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Improving breast cancer sensitivity to paclitaxel by increasing aneuploidy.
Rodrigues-Ferreira, S, Nehlig, A, Moindjie, H, Monchecourt, C, Seiler, C, Marangoni, E, Chateau-Joubert, S, Dujaric, ME, Servant, N, Asselain, B, et al
Proceedings of the National Academy of Sciences of the United States of America. 2019;(47):23691-23697
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Abstract
Predictive biomarkers for tumor response to neoadjuvant chemotherapy are needed in breast cancer. This study investigates the predictive value of 280 genes encoding proteins that regulate microtubule assembly and function. By analyzing 3 independent multicenter randomized cohorts of breast cancer patients, we identified 17 genes that are differentially regulated in tumors achieving pathological complete response (pCR) to neoadjuvant chemotherapy. We focused on the MTUS1 gene, whose major product, ATIP3, is a microtubule-associated protein down-regulated in aggressive breast tumors. We show here that low levels of ATIP3 are associated with an increased pCR rate, pointing to ATIP3 as a predictive biomarker of breast tumor chemosensitivity. Using preclinical models of patient-derived xenografts and 3-dimensional models of breast cancer cell lines, we show that low ATIP3 levels sensitize tumors to the effects of taxanes but not DNA-damaging agents. ATIP3 silencing improves the proapoptotic effects of paclitaxel and induces mitotic abnormalities, including centrosome amplification and multipolar spindle formation, which results in chromosome missegregation leading to aneuploidy. As shown by time-lapse video microscopy, ATIP3 depletion exacerbates cytokinesis failure and mitotic death induced by low doses of paclitaxel. Our results favor a mechanism by which the combination of ATIP3 deficiency and paclitaxel treatment induces excessive aneuploidy, which in turn results in elevated cell death. Together, these studies highlight ATIP3 as an important regulator of mitotic integrity and a useful predictive biomarker for a population of chemoresistant breast cancer patients.
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Current concepts regarding drug dosing for peripheral stents.
Ferrone, M, Cheng, Y, Granada, JF
The Journal of cardiovascular surgery. 2019;(4):439-449
Abstract
Drug-eluting stent (DES) are the mainstay therapy for the treatment of coronary artery disease. Stent design and drug-elution strategies have evolved over the years leading to the last generation DES which shows optimal safety and efficacy outcome. Peripheral arteries have different mechanical and biological features and the lessons learned from the coronary field have been difficult to introduce into the development of peripheral vascular technologies. First, due to its complex biomechanical behavior the use of metallic stents is limited in some vascular segments (i.e., distal superficial fermoral artery [SFA]). Also, peripheral vascular atherosclerosis is different containing higher levels of plaque burden and calcium. Finally, peripheral arterial disease tends to be more aggressive including longer lesions and higher incidence of total chronic occlusion. In general terms, restenosis in the peripheral vascular territory is more aggressive and occurs at a later time (~12 months) requiring a different pharmacokinetic profile compared to coronary technologies. Several strategies have been evaluated in the peripheral arteries raging from the bare metal stent to the drug coated balloon and drug eluting stent with outcome varying depending on the different field of application (i.e. SFA and below-the-knee). Results coming from the clinical trial are encouraging but further studies and direct comparison among the different technologies are demanded to determine the best therapy for peripheral vascular disease.
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Efficacy and safety evaluation of paclitaxel-loaded metal stents in patients with malignant biliary obstructions.
