Purpose The TAXYNERGY trial ( ClinicalTrials.gov identifier: NCT01718353) evaluated clinical benefit from early taxane switch and circulating tumor cell (CTC) biomarkers to interrogate mechanisms of ...sensitivity or resistance to taxanes in men with chemotherapy-naïve, metastatic, castration-resistant prostate cancer. Patients and Methods Patients were randomly assigned 2:1 to docetaxel or cabazitaxel. Men who did not achieve ≥ 30% prostate-specific antigen (PSA) decline by cycle 4 (C4) switched taxane. The primary clinical endpoint was confirmed ≥ 50% PSA decline versus historical control (TAX327). The primary biomarker endpoint was analysis of post-treatment CTCs to confirm the hypothesis that clinical response was associated with taxane drug-target engagement, evidenced by decreased percent androgen receptor nuclear localization (%ARNL) and increased microtubule bundling. Results Sixty-three patients were randomly assigned to docetaxel (n = 41) or cabazitaxel (n = 22); 44.4% received prior potent androgen receptor-targeted therapy. Overall, 35 patients (55.6%) had confirmed ≥ 50% PSA responses, exceeding the historical control rate of 45.4% (TAX327). Of 61 treated patients, 33 (54.1%) had ≥ 30% PSA declines by C4 and did not switch taxane, 15 patients (24.6%) who did not achieve ≥ 30% PSA declines by C4 switched taxane, and 13 patients (21.3%) discontinued therapy before or at C4. Of patients switching taxane, 46.7% subsequently achieved ≥ 50% PSA decrease. In 26 CTC-evaluable patients, taxane-induced decrease in %ARNL (cycle 1 day 1 v cycle 1 day 8) was associated with a higher rate of ≥ 50% PSA decrease at C4 ( P = .009). Median composite progression-free survival was 9.1 months (95% CI, 4.9 to 11.7 months); median overall survival was not reached at 14 months. Common grade 3 or 4 adverse events included fatigue (13.1%) and febrile neutropenia (11.5%). Conclusion The early taxane switch strategy was associated with improved PSA response rates versus TAX327. Taxane-induced shifts in %ARNL may serve as an early biomarker of clinical benefit in patients treated with taxanes.
Bacteriochlorins are crucial to photosynthesis in bacteria. Studies of air-stable,
-substituted bacteriochlorins are rare. We herein report the synthesis, properties, and photovoltaic performance of ...three new air-stable,
-substituted bacteriochlorins bearing a dioctylfluorenylethyne (denoted as LS-17), a dioctylaminophenylethynylanthrylethyne (LS-43), and a diarylaminoanthrylethyne (LS-45) as the electron-donating groups. Among these LS-bacteriochlorins, LS-17 displays sharp UV-visible absorption bands whereas LS-43 and LS-45 give rise to broadened and red-shifted absorptions. Electrochemical and DFT results suggest that the first oxidation and reduction reactions of these bacteriochlorins are consistent with the formation of the cation and anion radicals, respectively. For dye-sensitized solar cell applications, photovoltaic performance of the LS-45 cell achieves an overall efficiency of 6.04% under one-sun irradiation.
For decades, cytotoxic therapy was considered ineffective for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Earlier therapies such as estramustine and mitoxantrone ...received regulatory approval based upon improvement in palliative endpoints. In 2004, docetaxel became the first treatment to demonstrate a significant survival benefit in patients with mCRPC based on two randomized phase III studies, TAX327 and SWOG 99-16. Cabazitaxel, a third-generation taxane, was chosen for clinical development based on its decreased affinity for the drug efflux pump, p-glycoprotein, which is a frequent cause of drug resistance in docetaxel-resistant preclinical models. In 2010, cabazitaxel was approved by the US Food and Drug Administration as the first therapy to show a survival benefit for the treatment of patients with docetaxel-refractory mCRPC. This review summarizes the existing literature on the use of cabazitaxel, focusing on its efficacy and safety in combination with prednisone in the treatment of mCRPC, as well as its role in an era of new therapeutic options.
Purpose
Stress-induced adrenergic signaling can suppress the immune system. In animal models, pharmacological beta-blockade stimulates CD8 + T-cell activity and improves clinical activity of immune ...checkpoint blockade (ICB) in inhibiting tumor growth. Herein, we investigated the effect of BB on clinical outcomes of patients receiving ICB in advanced solid tumors.
