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BACKGROUND: Histone modifications alter transcriptional gene function and participate in cancer progression. Enhancer-of-Zeste-Homologue-2 (EZH2) and Nuclear-Receptor-Binding-SET-domain2 (NSD2) methylate H3K27 and H3K36, respectively, to regulate transcription. Given the therapeutic interest in these enzymes, we investigated expression and coregulation in hormone-sensitive (HS) and castrate-resistant (CR) prostate cancer (PC). METHODS: EZH2 and NSD2 levels were quantified using VECTRA analysis in HS and CRPC tissue microarrays (n = 105 + 66). Expression data from The Cancer Genome Atlas (n = 498), Memorial Sloan Kettering Cancer Center (n = 240), and Stand Up to Cancer/Prostate Cancer Foundation (n = 444) cBioportal datasets were queried, and associations between EZH2 and NSD2 and clinicopathologic variables determined. RESULTS: Tumour expression of NSD2, but not EZH2, increased in CRPC (p = 0.05, 0.09). Epithelial nuclei co-expressing NSD2 and EZH2 increased in CRPC compared to HSPC (69 vs 42%, p = 0.02), and in metastatic tissue relative to benign (55 vs 35%, p = 0.02). cBioportal analysis revealed collinear NSD2/EZH2 expression (Spearman = 0.57, 0.58, 0.58, all p < 0.001). NSD2/EZH2 co-expression significantly associates with clinicopathologic characteristics including grade group, stage and seminal vesicle involvement. On univariate and multivariate analysis tumours co-expressing NSD2 and EZH2 conferred increased risk of recurrence (hazard ratio: 2.6, 95% confidence inerval: 1.2-5.4, p = 0.01). Kaplan-Meier analysis revealed reduced progression-free-survival of NSD2 and EZH2 co-expression patients in datasets (p < 0.001, 0.002). CONCLUSIONS: Increased EZH2/NSD2 co-expression is overrepresented in CRPC, metastases and associates with shorter disease-free survival in PC patients. Coregulation of these two histone methyltransferases is a biomarker for aggressive PC and licenses them as therapeutic targets.
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Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Neoplasias da Próstata/patologia , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Bases de Dados Genéticas , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Código das Histonas , Humanos , Masculino , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Análise Serial de Tecidos , Regulação para CimaRESUMO
OBJECTIVE: To evaluate the effect of intravenous iodinated contrast on estimated glomerular filtration rate (eGFR) when administered immediately after thermal ablation of clinically localized T1a (cT1a) renal cell carcinoma (RCC). METHODS: This HIPAA-compliant, dual-center retrospective study was performed under a waiver of informed consent. Three hundred forty-two consecutive patients with cT1a biopsy-proven RCC were treated with percutaneous ablation between January 2010 and December 2017. Immediate post-ablation contrast-enhanced CT was the routine standard of care at one institution (contrast group), but not the other (control group). One-month pre- and 6-month post-ablation eGFR were compared using the Wilcoxon signed-rank test or the Kruskal-Wallis test. Multivariate linear regression was used to determine the effect of contrast on eGFR. A 1:1 propensity score matching was performed for all patients with a logistic model using patient, tumor, and procedural covariates. RESULTS: In total, 246 patients (158 M; median age 69 years, IQR 62-74) were included. Median tumor diameter (2.4 vs 2.5, p = 0.23) and RENAL nephrometry scores (6 vs 6, p = 0.92), surrogates for ablation zone size, were similar. Baseline kidney function was similar for the control and contrast groups, respectively (median eGFR: 70 vs 74 mL/min/1.73 m2, p = 0.29). There was an expected mild decline in eGFR after ablation (control: 70 vs 60 mL/min/1.73 m2, p < 0.001; contrast: 75 vs 71 mL/min/1.73 m2, p = 0.001). Intravenous iodinated contrast was not associated with a decline in eGFR on multivariate linear regression (1.91, 95% CI - 3.43-7.24, p = 0.46) or 1:1 propensity score-matched model (- 0.33, 95% CI - 6.81-6.15, p = 0.92). CONCLUSION: Intravenous iodinated contrast administered during ablation of cT1a RCC has no effect on eGFR. KEY POINTS: ⢠Intravenous iodinated contrast administered during thermal ablation of clinically localized T1a renal cell carcinoma has no effect on kidney function. ⢠Thermal ablation of clinically localized T1a renal cell carcinoma results in a mild decline in kidney function. ⢠A decline in kidney function is similar for radiofrequency and microwave ablation of clinically localized T1a renal cell carcinoma.
