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LESSONS LEARNED: The negative results are consistent with the negative results of large phase III trials in which docetaxel plus antiangiogenic agents were used in patients with metastatic castrate-resistant prostate cancer (mCRPC).The negative data underscore that, despite a sound biological rationale and supportive early-phase clinical results, adding antiangiogenic agents to docetaxel for mCRPC is a great challenge. BACKGROUND: Inhibition of vascular endothelial growth factor (VEGF) signaling abrogates tumor-induced angiogenesis to constrain tumor growth, and can be exploited therapeutically by using cediranib, an oral tyrosine kinase inhibitor of VEGF receptor signaling. Our preliminary phase I trial data showed that adding cediranib to docetaxel plus prednisone (DP) was safe and feasible, with early evidence for efficacy in patients with metastatic castrate-resistant prostate cancer (mCRPC). METHODS: This multicenter phase II trial assessed whether adding cediranib to DP improves efficacy of DP in patients with mCRPC. Chemotherapy-naive patients with mCRPC were randomly assigned to receive either docetaxel (75 mg/m2 intravenously every 3 weeks) with prednisone (5 mg twice daily) plus cediranib (30 mg once daily; the DP+C arm) or DP only (the DP arm). The primary endpoint was to compare 6-month progression-free survival (PFS) rate between the two arms. Secondary endpoints included 6-month overall survival (OS), objective tumor and prostate-specific antigen (PSA) response rates, biomarkers, and adverse events. RESULTS: The 6-month PFS rate in a total of 58 patients was only numerically higher in the DP+C arm (61%) compared with the DP arm (57%). Similarly, the 6-month OS rate, objective tumor and PSA response rates, and biomarkers were not significantly different between the two arms. Increased baseline levels of interleukin 6 (IL-6), however, were significantly associated with increased risk of progression. Neutropenia was the only grade 4 toxicity (38% in the DP+C arm vs. 18% in the DP arm). CONCLUSION: Combining cediranib with docetaxel + prednisone failed to demonstrate superior efficacy, compared with docetaxel + prednisone, and added toxicity. Our data do not support pursuing the combination further in patients with mCRPC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Docetaxel/administração & dosagem , Humanos , Calicreínas/sangue , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prednisona/administração & dosagem , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/patologia , Quinazolinas/administração & dosagem , Taxa de Sobrevida , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
BACKGROUND AND OBJECTIVES: This study is a systematic review with meta-analysis designed to compare the perioperative and oncological outcomes of the abdominoperineal resection (APR) carried out in the prone jack-knife position (P-APR) vs the classic lithotomy position (C-APR). METHODS: We conducted an electronic search through PubMed utilizing the PRISMA guidelines. We included all randomized and nonrandomized studies which allowed for comparative analysis between the two groups. Research that focused on and analyzed the extralevator abdominal excision were excluded. Pooled variables and number of events were analyzed using the random-effect model. RESULTS: The final analysis included seven nonrandomized retrospective cohorts encompassing 1663 patients. P-APR was associated with decreased operative time (OT) (DM, -43.8 minutes; P < 0.01) and estimated blood loss (EBL) (DM, 86.9 mL; P < 0.01). There were no observed differences regarding perineal wound infections (PWI) (odds ratio [OR], 0.36; P = 0.18), intraoperative perforation of rectum (IOP) (OR, 0.98; P = 0.97), circumferential resection margin (CRM) positivity (OR, 1.02; P = 0.98) or 5-year LR (OR, 1.00; P = 0.99). CONCLUSION: The prone approach for APR is associated with decreased EBL and OT, although not with any change in the incidence of PWI or IOP. Moreover, surgical positioning per se does not appear to affect the CRM positivity rates or LR rate.
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Posicionamento do Paciente/métodos , Protectomia/métodos , Neoplasias Retais/cirurgia , Humanos , Margens de Excisão , Decúbito Ventral , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Prostate cancer is one of the most common cancers in men worldwide. Currently available diagnostic and prognostic tools for this disease, such as prostate specific antigen, suffer from lack of specificity and sensitivity, resulting in over- and misdiagnosis. Hence, there is an urgent need for clinically relevant biomarkers capable of distinguishing between aggressive and nonaggressive forms of prostate cancer to aid in stratification, management and therapeutic decisions. To address this unmet need, we investigated the patterns of expression of a panel of 68 plasma-derived microRNAs (miRNAs) in a cohort of African American (AA) and European American (EA) prostate cancer patients (n = 114). miRNA qPCR results were analyzed using in-depth statistical methods, and a bioinformatics analysis was conducted to identify potential targets of the differentially expressed miRNAs. Our data demonstrate that a new previously unreported circulating miRNA signature consisting of a combination of interacting miRNAs (miR-17/miR-192) and an independent miRNA (miR-181a) are capable of segregating aggressive and nonaggressive prostate cancer in both AA and EA patients. The interacting miRNAs outperformed independent miRNAs in identifying aggressiveness. Our results suggest that these circulating miRNAs may constitute novel biomarkers of prostate cancer aggressiveness in both races and warrant further investigation.
