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BACKGROUND: Ultra-hypofractionated image-guided stereotactic body radiotherapy (SBRT) is increasingly used for definitive treatment of localized prostate cancer. Magnetic resonance imaging-guided radiotherapy (MRgRT) facilitates improved visualization, real-time tracking of targets and/or organs-at-risk (OAR), and capacity for adaptive planning which may translate to improved targeting and reduced toxicity to surrounding tissues. Given promising results from NRG-GU003 comparing conventional and moderate hypofractionation in the post-operative setting, there is growing interest in exploring ultra-hypofractionated post-operative regimens. It remains unclear whether this can be done safely and whether MRgRT may help mitigate potential toxicity. SHORTER (NCT04422132) is a phase II randomized trial prospectively evaluating whether salvage MRgRT delivered in 5 fractions versus 20 fractions is non-inferior with respect to gastrointestinal (GI) and genitourinary (GU) toxicities at 2-years post-treatment. METHODS: A total of 136 patients will be randomized in a 1:1 ratio to salvage MRgRT in 5 fractions or 20 fractions using permuted block randomization. Patients will be stratified according to baseline Expanded Prostate Cancer Index Composite (EPIC) bowel and urinary domain scores as well as nodal treatment and androgen deprivation therapy (ADT). Patients undergoing 5 fractions will receive a total of 32.5 Gy over 2 weeks and patients undergoing 20 fractions will receive a total of 55 Gy over 4 weeks, with or without nodal coverage (25.5 Gy over 2 weeks and 42 Gy over 4 weeks) and ADT as per the investigator's discretion. The co-primary endpoints are change scores in the bowel and the urinary domains of the EPIC. The change scores will reflect the 2-year score minus the pre-treatment (baseline) score. The secondary endpoints include safety endpoints, including change in GI and GU symptoms at 3, 6, 12 and 60 months from completion of treatment, and efficacy endpoints, including time to progression, prostate cancer specific survival and overall survival. DISCUSSION: The SHORTER trial is the first randomized phase II trial comparing toxicity of ultra-hypofractionated and hypofractionated MRgRT in the salvage setting. The primary hypothesis is that salvage MRgRT delivered in 5 fractions will not significantly increase GI and GU toxicities when compared to salvage MRgRT delivered in 20 fractions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04422132. Date of registration: June 9, 2020.
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Neoplasias da Próstata , Radioterapia Guiada por Imagem , Masculino , Humanos , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/radioterapia , Antagonistas de Androgênios , Imageamento por Ressonância Magnética , Radioterapia Guiada por Imagem/efeitos adversos , PróstataRESUMO
With the spring-block model proposed by Olami, Feder, and Christensen (OFC), we obtained a time series of synthetic earthquakes with different values of the conservation level (ß), which measures the fraction of the energy that a relaxing block passes to its neighbors. The time series have multifractal characteristics, and we analyzed them with the Chhabra and Jensen method. We calculated the width, symmetry, and curvature parameters for each spectrum. As the value of conservation level increases, the spectra widen, the symmetric parameter increases, and the curvature around the maximum of the spectra decreases. In a long series of synthetic seismicity, we located earthquakes of the greatest magnitude and built overlapping windows before and after them. For the time series in each window, we performed multifractal analysis to obtain multifractal spectra. We also calculated the width, symmetry, and curvature around the maximum of the multifractal spectrum. We followed the evolution of these parameters before and after large earthquakes. We found that the multifractal spectra had greater widths, were less skewed to the left, and were very pointed around the maximum before rather than after large earthquakes. We studied and calculated the same parameters and found the same results in the analysis of the Southern California seismicity catalog. This suggests that there seems to be a process of preparation for a great earthquake and that its dynamics are different from the one that occurs after this mainshock based on the behavior of the parameters mentioned before.
