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INTRODUCTION: Circulating tumor cells (CTCs) can provide important information on patient's prognosis and treatment efficacy. Currently, a plethora of methods is available for the detection of these rare cells. We compared the outcomes of two of those methods to enumerate and characterize CTCs in patients with locally advanced and metastatic prostate cancer (PCa). First, the selection-free AccuCyte® - CyteFinder® system (RareCyte® , Inc., Seattle, WA) and second, the ISET system (Rarecells Diagnostics, France), a CTC detection method based on cell size-exclusion. METHODS: Peripheral blood samples were obtained from 15 patients with metastatic PCa and processed in parallel, using both methods according to manufacturer's protocol. CTCs were identified by immunofluorescence, using commercially available antibodies to pancytokeratin (PanCK), EpCAM, CD45/CD66b/CD34/CD11b/CD14 (AccuCyte® - CyteFinder® system), and pancytokeratin, vimentin (Vim) and CD45 (ISET system). RESULTS: The median CTC count was 5 CTCs/7.5 mL (range, 0-20) for the AccuCyte® - CyteFinder® system and 37 CTCs/7.5 mL (range, 8-139) for the ISET system (P < 0.001). Total CTC counts obtained for the two methods were correlated (r = 0.750, P = 0.001). When separating the total CTC count obtained with the ISET system in PanCK+/Vim- and PanCK+/Vim+ CTCs, the total CTC count obtained with the AccuCyte® - CyteFinder® system was moderately correlated with the PanCK+/Vim- CTCs, and strongly correlated with the PanCK+/Vim+ CTCs (r = 0.700, P = 0.004 and r = 0.810, P < 0.001, respectively). CONCLUSION: Our results highlight significant disparities in the enumeration and phenotype of CTCs detected by both techniques. Although the median amount of CTCs/7.5 mL differed significantly, total CTC counts of both methods were strongly correlated. For future studies, a more uniform approach to the isolation and definition of CTCs based on immunofluorescent stains is needed to provide reproducible results that can be correlated with clinical outcomes.
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Biomarcadores Tumorais/sangue , Contagem de Células/métodos , Células Neoplásicas Circulantes/metabolismo , Neoplasias da Próstata/sangue , Idoso , Separação Celular/métodos , Molécula de Adesão da Célula Epitelial/metabolismo , Imunofluorescência , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Reprodutibilidade dos TestesRESUMO
PURPOSE: Prostate circulating tumor cells escape into peripheral blood and enter bone marrow as disseminated tumor cells, representing an early step before conventionally detectable metastasis. It is unclear how frequently this occurs in localized disease and existing detection methods rely on epithelial markers with low specificity and sensitivity. We used multiple methodologies of disseminated tumor cell detection in bone marrow harvested at radical prostatectomy. MATERIALS AND METHODS: Bone marrow was harvested from 208 clinically localized cases, 16 controls and 5 metastatic cases with peripheral blood obtained from 37 metastatic cases. Samples were evaluated at 4 centers with 4 distinct platforms using antibody enrichment with the AdnaTest (Qiagen®) or VERSA (versatile exclusion based rare sample analysis), or whole sample interrogation with the RareCyte platform (Seattle, Washington) or HD-SCA (high definition single cell assay) using traditional epithelial markers and prostate specific markers. We investigated the sensitivity and specificity of these markers by evaluating expression levels in control and metastatic cases. RESULTS: EpCAM, NKX3.1 and AR were nonspecifically expressed in controls and in most samples using AdnaTest with no relation to perioperative variables. Only 1 patient with localized disease showed positive results for the prostate specific marker PSA. With the VERSA platform no localized case demonstrated disseminated tumor cells. With the RareCyte and HD-SCA platforms only a single patient had 1 disseminated tumor cell. CONCLUSIONS: Evaluation across multiple platforms revealed that epithelial markers are nonspecific in bone marrow and, thus, not suitable for disseminated tumor cell detection. Using prostate specific markers disseminated tumor cells were typically not detected in patients with localized prostate cancer.