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Biomarcadores Tumorais/sangue , MicroRNAs/sangue , Neoplasias da Próstata/sangue , Adulto , Idoso , Biomarcadores Tumorais/genética , MicroRNA Circulante/análise , MicroRNA Circulante/genética , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologiaRESUMO
INTRODUCTION: Heat shock protein 90 (Hsp90) has been studied as a therapeutic target in many cancers. In preclinical trials, the Hsp90 ATPase inhibitor ganetespib demonstrated potent inhibition of solid tumor growth, with superior potency than prior Hsp90 inhibitors. Given the promising preclinical outcome and favorable pharmacologic properties of ganetespib, we conducted a phase II trial of single-agent ganetespib in patients with metastatic, castrate-resistant prostate cancer (mCRPC). The primary objective of the study was to determine the 6-month progression-free survival (PFS) rate. METHODS: Patients with mCRPC who had been previously treated with docetaxel were enrolled after meeting eligibility criteria. All patients received ganetespib at 200 mg/m(2) on days 1, 8, and 15 of every 28 days (one cycle). Subjects who tolerated therapy were continued on ganetespib until disease progression. Considering that Hsp90 acetylation may confer insensitivity to Hsp90 inhibitors and maspin inhibits protein deacetylation, maspin-associated molecular markers were evaluated. RESULTS: Eighteen patients were recruited into the trial; most were Caucasian, had performance status 1, had received prior docetaxel, and were heavily pretreated. Of the 17 patients who were treated, none attained 6-month PFS. Only 2 patients achieved PFS > 4 months. The median PFS was 1.9 months. As per the study design, the trial was terminated after the interim analysis. The most frequent types of Grade 3 toxicity were dehydration, diarrhea, and fatigue. Molecular markers provided little additional insight regarding drug activity. CONCLUSIONS: Ganetespib demonstrated minimal clinical activity in men with mCRPC. The true 6-month PFS rate was, at most, 0.20. Possible reasons for this include selection of a heavily pretreated patient population and lack of agent potency in patients with mCRPC.
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Antineoplásicos/administração & dosagem , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Triazóis/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Intervalo Livre de Doença , Docetaxel , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias de Próstata Resistentes à Castração/patologia , Taxoides/administração & dosagem , Resultado do Tratamento , Triazóis/efeitos adversos , Triazóis/uso terapêuticoRESUMO
PURPOSE: Bladder cancer is predominantly a disease of older individuals. Concurrent chemotherapy and radiation is a bladder-sparing strategy for management of muscle-invasive bladder cancer; however, many patients are not candidates for chemotherapy due to comorbidities or impaired performance status. We conducted a study in a chemotherapy-ineligible patient population with the objectives of evaluating the safety, efficacy, and quality-of-life effect of the combination of nivolumab and radiation therapy in patients with localized/locally advanced urothelial cancer. METHODS AND MATERIALS: Eligible patients had muscle-invasive bladder cancer and were not candidates for standard chemoradiation strategy due to at least one of the following: performance status of 2, creatinine clearance ≤60 mL/min, cardiac disease, neuropathy, and intolerance to previous treatment. Creatinine clearance ≥40 mL/min, normal marrow, and liver function were required. The primary endpoint was progression-free survival at 12 months. Nivolumab was started within 3 days of radiation therapy and administered at a dose of 240 mg intravenously every 2 weeks for a maximum of 6 months. Radiation therapy was per standard of care for bladder cancer. Imaging and cystoscopy and biopsy evaluation were required at months 3, 6, and 12 and then annually until progression. RESULTS: Twenty patients were enrolled, with a median age of 78.5 years (range, 58-95 years); 80% of patients were >70 years of age, and 8 (40%) were >80 years of age. Median creatinine clearance was 52 mL/min. Nine patients (48%) were progression free at 12 months. Median progression-free survival was 11.4 months (90% CI, 7.5-23.7 months), and median overall survival was 15.6 months (90% CI, 9.1-26.1 months). CONCLUSIONS: Concurrent nivolumab and radiation therapy is tolerable but demonstrated limited efficacy in an older population with multiple comorbidities. Immune correlates demonstrated that patients with baseline programmed cell death ligand 1 combined prognostic score ≥5% had numerically longer progression-free survival.