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Carcinoma de Células Renais , Ablação por Cateter , Neoplasias Renais , Idoso , Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/cirurgia , Meios de Contraste , Taxa de Filtração Glomerular , Humanos , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/cirurgia , Micro-Ondas , Estudos Retrospectivos , Resultado do TratamentoRESUMO
PURPOSE: The purpose of this study was to evaluate patient, tumor and technical factors associated with procedural complications and nondiagnostic findings following percutaneous core renal mass biopsy. MATERIALS AND METHODS: We reviewed core renal mass biopsies from 2000 to 2017. Complications at 30 days or less were graded using the Clavien-Dindo system. Univariate and multivariable analyses were done to evaluate associations between clinical characteristics and the risk of complications or nondiagnostic findings. RESULTS: Of the 1,155 biopsies performed in a total of 965 patients procedural complications were identified in 24 patients (2.2%), including 5 (0.4%) with major complications (Clavien 3a or greater). No patients were identified with tumor seeding of the biopsy tract. Patient age, body mass index, gender, Charlson comorbidity index, smoking, mass diameter, nephrometry score, number of cores and prior biopsy were not associated with complication risk (p = 0.06 to 0.53). Complications were not increased for patients on aspirin or those with low platelets (25,000 to 160,000/µl blood) or a mildly elevated INR (international normalized ratio) (1.2 to 2.0, p = 0.16, 0.07 and 0.50, respectively). The complication risk was not increased during the initial 50 cases of a radiologist or when a trainee was present (p = 0.35 and 0.12, respectively). Nondiagnostic findings were present in 14.6% of biopsies. Independent predictors included cystic features, contrast enhancement, mass diameter and skin-to-mass distance (p <0.001, 0.002, 0.02 and 0.049, respectively). Radiologist experience was not associated with the nondiagnostic rate (p = 0.23). Prior nondiagnostic biopsy was not associated with an increased nondiagnostic rate on subsequent attempts (19.2% vs 14.2%, p = 0.23). CONCLUSIONS: Procedural complications following biopsy are rare even with low serum platelets, a mildly elevated INR or when the patient remains on aspirin. Cystic features, hypo-enhancement on imaging, a smaller mass diameter and a longer skin-to-tumor distance increase the risk of nondiagnostic findings.
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Neoplasias Renais/diagnóstico , Rim/patologia , Complicações Pós-Operatórias/epidemiologia , Idoso , Biópsia por Agulha/efeitos adversos , Biópsia por Agulha/métodos , Biópsia por Agulha/estatística & dados numéricos , Índice de Massa Corporal , Reações Falso-Negativas , Feminino , Humanos , Biópsia Guiada por Imagem/efeitos adversos , Biópsia Guiada por Imagem/métodos , Biópsia Guiada por Imagem/estatística & dados numéricos , Rim/diagnóstico por imagem , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Fatores de Risco , Tomografia Computadorizada por Raios X , Ultrassonografia de IntervençãoRESUMO
BACKGROUND: Histones undergo extensive post-translational modifications and this epigenetic regulation plays an important role in modulating transcriptional programs capable of driving cancer progression. Acetylation of histone H3K18, associated with gene activation, is enhanced by P300 and opposed by the deacetylase Sirtuin2 (SIRT2). As these enzymes represent an important target for cancer therapy, we sought to determine whether the underlying genes are altered during prostate cancer (PCa) progression. METHODS: Tissue microarrays generated from 71 radical prostatectomy patients were initially immunostained for H3K18Ac, P300 and SIRT2. Protein levels were quantified using VECTRA automation and correlated with clinicopathologic parameters. The Cancer Genome Atlas (TGCA, n = 499) and Gene Expression Omnibus (n = 504) databases were queried for expression, genomic and clinical data. Statistics were performed using SPSSv23. RESULTS: Nuclear histone H3K18Ac staining increases in primary cancer (p = 0.05) and further in metastases (p < 0.01) compared to benign on tissue arrays. P300 protein expression increases in cancer (p = 0.04) and metastases (p < 0.001). A progressive decrease in nuclear SIRT2 staining occurs comparing benign to cancer or metastases (p = 0.04 and p = 0.03 respectively). Decreased SIRT2 correlates with higher grade cancer (p = 0.02). Time to Prostate Specific Antigen (PSA) recurrence is shorter in patients exhibiting high compared to low H3K18Ac expression (350 vs. 1542 days respectively, P = 0.03). In GEO, SIRT2 mRNA levels are lower in primary and metastatic tumors (p = 0.01 and 0.001, respectively). TGCA analysis demonstrates SIRT2 deletion in 6% and increasing clinical stage, positive margins and lower PSA recurrence-free survival in patients with SIRT2 loss/deletion (p = 0.01, 0.04 and 0.04 respectively). In this dataset, a correlation between decreasing SIRT2 and increasing P300 mRNA expression occurs in tumor samples (R = -0.46). CONCLUSIONS: In multiple datasets, decreases in SIRT2 expression portend worse clinicopathologic outcomes. Alterations in SIRT2-H3K18Ac suggest altered P300 activity and identify a subset of tumors that could benefit from histone deacetylation inhibition.