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Medula Óssea/patologia , Células Neoplásicas Circulantes/patologia , Prostatectomia/métodos , Neoplasias da Próstata/patologia , Adulto , Idoso , Biópsia , Estudos de Coortes , Molécula de Adesão da Célula Epitelial/análise , Proteínas de Homeodomínio/análise , Humanos , Calicreínas/análise , Masculino , Pessoa de Meia-Idade , Próstata/patologia , Próstata/cirurgia , Antígeno Prostático Específico/análise , Neoplasias da Próstata/cirurgia , Receptores Androgênicos/análise , Fatores de Transcrição/análiseRESUMO
PURPOSE: Gleason score is one of the most important prognostic indicators for prostate cancer. Downgrading from biopsy Gleason score 7 to radical prostatectomy Gleason score 6 occurs commonly and yet to our knowledge the impact on survival outcomes is unknown. We examined biochemical recurrence and prostate cancer specific mortality risk in a large cohort evaluated by a single group of expert urological pathologists. MATERIALS AND METHODS: Of 23,918 men who underwent radical prostatectomy at our institution between 1984 and 2014, 10,236 with biopsy and radical prostatectomy Gleason score 6 or 7 without upgrading were included in analysis. The cohort was divided into 3 groups, including group 1-biopsy and radical prostatectomy Gleason score 6 in 6,923 patients (67.6%), group 2-Gleason score 7 downgraded to radical prostatectomy Gleason score 6 in 648 (6.3%) and group 3-biopsy and radical prostatectomy Gleason score 7 in 2,665 (26.0%). Biochemical recurrence and prostate cancer specific mortality risks were compared using Cox regression and competing risk analyses adjusting for clinicopathological variables. RESULTS: At a median followup of 5 years (range 1 to 29), 992 men experienced biochemical recurrence and 95 had died of prostate cancer. Biochemical recurrence-free survival in downgraded cases (group 2) was better than in group 3 cases, which had Gleason score 7 on biopsy and radical prostatectomy (p <0.001), but worse than group 1 cases, which had Gleason score 6 on biopsy and radical prostatectomy (p <0.001). Downgrading was independently associated with biochemical recurrence (adjusted HR 1.87, p <0.0001) but not with prostate cancer specific mortality (adjusted HR 1.65, p = 0.636). CONCLUSIONS: Downgrading from biopsy Gleason score 7 to radical prostatectomy Gleason score 6 was an independent predictor of biochemical recurrence but not prostate cancer specific mortality, likely due to the presence of minor amounts of Gleason pattern 4.
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Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Adulto , Idoso , Biópsia , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/sangue , Prognóstico , Antígeno Prostático Específico/sangue , Prostatectomia , Neoplasias da Próstata/cirurgia , Medição de Risco , Taxa de SobrevidaRESUMO
PURPOSE: Perioperative blood transfusion (PBT) has been inconsistently associated with adverse outcomes. Bladder cancer patients are unique as they frequently undergo neoadjuvant chemotherapy (NAC) with resulting immunosuppression, which may be exacerbated by transfusion-related immunomodulation. We examined the effect of leukoreduced PBT on oncologic outcomes and perioperative morbidity in radical cystectomy (RC) patients who received NAC, quantifying exposure with a novel dose-index variable. METHODS: The Johns Hopkins Radical Cystectomy database was queried for patients who had undergone NAC followed by RC from 2010 to 2013. Overall, 119 patients had available PBT and survival data. A multivariable Cox model evaluated risk factors, including pathologic stage, Charlson Comorbidity Index, age, race, year of surgery, surgical margin status, PBT, and preoperative hemoglobin for bladder cancer-specific survival (CSS) and overall survival (OS). Logistic regression models determined factors that were independently associated with perioperative morbidity. RESULTS: Median follow-up was 7.8 months (range 0.2-41.8), and during follow-up there were 25 deaths and 21 cancer deaths. PBT significantly predicted OS (hazard ratio [HR] 1.26, 95 % confidence interval [CI] 1.07-1.49; p = 0.005), CSS (HR 1.32, 95 % CI 1.11-1.57; p = 0.002), and morbidity (odds ratio [OR] 1.67, 95 % CI 1.26-2.21; p = 0.004) in univariate analyses. In multivariable models, PBT was significantly associated with morbidity (OR 1.77, 95 % CI 1.30-2.39; p = 0.0002), but not OS or CSS. Intraoperative transfusion was associated with decreased OS and CSS, and increased morbidity, whereas postoperative transfusion was only associated with increased morbidity. CONCLUSIONS: Intraoperative blood transfusion was associated with increased perioperative morbidity and worsened OS and CSS in patients undergoing RC who had NAC. Although PBT may be life-saving in certain patients, a restrictive transfusion strategy may improve outcomes.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transfusão de Sangue/mortalidade , Cistectomia/mortalidade , Morbidade , Terapia Neoadjuvante/mortalidade , Neoplasias da Bexiga Urinária/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Assistência Perioperatória , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias da Bexiga Urinária/patologiaRESUMO
In the current era of individualized medicine, a biorepository of human samples is essential to support clinical and translational research. There have been limited efforts in this arena within the field of urology, as cost, logistical and ethical issues represent significant deterrents to biobanking. The Johns Hopkins Brady Urological Institute Biorepository was founded in 1994 as a resource to facilitate discovery. Since its inception, the biorepository has enabled numerous research endeavours including pivotal trials leading to the regulatory approval of four diagnostic tests for prostate cancer. In the present review, we discuss the current state of biobanking within urology, outline the specific ethical and financial challenges to biobanking as well as solutions, and describe the operations of a successful urological biorepository.
