Areas covered: We describe the recent advances in clinical development of anti-HER2 treatments. To this aim, we used literature search via Pubmed and made an inventory of abstracts published during the last two years in major oncology conferences.
Expert opinion: Further changes will probably occur during the next decade in the management of metastatic HER2-positive breast cancer. This is mainly driven by the fact that the two mainstay drugs (pertuzumab and TDM-1) that confer prolonged survival (56 months) to these patients are currently being used in the treatment of early-stage disease in a subset of patients. Thus, there is an urgent need to develop new, innovative approaches in those patients whose disease has become resistant to these highly potent drugs. Several new antibody-drug conjugates, bispecific antibodies or new generation tyrosine kinase inhibitor (TKIs) hold promise and should be assessed and compared with drugs currently used. 相似文献
Methods: We searched the Medline, Embase, and Cochrane Library electronic databases (through December 2016) for phase II/III randomized controlled trials that compared regimens of one or two HER2-targeted agents combined with trastuzumab or chemotherapy. A network meta-analysis including direct and indirect analyses was conducted in WinBUGS using fixed and random effects. Study quality was assessed following the Grading of Recommendations, Assessment, Development and Evaluations method. The primary outcome was overall survival.
Results: The network meta-analysis incorporated nine HER2-targeted regimens with 9 direct comparisons and 28 indirect comparisons for the main outcomes (8 studies; n = 3976). Combining direct and indirect effects showed significant increased efficacy of trastuzumab and docetaxel plus pertuzumab (TDP) over other regimens as first-line treatment. With indirect comparison of overall safety, TDP, TDM-1, and TDM-1 plus pertuzumab demonstrated a lower risk of grade 3–4 adverse events compared to other regimens.
Conclusions: TDPs are a preferred first-line treatment for HER2-positive metastatic breast cancer compared with other target agent regimens. 相似文献
Areas covered: Herein, the authors present the various pharmacotherapeutic options for refractory breast cancer including their perspectives on these options.
Expert opinion: In recent years, there has been significant progress in our understanding of the biological mechanisms that cause resistance to BC treatments. The targeted therapeutic approach particularly has improved patient outcomes for those with refractory BC, but some unresolved issues still remain. In particular, we need to identify biomarkers of resistance to better tailor treatments, toxicities, and costs. Moreover, we need to determine the best sequence of treatments in refractory BC patients. 相似文献
Areas covered: This article reviews preclinical data, clinical studies that have evaluated the efficacy and safety profiles of buparlisib as a monotherapy or in combination with targeted therapy (including endocrine and anti-HER2 therapy) or cytotoxics. The authors cover completed and ongoing studies to evaluate the benefit vs risk profile of buparlisib.
Expert opinion: Targeting PI3K showed efficacy in BC. Buparlisib, a pan PI3K inhibitor, presents manageable but not negligible toxicity with an activity/toxicity ratio in favor of the use of emerging second generation, α–selective PI3K inhibitors for ongoing and future trials. 相似文献
Methods: Post-menopausal women with HR+/HER2– mBC were identified from MarketScan claims databases between January 1, 2012 and October 31, 2017. Eligible mBC patients who received a CDKi-based line of therapy following metastasis diagnosis were selected. A line of therapy ended at the earlier of systemic therapy discontinuation, switch to new treatment, or censoring.
Results: In total, 525 patients that received systemic therapy after a CDKi-based line were included (39.6% transitioned from use of a CDKi-based regimen in first line following metastasis diagnosis to any second line, and 60.4% shifted from a CDKi-based [second, third, or fourth line] to a subsequent line). Of post-CDKi second line regimens (n?=?208), 38.0% were endocrine only, 35.6% were chemotherapy-based, 14.4% were everolimus-based, 9.6% were also CDKi-based line, and 2.4% were others. After adjusting for demographic and clinical characteristics, patients transitioning from a CDKi-based line to chemotherapy (vs others) had a trend of being more likely to have recurrent rapidly progressing disease, and were significantly less likely to have the prior CDKi-based line in combination with an AI (both p?<?.05).
Conclusions: This population-based study suggests that rapidly progressing disease, metastatic site location, age, and endocrine therapy partner may be predictive of subsequent systemic therapy regimen selection after progression on a CDKi-based line therapy in patients with HR+/HER2– mBC. 相似文献
Areas covered: We summarize the key features, pharmacokinetics, and the safety and efficacy data of sacituzumab govitecan. We also discuss the future directions of this novel therapeutic agent for mTNBC.