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Biomarcadores Tumorais/genética , Proteína p300 Associada a E1A/metabolismo , Histonas/metabolismo , Recidiva Local de Neoplasia/mortalidade , Neoplasias da Próstata/mortalidade , Processamento de Proteína Pós-Traducional , Sirtuína 2/genética , Acetilação , Idoso , Biomarcadores Tumorais/metabolismo , Progressão da Doença , Proteína p300 Associada a E1A/genética , Epigênese Genética , Seguimentos , Histonas/química , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Deleção de Sequência , Taxa de SobrevidaRESUMO
BACKGROUND: Survival benefit from adjuvant chemotherapy is established for stage III colon cancer; however, uncertainty exists for stage II patients. Tumor heterogeneity, specifically microsatellite instability (MSI), which is more common in right-sided cancers, may be the reason for this observation. We examined the relationship between adjuvant chemotherapy and overall 5-year mortality for stage II colon cancer by location (right- vs left-side) as a surrogate for MSI. METHODS: Using Surveillance, Epidemiology, and End Results (SEER)-Medicare data, we identified Medicare beneficiaries from 1992 to 2005 with AJCC stage II (n = 23,578) and III (n = 17,148) primary adenocarcinoma of the colon who underwent surgery for curative intent. Overall 5-year mortality was examined with Kaplan-Meier survival analysis and Cox proportional hazards regression with propensity score weighting. RESULTS: It was found that 18 % of stage II patients (n = 2941) with right-sided cancer and 22 % (n = 1693) with left-sided cancer received adjuvant chemotherapy. After adjustment, overall 5-year survival benefit from chemotherapy was observed only for stage III patients (right-sided: hazard ratio [HR], 0.64; 95 % CI, 0.59-0.68; p < .001 and left-sided: HR, 0.61; 95 % CI, 0.56-0.68; p < .001). No survival benefit was observed for stage II patients with either right-sided (HR, 0.97; 95 % CI, 0.87-1.09; p = .64) or left-sided cancer (HR, 0.97; 95 % CI, 0.84-1.12; p = .68). CONCLUSIONS: Among Medicare patients with stage II colon cancer, a substantial number receive adjuvant chemotherapy. Adjuvant chemotherapy did not improve overall 5-year survival for either right- or left-sided colon cancers. Our results reinforce existing guidelines and should be considered in treatment algorithms for older adults with stage II colon cancer.
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Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Adenocarcinoma/mortalidade , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante , Colo Ascendente , Colo Descendente , Colo Sigmoide , Colo Transverso , Neoplasias do Colo/mortalidade , Feminino , Humanos , Masculino , Medicare/estatística & dados numéricos , Estadiamento de Neoplasias , Programa de SEER/estatística & dados numéricos , Taxa de Sobrevida , Estados Unidos/epidemiologiaRESUMO
Triple negative breast cancer (TNBC) presents clinical challenges due to unknown etiology, lack of treatment targets, and poor prognosis. We examined combined genetic and nutritional risk models of TNBC in 354 breast cancer cases. We evaluated 18 DNA-repair nonsynonymous single nucleotide polymorphisms (nsSNPs) and dietary/nutritional intakes. Multivariate Adaptive Regression Splines models were used to select nutrients of interest and define cut-off values for logistic regression models. Our results suggest that TNBC was associated with 6 DNA-repair nsSNPs, ERCC4 R415Q (rs1800067), MSH3 R940Q (rs184967), MSH6 G39E (rs1042821), POLD1 R119H (rs1726801), XRCC1 R194W (rs1799782), and XPC A499V (rs2228000) and/or deficiencies in 3 micronutrients (zinc, folate, and ß-carotene). Combined analyses of these 6 nsSNPs and 3 micronutrients showed significant association with TNBC: odds ratios = 2.77 (95% confidence interval = 1.01-7.64) and 10.89 (95% confidence interval = 3.50-33.89) for 2 and at least 3 risk factors, respectively. To the best of our knowledge, this is the first study to suggest that multiple genetic and nutritional factors are associated with TNBC, particularly in combination. Our findings, if validated in larger studies, will have important clinical implication that dietary modulations and/or micronutrient supplementations may prevent or reverse TNBC phenotype, so tumors can be treated with less toxic therapeutic strategies, particularly in genetically susceptible women.
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Dieta , Interação Gene-Ambiente , Neoplasias de Mama Triplo Negativas/genética , Adulto , Idoso , Estudos de Casos e Controles , Reparo do DNA , Ingestão de Energia , Feminino , Ácido Fólico/sangue , Deficiência de Ácido Fólico , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Desnutrição/sangue , Desnutrição/complicações , Micronutrientes/sangue , Micronutrientes/deficiência , Pessoa de Meia-Idade , Análise Multivariada , Avaliação Nutricional , Projetos Piloto , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Inquéritos e Questionários , Neoplasias de Mama Triplo Negativas/sangue , Neoplasias de Mama Triplo Negativas/etiologia , Zinco/sangue , Zinco/deficiência , beta Caroteno/sangue , beta Caroteno/deficiênciaRESUMO
Radiation therapy-induced acute and late effects, particularly skin toxicities, have significant impact on cancer patients' quality of life and long-term survival. To date, no effective topical agents have been routinely used in the clinical setting to prevent skin toxicity. Using SKH-hr1 hairless mice, we investigated two complementary and alternative medicine in their effects on inflammation and ionizing radiation (IR)-induced skin toxicity: Calendula officinalis (CO) and Ching Wan Hung (CWH). They were applied immediately following each IR dosing of 10 Gy/day for 4 days. Skin toxicity and inflammatory factors were evaluated at multiple time points up to 15 days post-radiation. Serum interleukin (IL)-1α, monocyte chemotactic protein-1 (MCP1), keratinocyte-derived chemokine (KC), and granulocyte colony-stimulating factor (G-CSF) were significantly induced by radiation. Both CO and CWH significantly inhibited IR-induced MCP1 (p < 0.01), KC (p < 0.05), and G-CSF (p < 0.001). IR-induced erythema and blood vessel dilation were significantly reduced by CWH (p < 0.001) but not by CO at day 10 post-IR. Both agents inhibited IR-induced IL-1α (p < 0.01), MCP1 (p < 0.05), and vascular endothelial growth factor (p < 0.05). There were continuous inhibitory effects of CWH on IR-induced skin toxicities and inflammation. In contrast, CO treatment resulted in skin reactions compared to IR alone. Our results suggest that both CO and CWH reduce IR-induced inflammation and CWH reduced IR-induced erythema. In summary, CWH showed promising effects in reducing IR-related inflammation and skin toxicities, and future proof-of-principal testing in humans will be critical in evaluating its potential application in preventing IR-induced skin toxicities.