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OBJECTIVES: The non-randomised, open-label, phase IIIb/IV multicohort CheckMate 920 trial explored the safety and efficacy with a less frequent, but continual nivolumab plus ipilimumab (NIVO+IPI) dosing regimen (cohort 1) to determine whether this modification could potentially retain efficacy benefits while improving on the manageable safety profile previously observed with this combination in patients with advanced renal cell carcinoma (aRCC). SETTING: Patients were enrolled from 48 largely community-based sites in the USA. PARTICIPANTS: 106 patients with previously untreated, predominantly clear cell aRCC received treatment. INTERVENTIONS: Patients received NIVO 6 mg/kg plus IPI 1 mg/kg on day 1 of the first week of each 8-week cycle; the combination alternated with NIVO 480 mg monotherapy on day 1 of the fifth week of each 8-week cycle. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent or study end. The maximum treatment duration was 2 years. The primary endpoint was the incidence of high-grade (grade 3/4 and grade 5) immune-mediated adverse events (IMAEs) within 100 days of the last dose. Select secondary endpoints included time to onset and resolution of high-grade IMAEs, progression-free survival (PFS) and objective response rate (ORR). The incidence of treatment-related adverse events and the overall survival (OS) were the exploratory endpoints. RESULTS: The most common grade 3/4 IMAEs were diarrhoea/colitis (7.5%) and rash (6.6%) and no grade 5 IMAEs occurred, with a minimum follow-up of 28.5 months. The median PFS was 4.8 (95% CI 3.0 to 8.3) months, the ORR in evaluable patients (n=96) was 34.4% (95% CI 25.0 to 44.8), and the median OS was not reached (95% CI 24.8 months to not estimable). CONCLUSIONS: While no new safety signals were reported with less frequent, but continual NIVO+IPI dosing in CheckMate 920, the modified regimen was not associated with clinical benefits relative to the approved NIVO+IPI dose. These results support the continued use of the currently approved NIVO+IPI combination dosing schedule for patients with aRCC. TRIAL REGISTRATION NUMBER: NCT02982954.
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Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células Renais , Neoplasias Renais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Humanos , Ipilimumab/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Nivolumabe/uso terapêuticoRESUMO
PURPOSE: To provide recommendations for the management of patients with metastatic clear cell renal cell carcinoma (ccRCC). METHODS: An Expert Panel conducted a systematic literature review to obtain evidence to guide treatment recommendations. RESULTS: The panel considered peer-reviewed reports published in English. RECOMMENDATIONS: The diagnosis of metastatic ccRCC should be made using tissue biopsy of the primary tumor or a metastatic site with the inclusion of markers and/or stains to support the diagnosis. The International Metastatic RCC Database Consortium risk criteria should be used to inform treatment. Cytoreductive nephrectomy may be offered to select patients with kidney-in-place and favorable- or intermediate-risk disease. For those who have already had a nephrectomy, an initial period of active surveillance may be offered if they are asymptomatic with a low burden of disease. Patients with favorable-risk disease who need systemic therapy may be offered an immune checkpoint inhibitor (ICI) in combination with a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI); patients with intermediate or poor risk should be offered a doublet regimen (no recommendation was provided between ICIs or an ICI in combination with a VEGFR TKI). For select patients, monotherapy with either an ICI or a VEGFR TKI may be offered on the basis of comorbidities. Interleukin-2 remains an option, although selection criteria could not be identified. Recommendations are also provided for second- and subsequent-line therapy as well as the treatment of bone metastases, brain metastases, or the presence of sarcomatoid features. Participation in clinical trials is highly encouraged for patients with metastatic ccRCC.Additional information is available at www.asco.org/genitourinary-cancer-guidelines.
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Carcinoma de Células Renais , Neoplasias Renais , Inibidores da Angiogênese/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Fator A de Crescimento do Endotélio VascularRESUMO
Primary clear cell renal cell carcinoma (ccRCC) has been previously characterized, but the genomic landscape of metastatic ccRCC is largely unexplored. Here, we performed whole exome sequencing (WES) in 68 samples from 44 patients with ccRCC, including 52 samples from a metastatic site. SETD2, PBRM1, APC and VHL were the most frequently mutated genes in the metastatic ccRCC cohort. RBM10 and FBXW7 were also among the 10 most frequently mutated genes in metastatic tissues. Recurrent somatic copy number variations (CNV) were observed at the previously identified regions 3p25, 9p21 and 14q25, but also at 6p21 (CDKN1A) and 13q14 (RB1). No statistically significant differences were found between samples from therapy-naïve and pretreated patients. Clonal evolution analyses with multiple samples from 13 patients suggested that early appearance of CNVs at 3p25, 9p21 and 14q25 may be associated with rapid clinical progression. Overall, the genomic landscapes of primary and metastatic ccRCC seem to share frequent CNVs at 3p25, 9p21 and 14q25. Future work will clarify the implication of RBM10 and FBXW7 mutations and 6p21 and 13q14 CNVs in metastatic ccRCC.