Expert opinion: Based on the efficacy and tolerability observed in the phase 1/2 clinical trial, sacituzumab govitecan was granted breakthrough therapy designation by the Food and Drug Administration as ≥3rd line therapy for mTNBC. Novel treatment modalities for the management of mTNBC are necessary to improve the care of this aggressive disease. Sacituzumab govitecan represents an important advance in the treatment of mTNBC because of its efficacy and tolerability. 相似文献
Areas covered: This review article aims to discuss these concerns and to clarify the adequate steps and procedures needed to increase safety and alleviate the possible drawbacks of NAC. The author will discuss the adequate and meticulous technical procedures needed to stage and localize the breast tumor, detect any affected axillary lymph node, improve the accuracy and safety of doing sentinel lymph node biopsy (SLNB) after NAC, estimate the tumor response to NAC to determine the extent of surgery, and enhance the precise documentation of pCR.
Expert opinion: The use of breast MRI, image-detectable clips in the tumor bed, dual technique during SLNB, and target axillary dissection are among the required steps to maintain safety. In the future, ongoing prospective trials will allow us to select patients who can safely avoid breast and/or axillary surgery after systemic therapy. 相似文献
Objective: Evaluation of the peripapillary choroidal layer in the patients receiving oral isotretinoin therapy may aid in explaining the pathophysiology of ocular side effects.
Methods: In this study, peripapillary choroidal thickness was assessed in the patients receiving oral isotretinoin treatment via optical coherent tomography technique.
Results: Significant difference was found in the superotemporal and temporal areas.
Conclusion: Oral isotretinoin treatment may affect the thickness of the peripapillary choroidal layer. 相似文献
Areas covered: The authors review the key trials that have led to current standard of care treatment including pivotal chemotherapy and targeted therapy trials. The authors then discuss the current approved uses and future directions for immunotherapy.
Expert opinion: Current treatment options lack tailored treatment strategies based on the tumor’s biology. To date, approved targeted approaches only include HER2-directed and anti-VEGFR2 therapies. Furthermore, while immunotherapy treatment response is often durable, few clear predictive biomarkers for response have been identified. Future research should focus on characterizing additional molecular targets for therapeutic intervention and predictive biomarkers for immunotherapy, as well as combination approaches of immunotherapy with other therapeutic modalities to increase response rate. Ultimately, the field should strive to develop personalized treatment options based on a tumor’s molecular profile, microenvironment, and neo-antigen expression. 相似文献
Research design and methods: This multicenter, open-label, single-group, prospective interventional study evaluated changes in total gait-related scores of the Part II/III Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and Freezing of Gait Questionnaire (FOG-Q) in 31 Parkinson’s disease patients treated with istradefylline. Gait analysis by portable gait rhythmogram was performed.
Results: MDS-UPDRS Part III gait-related total scores significantly decreased at Weeks 4–12 from baseline with significant improvements in gait, freezing of gait, and postural stability. Significant decreases in MDS-UPDRS Part II total scores and individual item scores at Week 12 indicated improved daily living activities. At Week 12, there were significant improvements in FOG-Q, new FOG-Q, and overall movement per 48 h measured by portable gait rhythmogram. Adverse events occurred in 7/31 patients.
Conclusions: Istradefylline improved gait disorders in Parkinson’s disease patients complicated with freezing of gait, improving their quality of life. No unexpected adverse drug reactions were identified.
Trial registration: UMIN-CTR (UMIN000020288). 相似文献
Aim: Microencapsulate lavender oil by spray drying using a biocompatible polymeric blend of gum acacia and maltodextrin to protect the oil components. Effect of total polymer content, oil loading, gum acacia, and maltodextrin proportions on the size, yield, loading, and encapsulation efficiency of the microparticles was investigated.
Methods: Morphology and oil localisation within microparticles were assessed by confocal laser scanning electron microscope. Structural preservation and compatibility were assessed using Fourier transform infra-red spectroscopy, differential scanning calorimetry, and gas chromatography–mass spectrometry.
Results: Lavender microparticles of size 12.42?±?1.79?µm prepared at 30 w/w% polymer concentration, 16.67 w/w% oil loading, and 25w/w% gum acacia showed maximum oil protection at high loading (12?mg w/w%), and encapsulation efficiency (77.89 w/w%).