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Nivolumabe , Neoplasias da Bexiga Urinária , Humanos , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Criança , Nivolumabe/uso terapêutico , Nivolumabe/efeitos adversos , Creatinina/uso terapêutico , Neoplasias da Bexiga Urinária/radioterapia , Intervalo Livre de Progressão , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Músculos/patologiaRESUMO
Sipuleucel-T is an autologous cellular immunotherapy that targets prostatic acid phosphatase (PAP) and is available for treatment of men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). In this single-arm, two-cohort, multicenter clinical study, potential racial differences in immune responses to sipuleucel-T in men with mCRPC were explored. Patients' blood samples were obtained to assess serum cytokines, humoral responses, and cellular immunity markers before and after treatment. Baseline cumulative product parameters (total nucleated and CD54+ cell counts and CD54 upregulation) were evaluated. IgM titers against the immunogen PA2024, the target antigen PAP, prostate-specific membrane antigen (PSMA) and prostate-specific antigen (PSA) were quantified by ELISA. Cytotoxic T-lymphocyte activity was determined by ELISpots, and cytokine and chemokine concentrations were determined by Luminex.Twenty-nine African American (AA) men and 28 non-African American (non-AA) men with mCRPC received sipuleucel-T. Baseline total nucleated cell count, CD54+ cell count, CD54 expression, and cumulative product parameters were higher in non-AA men. Although PSA baseline levels were higher in AA men, there were no racial differences in IgM antibody and IFNγ ELISpots responses against PA2024, PAP, PSA, and PSMA before and after treatment. Expression of co-stimulatory receptor ICOS on CD4+ and CD8+ T cells, and the levels of Th1 cytokine granulocyte-macrophage colony-stimulating factor and chemokines CCL4 and CCL5, were significantly higher in AA men before and/or after treatment. Despite no difference in the overall survival, PSA changes from baseline were significantly different between the two races. The data suggest that immune correlates in blood differ in AA and non-AA men with mCRPC pre- and post-sipuleucel-T. SIGNIFICANCE: Our novel findings of higher expression of co-stimulatory receptor ICOS on CD4+ and CD8+ T cells in African American patients with metastatic castrate-resistant prostate cancer (mCRPC) prior and post-sipuleucel-T suggest activation of CD4+ and CD8+ T cells. The data indicate that racial differences observed in these and other immune correlates before and after sipuleucel-T warrant additional investigation to further our understanding of the immune system in African American men and other men with mCRPC.
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Neoplasias de Próstata Resistentes à Castração , Extratos de Tecidos , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Negro ou Afro-Americano , Vacinas Anticâncer/uso terapêutico , Citocinas/sangue , Metástase Neoplásica , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/imunologia , Neoplasias de Próstata Resistentes à Castração/patologia , Extratos de Tecidos/uso terapêutico , Extratos de Tecidos/farmacologiaAssuntos
Negro ou Afro-Americano , Neoplasias da Próstata/epidemiologia , Humanos , Masculino , Risco , População BrancaRESUMO
PURPOSE: To assess whether diverse tumor location(s) show differences in percutaneous cryoablation (PCA) outcomes of cancer control, morbidity, and ablation volume reduction for many soft-tissue tumor types. MATERIALS AND METHODS: A total of 220 computed tomography (CT)- and/or ultrasonography-guided percutaneous cryotherapy procedures were performed for 251 oligometastatic tumors from multiple primary cancers in 126 patients. Tumor location was grouped according to regional sites: retroperitoneal, superficial, intraperitoneal, bone, and head and neck. PCA complications were graded according to Common Terminology Criteria for Adverse Events (version 4.0). Local tumor recurrence and involution were calculated from ablation zone measurements, grouped into 1-, 3-, 6-, 12-, 18-, and 24-month (or later) statistical bins. RESULTS: Tumor and procedure numbers for each site were 75 and 69 retroperitoneal, 76 and 62 superficial, 39 and 32 intraperitoneal, 34 and 34 bone, and 27 and 26 head and neck. Average diameters of tumor and visible ice during ablation were 3.4 and 5.5 cm, respectively. Major complications (ie, grade >3) attributable to PCA occurred after five procedures (2.3%). At 11 months average follow-up (range, 0-82 mo), a 10% total recurrence rate (26 of 251) was noted; three occurred within the ablation zone, for a local progression rate of 1.2%. Average time to recurrence was 4.9 months, and, at 21 months, the initial ablation zone had reduced in volume by 93%. CONCLUSIONS: CT-guided PCA is a broadly safe, effective local cancer control option for oligometastatic disease with soft-tissue tumors in most anatomic sites. Other than bowel and nerve proximity, PCA also shows good healing if proper visualization and precautions are followed.