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Carcinoma de Células Renais , Neoplasias Renais , Carcinoma de Células Renais/patologia , Variações do Número de Cópias de DNA/genética , Proteína 7 com Repetições F-Box-WD/genética , Genômica , Humanos , Neoplasias Renais/patologia , Mutação/genética , Proteínas Nucleares/metabolismo , Proteínas de Ligação a RNA/genéticaRESUMO
BACKGROUND: Targeted sequencing of circulating tumour DNA (ctDNA) is a promising tool to monitor dynamic changes in the variant allele frequencies (VAF) of genomic alterations and predict clinical outcomes in patients with advanced urothelial carcinoma (UC). METHODS: We performed targeted sequencing of 182 serial ctDNA samples from 53 patients with advanced UC. RESULTS: Serial ctDNA-derived metrics predicted the clinical outcomes in patients with advanced UC. Combining serial ctDNA aggregate VAF (aVAF) values with clinical factors, including age, sex, and liver metastasis, improved the performance of prognostic models. An increase of the ctDNA aVAF by ≥1 in serial ctDNA samples predicted disease progression within 6 months in 90% of patients. The majority of patients with aVAFs ≤0.7 in three consecutive ctDNA samples achieved durable clinical responses (≥6 months). CONCLUSIONS: Serial ctDNA analysis predicts disease progression and enables dynamic monitoring to guide precision medicine in patients with advanced UC.
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Biomarcadores Tumorais/genética , Carcinoma de Células de Transição/patologia , DNA Tumoral Circulante/genética , Mutação , Medicina de Precisão/métodos , Neoplasias da Bexiga Urinária/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Carcinoma de Células de Transição/sangue , Carcinoma de Células de Transição/genética , DNA Tumoral Circulante/sangue , Progressão da Doença , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Neoplasias da Bexiga Urinária/sangue , Neoplasias da Bexiga Urinária/genéticaRESUMO
BACKGROUND: Nivolumab plus ipilimumab (NIVO + IPI) has demonstrated long-term efficacy and safety in patients with previously untreated, advanced renal cell carcinoma (aRCC). Although most phase 3 clinical trials exclude patients with brain metastases, the ongoing, multicohort phase 3b/4 CheckMate 920 trial (ClincalTrials.gov identifier NCT02982954) evaluated the safety and efficacy of NIVO + IPI in a cohort that included patients with aRCC and brain metastases, as reported here. METHODS: Patients with previously untreated aRCC and asymptomatic brain metastases received NIVO 3 mg/kg plus IPI 1 mg/kg every 3 weeks × 4 followed by NIVO 480 mg every 4 weeks. The primary end point was the incidence of grade ≥3 immune-mediated adverse events (imAEs) within 100 days of the last dose of study drug. Key secondary end points were progression-free survival and the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1 (both determined by the investigator). Exploratory end points included overall survival, among others. RESULTS: After a minimum follow-up of 24.5 months (N = 28), no grade 5 imAEs occurred. The most common grade 3 and 4 imAEs were diarrhea/colitis (n = 2; 7%) and hypophysitis, rash, hepatitis, and diabetes mellitus (n = 1 each; 4%). The objective response rate was 32% (95% CI, 14.9%-53.5%) with a median duration of response of 24.0 months; 4 of 8 responders remained without reported progression. Seven patients (25%) had intracranial progression. The median progression-free survival was 9.0 months (95% CI, 2.9-12.0 months), and the median overall survival was not reached (95% CI, 14.1 months to not estimable). CONCLUSIONS: In patients who had previously untreated aRCC and brain metastases-a population with a high unmet medical need that often is underrepresented in clinical trials-the approved regimen of NIVO + IPI followed by NIVO showed encouraging antitumor activity and no new safety signals.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Encefálicas , Carcinoma de Células Renais , Neoplasias Renais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Estudos de Coortes , Humanos , Ipilimumab/efeitos adversos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Nivolumabe/efeitos adversosRESUMO
INTRODUCTION: The Metastatic Renal Cell Carcinoma (MaRCC) Registry provides prospective data on real-world treatment patterns and outcomes in patients with metastatic renal cell carcinoma (mRCC). METHODS AND MATERIALS: Patients with mRCC and no prior systemic therapy were enrolled at academic and community sites. End of study data collection was in March 2019. Outcomes included overall survival (OS). A survey of treating physicians assessed reasons for treatment initiations and discontinuations. RESULTS: Overall, 376 patients with mRCC initiated first-line therapy; 171 (45.5%) received pazopanib, 75 (19.9%) sunitinib, and 74 (19.7%) participated in a clinical trial. Median (95% confidence interval) OS was longest in the clinical trial group (50.3 [35.8-not reached] months) versus pazopanib (39.0 [29.7-50.9] months) and sunitinib 26.2 [19.9-61.5] months). Non-clear cell RCC (21.5% of patients) was associated with worse median OS than clear cell RCC (18.0 vs. 47.3 months). Differences in baseline characteristics, treatment starting dose, and relative dose exposure among treatment groups suggest selection bias. Survey results revealed a de-emphasis on quality of life, toxicity, and patient preference compared with efficacy in treatment selection. CONCLUSION: The MaRCC Registry gives insights into real-world first-line treatment selection, outcomes, and physician rationale regarding initial treatment selection prior to the immunotherapy era. Differences in outcomes between clinical trial and off-study patients reflect the difficulty in translating trial results to real-world patients, and emphasize the need to broaden clinical trial eligibility. Physician emphasis on efficacy over quality of life and toxicity suggests more data and education are needed regarding these endpoints.