Methods
We retrospectively evaluated patients with solid tumors treated with ICB at our institution from January 1, 2011 to April 28, 2017. The primary clinical outcome was disease control. Secondary clinical outcomes were overall survival (OS), and duration of therapy (DoT). The primary predictor was use of BB. Association between disease control status and BB use was assessed in univariable and multivariable logistic regression. OS was calculated using hazard ratios of BB-recipient patients vs. BB non-recipient patients via Cox proportional hazards regression models. All tests were two-sided at a significance level of 0.05.
Results
Of 339 identified patients receiving ICB, 109 (32%) also received BB. In covariate-adjusted analysis, odds of disease control were significantly higher among BB recipients compared to BB-non-recipients (2.79; 1.54–5.03;
P
= 0.001). While we did not observe significant association of OS with the use of BB overall, significant association with better OS was observed for the urothelial carcinoma cohort (HR: 0.24; 0.09, 0.62;
P
= 0.0031).
Conclusions
Concurrent use of BB may enhance the clinical activity of ICB and influence overall survival, particularly in patients with urothelial carcinoma. Our findings warrant further investigation to understand the interaction of beta adrenergic signaling and antitumor immune activity and explore a combination strategy.
Introduction:
Although pharmacist-driven patient education has been shown to increase adherence, reduce medication errors, and lower 30-day readmission rates, the data in the ambulatory oncology ...setting is limited. This pilot quality initiative study was conducted from June 1, 2018, to November 15, 2018, in the ambulatory cancer center affiliated with The Mount Sinai Hospital in New York, NY, to determine the impact of pharmacist counseling on chemotherapy regimens.
Methods and Materials:
English-speaking patients with gastrointestinal malignancies who were newly started on chemotherapy were selected for this study. They received a pharmacist-led education session regarding their medications, potential side effects, and how to manage them at home. After each session, they completed a 5-question survey on a 5-point Likert-scale about how they felt before and after speaking with a pharmacist. Survey results were analyzed by median scores and Wilcoxon signed-rank test.
Results:
Of the 96 patients who were counseled, 71 patients were included in this analysis. The median score increased from 3 to 5 for the understanding of their chemotherapy regimen and side effects (questions 1 and 2), 3 to 4.5 for knowledge about interactions with their oral chemotherapy (question 3), 4 to 5 for overall experience in the cancer center (question 5). The median score for anxiety level was unchanged at 3 (question 4).
Conclusion:
This survey-based study demonstrated the benefit of a pharmacist-led counseling session. An interdisciplinary approach involving the integration of oncology pharmacists in patient education can greatly impact the quality of care for oncology patients.
Lessons Learned
The safety and activity findings of abiraterone acetate plus prednisone treatment in black men with mCRPC were similar to results from previously conducted studies with largely white ...populations.
Poor trial accrual continues to be a challenge in black men with mCRPC and further efforts are needed to address such underrepresentation.
Background.
Self‐identified black men have higher incidence and mortality from prostate cancer in the United States compared with white men but are dramatically underrepresented in clinical trials exploring novel therapies for metastatic castration‐resistant prostate cancer (mCRPC).
Methods.
Black men with mCRPC were treated with abiraterone acetate (AA), 1,000 mg daily, and prednisone (P), 5 mg twice daily. The primary objective was to determine antitumor activity (defined by a ≥30% decline in prostate‐specific antigen PSA level) and to correlate germline polymorphisms in androgen metabolism genes with antitumor activity. Secondary objectives included determining safety, post‐treatment changes in measurable disease, and time to disease progression.
Results.
From April 2013 to March 2016, a total of 11 black men were enrolled and received AA plus P (AA+P); 7 of 10 evaluable patients were docetaxel naive. Post‐treatment declines in PSA level of ≥30% were achieved in 90% of patients. The side effect profile was consistent with prior clinical trials exploring AA+P in mCRPC. Due to poor accrual, the study was closed prematurely with insufficient sample size for the planned pharmacogenetic analyses.
Conclusion.
In this small prospective study terminated for poor accrual, the safety and activity of AA+P in black men with mCRPC was similar to that reported in prior studies exploring AA in largely white populations. Further efforts are needed to address underrepresentation of black men in mCRPC trials.