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Criocirurgia , Neoplasias de Tecidos Moles/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criocirurgia/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neoplasia Residual , Estudos Prospectivos , Radiografia Intervencionista/métodos , Neoplasias de Tecidos Moles/secundário , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Carga Tumoral , Ultrassonografia de Intervenção , Adulto JovemRESUMO
PURPOSE: To assess feasibility, complications, local tumor recurrences, overall survival (OS), and estimates of cost effectiveness for multisite cryoablation (MCA) of oligometastatic non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: A total of 49 computed tomography- and/or ultrasound-guided percutaneous MCA procedures were performed on 60 tumors in 31 patients (19 women and 12 men) with oligometastatic NSCLC. Average patient age was 65 years. Tumor location was grouped according to common metastatic sites. Median OS was determined by Kaplan-Meier method and defined life-years gained (LYGs). Estimates of MCA costs per LYG were compared with established values for systemic therapies. RESULTS: Total numbers of tumors and cryoablation procedures for each anatomic site were as follows: lung, 20 and 18; liver, nine and seven; superficial, 12 and 11; adrenal, seven and seven; paraaortic/isolated, two and two; and bone, 10 and seven. A mean of 1.6 procedures per patient were performed, with a median clinical follow-up of 11 months. Major complication and local recurrence rates were 8% (four of 49) and 8% (five of 60), respectively. Median OS for MCA was 1.33 years, with an estimated 1-year survival rate of approximately 53%. MCA appeared cost-effective even when added to the cost of best supportive care or systemic regimens, with an adjunctive cost-effectiveness ratio of $49,008-$87,074. CONCLUSIONS: MCA was associated with very low morbidity and local tumor recurrence rates for all anatomic sites, and possibly increased OS. Even as an adjunct to systemic therapies, MCA appeared cost-effective for palliation of oligometastatic NSCLC.
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Carcinoma Pulmonar de Células não Pequenas/economia , Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Criocirurgia/economia , Custos de Cuidados de Saúde , Neoplasias Pulmonares/economia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Metastasectomia/economia , Recidiva Local de Neoplasia , Cuidados Paliativos/economia , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Análise Custo-Benefício , Criocirurgia/efeitos adversos , Criocirurgia/mortalidade , Estudos de Viabilidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Masculino , Metastasectomia/efeitos adversos , Metastasectomia/mortalidade , Michigan , Pessoa de Meia-Idade , Anos de Vida Ajustados por Qualidade de Vida , Radiografia Intervencionista/economia , Radiografia Intervencionista/métodos , Estudos Retrospectivos , Fatores de Tempo , Tomografia Computadorizada por Raios X/economia , Resultado do Tratamento , Ultrassonografia de Intervenção/economiaRESUMO
PURPOSE: To assess complications, local tumor recurrences, overall survival (OS), and estimates of cost-effectiveness for multisite cryoablation (MCA) of oligometastatic renal cell carcinoma (RCC). MATERIALS AND METHODS: A total of 60 computed tomography- and/or ultrasound-guided percutaneous MCA procedures were performed on 72 tumors in 27 patients (three women and 24 men). Average patient age was 63 years. Tumor location was grouped according to common metastatic sites. Established surgical selection criteria graded patient status. Median OS was determined by Kaplan-Meier method and defined life-years gained (LYGs). Estimates of MCA costs per LYG were compared with established values for systemic therapies. RESULTS: Total number of tumors and cryoablation procedures for each anatomic site are as follows: nephrectomy bed, 11 and 11; adrenal gland, nine and eight; paraaortic, seven and six; lung, 14 and 13; bone, 13 and 13; superficial, 12 and nine; intraperitoneal, five and three; and liver, one and one. A mean of 2.2 procedures per patient were performed, with a median clinical follow-up of 16 months. Major complication and local recurrence rates were 2% (one of 60) and 3% (two of 72), respectively. No patients were graded as having good surgical risk, but median OS was 2.69 years, with an estimated 5-year survival rate of 27%. Cryoablation remained cost-effective with or without the presence of systemic therapies according to historical cost comparisons, with an adjunctive cost-effectiveness ratio of $28,312-$59,554 per LYG. CONCLUSIONS: MCA was associated with very low morbidity and local tumor recurrence rates for all anatomic sites, with apparent increased OS. Even as an adjunct to systemic therapies, MCA appeared cost-effective for palliation of oligometastatic RCC.