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Bancos de Espécimes Biológicos , Urologia , Bancos de Espécimes Biológicos/economia , Bancos de Espécimes Biológicos/ética , HumanosRESUMO
Patients diagnosed with stage I non-seminomatous germ cell tumor (NSGCT) face the task of selecting a management strategy. Whereas these options all offer excellent survival, unfortunately, each has drawbacks. Retroperitoneal lymph node dissection (RPLND) is a major operation with low, but significant risks of bleeding, chylous ascites, and retrograde ejaculation. Platinum-based chemotherapy is associated with a number of long-term side effects, not all of which are quantified, but include secondary malignancy and early cardiovascular disease. While surveillance minimizes the chances of exposure to unnecessary treatment, it is not infrequently salvaged with chemotherapy and requires a compliant patient willing to undergo serial imaging often with ionizing radiation. Although fewer than one-third of patients will relapse without intervention, the current guidelines propose treatment for stage I patients with high-risk features. New developments in minimally invasive techniques may mitigate the harms of RPLND and avoid the side effects of chemotherapy, making it an ideal option for this cohort of patients. Unlike laparoscopic RPLND, which was introduced as a staging procedure and heavily criticized for the advanced skill set required to achieve oncologic equivalence, robotic RPLND may offer the benefits of a minimally invasive technique without a steep learning curve and a true therapeutic operation in experienced hands.
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Procedimentos Cirúrgicos Robóticos , Neoplasias Testiculares/cirurgia , Humanos , Laparoscopia/métodos , Masculino , Procedimentos Cirúrgicos Minimamente Invasivos , Estadiamento de Neoplasias , Neoplasias Embrionárias de Células Germinativas , Neoplasias Testiculares/tratamento farmacológicoRESUMO
PURPOSE: Obesity is a modifiable risk factor associated with worse outcomes for many cancers, yet implications for prostate cancer are not well understood. Notably the impact of body mass index on long-term survival after treatment is unclear. We performed a retrospective cohort study on a large series of men who underwent radical prostatectomy to assess the impact of obesity on long-term biochemical recurrence-free survival, prostate cancer specific survival and overall survival. MATERIALS AND METHODS: Between 1982 and 2012, 11,152 men underwent radical prostatectomy at a single tertiary referral center. Patients were stratified according to body mass index as normal weight (body mass index less than 25 kg/m(2)), overweight (body mass index 25 to less than 30 kg/m(2)), mild obesity (body mass index 30 to less than 35 kg/m(2)) and moderate/severe obesity (body mass index 35 kg/m(2) or greater), comprising 27.6%, 56.0%, 14.1% and 2.3% of the cohort, respectively. Covariates included age, preoperative prostate specific antigen, surgery year, Gleason score, pathological stage, surgical margin and race. Predictors of biochemical recurrence-free survival, prostate cancer specific survival and overall survival were identified using Cox proportional hazard models. RESULTS: Median followup was 5 years (range 1 to 27). Actuarial 20-year biochemical recurrence-free survival for mild and moderate/severe obesity was 65% and 51%, respectively, compared to 76% for normal weight men (p ≤0.001). In a multivariate model obesity was a significant predictor of biochemical recurrence-free survival (mild HR 1.30, p = 0.002; moderate/severe HR 1.45, p = 0.028) and overall survival (mild HR 1.41, p = 0.003; moderate/severe HR 1.81, p = 0.033). However, only mild obesity was significantly associated with prostate cancer specific survival (HR 1.51, p = 0.040), whereas moderate/severe obesity was not (HR 1.58, p = 0.356). CONCLUSIONS: Obese men have higher rates of biochemical recurrence than normal weight patients during long-term followup. Obesity at the time of surgery independently predicts overall survival and biochemical recurrence-free survival but not prostate cancer specific survival.
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Previsões , Obesidade/mortalidade , Prostatectomia , Neoplasias da Próstata/cirurgia , Adenocarcinoma/complicações , Adenocarcinoma/mortalidade , Adenocarcinoma/cirurgia , Índice de Massa Corporal , Intervalo Livre de Doença , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Obesidade/complicações , Prognóstico , Neoplasias da Próstata/complicações , Neoplasias da Próstata/mortalidade , República da Coreia/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida/tendênciasRESUMO
BACKGROUND: Potential adverse effects of blood transfusion (BT) remain controversial, especially for clinical outcomes after curative cancer surgery. Some postulate that immune modulation after allogeneic BT predisposes to recurrence and death, but autologous superiority is not established. This study assessed whether BT is associated with long-term prostate cancer recurrence and survival with a large single-institutional radical prostatectomy (RP) database. STUDY DESIGN AND METHODS: Between 1994 and 2012, a total of 11,680 patients had RP with available outcome and transfusion data. A total of 7443 (64%) had complete covariate data. Clinical variables associated with biochemical recurrence-free survival (BRFS), cancer-specific survival (CSS), and overall survival (OS) were identified with Cox proportional hazards models for three groups: no BT (reference, 27.7%, n = 2061), autologous BT only (68.8%, n = 5124), and any allogeneic BT (with or without autologous, 3.5%, n = 258). RESULTS: Median (range) follow-up was 6 (1-18) years. Kaplan-Meier analysis showed significantly decreased OS (but not BRFS or PCSS) in the allogeneic group versus autologous and no BT groups (p = 0.006). With univariate analysis, any allogeneic BT had a hazard ratio (HR) of 2.29 (range, 1.52-3.46; p < 0.0001) for OS, whereas autologous BT was not significant (HR, 1.04 [range, 0.82-1.32], p = 0.752). In multivariable models, neither autologous nor allogeneic BT was independently associated with BRFS, CSS, or OS, and a dose response was not observed for allogeneic units and BRFS. CONCLUSION: Although allogeneic but not autologous BT was associated with decreased long-term OS, after adjustment for confounding clinical variables, BT was not independently associated with OS, BRFS, or CSS regardless of transfusion type. Notably, no association was observed between allogeneic BT and cancer recurrence. Observed differences in OS may reflect confounding.