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Carcinoma de Células Renais , Neoplasias Renais , Carcinoma de Células Renais/patologia , Feminino , Humanos , Imunoterapia , Indazóis/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Masculino , Estudos Prospectivos , Qualidade de Vida , Sistema de Registros , Estudos Retrospectivos , Sunitinibe/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Characterization of circulating tumor DNA (ctDNA) has been integrated into clinical practice. Although labs have standardized validation procedures to develop single locus tests, the efficacy of on-site plasma-based next-generation sequencing (NGS) assays still needs to be proved. MATERIALS AND METHODS: In this retrospective study, we profiled DNA from matched tissue and plasma samples from 75 patients with cancer. We applied an NGS test that detects clinically relevant alterations in 33 genes and microsatellite instability (MSI) to analyze plasma cell-free DNA (cfDNA). RESULTS: The concordance between alterations detected in both tissue and plasma samples was higher in patients with metastatic disease. The NGS test detected 77% of sequence alterations, amplifications, and fusions that were found in metastatic samples compared with 45% of those alterations found in the primary tumor samples (p = .00005). There was 87% agreement on MSI status between the NGS test and tumor tissue results. In three patients, MSI-high ctDNA correlated with response to immunotherapy. In addition, the NGS test revealed an FGFR2 amplification that was not detected in tumor tissue from a patient with metastatic gastric cancer, emphasizing the importance of profiling plasma samples in patients with advanced cancer. CONCLUSION: Our validation experience of a plasma-based NGS assay advances current knowledge about translating cfDNA testing into clinical practice and supports the application of plasma assays in the management of oncology patients with metastatic disease. With an in-house method that minimizes the need for invasive procedures, on-site cfDNA testing supplements tissue biopsy to guide precision therapy and is entitled to become a routine practice. IMPLICATIONS FOR PRACTICE: This study proposes a solution for decentralized liquid biopsy testing based on validation of a next-generation sequencing (NGS) test that detects four classes of genomic alterations in blood: sequence mutations (single nucleotide substitutions or insertions and deletions), fusions, amplifications, and microsatellite instability (MSI). Although there are reference labs that perform single-site comprehensive liquid biopsy testing, the targeted assay this study validated can be established locally in any lab with capacity to offer clinical molecular pathology assays. To the authors' knowledge, this is the first report that validates evaluating an on-site plasma-based NGS test that detects the MSI status along with common sequence alterations encountered in solid tumors.
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DNA Tumoral Circulante , Neoplasias , DNA Tumoral Circulante/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Instabilidade de Microssatélites , Neoplasias/genética , Estudos RetrospectivosRESUMO
Human exposure to bisphenol-A (BPA) is largely unavoidable because BPA is an environmental contaminant found in soil, water, food and indoor dust. The safety of authorized BPA amounts in consumer products is under question because new studies have reported adverse effects of BPA at doses far below that previously established by the NOAEL (50 µg/kg per day). To protect public health, the consequences of low-dose BPA exposure in different organs and organismal functions must be further studied to generate relevant data. This study attempted to investigate the effects and potential molecular mechanisms of short-term exposure to 1 µg/L BPA on zebrafish ovarian follicular development. We observed only minor changes at the histopathological level with a small (3 %) increase in follicular atresia. However, a shotgun proteomics approach indicated deep alterations in BPA-exposed ovarian cells, including induction of the oxidative stress response, metabolic shifts and degradome perturbations, which could drive oocytes towards premature maturation. Based on these results, it could be suggested that inadvertent exposure to small concentrations of BPA on a continuous basis causes alteration in biological processes that are essential for healthy reproduction.
