Clínico , Humanos , Nefrectomia , PrognósticoRESUMO
PURPOSE: High-grade T1 (HGT1) bladder cancer is the highest risk subtype of non-muscle-invasive bladder cancer, with highly variable prognosis, poorly understood risk factors, and considerable debate about the role of early cystectomy. We aimed to address these questions through a meta-analysis of outcomes and prognostic factors. METHODS: PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and American Society of Clinical Oncology abstracts were searched for cohort studies in HGT1. We pooled data on recurrence, progression, and cancer-specific survival from 73 studies. RESULTS: Five-year rates of recurrence, progression, and cancer-specific survival were 42% (95% CI, 39% to 45%), 21% (95% CI, 18% to 23%), and 87% (95% CI, 85% to 89%), respectively (56 studies, n = 15,215). In the prognostic factor meta-analysis (33 studies, n = 8,880), the highest impact risk factor was depth of invasion (T1b/c) into lamina propria (progression: hazard ratio [HR], 3.34; P < .001; cancer-specific survival: HR, 2.02; P = .001). Several other previously proposed factors also predicted progression and cancer-specific survival (lymphovascular invasion, associated carcinoma in situ, nonuse of bacillus Calmette-Guérin, tumor size > 3 cm, and older age; HRs for progression between 1.32 and 2.88, P ≤ .002; HRs for cancer-specific survival between 1.28 and 2.08, P ≤ .02). CONCLUSION: In this large analysis of outcomes and prognostic factors in HGT1 bladder cancer, deep lamina propria invasion had the largest negative impact, and other previously proposed prognostic factors were also confirmed. These factors should be used for prognostication and patient stratification in future clinical trials, and depth of invasion should be considered for inclusion in TNM staging criteria. This meta-analysis can also help define selection criteria for early cystectomy in HGT1 bladder cancer, particularly for patients with deep lamina propria invasion combined with other risk factors.
Assuntos
Neoplasias da Bexiga Urinária/cirurgia , Estudos de Coortes , Cistectomia , Humanos , Gradação de Tumores , Recidiva Local de Neoplasia/patologia , Prognóstico , Resultado do Tratamento , Neoplasias da Bexiga Urinária/patologiaRESUMO
The use of testosterone supplementation for elderly men has increased markedly over the last decade due to a recognized gradual decline in serum testosterone, which may lead to decreased bone mass, muscle strength, and libido. Testosterone supplementation is also used widely to treat some forms of erectile dysfunction, androgen deficiency, and infertility. However, long-term exogenous testosterone therapy has been associated with several complications, such as fluid retention, nitrogen retention, and hypertension. Due to these problems, alternate treatment modalities, involving more physiological and longer-acting systems for androgen delivery, have been pursued. Alginate-poly-L-lysine-encapsulated Leydig cell microspheres were used as a novel method for the delivery of testosterone in vivo. Encapsulated Leydig cells, which were stimulated with human chorionic gonadotropin, secreted high levels of testosterone in culture. Unencapsulated cells injected i.p. or s.c. failed to produce any testosterone levels, even with human chorionic gonadotropin stimulation. Castrated rats that were administered encapsulated Leydig cells i.p. or s.c. maintained a serum testosterone level between 0.23 and 0.51 ng/ml. Similar levels of testosterone were obtained for 43 d when the encapsulated Leydig cells were injected s.c. (0.28-0.48 ng/ml). Approximately 10% of a normal adult rat Leydig cell population was injected into each castrated animal; however, this resulted in serum testosterone levels of up to 40% of normal. Clinically, testosterone is usually delivered for supplementation and not for full replacement therapy. Therefore, the findings of this study suggest that microencapsulated Leydig cells may be a viable option as a therapeutic modality involving testosterone supplementation.
Assuntos
Sistemas de Liberação de Medicamentos , Células Intersticiais do Testículo/metabolismo , Polilisina/análogos & derivados , Testosterona/administração & dosagem , Testosterona/biossíntese , Alginatos , Animais , Materiais Biocompatíveis , Células Cultivadas , Masculino , Microesferas , Orquiectomia , Ratos , Ratos Sprague-Dawley , Testosterona/sangue , Testosterona/metabolismoRESUMO
Peptide growth factors have been implicated in progression of prostate cancer (PCa) to the androgen-independent state; however, much of the evidence linking diffusible mitogens and survival factors to this process remains circumstantial. Heparin-binding epidermal growth factor-like growth factor (HB-EGF), a prostate stroma-derived factor, promotes survival, proliferation, and neuroendocrine differentiation of androgen-dependent LNCaP PCa cells in vitro. To test whether sustained exposure to HB-EGF can confer an androgen-independent phenotype, we generated stable populations of LNCaP cells that express constitutively a secreted form of HB-EGF (LNCaP/sHB). LNCaP/sHB cells proliferated more rapidly under androgen-depleted conditions in vitro and formed larger tumors with higher frequency in intact and castrated severe combined immunodeficient mice, in comparison to control cells. LNCaP/sHB tumors also expressed higher levels of the neuroendocrine marker, neuron-specific enolase, compared with control tumors. In castrates, increased neuron-specific enolase expression in LNCaP/sHB tumors was associated with reduced androgen receptor (AR) levels. In vitro, AR protein levels were reduced in LNCaP/sHB cells, and in transient transfection assays using an androgen-responsive promoter (mouse mammary tumor virus-long terminal repeat), LNCaP/sHB cells showed reduced sensitivity to dihydrotestosterone compared with controls. This is the first demonstration that continuous exposure of AR-positive PCa cells to a single growth factor can promote an androgen-independent phenotype in vivo. These findings also emphasize the potential role of pathways other than the AR axis in acquisition of androgen independence.