Yuan, T, Zhu, Y, Wang, X, Cui, W, Cao, J
European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2019;(5):816-819
Abstract
Paclitaxel-eluting covered metal stents (PECMSs) and metallic stents covered with a paclitaxel-incorporated membrane (MSCPMs) have been developed to increase stent patency by preventing tumor ingrowth. However, few studies have compared their efficacy and safety compared with conventional covered metal stents (CMSs). This study aimed to compare differences in efficacy and safety between PECMS/MSCPM and CMS by meta-analysis. A search of PubMed and Embase was conducted for randomized controlled trials of PECMS/MSCPM and CMS in patients with malignant biliary obstructions published between January 1966 and August 2017. A meta-analysis was performed to compare clinical outcomes and complications between stent types. A total of 221 patients from three studies were included. There were no significant differences between PECMS/MSCPM and CMS in stent patency duration (P = 0.128) or survival time (P = 0.363). Risk did not differ between PECMS/MSCPM and CMS for stent malfunction (hazard ratio [HR]: 1.13, 95% confidence interval [CI]: 0.63-2.02, P = 0.677 for all stent malfunction; HR: 1.39, 95% CI: 0.68-2.85, P = 0.362 for stent occlusion caused by tumor ingrowth; HR: 0.80, 95% CI: 0.34-1.91, P = 0.617 for stent occlusion caused by distal stent migration or sludge impaction), or complications (HR: 1.54, 95% CI: 0.70-3.39, P = 0.280 for all complications; HR: 0.42, 95% CI: 0.14-1.30, P = 0.131 for pancreatitis). The exception was cholangitis-like symptoms, the risk for which was higher in PECMS/MSCPM compared with CMS (HR: 3.93, 95% CI: 1.08-14.29, P = 0.038). Although PECMS/MSCPM may be associated with higher risk of cholangitis-like symptoms, the overall results were similar between PECMS/MSCPM and CMS. Further studies are warranted in larger populations of patients.
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Mortality Not Correlated With Paclitaxel Exposure: An Independent Patient-Level Meta-Analysis of a Drug-Coated Balloon.
Schneider, PA, Laird, JR, Doros, G, Gao, Q, Ansel, G, Brodmann, M, Micari, A, Shishehbor, MH, Tepe, G, Zeller, T
Journal of the American College of Cardiology. 2019;(20):2550-2563
Abstract
BACKGROUND Five years of prospective clinical trials confirm that the paclitaxel drug-coated balloon (DCB) (IN.PACT Admiral, Medtronic, Dublin, Ireland) is safe and effective to treat femoropopliteal artery disease. A recent meta-analysis of heterogeneous trials of paclitaxel-based balloons and stents reported that they are associated with increased mortality and that higher doses are linked to higher mortality from 2 to 5 years. OBJECTIVES The purpose of this study was to determine if there is a correlation between paclitaxel exposure and mortality by conducting an independent patient-level meta-analysis of 1,980 patients with up to 5-year follow-up. METHODS Data from 2 single-arm and 2 randomized independently adjudicated prospective studies of a paclitaxel DCB (n = 1,837) and uncoated percutaneous transluminal angioplasty (PTA) (n = 143) were included. Analyses of baseline, procedure, and follow-up data of individual patients were performed to explore correlations of paclitaxel dose with long-term mortality. Survival time by paclitaxel dose tercile was analyzed with adjustment of inverse probability weighting to correct baseline imbalances and study as random effect. A standard cohort was defined to compare DCB- and PTA-treated patients with similar characteristics by applying criteria from pivotal studies (n = 712 DCB, n = 143 PTA). RESULTS A survival analysis stratified nominal paclitaxel dose by low, mid, and upper terciles; mean doses were 5,019.0, 10,007.5, and 19,978.2 μg, respectively. Rates of freedom from all-cause mortality between the 3 groups through 5 years were 85.8%, 84.2%, and 88.2%, respectively (p = 0.731). There was no significant difference in all-cause mortality between DCB and PTA through 5 years comparing all patients (unadjusted p = 0.092) or patients with similar characteristics (adjusted p = 0.188). CONCLUSIONS This independent patient-level meta-analysis demonstrates that this paclitaxel DCB is safe. Within DCB patients, there was no correlation between level of paclitaxel exposure and mortality. (Randomized Trial of IN.PACT Admiral® Drug Coated Balloon vs Standard PTA for the Treatment of SFA and Proximal Popliteal Arterial Disease [INPACT SFA I], NCT01175850; IN.PACT Admiral Drug-Coated Balloon vs. Standard Balloon Angioplasty for the Treatment of Superficial Femoral Artery [SFA] and Proximal Popliteal Artery [PPA] [INPACT SFA II], NCT01566461; MDT-2113 Drug-Eluting Balloon vs. Standard PTA for the Treatment of Atherosclerotic Lesions in the Superficial Femoral Artery and/or Proximal Popliteal Artery [MDT-2113 SFA], NCT01947478; The IN.PACT SFA Clinical Study for the Treatment of Atherosclerotic Lesions in the Superficial Femoral Artery and/or Proximal Popliteal Artery Using the IN.PACT Admiral™ Drug-Eluting Balloon in a Chinese Patient Population, NCT02118532; and IN.PACT Global Clinical Study, NCT01609296).
