Early intervention in myelofibrosis and impact on outcomes: A pooled analysis of the COMFORT-I and COMFORT-II studies

Background

In a pooled analysis of the phase 3 Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment I (COMFORT-I) and COMFORT-II clinical trials, adult patients with intermediate-2 or high-risk myelofibrosis who received oral ruxolitinib at randomization or after crossover from placebo or best available therapy (BAT) had improved overall survival (OS).

Methods

This post hoc analysis of pooled COMFORT data examined relevant disease outcomes based on the disease duration (≤12 or >12 months from diagnosis) before ruxolitinib initiation.

Results

The analysis included 525 patients (ruxolitinib: ≤12 months, n = 84; >12 months, n = 216; placebo/BAT: ≤12 months, n = 66; >12 months, n = 159); the median age was 65.0–70.0 years. Fewer thrombocytopenia and anemia events were observed among patients who initiated ruxolitinib treatment earlier. At Weeks 24 and 48, the spleen volume response (SVR) was higher for patients who initiated ruxolitinib earlier (47.6% vs. 32.9% at Week 24, p = .0610; 44.0% vs. 26.9% at Week 48, p = .0149). In a multivariable analysis of factors associated with spleen volume reduction, a logistic regression model that controlled for confounding factors found that a significantly greater binary reduction was observed among patients with shorter versus longer disease duration (p = .022). At Week 240, OS was significantly improved among patients who initiated ruxolitinib earlier (63% [95% CI, 51%‒73%] vs. 57% [95% CI, 49%‒64%]; hazard ratio, 1.53; 95% CI, 1.01‒2.31; p = .0430). Regardless of disease duration, a longer OS was observed for patients who received ruxolitinib versus those who received placebo/BAT.

Conclusions

These findings suggest that earlier ruxolitinib initiation for adult patients with intermediate-2 and high-risk myelofibrosis may improve clinical outcomes, including fewer cytopenia events, durable SVR, and prolonged OS.

Plain Language Summary

• Patients with myelofibrosis, a bone marrow cancer, often do not live as long as the general population. These patients may also have an enlarged spleen and difficult symptoms such as fatigue.
• Two large clinical trials showed that patients treated with the drug ruxolitinib lived longer and had improved symptoms compared to those treated with placebo or other standard treatments.
• Here it was examined whether starting treatment with ruxolitinib earlier (i.e., within a year of diagnosis) provided benefits versus delaying treatment.
• Patients who received ruxolitinib within a year of diagnosis lived longer and experienced fewer disease symptoms than those whose treatment was delayed.

     

Validation of PATHFx 2.0: An open-source tool for estimating survival in patients undergoing pathologic fracture fixation

Treatment decisions in patients with metastatic bone disease rely on accurate survival estimation. We developed the original PATHFx models using expensive, proprietary software and now seek to provide a more cost-effective solution. Using open-source machine learning software to create PATHFx version 2.0, we asked whether PATHFx 2.0 could be created using open-source methods and externally validated in two unique patient populations. The training set of a well-characterized, database records of 189 patients and the bnlearn package within R Version 3.5.1 (R Foundation for Statistical Computing), was used to establish a series of Bayesian belief network models designed to predict survival at 1, 3, 6, 12, 18, and 24 months. Each was externally validated in both a Scandinavian (n = 815 patients) and a Japanese (n = 261 patients) data set. Brier scores and receiver operating characteristic curves to assessed discriminatory ability. Decision curve analysis (DCA) evaluated whether models should be used clinically. DCA showed that the model should be used clinically at all time points in the Scandinavian data set. For the 1-month time point, DCA of the Japanese data set suggested to expect better outcomes assuming all patients will survive greater than 1 month. Brier scores for each curve demonstrate that the models are accurate at each time point. Statement of Clinical Significance: we successfully transitioned to PATHFx 2.0 using open-source software and externally validated it in two unique patient populations, which can be used as a cost-effective option to guide surgical decisions in patients with metastatic bone disease.     