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Carcinoma de Células Renais/economia , Carcinoma de Células Renais/secundário , Carcinoma de Células Renais/cirurgia , Criocirurgia/economia , Custos de Cuidados de Saúde , Neoplasias Renais/economia , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Metastasectomia/economia , Recidiva Local de Neoplasia , Cuidados Paliativos/economia , Carcinoma de Células Renais/mortalidade , Análise Custo-Benefício , Criocirurgia/efeitos adversos , Criocirurgia/mortalidade , Estudos de Viabilidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/mortalidade , Masculino , Metastasectomia/efeitos adversos , Metastasectomia/mortalidade , Michigan , Pessoa de Meia-Idade , Anos de Vida Ajustados por Qualidade de Vida , Radiografia Intervencionista/economia , Radiografia Intervencionista/métodos , Fatores de Tempo , Tomografia Computadorizada por Raios X/economia , Resultado do Tratamento , Ultrassonografia de Intervenção/economia , Adulto JovemRESUMO
Introduction In the era of MRI-guided external beam radiation therapy (EBRT), complete radiological response (CR) is often seen in cervical cancer (CC) with 4-6 weeks of chemotherapy and EBRT. The clinical and radiological factors associated with this observation were investigated in this study. Materials and methods One hundred and twenty-four CC patients treated with concurrent chemotherapy, EBRT, and brachytherapy (BT) from January 2008 to July 2015 were retrospectively screened. Initial primary gross tumor volume (GTVINITIAL) was estimated after contouring on a planning CT scan registered with pre-EBRT PET and MRI. The maximum standardized uptake value (SUV) of GTVINITIAL from each PET scan report was collected. Spearman's rank correlation coefficient (rho) values were calculated to assess the relationships among age, tumor size, and SUV. Tumor radiological response during EBRT prior to BT was calculated by contouring the final primary gross tumor volume (GTVFINAL) using MRI obtained prior to BT. CR rates during EBRT were estimated from GTVINITIAL and GTVFINAL and compared by the level of various factors using Fisher's exact test (two-sided). Results Forty-eight patients met the inclusion criteria of the study with a median age of 50 years. The median GTVINITIAL was 82 cc. The median SUV was 14.9. A significant correlation was seen between SUV and GTVINITIAL with a larger tumor size associated with a higher SUV. CR rates were numerically higher for patients who were aged <50 years, or with >37.5 Gy radiation dose at or before the second MRI, or with GTVINITIAL <100 cc, or with no nodes involved or with stages IB or IIA. Conclusions Our study identified higher CC primary tumor CR rates during EBRT in younger patients (<50) with smaller tumors (100 cc) without nodal involvements as well as a positive correlation between PET FDG (18F-fluorodeoxyglucose)-SUV and CC primary tumor size.
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Multiple molecularly targeted agents (MTAs) have been approved for the management of metastatic renal cell carcinoma (mRCC). Sunitinib and mammalian target of rapamycin inhibitors (temsirolimus, everolimus) are primarily metabolized in the liver, whereas the metabolism of bevacizumab is unclear. There are limited data on the toxicity profile and the efficacy of these agents in patients with renal insufficiency (RI). This is clinically relevant, especially as about one-third of patients with mRCC have renal dysfunction. The primary objective was to assess the safety and efficacy of targeted agents in patients with mRCC with RI. Medical records of patients with mRCC at Wayne State University, started on sunitinib, temsirolimus, everolimus, or bevacizumab, were reviewed. Patients with a calculated creatinine clearance of less than or equal to 60 ml/min were deemed to have RI. Data on safety and efficacy of MTA therapy were collected and analyzed with respect to renal function. RI was observed in 33% of our patients with mRCC. The incidence of toxicities, responses, time to progression, and overall survival were not significantly different in patients with RI compared with patients with normal renal function. Patients with RI had larger median increases in blood pressure with sunitinib and bevacizumab, increased incidence of thyroid dysfunction with sunitinib, and increased incidence of rash and dose interruptions with mammalian target of rapamycin inhibitors, than did patients with normal renal function. In conclusion, RI was commonly observed in our patients with mRCC. Molecularly targeted agents are well tolerated, and efficacy seems to be maintained in patients with RI. Vigilant monitoring of hypertension would be recommended for patients receiving sunitinib and bevacizumab.