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Transfusão de Sangue Autóloga/efeitos adversos , Prostatectomia/métodos , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/cirurgia , Transplante Homólogo/efeitos adversos , Adulto , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos ProporcionaisRESUMO
PURPOSE: Cabozantinib and nivolumab (CaboNivo) alone or with ipilimumab (CaboNivoIpi) have shown promising efficacy and safety in patients with metastatic urothelial carcinoma (mUC), metastatic renal cell carcinoma (mRCC), and rare genitourinary (GU) tumors in a dose-escalation phase I study. We report the final data analysis of the safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) of the phase I patients and seven expansion cohorts. METHODS: This is an investigator-initiated, multicenter, phase I trial. CaboNivo doublet expansion cohorts included (1) mUC, (2) mRCC, and (3) adenocarcinoma of the bladder/urachal; CaboNivoIpi triplet expansion cohorts included (1) mUC, (2) mRCC, (3) penile cancer, and (4) squamous cell carcinoma of the bladder and other rare GU tumors (ClinicalTrials.gov identifier: NCT02496208). RESULTS: The study enrolled 120 patients treated with CaboNivo (n = 64) or CaboNivoIpi (n = 56), with a median follow-up of 49.2 months. In 108 evaluable patients (CaboNivo n = 59; CaboNivoIpi n = 49), the ORR was 38% (complete response rate 11%) and the median duration of response was 20 months. The ORR was 42.4% for mUC, 62.5% for mRCC (n = 16), 85.7% for squamous cell carcinoma of the bladder (n = 7), 44.4% for penile cancer (n = 9), and 50.0% for renal medullary carcinoma (n = 2). Grade ≥ 3 treatment-related adverse events occurred in 84% of CaboNivo patients and 80% of CaboNivoIpi patients. CONCLUSION: CaboNivo and CaboNivoIpi demonstrated clinical activity and safety in patients with multiple GU malignancies, especially clear cell RCC, urothelial carcinoma, and rare GU tumors such as squamous cell carcinoma of the bladder, small cell carcinoma of the bladder, adenocarcinoma of the bladder, renal medullary carcinoma, and penile cancer.
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Small renal cell carcinoma (RCC) tumors are believed to have a negligible risk of metastasis. We report on a 77-year-old man presenting with extremity weakness who was found to have a 2.5 cm brain metastasis from a subsequently discovered 1.6 cm clear cell RCC primary tumor. We review what is known about synchronous and metachronous metastasis from small renal tumors and prognostic features informing treatment for such lesions.
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Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/secundário , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/secundário , Neoplasias Renais/patologia , Idoso , Neoplasias Encefálicas/terapia , Carcinoma de Células Renais/terapia , Humanos , Neoplasias Renais/cirurgia , Imageamento por Ressonância Magnética , Masculino , Metastasectomia , Nefrectomia , Prognóstico , Radioterapia , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: The RENAL nephrometry score (RNS) is widely used to describe renal mass complexity and inform patient counseling for partial nephrectomy (PN). However, in cases with multiple tumors, it is unknown which features drive perioperative outcomes. OBJECTIVE: To employ a novel scoring equation (multiplex score [MS]) derived from RNS to assess outcomes of multiplex PN at our institution. DESIGN, SETTING, AND PARTICIPANTS: A total of 62 consecutive multiplex PN (median (range) # tumorsâ¯=â¯4(2-11), 65% robotic) were performed by a single surgeon. The MS was defined a priori as a weighted score derived from RNS (# low risk ([LR] lesions)â¯+â¯2*(# intermediate risk [IR])â¯+â¯4*(# high risk [HR]) based on published complication rates. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: MS was dichotomized into favorable/unfavorable based on median score. Patient outcomes were maintained prospectively. MS was compared with other potential RNS derived scoring systems. RESULTS AND LIMITATION: A total of 249 tumors were scored. Median (range) MS was 6(range 2-20, IQR 3-8). Complications occurred in 10 patients (16.1%). Only 1 complication occurred in the favorable MS(<6) group, and MS was associated with perioperative complication (Pâ¯=â¯0.02) and blood loss (P < .001). When compared to other potential scoring systems, MS had the best area under the curve (AUC) to predict operative complications (0.75). CONCLUSIONS: The novel MS was associated with complications and blood loss. This tool may facilitate standardized reporting of complexity for multiplex series, with special relevance for hereditary cancer syndromes. PATIENT SUMMARY: For patients who have one kidney tumor, there are established scoring systems to help patients and surgeons decide on the surgical plan. However currently, for patients with more than one renal tumor, there is no such scoring system. Here, we present the "Multiplex Score" to aid shared-decision-making in cases with more than one renal tumor.