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Efficacy of a paclitaxel-eluting biliary metal stent with sodium caprate in malignant biliary obstruction: a prospective randomized comparative study.
Jang, SI, Lee, KT, Choi, JS, Jeong, S, Lee, DH, Kim, YT, Lee, SH, Yu, JS, Lee, DK
Endoscopy. 2019;(9):843-851
Abstract
BACKGROUNDS The placement of a self-expandable metal stent (SEMS) is widely used in patients with unresectable malignant biliary obstructions, but SEMSs are susceptible to occlusion by tumor ingrowth or overgrowth. The efficacy and safety of a novel paclitaxel-eluting biliary metal stent incorporating sodium caprate (MSCPM-III) were compared prospectively with those of a covered metal stent (CMS) in patients with malignant biliary obstructions. METHODS Patients with unresectable distal malignant biliary obstructions (n = 106) were prospectively enrolled in this study at multiple treatment centers. Stents were placed endoscopically: MSCPM-III in 54 patients and CMS in 51 patients. The patients received systemic chemotherapy regimens according to their disease characteristics. RESULTS The two groups did not differ significantly in basic characteristics or mean follow-up period. Stent occlusion occurred in 14 patients who received MSCPM-III and in 11 patients who received CMS. Time to recurrent biliary obstruction (RBO) and survival time did not differ significantly between the two groups (P = 0.84 and P = 0.29, respectively). However, tumor size at 2 months after stent insertion was significantly decreased in patients in the MSCPM-III group with bile duct cancers or those who experienced stent migration compared with the CMS group. Complications, including cholangitis and pancreatitis, were found to be acceptable in both groups. CONCLUSIONS Although compared with a CMS the MSCPM-III did not significantly influence time to RBO or survival duration in patients with malignant biliary obstructions, MSCPM-III reduced tumor volume and was used safely in humans.
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Inhibition of SOX15 Sensitizes Esophageal Squamous Carcinoma Cells to Paclitaxel.
Zhang, M, Wang, J, Gao, T, Chen, X, Xu, Y, Yu, X, Guo, X, Zhuang, R, Li, Z, Wu, H, et al
Current molecular medicine. 2019;(5):349-356
Abstract
BACKGROUND SOX15 is a crucial transcription factor involved in the regulation of embryonic development and in the cell fate determination. It is also an important mediator of tumorigenesis in cancer. METHODS Here, we sought to explore the expression patterns and biological functions of SOX15 in esophageal squamous cell carcinomas (ESCC). SOX15 was found aberrantly overexpressed in ESCC tumors. RESULTS Experimentally, inhibition of SOX15 through RNAi suppressed cell proliferation in ESCC cells and sensitized cancer cells to paclitaxel, but not to Cisplatin. Moreover, inhibition of SOX15 significantly repressed the expression of genes associated with WNT and NOTCH signaling pathways, which may contribute to the increased sensitivity to paclitaxel. CONCLUSION In conclusion, the current study revealed that inhibition of SOX15 in ESCC cells sensitizes the ESCC cells to paclitaxel, suggesting that the SOX15 expression level may predict the therapeutic outcomes for paclitaxel treatment for ESCC.