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Antineoplásicos/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Terapia de Alvo Molecular , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/patologia , Progressão da Doença , Monitoramento de Medicamentos , Feminino , Seguimentos , Humanos , Hipertensão/etiologia , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Insuficiência Renal/complicações , Estudos Retrospectivos , SobrevidaRESUMO
Given the limited information on Clostridium difficile infection (CDI) during hematopoietic stem cell transplantation (HSCT), we examined the recent epidemiology of CDI in HSCT recipients at our institution. During the two-yr retrospective study period (2005-2006), 361 transplants were performed: 60% allogeneic and 40% autologous. Among all hospitalized patients in a non-outbreak setting, CDI rates in HSCT recipients were ninefold higher than those in general patients and 1.4-fold higher than those in patients with cancer (24.0 vs. 2.6 vs. 16.8/10,000 patient-days respectively). Sixty-two episodes of CDI occurred in 51 (14%) HSCT recipients: 39 (18%) allogeneic vs. 12 (8%) autologous (p = 0.01). Almost half of CDI episodes occurred within 30 d post-HSCT and 22% before HSCT. Clostridium difficile toxin assay was initially positive in 28% of the first, 31% of the second and 27% of the third stool samples tested. All but one patient responded to therapy with metronidazole or vancomycin. Severe CDI occurred in one patient and recurrent CDI in two patients. CDI is common during HSCT especially in allogeneic transplants during the peri-HSCT period. Prospective studies to better define the epidemiology and identify unique risk factors for CDI and more accurate tests to confirm the diagnosis in this population are needed.
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Clostridioides difficile/patogenicidade , Enterocolite Pseudomembranosa/epidemiologia , Transplante de Células-Tronco Hematopoéticas , Neoplasias/terapia , Adulto , Enterocolite Pseudomembranosa/diagnóstico , Enterocolite Pseudomembranosa/microbiologia , Feminino , Seguimentos , Humanos , Masculino , Metronidazol/uso terapêutico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Transplante Homólogo , Resultado do Tratamento , Vancomicina/uso terapêuticoRESUMO
PURPOSE: This study aimed to evaluate a combination of radiation therapy (RT), androgen deprivation therapy (ADT), and pexidartinib (colony-stimulating factor 1 receptor [CSF1R]) inhibitor in men with intermediate- and high-risk prostate cancer. CSF1R signaling promotes tumor infiltration and survival of tumor-associated macrophages, which in turn promote progression and resistance. Counteracting protumorigenic actions of tumor-associated macrophages via CSF1R inhibition may enhance therapeutic efficacy of RT and ADT for prostate cancer. METHODS AND MATERIALS: In this phase 1 study, the treatment regimen consisted of pexidartinib (800 mg, administered as a split-dose twice daily) and ADT (both for a total of 6 months), and RT that was initiated at the start of month 3. RT volumes included the prostate and proximal seminal vesicles. The delivered dose was 7920 cGy (180 cGy per fraction) using intensity modulated RT with daily image guidance for prostate localization. The primary objective was to identify the maximum tolerated dose based on dose-limiting toxicities. RESULTS: All 4 enrolled patients who were eligible to receive RT had T1 stage prostate cancer, 2 were intermediate risk, and 2 were high risk. The median age was 62.5 years, and the prostate-specific antigen levels were in the range 6.4 to 10.7 ng/mL. The patients' individual Gleason scores were 3 + 3, 4 + 3, 4 + 4, and 4 + 5. All 4 patients reported ≥1 adverse events before RT. Grade 1 hypopigmentation was observed in 1 patient, and grade 3 pulmonary embolus in another. One patient experienced fatigue and joint pain, and another elevated amylase and pruritus (all grade 3 toxicities). Five of the 6 adverse events noted in 3 patients were all grade 3 toxicities attributable to pexidartinib, qualifying as dose-limiting toxicities and ultimately resulting in the study closure. CONCLUSIONS: The combination was not well tolerated and does not warrant further investigation in men with intermediate- and high-risk prostate cancer.