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Compostos Benzidrílicos/toxicidade , Ovário/efeitos dos fármacos , Fenóis/toxicidade , Proteômica/métodos , Animais , Compostos Benzidrílicos/administração & dosagem , Metilação de DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Ovário/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fenóis/administração & dosagem , Proteostase/efeitos dos fármacos , Peixe-ZebraRESUMO
BACKGROUND: Non-clear cell renal cell carcinoma (nccRCC) accounts for ≤20% of RCC cases. Lenvatinib (a multitargeted tyrosine kinase inhibitor) in combination with everolimus (an mTOR inhibitor) is approved for the treatment of advanced RCC after one prior antiangiogenic therapy. OBJECTIVE: To determine the safety and efficacy of lenvatinib plus everolimus as a first-line treatment for patients with advanced nccRCC. DESIGN, SETTING, AND PARTICIPANTS: This open-label, single-arm, multicenter, phase 2 study enrolled patients with unresectable advanced or metastatic nccRCC and no prior anticancer therapy for advanced disease. INTERVENTION: Lenvatinib (18 mg) plus everolimus (5 mg) orally once daily. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was the objective response rate (ORR) as assessed by investigators according to Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety assessments. The 95% confidence intervals (CIs) for ORRs were calculated using the two-sided Clopper-Pearson method. Median PFS and median OS were estimated using the Kaplan-Meier product-limit method and their 95% CIs were estimated via a generalized Brookmeyer and Crowley method. RESULTS AND LIMITATIONS: The study (start date: February 20, 2017) enrolled 31 patients with nccRCC (papillary, n = 20; chromophobe, n = 9; unclassified, n = 2). At the data cutoff date (July 17, 2019), the best overall response was a partial response (eight patients: papillary, n = 3; chromophobe, n = 4; unclassified, n = 1) for an overall ORR of 26% (95% CI 12-45). Median PFS was 9.2 mo (95% CI 5.5-not estimable), and median OS was 15.6 mo (95% CI 9.2-not estimable). The most common treatment-emergent adverse events were fatigue (71%), diarrhea (58%), decreased appetite (55%), nausea (55%), and vomiting (52%). Limitations include the small sample size and single-arm design. CONCLUSIONS: Lenvatinib plus everolimus showed promising anticancer activity in patients with advanced nccRCC with an ORR of 26% and is worthy of further study. The safety profile was consistent with the established profile of the study-drug combination. PATIENT SUMMARY: We examined the combination of lenvatinib plus everolimus as the first therapy for 31 patients who had advanced nccRCC. We found that this treatment seemed effective, because most patients had a decrease in tumor size and manageable treatment-related side effects. CLINICAL REGISTRATION: This trial is registered at ClinicalTrials.Gov as NCT02915783.
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Carcinoma de Células Renais , Neoplasias Renais , Carcinoma de Células Renais/tratamento farmacológico , Everolimo/efeitos adversos , Humanos , Neoplasias Renais/tratamento farmacológico , Compostos de Fenilureia , QuinolinasRESUMO
BACKGROUND: Systemic therapy (ST) can be deferred in patients who have metastatic renal cell carcinoma (mRCC) and slow-growing metastases. Currently, this subset of patients managed with active surveillance (AS) is not well described in the literature. METHODS: This was a prospective observational study of patients with mRCC across 46 US community and academic centers. The objective was to describe baseline characteristics and demographics of patients with mRCC initially managed by AS, reasons for AS, and patient outcomes. Descriptive statistics were used to characterize demographics, baseline characteristics, and patient-related outcomes. Wilcoxon 2-sample rank-sum tests and χ2 tests were used to assess differences between ST and AS cohorts in continuous and categorical variables, respectively. Kaplan-Meier survival curves were used to assess survival. RESULTS: Of 504 patients, mRCC was initially managed by AS (n = 143) or ST (n = 305); 56 patients were excluded from the analysis. Disease was present in 69% of patients who received AS, whereas the remaining 31% had no evidence of disease. At data cutoff, 72 of 143 patients (50%) in the AS cohort had not received ST. The median overall survival was not reached (95% CI, 122 months to not estimable) in patients who received AS versus 30 months (95% CI, 25-44 months) in those who received ST. Quality of life at baseline was significantly better in patients who were managed with AS versus ST. CONCLUSIONS: AS occurs frequently (32%) in real-world clinical practice and appears to be a safe and appropriate alternative to immediate ST in selected patients.