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[New progress in the treatment of locally advance pancreatic cancer].
de Santibañes, M, Sanchez Clariá, R, de Santibañes, E, Pekolj, J, Mazza, O
Medicina. 2019;(Spec 6/1):576-581
Abstract
Locally advanced pancreatic cancer (LAPC) has several definitions, but it is essentially a non-metastatic tumor, in which the initial surgical resection is not considered beneficial due to the extensive vascular involvement and consequent high chance of a nonradical resection. The introduction of chemotherapy with calcium leucovorin, fluorouracil, irinotecan hydrochloride and oxaliplatin (FOLFIRINOX) and gemcitabine-nab (nanoparticle albumin-bound)-paclitaxel (gem-nab) had very important implications for the management of patients with LAPC. After 4 to 6 months of induction chemotherapy, a large proportion of them have stable disease or even tumor regression, allowing to rescue those who initially were not candidates for surgery, with 30-35 months overall survival after surgery.
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Paclitaxel Drug-Coated Balloon After Bare-Metal Stent Implantation, an Alternative Treatment to Drug-Eluting Stent in High Bleeding Risk Patients (The Panelux Trial).
Roncalli, J, Godin, M, Boughalem, K, Shayne, J, Piot, C, Huret, B, Belle, L, Cayla, G, Faurie, B, Amor, M, et al
The Journal of invasive cardiology. 2019;(4):94-100
Abstract
BACKGROUND Prolonged dual-antiplatelet therapy (DAPT) in high bleeding risk (HBR) patients undergoing percutaneous coronary intervention can be challenging. We assessed the clinical safety of bare-metal stent (BMS) implantation followed by drug-coated balloon (DCB) treatment in HBR patients for whom drug-eluting stent implantation could be problematic in maintaining low ischemic event rate without increasing hemorrhagic events. METHODS The study included patients with at least 1 de novo lesion who were either under long-term anticoagulant treatment or required semi-urgent non-coronary intervention. The strategy consisted of PRO-Kinetic Energy BMS stent (Biotronik AG) implantation followed by Pantera Lux DCB (Biotronik AG) and patients were followed for up to 12 months in 37 French centers. RESULTS Between October 2013 and April 2015, a total of 432 patients with 623 de novo lesions who were either under long-term anticoagulant treatment (n = 300) or required semi-urgent non-cardiac surgery (n = 132) were treated by BMS plus DCB. Mean patient age was 74.1 ± 9.1 years, 76.4% were men, and 38% were diabetic. The composite primary endpoint rate (defined as target-lesion failure at 12 months) was 5.6% (95% confidence interval, 3.3-7.9). Median duration for DAPT treatment was 33 days. Hemorrhagic events, as defined by the Bleeding Academic Research Consortium, occurred in 31 patients (7.2%) and definite stent thrombosis occurred in 5 patients (1.3%). CONCLUSIONS The combination of BMS plus DCB intervention is safe even with a short duration of DAPT. This strategy might be an alternative to DES implantation in HBR patients if future randomized trials support this approach.
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Clinical efficacy and safety of Aidi injection plus paclitaxel-based chemotherapy for advanced non-small cell lung cancer: A meta-analysis of 31 randomized controlled trials following the PRISMA guidelines.