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Importance: Black patients have been underrepresented in prospective clinical trials of advanced prostate cancer. This study evaluated the efficacy of enzalutamide compared with bicalutamide, with planned subset analysis of Black patients with metastatic hormone-sensitive prostate cancer (mHSPC), which is a disease state responsive to androgen deprivation therapy (ADT). Objective: To compare the efficacy of enzalutamide vs bicalutamide in combination with ADT in men with mHSPC, with a subset analysis of Black patients. Design, Setting, and Participants: In this randomized clinical trial, a phase 2 screening design enabled a nondefinitive comparison of the primary outcome by treatment. Patients were stratified by race (Black or other) and bone pain (present or absent). Accrual of at least 30% Black patients was required. This multicenter trial was conducted at 4 centers in the US. Men with mHSPC with no history of seizures and adequate marrow, renal, and liver function were eligible. Data analysis was performed from February 2019 to March 2020. Interventions: Participants were randomized 1:1 to receive oral enzalutamide (160 mg daily) or bicalutamide (50 mg daily) in addition to ADT. Main Outcomes and Measures: The primary end point was the 7-month prostate-specific antigen (PSA) response (SMPR) rate, a previously accepted surrogate for overall survival (OS) outcome. Secondary end points included adverse reactions, time to PSA progression, and OS. Results: A total of 71 men (median [range] age, 65 [51-86] years) were enrolled; 29 (41%) were Black, 41 (58%) were White, and 1 (1%) was Asian. Thirty-six patients were randomized to receive enzalutamide, and 35 were randomized to receive bicalutamide. Twenty-six patients (37%) had bone pain and 37 patients (52%) had extensive disease. SMPR was achieved in 30 of 32 patients (94%; 95% CI, 80%-98%) taking enzalutamide and 17 of 26 patients (65%; 95% CI, 46%-81%) taking bicalutamide (P = .008) (difference, 29%; 95% CI, 5%-50%). Among Black patients, the SMPR was 93% (95% CI, 69%-99%) among those taking enzalutamide and 42% (95% CI, 19%-68%) among those taking bicalutamide (P = .009); among non-Black patients, the SMPR was 94% (95% CI, 74%-99%) among those taking enzalutamide and 86% (95% CI, 60%-96%) among those taking bicalutamide. The 12-month PSA response rates were 84% with enzalutamide and 34% with bicalutamide. Conclusions and Relevance: The findings of this randomized clinical trial comparing enzalutamide with bicalutamide suggest that enzalutamide is associated with improved outcomes compared with bicalutamide, in terms of the rate and duration of PSA response, in Black patients with mHSPC. Trial Registration: ClinicalTrials.gov Identifier: NCT02058706.
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Antagonistas de Androgênios/uso terapêutico , Anilidas/uso terapêutico , Antineoplásicos/uso terapêutico , Negro ou Afro-Americano , Nitrilas/uso terapêutico , Feniltioidantoína/análogos & derivados , Neoplasias da Próstata/tratamento farmacológico , Compostos de Tosil/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Benzamidas , Biomarcadores Tumorais/sangue , Quimioterapia Combinada , Humanos , Masculino , Pessoa de Meia-Idade , Feniltioidantoína/uso terapêutico , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/etnologia , Resultado do TratamentoRESUMO
Humans typically consume "natural agents" that are believed to be chemoprotective and are known to decrease inflammation biomarker NF-kappaB in vitro; however, no intervention studies in humans have been done to date. This commentary documents the in vivo results as a powerful example for supporting the superiority of a complex mixture of natural agents. Human volunteers consumed two 500 mg capsules (BID) containing a mixture of natural agents for a period of 2 weeks, and blood samples were collected pre- and post-intervention. The purified lymphocytes were subjected to ex-vivo exposure to TNF-alpha or kept as untreated control. The mean NF-kappaB DNA binding activity was increased upon TNF-alpha treatment in pre-intervention samples; however, TNF-alpha was unable to induce NF-kappaB in post-intervention samples, suggesting that the mixture of four important natural agents could be useful to protect humans against oxidative stress.
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Produtos Biológicos/uso terapêutico , Linfócitos/efeitos dos fármacos , NF-kappa B/imunologia , Estresse Oxidativo/efeitos dos fármacos , Fator de Necrose Tumoral alfa/imunologia , Adulto , Produtos Biológicos/farmacologia , Catequina/análogos & derivados , Catequina/uso terapêutico , Curcumina/uso terapêutico , DNA/metabolismo , Feminino , Humanos , Isoflavonas/uso terapêutico , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Neoplasias/prevenção & controle , Adulto JovemRESUMO
OBJECTIVES: To estimate the probability of downgrading to Gleason score ≤7 at radical prostatectomy for men with a prostate needle biopsy demonstrating Gleason score 8 (4â¯+â¯4). METHODS: This is a retrospective review of men with Gleason score 8 (4â¯+â¯4) prostate cancer on needle biopsy who then underwent a radical prostatectomy at the Karmanos Cancer Institute or the University of Michigan. Men with any pattern 5 on the diagnostic biopsy were excluded. The objective was to estimate the proportion of patients whose tumors were downgraded to Gleason score ≤7 at radical prostatectomy and to identify clinical and biopsy parameters associated with downgrading. RESULTS: Median age of our cohort was 63 years (IQR: 59, 67.5) and median follow-up was 15 months (IQR: 7, 37). Of the 105 men that met inclusion criteria, 59% (62/105) were downgraded to Gleason score ≤7 at radical prostatectomy. Having ≤2 cores demonstrating Gleason score 8, ≤50% maximal tumor involvement of any individual core positive for Gleason score 8, or the presence of Gleason pattern 3 (such as 3â¯+â¯4, 4â¯+â¯3, or 3â¯+â¯3) in other biopsy cores were all independently associated with downgrading in our multivariable model. Depending on the absence, presence, or combination of these 3 factors, patients had an estimated 6% to 82% probability of having their tumor downgraded at radical prostatectomy. CONCLUSIONS: Men with low volume Gleason 8 (4â¯+â¯4) and/or the presence Gleason pattern 3 on prostate needle biopsy often have their tumors downgraded at radical prostatectomy. The presence of these preoperative biopsy parameters could affect pretreatment counseling and impact patient management.