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Neoplasias Renais , Procedimentos Cirúrgicos Robóticos , Robótica , Humanos , Estudos Retrospectivos , Nefrectomia/métodos , Rim/patologia , Neoplasias Renais/patologia , Resultado do Tratamento , Procedimentos Cirúrgicos Robóticos/métodosRESUMO
UNLABELLED: Study Type--Diagnostic (exploratory cohort) Level of Evidence 2b. What's known on the subject? and What does the study add? Surgical margin status at radical prostatectomy (RP) has been shown to be a predictor of disease progression and the strongest predictor of benefit from adjuvant therapy, but the impact of a positive surgical margin (PSM) on long-term prostate-cancer-specific survival is unknown. The PSM rate is dependent on the pathological stage of the cancer. In a recent multicentre nomogram for 15-year prostate-cancer-specific mortality (PCSM) after RP, PSM was not significantly associated with PCSM, while Gleason score and pathological stage were the only significant predictors. This has not been validated in a single centre, and PSM has been shown to vary greatly with surgical technique. This is the first study on the impact of PSM on PCSM in a single surgeon's cohort. In other centres, the decision to administer adjuvant therapy may be influenced by surgical margin status. In this cohort, men routinely did not receive adjuvant therapy, affording the unique opportunity to study the long-term implications of a PSM. OBJECTIVE: ⢠To examine the relative impact of a positive surgical margin (PSM) and other clinicopathological variables on prostate-cancer-specific mortality (PCSM) in a large retrospective cohort of patients undergoing radical prostatectomy (RP). PATIENTS AND METHODS: ⢠Between 1982 and 2011, 4569 men underwent RP performed by a single surgeon. ⢠Of the patient population, 4461 (97.6%) met all the inclusion criteria. ⢠The median (range) age was 58 (33-75) years and the median prostate-specific antigen (PSA) was 5.4 ng/mL; RP Gleason score was ≤ 6 in 2834 (63.7%), 7 in 1351 (30.3%), and 8-10 in 260 (6.0%) patients; PSMs were found in 462 (10.4%) patients. ⢠Cox proportional hazards models were used to determine the impact of a PSM on PCSM. RESULTS: ⢠At a median (range) follow-up of 10 years (1-29), 187 men (4.3%) had died from prostate cancer. ⢠The 20-year prostate-cancer-specific survival rate was 75% for those with a PSM and 93% for those without. ⢠Compared with those with a negative surgical margin, men with a PSM were more likely to be older (median age 60 vs 58 years) and to have undergone RP in the pre-PSA era (36.6% vs 11.8%). Additionally, they were more likely to have a higher PSA level (median 7.6 vs 5.2 ng/mL), a Gleason score of ≥ 7 (58.7% vs 33.7%), and a non-organ-confined tumour (90.9% vs 30.6% [P < 0.001 for all]). ⢠In a univariate model for PCSM, PSM was highly significant (hazard ratio [HR] 5.0, 95% confidence interval [CI] 3.7-6.7, P < 0.001). ⢠In a multivariable model, adjusting for pathological variables and RP year, PSM remained an independent predictor of PCSM (HR 1.4, 95% CI 1.0-1.9, P = 0.036) with a modest effect relative to RP Gleason score (HR 5.7-12.6) and pathological stage (HR 2.2-11.0 [P < 0.001]). CONCLUSION: ⢠Although a PSM has a statistically significant adverse effect on prostate-cancer-specific survival in multivariable analysis, Gleason grade and pathological stage were stronger predictors.