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Carcinoma de Células Renais , Neoplasias Renais , Carcinoma de Células Renais/patologia , Humanos , Neoplasias Renais/patologia , Qualidade de Vida , Estudos Retrospectivos , Resultado do Tratamento , Conduta ExpectanteRESUMO
BACKGROUND: Prostate-specific membrane antigen (PSMA) imaging has been suggested as highly sensitive modality for detection of metastases in patients with biochemically recurrent or advanced prostate cancer (PCa). PSMA expression is associated with grade and stage and has a relationship with androgen receptor signaling. The aim of this study was to evaluate the prognostic utility of radiographic PSMA expression in men with metastatic castration-resistant prostate cancer (mCRPC). METHODS: Patients with mCRPC and available baseline PSMA imaging were studied. Images by planar/single-photon emission computed tomography (SPECT) or positron emission tomography (PET)/CT were reviewed. Planar/SPECT images were scored semi-quantitatively and PET/CT scored quantitatively with comparison of tumor uptake to liver uptake on a scale of 0-4 in order to determine an imaging score (IS). The IS (high: 2-4 versus low: 0-1), subsequent receipt of life-prolonging systemic therapies (taxane chemotherapy, potent androgen receptor pathway inhibitors, sipuleucel-T, and radium-223), and the CALGB prognostic risk stratification of patients were analyzed according to overall survival (OS) in univariate and multivariate Cox's proportional hazards models. RESULTS: High PSMA expression (IS 2-4) was found in 179 (75.21%) patients, and 59 (24.79%) patients had low PSMA uptake. The median OS of the entire cohort was 16.8 (95%CI: 14.9-19.3) months. Patients with a high IS had a significantly shorter OS of 15.8 (95%CI 13.0-18.1) months compared to those with low expression [22.7 (95%CI: 17.7-30.7) months, p = 0.002]. After accounting for use of life-prolonging therapies (p<0.001) and CALGB prognostic groups (p = 0.001), high PSMA IS emerged as an independent prognostic factor for OS [HR(95%CI): 1.7 (1.2-2.2); p = 0.003]. CONCLUSION: Presence of high radiographic PSMA expression on SPECT or PET/CT may portend a poor prognosis in patients with mCRPC treated with standard systemic therapies. This provides implications for therapeutic targeting of PSMA-avid disease as a means to improve outcomes.
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BACKGROUND: Prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy (TRT) has demonstrated efficacy and tolerability with a dose-response effect in phase I/II trials in men with metastatic castration-resistant prostate cancer (mCRPC). The need for positive PSMA imaging before PSMA-TRT to select patients is largely practiced, but its utility is not proven. Given target heterogeneity, developing a biomarker to identify the optimal patient population remains an unmet need. The aim of this study was to assess PSMA uptake by imaging and response to PSMA-TRT. METHODS: We performed an analysis of men with mCRPC enrolled in sequential prospective phase I/II trials of PSMA-TRT. Each patient had baseline PSMA imaging by planar 111 In and/or 177 Lu SPECT (N = 171) or 68 Ga-PSMA-11 PET/CT (N = 44), but the results were not used to include/exclude treatment. Semiquantitative imaging scores (IS) on a 0-4 scale were assigned based on PSMA uptake in tumors compared to liver uptake. We compared the ≥50% PSA decline response proportions between low (0-1) and high (2-4) PSMA IS using the χ2 -test. We used multivariable logistic regression analysis to understand the relationship between independent and dependent variables, including IS, radionuclide activity (dose) administered, CALGB (Halabi) prognostic risk score, prior taxane use. RESULTS: 215 men with progressive mCRPC received PSMA-TRT as follows: 177 Lu-J591 (n = 137), 177 Lu-PSMA-617 (n = 44), 90 Y-J591 (n = 28), 177 Lu-J591 + 177 Lu-PSMA-617 (n = 6). High PSMA expression (IS 2-4) was found in 160 (74.4%) patients and was significantly associated with more frequent ≥ 50% PSA reduction (26.2 vs. 7.3%, p = .006). On multivariate logistic regression analysis, higher IS was associated with a ≥50% decrease in PSA, even after accounting for CALGB (Halabi) prognostic score, the dose administered, and previous taxane use (OR, 4.72; 95% CI, 1.71-16.85; p = .006). Patients with low PSMA expression (N = 55, 24.7%) were less likely to respond. Thirteen of 26 (50%) with no PSMA uptake (IS = 0) had post-PSMA-TRT PSA decline with 2 (7.7%) having ≥ 50% PSA declines. CONCLUSION: Collectively, the data provide evidence in favor of the hypothesis that patients with high PSMA uptake and high administered radionuclide dose correlate with a higher chance of response.