Xiao, Z, Wang, C, Zhou, M, Hu, S, Jiang, Y, Huang, X, Li, N, Feng, J, Tang, F, Chen, X, et al
Journal of ethnopharmacology. 2019;:110-122
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE As an important Chinese herb injection, Aidi injection is composed of the extracts from Astragalus, Eleutherococcus senticosus, Ginseng, and Cantharis. Aidi injection plus paclitaxel-based chemotherapy is often used to in the treatment of non-small cell lung cancer (NSCLC) in China. AIM OF THE STUDY The objective of this study is to further confirm whether Aidi injection can improve the tumor responses and survivals, and reveal its safety, optimal usage and combination with paclitaxel. MATERIALS AND METHODS A meta-analysis was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. All randomized controlled trials (RCTs) concerning the Aidi injection plus paclitaxel-based chemotherapy for NSCLC were selected. Main outcomes were objective response rate (ORR), disease control rate (DCR), survivals, quality of life (QOL) and adverse drug reactions (ADRs). All data were extracted by using a standard data extraction form and synthesized through meta-analysis. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used for rating the quality of evidence. RESULTS Thirty-one RCTs involving 2058 patients were included, and most trials had an unclear methodological bias risk. The risk ratio (RR) and 95% confidence intervals (CI) of ORR, DCR, QOL, neutropenia, thrombocytopenia, gastrointestinal toxicity and liver injury were as following: 1.32 (1.20-1.46), 1.14 (1.09-1.20), 1.89 (1.66-2.16), 0.61 (0.51-0.74), 0.62 (0.45-0.87), 0.59 (0.49-0.72) and 0.52 (0.36-0.75). Compared to chemotherapy alone, all differences were statistically significant. Subgroup analysis showed that only with the TP, Aidi injection could increase the ORR and DCR. Treatment with 100 ml, 80 ml or 50 ml/time, and 14 days/2 cycles or 21 days/2-4 cycles, Aidi injection could increase the ORR and DCR, respectively. Sensitivity analysis showed that the results had good robustness. None of the trials reported the overall survivals (OS), progression free survival (PFS). The quality of evidences was moderate. CONCLUSIONS Current moderate evidence revealed that Aidi injection plus paclitaxel-based chemotherapy, especially TP can significantly improve the clinical efficacy and QOL for patients with stage III/IV NSCLC. Aidi injection can relieve the risk of hematotoxicity, gastrointestinal toxicity and liver injury in patient with NSCLC receiving paclitaxel-based chemotherapy. The optimal usage may be 50 ml/time and 14 days/2 cycles.
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Prospective Multicentered Safety and Feasibility Pilot for Endobronchial Intratumoral Chemotherapy.
Yarmus, L, Mallow, C, Akulian, J, Lin, CT, Ettinger, D, Hales, R, Voong, KR, Lee, H, Feller-Kopman, D, Semaan, R, et al
Chest. 2019;(3):562-570
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Abstract
BACKGROUND Malignant airway obstruction (MAO) occurs in 30% of patients with advanced-stage lung cancer, leading to debilitating dyspnea, cough, and hemoptysis. Other than recanalization of the airways, these patients lack long-lasting palliative therapy. The goal of this study was to determine the safety and feasibility of local injection of paclitaxel into the airway wall with a novel microinjection catheter. METHODS In this multicentered prospective trial, 23 patients with non-small cell lung cancer and MAO were enrolled from July 2014 through June 2016 to undergo rigid bronchoscopy with recanalization, followed by injection of 1.5 mg of paclitaxel with a novel injection catheter. Primary end points consisted of safety (adverse events, severe adverse events, and unanticipated adverse device effects) as well as feasibility (number of injections, injection success). Secondary end points consisted of airway patency improvement, quality of life metrics, and need for further interventions and/or stenting. RESULTS Nineteen patients underwent rigid bronchoscopy with successful recanalization and paclitaxel injection. There were no adverse events, severe adverse events, or unanticipated adverse device effects. There was an average of 3.4 injections given for a total dose of 1.5 mg of paclitaxel in all patients. There was significantly less stenosis postprocedure vs preprocedure (25%-50% vs 75%-90%; P < .001), which was unchanged at 6 weeks (25%-50%). None of the participants required further interventions or airway stenting. CONCLUSIONS The injection of paclitaxel after recanalization of MAO in patients with non-small cell lung cancer is safe and feasible, using a novel airway injection device. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT02066103; URL: www.clinicaltrials.gov.