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Tomada de Decisão Compartilhada , Aconselhamento Diretivo , Próstata/patologia , Neoplasias da Próstata/patologia , Idoso , Biópsia por Agulha , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Prostatectomia , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/cirurgia , Estudos Retrospectivos , Medição de RiscoRESUMO
PURPOSE: Synergy is observed with the combination of capecitabine and docetaxel due to docetaxel mediated up-regulation of thymidine phosphorylase. A phase II trial was performed with the combination for metastatic, castrate resistant prostate cancer. MATERIALS AND METHODS: Eligible patients had metastatic, castrate resistant prostate cancer, no prior chemotherapy for metastatic disease and normal organ function. Docetaxel (36 mg/m(2) per week intravenously) on days 1, 8 and 15, and capecitabine (1,250 mg/m(2) per day in 2 divided doses) on days 5 to 18 were administered in 28-day cycles. The response was assessed every 2 cycles. Biomarker correlative studies were performed on blood dihydropyrimidine dehydrogenase, and the thymidine phosphorylase-to-dihydropyrimidine dehydrogenase and thymidine synthase-to-dihydropyrimidine dehydrogenase ratios in available prostate tumor tissue. RESULTS: A total of 30 patients with a median age of 69 years were enrolled in the study. We noted bone pain in 21 patients (70%), Gleason score 8 or higher in 18 (60%), measurable disease progression in 9, bone scan progression in 18 and prostate specific antigen progression in 22. Grade 3 or 4 neutropenia was seen in 3 patients and grade 3 hand-foot syndrome was found in 2. No treatment related deaths occurred. A prostate specific antigen response of 50% or greater decrease was observed in 22 patients (73%), of whom 9 (30%) had 90% or greater decrease. A partial response was noted in 5 of 9 patients (56%) with measurable disease. Median time to progression was 6.7 months (90% CI 4.2-7.7) and median overall survival was 22.0 months (90% CI 18.4-25.3). CONCLUSIONS: The combination was well tolerated and it demonstrated favorable response rates with durable remission and survival outcomes.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/mortalidade , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina , Intervalos de Confiança , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Docetaxel , Relação Dose-Resposta a Droga , Esquema de Medicação , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/análogos & derivados , Humanos , Estimativa de Kaplan-Meier , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Probabilidade , Prognóstico , Prostatectomia/métodos , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Estatísticas não Paramétricas , Análise de Sobrevida , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Falha de Tratamento , Resultado do TratamentoRESUMO
PURPOSE: Imaging tumor proliferation with 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) and positron emission tomography is being developed with the goal of monitoring antineoplastic therapy. This study assessed the methods to measure FLT retention in patients with non-small cell lung cancer (NSCLC) to measure the reproducibility of this approach. EXPERIMENTAL DESIGN: Nine patients with NSCLC who were untreated or had progressed after previous therapy were imaged twice using FLT and positron emission tomography within 2 to 7 days. Reproducibility (that is, error) was measured as the percent difference between the two patient scans. Dynamic imaging was obtained during the first 60 min after injection. Activity in the blood was assessed from aortic images and the fraction of unmetabolized FLT was measured. Regions of interest were drawn on the plane with the highest activity and the adjacent planes to measure standardized uptake value (SUV(mean)) and kinetic variables of FLT flux. RESULTS: We found that the SUV(mean) obtained from 30 to 60 min had a mean error of 3.6% (range, 0.6-6.9%; SD, 2.3%) and the first and second scans were highly correlated (r(2) = 0.99; P < 0.0001). Using shorter imaging times from 25 to 30 min or from 55 to 60 min postinjection also resulted in small error rates; SUV(mean) mean errors were 8.4% and 5.7%, respectively. Compartmental and graphical kinetic analyses were also fairly reproducible (r(2) = 0.59; P = 0.0152 and r(2) = 0.58; P = 0.0175 respectively). CONCLUSION: FLT imaging of patients with NSCLC was quite reproducible with a worst case SUV(mean) error of 21% when using a short imaging time.