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Prostatectomia/métodos , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/cirurgia , Adulto , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/mortalidade , Neoplasia Residual , Antígeno Prostático Específico/sangue , Prostatectomia/mortalidade , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
PURPOSE: This study investigated the efficacy and tolerability of cabozantinib plus nivolumab (CaboNivo) in patients with metastatic urothelial carcinoma (mUC) that progressed on checkpoint inhibition (CPI). PATIENTS AND METHODS: A phase I expansion cohort of patients with mUC who received prior CPI was treated with cabozantinib 40 mg/day and nivolumab 3 mg/kg every 2 weeks until disease progression/unacceptable toxicity. The primary goal was objective response rate (ORR) per RECIST v.1.1. Secondary objectives included progression-free survival (PFS), duration of response (DoR), overall survival (OS), safety, and tolerability. RESULTS: Twenty-nine out of 30 patients enrolled were evaluable for efficacy. Median follow-up was 22.2 months. Most patients (86.7%) received prior chemotherapy and all patients received prior CPI (median seven cycles). ORR was 16.0%, with one complete response and three partial responses (PR). Among 4 responders, 2 were primary refractory, 1 had a PR, and 1 had stable disease on prior CPI. Median DoR was 33.5 months [95% confidence interval (CI), 3.7-33.5], median PFS was 3.6 months (95% CI, 2.1-5.5), and median OS was 10.4 months (95% CI, 5.8-19.5). CaboNivo decreased immunosuppressive subsets such as regulatory T cells (Tregs) and increased potential antitumor immune subsets such as nonclassical monocytes and effector T cells. A lower percentage of monocytic myeloid-derived suppressor cells (M-MDSC) and polymorphonuclear MDSCs, lower CTLA-4 and TIM-3 expression on Tregs, and higher effector CD4+ T cells at baseline were associated with better PFS and/or OS. CONCLUSIONS: CaboNivo was clinically active, well tolerated, and favorably modulated peripheral blood immune subsets in patients with mUC refractory to CPI.
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Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Anilidas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células de Transição/tratamento farmacológico , Humanos , Inibidores de Checkpoint Imunológico , Nivolumabe , Piridinas , Neoplasias da Bexiga Urinária/tratamento farmacológicoRESUMO
OBJECTIVE: Metastatic bladder cancer is an aggressive disease that can often be difficult to diagnose and stage with conventional cross-sectional imaging. The primary objective of this study was to determine the clinical value of fluorine-18 2-fluoro-2-deoxy-D-glucose (18F-FDG) PET/MRI for surveillance and restaging of patients with muscle-invasive, locally advanced, and metastatic bladder cancer compared to conventional imaging methods. MATERIALS AND METHODS: This retrospective study enrolled patients with muscle-invasive, locally advanced and metastatic bladder cancer in a single institute evaluated with 18F-FDG PET/MRI. All patients also underwent conventional imaging with CT. Additional imaging may also have included 18F-FDG PET/CT (18F-FDG PET), or sodium fluoride (NaF) PET/CT in some patients. Images were reviewed by a diagnostic radiologist/nuclear medicine physician. Number of lesions and sites of disease were captured and compared between 18F-FDG PET/MRI and conventional imaging. Lesions were confirmed by sequential imaging or lesion biopsy. All patients were followed for survival. RESULTS: Fifteen patients (4 for surveillance; 11 for restaging) underwent 34 18F-FDG PET/MRI scans. Each patient received a corresponding conventional CT around the time of the 18F-FDG PET/MRI (median 6 days). The 15 patients (11 male; 4 female) had a median age of 61.5 years (range 37-73) and histologies of urothelial carcinoma (nâ¯=â¯13) and small-cell carcinoma of the bladder (nâ¯=â¯2) diagnosed as stage 4 (nâ¯=â¯13), stage 3 (nâ¯=â¯1), or stage 2 (nâ¯=â¯1). 18F-FDG PET/MRI detected 82 metastatic malignant lesions involving lymph nodes (nâ¯=â¯22), liver (nâ¯=â¯10), lung (nâ¯=â¯34), soft tissue (nâ¯=â¯12), adrenal glands (nâ¯=â¯1), prostate (nâ¯=â¯1), and bone (nâ¯=â¯2) with a resultant advantage of 36% for lesion visibility in comparison with CT. Serial imaging or biopsy confirmed these lesions as malignant. CONCLUSION: 18F-FDG PET/MRI can detect metastatic lesions which cannot be identified on conventional CT, and this can allow for better treatment planning and improved disease monitoring during therapy.
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Fluordesoxiglucose F18/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Neoplasias da Bexiga Urinária/diagnóstico por imagem , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Retrospectivos , Neoplasias da Bexiga Urinária/patologiaRESUMO
Despite considerable advances in the management of urothelial carcinoma (UC), better risk stratification and enhanced detection of minimal residual disease are still urgent priorities to prolong survival while avoiding the morbidity of overtreatment. Circulating tumor cells and DNA (CTCs, ctDNA) are two biologically distinct "liquid biopsies" that may potentially address this need, although they have been understudied in UC to date and their relative utility is unknown. To this end, matched CTC and ctDNA samples were collected for a head-to-head comparison in a pilot study of 16 patients with metastatic UC. CTCs were defined as cytokeratin- and/or EpCAM-positive using the RareCyte direct imaging platform. ctDNA was assayed using the PlasmaSelect64 probe-capture assay. 75% of patients had detectable CTCs, and 73% had detectable somatic mutations, with no correlation between CTC count and ctDNA. 91% of patients had tissue confirmation of at least one plasma mutation and, importantly, several clinically actionable mutations were detected in plasma that were not found in the matching tumor. A ctDNA fraction of >2% was significantly associated with worse overall survival (p=0.039) whereas CTC detection was not (p=0.46). Notably, using a predefined gene panel for ctDNA detection had a high but not complete detection rate in metastatic UC, similar to what has been described for a custom tissue-personalized assay approach. In sum, both liquid biopsies show promise in UC and deserve further investigation. PATIENT SUMMARY: New "liquid biopsy" blood tests are emerging for urothelial cancer aimed at early detection and avoiding overtreatment. Our results suggest that two such tests provide complementary information: circulating tumor cells may be best for studying the biological features of a person's cancer, whereas circulating tumor DNA may be better for early detection.