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Terapias Complementares , Medicamentos de Ervas Chinesas/farmacologia , Lesões Experimentais por Radiação/etiologia , Lesões Experimentais por Radiação/prevenção & controle , Radioterapia/efeitos adversos , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Indutores da Angiogênese/metabolismo , Animais , Calendula/química , Dermatite/etiologia , Dermatite/metabolismo , Dermatite/prevenção & controle , Feminino , Camundongos , Neoplasias/complicações , Neoplasias/radioterapia , Lesões Experimentais por Radiação/metabolismo , Pele/lesões , Pele/patologiaRESUMO
OBJECTIVE: To evaluate rebiopsy rates and clinicopathologic outcomes in patients after a negative MRI-guided biopsy to better inform the management of these patients. METHODS: Patients were included with a clinical suspicion of prostate cancer (PCa) referred for fusion biopsy for a PI-RADS v2.1 lesion ≥ 3 on multiparametric MRI and a negative MRI fusion biopsy. Biopsies included targeted and systematic cores. Patients with a prior cancer diagnosis were excluded. Both baseline and follow-up clinicopathological data, and long-term PSA values were examined in these patients. Statistical analyses included Wilcoxon rank-sum test and one-way tests. RESULTS: Of 685 total patients, 188 (27%) had a negative fusion biopsy. Of these 88 (47%), 74 (39%), and 26 (14%) had PI-RADS 3, 4, 5 lesions, respectively. Complete follow-up was available for 182/188 patients (97%), with a median of 24 months (interquartile range: 12-38). Post-biopsy PSA levels decreased the first and the second year (-0.24; and -0.84 ng/ml/yrs respectively). In follow-up, 44 patients had an MRI (24%) and 20 had a biopsy (10%). A positive PSA velocity was the only predictive variable for repeat MRI in univariate analysis. On repeat MRI, 9 (27%) patients had disappearance of the initial lesion, 21 (48%) had a lower PIRADS score and 14 (32%) higher. Only 12/182 (6.6%) were found to have PCa during follow-up, of those 7 (3.8%) were clinically significant. CONCLUSION: For patients with nonmalignant biopsy findings after an initial mpMRI showing a suspicious PI-RADS lesion, the majority of patients will have their PSAs return to baseline over time. To support this, repeat MRI frequently demonstrated a disappearance or downgrading of PIRADS lesions. These data support monitoring patients with this clinical scenario.
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OBJECTIVE: To determine the incidence of incidental prostate cancer detection (iPCa) after holmium laser enucleation of the prostate (HoLEP). The published rate of iPCa after HoLEP is widely variable from 7% to 23% and we aim to define preoperative risk factors for iPCa to inform risk-adjusted preoperative evaluation for PCa. METHODS: Consecutive patients undergoing HoLEP from 2018 to 2022 were included and comprehensive clinical data abstracted from a prospectively maintained database. iPCa was defined as a diagnosis of PCa on pathologic examination of the HoLEP specimen. Patients with and without iPCa were compared with respect to preoperative clinical variables. RESULTS: Of 913 HoLEP patients, 183 (20%) were diagnosed with iPCa. Most patients (95%) had a preoperative prostate-specific antigen (PSA), 9% had negative MRI, and 30% had negative prostate biopsy. On multivariable analysis, PSA density (OR 1.06; 95% CI 1.03, 1.10; P < .001), preoperative biopsy status (OR 0.47, CI 0.30, 0.75; P = .002), and current 5-alpha reductase inhibitor use (OR 0.64, CI 0.43, 0.97; P = .034), were associated with iPCa diagnosis. CONCLUSION: In a significantly prescreened population, we identified a 20% rate of iPCa after HoLEP. Preoperative characteristics associated with iPCa diagnosis included increasing age, increasing PSA density, and current 5-alpha reductase inhibitor use. However, these factors alone may be of limited clinical utility to prospectively identify patients at high risk of iPCa diagnosis. We suggest and advocate for development of a standardized, risk-adapted evaluation focused on expanded use of imaging and selective biopsy to prioritize identification of clinically significant PCa prior to nononcologic surgery.