作者总结
经验
• 醋酸阿比特龙联合泼尼松治疗转移性去势抵抗性前列腺癌 (mCRPC) 黑人男性患者的安全性和有效性与既往主要在白人群体中开展的研究结果相似。
• mCRPC 临床试验中黑人男性患者入组不理想仍然是该人群研究的一大难题, 有必要进一步努力解决这一人群代表性不足的问题。
摘要
背景. 美国黑人男性前列腺癌的发病率和死亡率均高于白人男性, 但在转移性去势抵抗性前列腺癌 (mCRPC) 新治疗研发的临床试验中, 黑人男性的代表性却明显不足。
方法. 患有mCRPC的黑人男性接受醋酸阿比特龙 (AA) 1 000 mg每日1次和泼尼松 (P) 5 mg每日2次治疗。主要目的为确定该治疗方案的抗肿瘤活性定义为前列腺特异性抗原 (PSA) 水平下降≥30%, 以及雄激素代谢基因生殖系多态性与抗肿瘤活性之间的相关性。次要目的包括确定安全性、可测量病灶在治疗后的改变, 以及至疾病进展时间。
结果. 从2013年4月至2016年3月, 研究共入组11例黑人男性接受AA+P治疗, 7/10例可评价患者未接受过多西他赛治疗。90%的患者治疗后PSA水平下降≥30%。副作用特征与既往研究AA+P治疗mCRPC的临床试验情况一致。研究因招募入组极不理想而提前关闭, 计划的药物遗传学分析样本量不足。
结论. 本项小型前瞻性研究因招募入组过慢而终止, AA+P在mCRPC黑人男性患者中的安全性和有效性与既往主要在白人男性中开展的AA研究相似。有必要进一步努力解决黑人男性在mCRPC临床试验中代表性不足的问题。The Oncologist 2016;21:1414–1415
Castration-resistant prostate cancer (CRPC) is associated with wide variations in survival. Recent studies of whole blood mRNA expression-based biomarkers strongly predicted survival but the genes ...used in these biomarker models were non-overlapping and their relationship was unknown. We developed a biomarker model for CRPC that is robust, but also captures underlying biological processes that drive prostate cancer lethality.
Using three independent cohorts of CRPC patients, we developed an integrative genomic approach for understanding the biological processes underlying genes associated with cancer progression, constructed a novel four-gene model that captured these changes, and compared the performance of the new model with existing gene models and other clinical parameters.
Our analysis revealed striking patterns of myeloid- and lymphoid-specific distribution of genes that were differentially expressed in whole blood mRNA profiles: up-regulated genes in patients with worse survival were overexpressed in myeloid cells, whereas down-regulated genes were noted in lymphocytes. A resulting novel four-gene model showed significant prognostic power independent of known clinical predictors in two independent datasets totaling 90 patients with CRPC, and was superior to the two existing gene models.
Whole blood mRNA profiling provides clinically relevant information in patients with CRPC. Integrative genomic analysis revealed patterns of differential mRNA expression with changes in gene expression in immune cell components which robustly predicted the survival of CRPC patients. The next step would be validation in a cohort of suitable size to quantify the prognostic improvement by the gene score upon the standard set of clinical parameters.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
Two randomized trials published in 2001 provided level 1 evidence for the use of cytoreductive nephrectomy (CyNx) for the treatment of metastatic renal cell carcinoma (mRCC). However, the ...regulatory approval of vascular endothelial growth factor tyrosine kinase inhibitors (VEGFR-TKI) in 2005 has left an “evidence void” regarding the use of CyNx. We evaluated the patterns in the use of CyNx in the cytokine and VEGFR-TKI eras, and the patient characteristics associated with the use of CyNx.
Methods
The Surveillance, Epidemiology, and End Results registry was used to identify patients with histologically or cytologically confirmed stage IV RCC between 2001 and 2008. Patients were classified as treated during the cytokine (2001–2005) or VEGFR-TKI (2006–2008) eras. A multivariate logistic regression analysis was performed to calculate the odds of undergoing CyNx according to treatment era and socioeconomic characteristics.
Results
Overall, 1,112 of 2,448 patients (45 %) underwent CyNx. CyNx use remained stable between 2001 and 2005 (50 %), but decreased to 38 % in 2008. Logistic regression analysis revealed that older age (OR 0.82, 95 % CI: 0.68, 0.99), black race (OR 0.64, 95 % CI: 0.46, 0.91), Hispanic ethnicity (OR 0.71, 95 % CI: 0.54, 0.93), and treatment in the VEGFR-TKI era (OR 0.82, 95 % CI: 0.68, 0.99) were independently associated with decreased use of CyNx.
Conclusions
Use of CyNx in the United States has declined in the VEGFR-TKI era. Older patients and minorities are less likely to receive CyNx. Results of ongoing phase III trials are needed to refine the role of this treatment modality.
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