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Carcinoma de Células de Transição , DNA Tumoral Circulante , Células Neoplásicas Circulantes , Neoplasias da Bexiga Urinária , Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Humanos , Projetos PilotoRESUMO
PURPOSE: Circulating tumor cells (CTC) are under investigation as a minimally invasive liquid biopsy that may improve risk stratification and treatment selection. CTCs uniquely allow for digital pathology of individual malignant cell morphology and marker expression. We compared CTC features and T-cell counts with survival endpoints in a cohort of patients with metastatic genitourinary cancer treated with combination immunotherapy. EXPERIMENTAL DESIGN: Markers evaluated included pan-CK/CD45/PD-L1/DAPI for CTCs and CD4/CD8/Ki-67/DAPI for T cells. ANOVA was used to compare CTC burden and T-cell populations across timepoints. Differences in survival and disease progression were evaluated using the maximum log-rank test. RESULTS: From December 2016 to January 2019, 183 samples from 81 patients were tested. CTCs were found in 75% of patients at baseline. CTC burden was associated with shorter overall survival (OS) at baseline (P = 0.022), but not on-therapy. Five morphologic subtypes were detected, and the presence of two specific subtypes with unique cellular features at baseline and on-therapy was associated with worse OS (0.9-2.3 vs. 28.2 months; P < 0.0001-0.013). Increasing CTC heterogeneity on-therapy had a trend toward worse OS (P = 0.045). PD-L1+ CTCs on-therapy were associated with worse OS (P < 0.01, cycle 2). Low baseline and on-therapy CD4/CD8 counts were also associated with poor OS and response category. CONCLUSIONS: Shorter survival may be associated with high CTC counts at baseline, presence of specific CTC morphologic subtypes, PD-L1+ CTCs, and low %CD4/8 T cells in patients with metastatic genitourinary cancer. A future study is warranted to validate the prognostic utility of CTC heterogeneity and detection of specific CTC morphologies.
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Biomarcadores Tumorais/análise , Imunoterapia/métodos , Células Neoplásicas Circulantes/patologia , Linfócitos T/imunologia , Neoplasias Urogenitais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Linfócitos T/classificação , Neoplasias Urogenitais/imunologia , Neoplasias Urogenitais/terapia , Adulto JovemRESUMO
PURPOSE: We assessed the safety and efficacy of cabozantinib and nivolumab (CaboNivo) and CaboNivo plus ipilimumab (CaboNivoIpi) in patients with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignances. PATIENTS AND METHODS: Patients received escalating doses of CaboNivo or CaboNivoIpi. The primary objective was to establish a recommended phase II dose (RP2D). Secondary objectives included objective response rate (ORR), progression-free survival (PFS), duration of response (DoR), and overall survival (OS). RESULTS: Fifty-four patients were enrolled at eight dose levels with a median follow-up time of 44.6 months; data cutoff was January 20, 2020. Grade 3 or 4 treatment-related adverse events (AEs) occurred in 75% and 87% of patients treated with CaboNivo and CaboNivoIpi, respectively, and included fatigue (17% and 10%, respectively), diarrhea (4% and 7%, respectively), and hypertension (21% and 10%, respectively); grade 3 or 4 immune-related AEs included hepatitis (0% and 13%, respectively) and colitis (0% and 7%, respectively). The RP2D was cabozantinib 40 mg/d plus nivolumab 3 mg/kg for CaboNivo and cabozantinib 40 mg/d, nivolumab 3 mg/kg, and ipilimumab 1 mg/kg for CaboNivoIpi. ORR was 30.6% (95% CI, 20.0% to 47.5%) for all patients and 38.5% (95% CI, 13.9% to 68.4%) for patients with mUC. Median DoR was 21.0 months (95% CI, 5.4 to 24.1 months) for all patients and not reached for patients with mUC. Median PFS was 5.1 months (95% CI, 3.5 to 6.9 months) for all patients and 12.8 months (95% CI, 1.8 to 24.1 months) for patients with mUC. Median OS was 12.6 months (95% CI, 6.9 to 18.8 months) for all patients and 25.4 months (95% CI, 5.7 to 41.6 months) for patients with mUC. CONCLUSION: CaboNivo and CaboNivoIpi demonstrated manageable toxicities with durable responses and encouraging survival in patients with mUC and other GU tumors. Multiple phase II and III trials are ongoing for these combinations.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Neoplasias Urogenitais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anilidas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígeno B7-H1/metabolismo , Carcinoma de Células de Transição/secundário , Colite/induzido quimicamente , Diarreia/induzido quimicamente , Molécula de Adesão da Célula Epitelial/metabolismo , Fadiga/induzido quimicamente , Feminino , Hepatite/etiologia , Humanos , Hipertensão/induzido quimicamente , Ipilimumab/administração & dosagem , Masculino , Pessoa de Meia-Idade , Células Neoplásicas Circulantes/metabolismo , Nivolumabe/administração & dosagem , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas c-met/metabolismo , Piridinas/administração & dosagem , Receptores CXCR4/metabolismo , Critérios de Avaliação de Resposta em Tumores Sólidos , Taxa de Sobrevida , Adulto JovemRESUMO