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Terapia a Laser , Lasers de Estado Sólido , Hiperplasia Prostática , Neoplasias da Próstata , Masculino , Humanos , Próstata/cirurgia , Próstata/patologia , Antígeno Prostático Específico , Hiperplasia Prostática/diagnóstico , Hiperplasia Prostática/cirurgia , Hiperplasia Prostática/complicações , Lasers de Estado Sólido/uso terapêutico , Inibidores de 5-alfa Redutase , Estudos Retrospectivos , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/cirurgia , Terapia a Laser/efeitos adversos , Terapia a Laser/métodos , Hólmio , Resultado do TratamentoRESUMO
BACKGROUND: Careful patient selection is critical when considering cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) but few studies have investigated the prognostic value of radiologic features that measure tumor burden. OBJECTIVE: To develop a prognostic model to improve CN selection with integration of common radiologic features with known prognostic factors associated with mortality in the first year following surgery. DESIGN, SETTINGS, AND PARTICIPANTS: Data were analyzed for consecutive patients with mRCC treated with upfront CN at five institutions from 2006 to 2017. Univariable and multivariable models were used to evaluate radiographic features and known risk factors for associations with overall survival. Relevant factors were used to create the SCREEN model and compared to the International mRCC Database Consortium (IMDC) model for predictive accuracy and clinical usefulness. RESULTS AND LIMITATIONS: A total of 914 patients with mRCC were treated with upfront CN during the study period. Seven independently predictive variables were used in the SCREEN score: three or more metastatic sites, total metastatic tumor burden ≥5 cm, bone metastasis, systemic symptoms, low serum hemoglobin, low serum albumin, and neutrophil/lymphocyte ratio ≥4. Predictive accuracy measured as the area under the receiver operating characteristic curves was 0.76 for the SCREEN score and 0.55 for the IMDC model. Decision curve analysis showed that the SCREEN model was useful beyond the IMDC classifier for threshold first-year mortality probabilities between 15% and 70%. CONCLUSIONS: The SCREEN score had higher predictive accuracy for first-year mortality compared to the IMDC scheme in a multi-institutional cohort and may be used to improve CN selection. PATIENT SUMMARY: This study provides a model to improve selection of patients with metastatic kidney cancer who may benefit from surgical removal of the primary kidney tumor. We found that radiographic measurements of the tumor burden predicted the risk of death in the first year after surgery. The model can be used to improve decision-making by these patients and their physicians.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/cirurgia , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/cirurgia , Procedimentos Cirúrgicos de Citorredução/métodos , Estudos Retrospectivos , Nefrectomia/métodos , Medição de RiscoRESUMO
Predicting which patients will progress to metastatic disease after surgery for non-metastatic clear cell renal cell carcinoma (ccRCC) is difficult; however, recent data suggest that tumor immune cell infiltration could be used as a biomarker. We evaluated the quantity and type of immune cells infiltrating ccRCC tumors for associations with metastatic progression following attempted curative surgery. We quantified immune cell densities in the tumor microenvironment and validated our findings in two independent patient cohorts with multi-region sampling to investigate the impact of heterogeneity on prognostic accuracy. For non-metastatic ccRCC, increased CD8+ T cell infiltration was associated with a reduced likelihood of progression to metastatic disease. Interestingly, patients who progressed to metastatic disease also had increased percentages of exhausted CD8+ T cells. Finally, we evaluated the spatial heterogeneity of the immune infiltration and demonstrated that patients without metastatic progression had CD8+ T cells in closer proximity to ccRCC cells. These data strengthen the evidence for CD8+ T cell infiltration as a prognostic biomarker in non-metastatic ccRCC and demonstrate that multi-region sampling may be necessary to fully characterize immune infiltration within heterogeneous tumors. Tumor CD8+ T cell infiltration should be investigated as a biomarker in adjuvant systemic therapy clinical trials for high-risk non-metastatic RCC.