中性粒细胞与淋巴细胞比值对三阴性乳腺癌临床预后及与Ki - 67表达的影响

目的 探讨中性粒细胞与淋巴细胞比值（neutrophil to lymphocyte ratio，NLR）对三阴性乳腺癌的临床预后影响及与Ki - 67表达的关系。方法 回顾性分析2006年1月 - 2012年12月于我院乳腺外科住院治疗的134例三阴性乳腺癌患者。NLR最佳临床分界值采用ROC曲线确定，并依此分NLR＜2.64组和NLR≥2.64组。临床独立预后因素采用单因素和多因素Cox回归模型分析。术后生存时间和生存曲线比较采用Kaplan - Meier和log - rank方法。Ki - 67的表达采用免疫组织化学方法检测。结果 NLR是三阴性乳腺癌的独立预后因素，最佳临界值为2.64。NLR＜2.64组术后中位DFS为39.10月，中位OS为52.30月；NLR≥2.64组术后中位DFS为27.35月，中位OS为37.35月。2组术后DFS和OS比较，差异具有统计学意义（P＜0.05）。NLR低组伴Ki - 67表达阴性的三阴性患者术后中位DFS和OS生存时间显著高于其他情况。结论 NLR是三阴性乳腺癌的关键影响预后因素，具有重复性强、非侵袭性、方便实用等特性，可用于预测三阴性乳腺癌临床预后。     

Prognostic and clinicopathological utility of programmed death-ligand 1 in malignant pleural mesothelioma: A meta-analysis

ObjectiveProgrammed death ligand 1 (PD-L1) has been reported to be connected to prognosis in individuals with malignant pleural mesothelioma (MPM), although there is no consensus based on data from previous studies. Accordingly, this quantitative meta-analysis investigated prognostic and clinicopathological utility of PD-L1 in patients with MPM.MethodsA comprehensive search of the PubMed, Web of Science, Embase, and Cochrane Library databases for articles published up to October 4, 2019 was performed. Studies using immunohistochemical techniques to detect/quantify the expression of PD-L1 in MPM tissue were enrolled in the analysis. The combined hazard ratio (HR) and corresponding 95% confidence interval (CI) was applied to assess the association between PD-L1 expression and overall survival (OS).ResultsA total of 11 studies comprising 1606 patients was included in the present meta-analysis. For OS, pooled data revealed an HR of 1.50 (95% CI 1.32–1.70; p < 0.001), suggesting that patients with PD-L1 overexpression experience inferior OS. Subgroup analysis revealed that elevated PD-L1 remained a significant prognostic indicator for worse OS, irrespective of sample size, cut-off value, ethnicity, and Newcastle-Ottawa Scale score. Moreover, PD-L1 overexpression was associated with non-epithelioid histology (odds ratio 4.30 [95% CI 1.89–9.74]; p < 0.001).ConclusionsResults of this meta-analysis show that elevated expression of PD-L1 could be a factor predicting poorer survival in patients with MPM.     

AKR7A3在肺腺癌中异常表达及临床意义

目的:探讨醛-酮还原酶家族7成员A3（AKR7A3）在肺腺癌中的异常表达及与临床病理特征的关系，并探究其临床意义。方法:采用生物信息学数据库分析、免疫组化、Western Blot、Real-time PCR等方法对肺腺癌组织及不同细胞中AKR7A3的表达进行检测与分析。结果:Oncomine数据库分析结果显示，在肺腺癌中，AKR7A3的表达普遍高于正常肺组织，分别为正常肺组织的1.811倍（P=0.022）、1.356倍（P<0.01）、1.413倍（P=0.002）。Kaplan-Meier Plotter数据库分析结果显示，AKR7A3高表达的患者较低表达的患者生存时间缩短，差异具有统计学意义（P=0.003 7）。免疫组化染色显示肺腺癌组织中AKR7A3的表达较癌旁增高，在与临床病理特征的相关性分析中，发现其与肿瘤分化程度（P<0.01）、淋巴结转移情况（P=0.029）以及TNM分期（P<0.01）相关，且会造成患者生存时间缩短（P=0.031）。Cox多因素分析表明AKR7A3可能是影响肺腺癌患者预后的独立危险因素(P=0.012)。Western Blot及Real-time PCR实验提示不同肺腺癌细胞中AKR7A3蛋白及mRNA表达普遍增高。结论:AKR7A3在肺腺癌中表达增高，对预后有不良影响，有促进肿瘤发生发展的作用。