OBJECTIVE: To investigate circulating tumor cells (CTCs) as biomarkers of urothelial carcinoma (UC). To date, the majority of work on this topic has utilized the CellSearch test, which has limited sensitivity due to reliance on positive selection for the cell surface protein epithelial cell adhesion molecule (EpCAM). We used a novel selection-free method to enumerate and characterize CTCs across a range of UC stages. MATERIALS AND METHODS: Blood samples from 38 patients (9 controls, 8 nonmuscle invasive bladder cancer [NMIBC], 12 muscle-invasive bladder cancer [MIBC], and 9 metastatic UC) were processed with the AccuCyte-CyteFinder system. Slides were stained for the white blood cell markers CD45 and CD66b and the epithelial markers EpCAM and pancytokeratin. CTCs were defined as any cytokeratin postive and white blood cell marker negative cell. Separately, the more restrictive CellSearch definition was applied, with the additional requirement of EpCAM positivity. The Kruskal-Wallis ANOVA test compared CTC counts by stage. RESULTS: Greater than or equal to 1 CTC was detected in 2 of 8 (25%) patients with NMIBC, 7 of 12 (58%) with MIBC, and 6of 9 (67%) with metastatic disease. No control had CTCs. Comparing CTC counts between groups, the only statistically significant comparison was between controls and patients with metastatic UC (P = .009). With EpCAM positivity as a CTC requirement, no CTCs were detected in any patient with NMIBC, and only 2 (17%) patients with MIBC had CTCs. CTCs tended to be larger in metastatic patients. CONCLUSION: CTCs were detected at all UC stages and exhibited phenotypic diversity of cell size and EpCAM expression. EpCAM negative CTCs that would be missed with the CellSearch test were detected in patients with NMIBC and patients with MIBC.
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Carcinoma de Células de Transição/sangue , Células Neoplásicas Circulantes/patologia , Neoplasias da Bexiga Urinária/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Carcinoma de Células de Transição/metabolismo , Carcinoma de Células de Transição/patologia , Estudos de Casos e Controles , Contagem de Células , Molécula de Adesão da Célula Epitelial/metabolismo , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Células Neoplásicas Circulantes/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/secundárioRESUMO
OBJECTIVE: To report our center's experience with enhanced recovery after surgery (ERAS) pathway for radical cystectomy (RC), specifically evaluating complications, LOS, 30- and 90-day readmissions, and hospital charges. Pathways of this type have been shown to decrease the length of stay (LOS) and postoperative ileus. However, concerns persist that ERAS is costly and increases readmissions. To date, limited studies have evaluated these concerns. MATERIALS AND METHODS: Our ERAS protocol was implemented for RC in December 2015. Outcomes in ERAS patients were compared with those in RC patients from the time period before ERAS. Patients were excluded if they underwent concomitant nephroureterectomy. RESULTS: Fifty-six consecutive ERAS patients were compared with 54 pre-ERAS patients. The median charge for index hospitalization was $31,090 in the ERAS group and $35,489 in the pre-ERAS group (P = .036). The median LOS was 5.0 days in the ERAS group and 8.5 days in the pre-ERAS group (P = < .001). The pre-ERAS group had a significantly increased use of nasogastric tube (13.8% vs 30.0%) and parenteral nutrition (6.9% vs 20.4%). The overall complication rate (including infectious, renal, deep vein thrombosis and pulmonary embolism, myocardial infarction and stroke, and respiratory and gastrointestinal-related complications) was similar between the 2 groups (51.7% in the ERAS group and 62.0% in the pre-ERAS group, P = .28). Thirty- and 90-day readmissions also remained similar (19.0% vs 14.8%, P = .55, and 31.0% vs 27.7%, P = .64). The most common readmission reason was infection, specifically urinary tract infection. CONCLUSION: Implementation of the ERAS pathway at our center resulted in significantly reduced LOS and total hospital charge, with comparable rates of complication and readmission, highlighting the need for ERAS pathways in patients undergoing RC.