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OBJECTIVE: To evaluate factors associated with perioperative outcomes in a multi-institutional cohort of patients treated with cytoreductive nephrectomy (CN). METHODS: Data were analyzed for metastatic renal cell carcinoma patients treated with CN at 6 tertiary academic centers from 2005 to 2019. Outcomes included: Clavien-Dindo complications, mortality, length of hospitalization, 30-day readmission rate, and time to systemic therapy. Univariate and multivariable models evaluated associations between outcomes and prognostic variables including the year of surgery. RESULTS: A total of 1272 consecutive patients were treated with CN. Patients treated in 2015-2019 vs 2005-2009 had better performance status (P<.001), higher pathologic N stage (P = .04), more frequent lymph node dissections (P<.001), and less frequent presurgical therapy (P = .02). Patients treated in 2015-2019 vs 2005-2009 had lower overall and major complications from surgery, 22% vs 39%, P<.001% and 10% vs 16%, P = .03. Mortality at 90days was higher for patients treated 2005-2009 vs 2015-2019; 10% vs 5%, P = .02. After multivariable analysis, surgical time period was an independent predictor of major complications and 90-day mortality following cytoreductive surgery. CONCLUSION: Postoperative major complications and mortality rates following CN are significantly lower in patients treated within the most recent time period.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Procedimentos Cirúrgicos de Citorredução/efeitos adversos , Prognóstico , Complicações Pós-Operatórias/etiologia , Nefrectomia/efeitos adversos , Estudos RetrospectivosRESUMO
OBJECTIVE: To evaluate the effect of intra-procedural contrast-enhanced CT (CECT) and same-session repeat ablation (SSRA) on primary efficacy, the complete eradication of tumor after the first ablation session as confirmed on first imaging follow-up, of clinically localized T1a (cT1a) renal cell carcinoma (RCC). METHODS: 398 consecutive patients with cT1a RCC were treated with cryoablation between 10/2003 and 12/2017, radiofrequency (RFA) or microwave ablation (MWA) between 1/2010 and 12/2017. SSRA was performed for residual tumor identified on intra-procedural CECT. Kruskal-Wallis and Pearson's chi-squared tests were performed to assess differences in continuous and categorical variables, respectively. Multivariate linear regression was used to determine predictors for primary efficacy and decline in estimated glomerular filtration rate. RESULTS: 347 consecutive patients (231 M, mean age 67.5 ± 9.1 years) were included. Median tumor diameter was smaller [2.5 vs 2.7 vs 2.6 (p = 0.03)] and RENAL Nephrometry Score (NS) was lower [6 vs 7 vs 7 (p = 0.009] for MWA compared to the RFA and cryoablation cohorts, respectively. Primary efficacy was higher in the MWA cohort [99.4% (170/171)] compared to the RFA [91.4% (85/93)] and cryoablation [92.8% (77/83)] cohorts (p = 0.001). Microwave ablation and SSRA was associated with higher primary efficacy on multivariate linear regression (p = 0.01-0.03). CONCLUSION: MWA augmented by SSRA, when residual tumor is identified on intra-procedural CECT, may improve primary efficacy for cT1a RCC.
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Carcinoma de Células Renais , Ablação por Cateter , Neoplasias Renais , Idoso , Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/cirurgia , Ablação por Cateter/métodos , Humanos , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Micro-Ondas/uso terapêutico , Pessoa de Meia-Idade , Neoplasia Residual , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
OBJECTIVE: To compare image quality and radiation dose between single-bolus 2-phase and split-bolus 1-phase CT Urography (CTU) performed immediately after microwave ablation (MWA) of clinically localized T1 (cT1) RCC. METHODS: Forty-two consecutive patients (30 M, mean age 67.5 ± 9.0) with cT1 RCC were treated with MWA from 7/2013 to 12/2013 at two academic quaternary-care institutions. Renal parenchymal enhancement, collecting system opacification and distention and size-specific dose estimate (SSDE) were quantified and image quality subjectively assessed on single-bolus 2-phase versus split-bolus 1-phase CTU. Kruskal-Wallis and Pearson's Chi-squared tests were performed to assess differences in continuous and categorical variables, respectively. Two-sample T test with equal variances was used to determine differences in quantitative and qualitative image data. RESULTS: Median tumor diameter was larger [2.9 cm (IQR 1.7-5.3) vs 3.6 cm (IQR 1.7-5.7), p = 0.01] in the split-bolus cohort. Mean abdominal girth (p = 0.20) was similar. Number of antennas used and unenhanced CTs obtained before and during MWA were similar (p = 0.11-0.32). Renal pelvis opacification (2.5 vs 3.5, p < 0.001) and distention (4 mm vs 8 mm, p < 0.001) were improved and renal enhancement (Right: 127 HU vs 177 HU, p = 0.001; Left: 124 HU vs 185 HU, p < 0.001) was higher for the split-bolus CTU. Image quality was superior for split-bolus CTU (3.2 vs 4.0, p = 0.004). Mean SSDE for the split-bolus CTU was significantly lower [163.9 mGy (SD ± 73.9) vs 36.3 mGy (SD ± 7.7), p < 0.001]. CONCLUSION: Split-bolus CTU immediately after MWA of cT1 RCC offers higher image quality, improved opacification/distention of the collecting system and renal parenchymal enhancement at a lower radiation dose.