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Antígenos de Superfície/análise , Glutamato Carboxipeptidase II/análise , Lutécio/uso terapêutico , Metástase Neoplásica/radioterapia , Neoplasias de Próstata Resistentes à Castração/radioterapia , Radioisótopos/uso terapêutico , Radioterapia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Superfície/metabolismo , Glutamato Carboxipeptidase II/metabolismo , Humanos , Lutécio/administração & dosagem , Lutécio/metabolismo , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Estudos Prospectivos , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Neoplasias de Próstata Resistentes à Castração/metabolismo , Compostos Radiofarmacêuticos/uso terapêutico , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único/métodosRESUMO
The prevalence and biological consequences of deleterious germline variants in urothelial cancer (UC) are not fully characterized. We performed whole-exome sequencing (WES) of germline DNA and 157 primary and metastatic tumors from 80 UC patients. We developed a computational framework for identifying putative deleterious germline variants (pDGVs) from WES data. Here, we show that UC patients harbor a high prevalence of pDGVs that truncate tumor suppressor proteins. Deepening somatic loss of heterozygosity in serial tumor samples is observed, suggesting a critical role for these pDGVs in tumor progression. Significant intra-patient heterogeneity in germline-somatic variant interactions results in divergent biological pathway alterations between primary and metastatic tumors. Our results characterize the spectrum of germline variants in UC and highlight their roles in shaping the natural history of the disease. These findings could have broad clinical implications for cancer patients.
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Mutação em Linhagem Germinativa/genética , Neoplasias Urológicas/genética , Neoplasias Urológicas/patologia , Evolução Biológica , Estudos de Coortes , Genoma Humano , Humanos , Perda de Heterozigosidade/genética , Estadiamento de Neoplasias , Domínios Proteicos , Proteínas/química , Proteínas/genéticaRESUMO
BACKGROUND: We previously reported on a phase 2 study of everolimus plus bevacizumab across various nonclear cell renal cell carcinoma (nccRCC) histologies and observed encouraging activity among patients with papillary RCC (pRCC) and unclassified RCC (uRCC) with a major papillary component. We subsequently expanded the study to enroll additional patients with pRCC variants. METHODS: Everolimus plus bevacizumab was administered at standard doses until disease progression or intolerance to therapy. The primary endpoint was the 6-month progression-free survival (PFS) rate; secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Correlative analyses included next-generation sequencing (NGS) from tumor and germline across >341 genes of interest. RESULTS: In addition to 19 patients with pRCC variants in the original cohort, 20 patients with similar features were enrolled on the expansion cohort (uRCC with papillary features [n = 24], pRCC [n = 14], and translocation-associated RCC with papillary features [n = 1]). Among 37 evaluable patients, the 6-month PFS rate was 78%, the median PFS was 13.7 months (95% CI, 10.8-16.4 months), and the ORR was 35%. With a median follow-up of 17.6 months, the median OS was 33.9 months (95% CI, 23.3-71.9). Tolerance was consistent with prior reports for everolimus plus bevacizumab. NGS results (n = 33) identified responses in patients with a wide spectrum of genomic alterations, including ARID1A, FH, and MET mutations. CONCLUSION: The expansion cohort results confirm robust activity of everolimus plus bevacizumab in metastatic pRCC variants, supporting this regimen as a standard option for this patient population.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab/administração & dosagem , Carcinoma de Células Renais/tratamento farmacológico , Everolimo/administração & dosagem , Neoplasias Renais/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Proteínas de Ligação a DNA/genética , Everolimo/uso terapêutico , Feminino , Fumarato Hidratase/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas c-met/genética , Análise de Sequência de DNA , Análise de Sobrevida , Fatores de Transcrição/genética , Resultado do TratamentoRESUMO
Germline genetic testing is now routinely recommended for patients with prostate cancer (PCa) because of expanded guidelines and options for targeted treatments. However, integrating genetic testing into oncology and urology clinical workflows remains a challenge because of the increased number of patients with PCa requiring testing and the limited access to genetics providers. This suggests a critical unmet need for genetic services outside of historical models. This review addresses current guidelines, considerations, and challenges for PCa genetic testing and offers a practical guide for genetic counseling and testing delivery, with solutions to help address potential barriers and challenges for both providers and patients. As genetic and genomic testing become integral to PCa care, developing standardized systems for implementation in the clinic is essential for delivering precision oncology to patients with PCa and realizing the full scope and impact of genetic testing.