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Carcinoma de Células Renais , Neoplasias Renais , Exposição à Radiação , Idoso , Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/cirurgia , Meios de Contraste , Feminino , Humanos , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/cirurgia , Masculino , Micro-Ondas/uso terapêutico , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X/métodos , Urografia/métodosRESUMO
Defective DNA repair may contribute to early age and late stage at time of diagnosis and mutations in critical tumor suppressor genes, such as TP53 in breast cancer. Using DNA samples from 436 breast cancer cases (374 Caucasians and 62 African-Americans), we tested these associations with 18 non-synonymous single-nucleotide polymorphisms (nsSNPs) in four DNA repair pathways: (i) base excision repair: ADPRT V762A, APE1 D148E, XRCC1 R194W/R280H/R399Q and POLD1 R119H; (ii) double-strand break repair: NBS1 E185Q and XRCC3 T241M; (iii) mismatch repair: MLH1 I219V, MSH3 R940Q/T1036A and MSH6 G39E and (iv) nucleotide excision repair: ERCC2 D312N/K751Q, ERCC4 R415Q, ERCC5 D1104H and XPC A499V/K939Q. Younger age at diagnosis (<50) was associated with ERCC2 312 DN/NN genotypes [odds ratio (OR) = 1.76; 95% confidence interval (CI) = 1.10, 2.81] and NBS1 185 QQ genotype (OR = 3.09; 95% CI = 1.47, 6.49). The XPC 939 QQ genotype was associated with TP53 mutations (OR = 5.80; 95% CI = 2.23, 15.09). There was a significant trend associating younger age at diagnosis (<50) with increasing numbers of risk genotypes for ERCC2 312 DN/NN, MSH6 39 EE and NBS1 185 QQ (P(trend) < 0.001). A similar significant trend was also observed associating TP53 mutations with increasing numbers of risk genotypes for XRCC1 399 QQ, XPC 939 QQ, ERCC4 415 QQ and XPC 499 AA (P(trend) < 0.001). Our pilot data suggest that nsSNPs of multiple DNA repair pathways are associated with younger age at diagnosis and TP53 mutations in breast cancer and larger studies are warranted to further evaluate these associations.
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Neoplasias da Mama/genética , Reparo do DNA , Genes p53 , Mutação , Polimorfismo Genético , Adulto , Fatores Etários , Idoso , Índice de Massa Corporal , Neoplasias da Mama/patologia , Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Proteína 1 Complementadora Cruzada de Reparo de Raio-XRESUMO
BACKGROUND: In this study, we pilot tested an in vitro assay of cancer killing activity (CKA) in circulating leukocytes of 22 cancer cases and 25 healthy controls. METHODS: Using a human cervical cancer cell line, HeLa, as target cells, we compared the CKA in circulating leukocytes, as effector cells, of cancer cases and controls. The CKA was normalized as percentages of total target cells during selected periods of incubation time and at selected effector/target cell ratios in comparison to no-effector-cell controls. RESULTS: Our results showed that CKA similar to that of our previous study of SR/CR mice was present in human circulating leukocytes but at profoundly different levels in individuals. Overall, males have a significantly higher CKA than females. The CKA levels in cancer cases were lower than that in healthy controls (mean ± SD: 36.97 ± 21.39 vs. 46.28 ± 27.22). Below-median CKA was significantly associated with case status (odds ratio = 4.36; 95% Confidence Interval = 1.06, 17.88) after adjustment of gender and race. CONCLUSIONS: In freshly isolated human leukocytes, we were able to detect an apparent CKA in a similar manner to that of cancer-resistant SR/CR mice. The finding of CKA at lower levels in cancer patients suggests the possibility that it may be of a consequence of genetic, physiological, or pathological conditions, pending future studies with larger sample size.
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Prostate cancer (PC) development involves epigenetic DNA methylation changes that occur in the tumor. However, distinct DNA methylation changes have been previously found to encompass a widespread cancer field defect involving normal prostate tissue. In the current study, we analyzed a series of DNA methylation field markers to determine if they predict the presence of PC in urine. Urine samples were collected from patients undergoing prostate biopsy with biopsy-proven PC (90), and without PC (77). From the urine pellet, methylated DNA was quantified across several previously identified CpG island regions near the caveolin 1 (CAV1), even-skipped homeobox 1 (EVX1), fibroblast growth factor 1 (FGF1), natural cytotoxicity triggering receptor 2 (NCR2) and phospholipase A and acyltransferase 3 (PLA2G16) genes using bisulfite pyrosequencing. Univariate and multivariate analyses were performed. Urine cell pellets show significant increases in methylation in four of the markers from patients with PC compared to those without PC including EVX1 12.2 vs. 7.7%, CAV1 15.7 vs. 10.36%, FGF1 12.0 vs. 7.1%, and PLA2G16 12.2 vs. 8.3% [all P<0.01]. Area under the ROC Curve (AUCs) were generated for EXV1 (0.74, Odds ratios (OR) 1.09; 95% confidence intervals (CI) 0.94-1.25, CAV1 (0.72, OR 1.18; 95% CI 1.09-1.28) and PLA2G16 (0.76, OR 1.35; 95% CI 1.199-1.51). In combination, a two-marker assay performs better than prostate specific antigen (PSA), AUC 0.77 vs. PSA AUC of 0.6 (P = 0.01) with the lowest error. In addition, FGF1 distinguished between grade group 1 (GG1) and higher grade cancers (P<0.03). In conclusion, applying methylation of field defect loci to urine samples provides a novel approach to distinguish patients with and without cancer.
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Epidural anesthesia is used to improve pain control after major surgeries. Few data describe the impact of epidural use for bladder cancer patients treated with radical cystectomy (RC). Here, we evaluate epidural use on perioperative and long-term outcomes for patients treated with radical cystectomy for bladder cancer. Patients who received radical cystectomy for non-metastatic bladder urothelial carcinoma with epidural (n=1,748) and without epidural (n=6,109) anesthesia from 2002-2014 were identified using Surveillance, Epidemiology and End Results-Medicare data. Radical cystectomy outcomes with and without epidural anesthesia were compared using propensity score weighting. Epidural use at time of radical cystectomy was identified in 1,748 (22.2%) of 7,857 patients who met inclusion criteria. After propensity score weighted adjustment, epidural use was associated with increased 30-day readmission (29.6% vs. 26.2%, P<0.001), increased median length of stay in days (9.0, IQR 7.0-12.0 vs 8.0, IQR 6.0-12.0, P<0.01), and decreased likelihood of being discharged directly to home without need for home health or skilled nursing care (21.6% vs 29.1%, P<0.001). Post-operative MI (2.6% vs 1.3%, P<0.001) in the first 30 days after radical cystectomy was more common in the epidural group, but perioperative 30-day mortality was similar (3.3% vs 2.9%, P=0.21). Epidural use was not associated with increased cancer specific (HR 0.96, 0.90-1.02, P=0.20) or overall survival (HR 0.99, 0.95-1.04, P=0.73). Epidural use at time of radical cystectomy is associated with increased risk of perioperative complications, hospital readmission, and longer hospitalization without improving disease specific survival. Prospective studies are needed to confirm these findings.
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OBJECTIVE: To compare perioperative and oncologic outcomes for patients with clinical T1b renal cell carcinoma following treatment with microwave ablation (MW), partial nephrectomy (PN), or radical nephrectomy (RN). METHODS: Comprehensive clinical and pathologic data were collected for nonmetastatic renal cell carcinoma patients with cT1b tumors following MW, PN, or RN from 2000 to 2018. Local recurrence-free, metastasis-free, cancer-specific and overall survival were estimated using Kaplan-Meier method. Prognostic factors for complications and survival were determined using logistic regression and Cox hazard models, respectively. RESULTS: A total of 325 patients (40 MW, 74 PN, and 211 RN) were identified. Patients treated with MW were older with higher Charlson comorbidity indices compared to surgical patients. Median length of hospitalization was shorter for MW compared to surgical patients (1 day vs 4 days, P <.0001). Post-treatment estimated glomerular filtration rate decreased by median 4.5% for MW compared to 3.2% for PN (Pâ¯=â¯.58) and 29% for RN (P <.001). Median follow-up was 34, 35, and 49 months following MW, PN, and RN, respectively. Estimated 5-year local recurrence-free survival was 94.5% for MW vs 97.9% for PN (Pâ¯=â¯.34) and 99.2% for RN (Pâ¯=â¯.02). Two patients recurred after MW and underwent repeat ablation without subsequent recurrence. No difference in 5-year metastasis-free survival or cancer-specific survival was found among MW, PN, or RN. Four (10%) MW patients had high-grade complication. Only prior abdominal surgery predicted high-grade complication (OR 6.29, Pâ¯=â¯.017). CONCLUSION: Microwave ablation is a feasible alternative to surgery in select comorbid patients with clinical T1b renal cell carcinoma.
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Carcinoma de Células Renais/cirurgia , Neoplasias Renais/cirurgia , Recidiva Local de Neoplasia/cirurgia , Nefrectomia/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Ablação por Radiofrequência/efeitos adversos , Idoso , Carcinoma de Células Renais/mortalidade , Intervalo Livre de Doença , Estudos de Viabilidade , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/mortalidade , Masculino , Micro-Ondas/uso terapêutico , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/prevenção & controle , Estadiamento de Neoplasias , Nefrectomia/métodos , Complicações Pós-Operatórias/etiologia , Ablação por Radiofrequência/métodos , Reoperação/estatística & dados numéricosRESUMO
OBJECTIVE: To evaluate postoperative recurrence patterns for high-risk nonmetastatic renal cell carcinoma (RCC) and to identify prognostic factors associated with site-specific metastatic recurrence using a multi-institutional contemporary cohort. METHODS: Data for nonmetastatic ≥pT3a RCC patients treated with surgery at 4 independent centers was analyzed. Initial recurrence locations were identified, and imaging templates were defined by anatomic landmarks using radiologic definitions. Prognostic factors for site specific recurrence were evaluated with univariate and multivariable analyses. RESULTS: A total of 1057 patients were treated surgically for ≥pT3a RCC. Initial recurrence location was in a single site for 160 (59.3%) patients and at multiple locations in 110 (41.7%) patients. The most common sites of metastatic recurrence were lung (144/270, 53.3%), liver (54/270, 20.0%), and bone (48/270, 17.8%). Recurrence was identified in 52 of 270 (19.3%) patients outside the chest/abdomen template, most commonly in the pelvis (25/270, 9.3%). Bone and brain metastases were the most common organs for metastases outside chest/abdomen. Patients with tumor diameter >10 cm and grade 4 were more likely to recur in the bone (HR 3.61, P <.001) and brain (HR 16.5, P <.001). CONCLUSION: Metastatic progression outside chest/abdomen imaging templates was present in 1 of 5 high risk patients at initial metastatic RCC diagnosis, most commonly in the pelvis. Patients with large (>10 cm) tumors and grade 4 histology are at highest risk for bone and brain metastases.