Assuntos
Mutação em Linhagem Germinativa , Neoplasias da Próstata , Testes Genéticos , Células Germinativas , Humanos , Masculino , Medicina de Precisão , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/terapiaRESUMO
BACKGROUND: Docetaxel remains a standard of care for metatsatic castration resistant porstate cancer (mCRPC) and has radiosensitizing properties. The dose limiting toxicity (DLT) of radioimmunotherapy is myelosuppression; dose fractionation of 177Lu-J591 allows similar administered doses with less toxicity. This study (NCT00916123) was designed to determine the safety, DLT, and maximum tolerated dose of fractionated 177Lu-J591 administered concurrently with standard docetaxel. METHODS: Men with progressive mCRPC received docetaxel 75 mg/m2 every 3 weeks with escalating 2 fractionated doses of 177Lu-J591 (1.48 GBq/m2 up to max of 2.96 GBq/m2) with cycle 3. Cycle 4 of docetaxel was planned 6 weeks after cycle 3 to allow for recovery from 177Lu-J591-associated hematologic toxicity. DLT was defined as delay in docetaxel >3 weeks, prolonged myelosuppression or need for >2 platelet transfusions, febrile neutropenia, or grade ≥3 nonhematological toxicity following 177Lu-J591. PSA was assessed prior to each cycle and serial computed tomography (CT) and bone scan were performed. RESULTS: Fifteen men with progressive mCRPC received dose-escalated targeted radionuclide therapy in 4 cohorts up to the highest planned dose (2.96 GBq/m2). No DLT was seen at any dose level. Grade 4 neutropenia without fever occurred in 8 (53.5%) and thromboytopenia in 2 (13.3%), with 2 receiving prophylactic platelet transfusion. No grade ≥3 nonhematological toxicity was observed. 11 (73.3%) had >50% PSA decline, with 78.6% having favorable circulating tumor cell counts after 177Lu-J591. All patients had targeting of known sites of disease by planar 177Lu-J591 imaging. CONCLUSION: The combination of 177Lu-J591 delivered as a single fractionated cycle with docetaxel/prednisone is feasible in patients with mCRPC. Without preselection for prostate-specific membrane antigen, accurate targeting of known sites of disease and a strong preliminary efficacy signal was observed.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Docetaxel/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Prospectivos , Neoplasias de Próstata Resistentes à Castração/patologiaRESUMO
During the last decades, essential oils (EOs) have been proven to be a natural alternative to additives or pasteurization for the prevention of microbial spoilage in several food matrices. In this work, we tested the antimicrobial activity of EOs from Melissa officinalis, Ocimum basilicum, and Thymus vulgaris against three different microorganisms: Escherichia coli, Clostridium tyrobutyricum, and Penicillium verrucosum. Pressed ewes' cheese made from milk fortified with EOs (250 mg/kg) was used as a model. The carryover effect of each oil was studied by analyzing the volatile fraction of dairy samples along the cheese-making process using headspace stir bar sorptive extraction coupled to gas chromatography/mass spectrometry. Results showed that the EOs contained in T. vulgaris effectively reduced the counts of C. tyrobutyricum and inhibited completely the growth of P. verrucosum without affecting the natural flora present in the cheese. By contrast, the inhibitory effect of M. officinalis against lactic acid bacteria starter cultures rendered this oil unsuitable for this matrix.