Conclusion: Lavender oil was successfully microencapsulated into stable microparticles by spray drying using gum acacia/maltodextrin polymeric blend. 相似文献
Areas covered: Multitargeted kinase inhibitors are small molecule inhibitors with limited toxicity. This review will focus on early-stage investigations of multitargeted tyrosine kinase inhibitors (m-TKIs) (those that target at least two tyrosine kinases) for HNSCC. Preclinical and early trials investigating m-TKIs for various disease settings of HNSCC will be evaluated for efficacy, identification of significant biomarkers and potential for combination therapy.
Expert opinion: Few single agent m-TKIs have demonstrated efficacy in unselected HNSCC populations. The most promising clinical results have been obtained when m-TKIs are tested in combination with other therapies, including immunotherapy, or in mutation-defined subgroups of patients. The future success of m-TKIs will rely on identification, in preclinical models and clinical trials, of predictive biomarkers of response and mechanisms of innate and acquired resistance. 相似文献
Methods: To this end, we synthesized Ge-DOX-5-ALA/NPs, which can enter tumor tissue by the enhanced permeability and retention (EPR) effect and release drugs by utilizing matrix metalloproteinase-2 (MMP-2).
Results: The Ge-DOX-5-ALA/NPs were synthesized by a single-phase coacervation method, and the hydrodynamic diameters of all nanoparticles were under 200?nm. The drug encapsulation and loading efficiency were 92%±1.13% and 6.02%?±?0.48%, respectively. Gelatin zymography was performed to detect the expression of MMP-2 in MCF-7 and Hs578Bst cells. The nanoparticle sensitivity to MMP-2 was examined by comparing the release behavior and cellular uptake in MCF-7 and Hs578Bst cells. In vitro cytotoxicity of the nanoparticles was measured by an MTT assay. An in vivo anticancer efficacy study in S180-bearing mice demonstrated that Ge-DOX-5-ALA/NPs provide a substantial curative effect. A pharmacokinetics experiment demonstrated that the nanoparticles have a sustained release effect.
Conclusions: The MMP-2-triggered nanoparticles can transport drugs successfully into the tumor site and enable combined chemotherapy and photodynamic therapy. 相似文献
Areas covered: This paper focuses on the pathophysiology of transplantation-related AKI and recent findings on cellular stress responses at the intersection of 1. The Unfolded protein response; 2. Mitochondrial dysfunction; 3. The benefits of mineralocorticoid receptor antagonists. Lastly, perspectives are offered to the readers.
Expert opinion: Renal IRI is caused by a sudden and temporary impairment of blood flow to the organ.
Defining the underlying cellular cascades involved in IRI will assist us in the identification of novel interventional targets to attenuate IRI with the potential to improve transplantation outcomes. Targeting mitochondrial function and cellular bioenergetics upstream of cellular damage may offer several advantages compared to targeting downstream inflammatory and fibrosis processes.
An improved understanding of the cellular pathophysiological mechanisms leading to kidney injury will hopefully offer improved targeted therapies to prevent and treat the injury in the future. 相似文献
Objective: The purpose of this investigation is to characterize the expression of cyclooxygenase-2 (COX-2), 12-lipoxygenase (12-LO), inducible nitric oxide synthase 2 (iNOS2), and surfactant protein D (SFTPD) in lungs of patients who exposed to SM.
Methods: Lung biopsies were provided from SM-exposed patients (n?=?6) and controls (n?=?5). Total RNA were extracted from all specimens and then cDNA was synthesized for each sample. Changes in gene expression were measured using RT2 Profiler ?PCR Array.
Results: Pulmonary function tests revealed more obstructive and restrictive spirometric patterns among patients compared to the control group. Expression of COX-2 and 12-LO in the lung of patients was increased by 6.2555 (p?=?0.004) and 6.2379-folds (p?=?0.002), respectively. In contrast, expression of SF-D and iNOS genes was reduced by 8.5869-fold (p?=?0.005) and 2.4466-folds (p?=?0.011), respectively.
Conclusions: Mustard lungs were associated with overexpression of COX-2 and 12-LO, which are responsible for inflammation, overproduction of free radicals and oxidative stress. Downregulation of iNOS2 and SF-D are probably the reason for lung disease and dysfunction among these patients. Therefore, the expression of these genes could be an important, routine part of the management of such patients. 相似文献
Methods: A randomized crossover study in healthy subjects (N = 161) examined the bioequivalence, safety, and tolerability of tocilizumab after a single subcutaneous injection by AI versus PFS. A nonrandomized observational, real-life human factors study in RA patients (N = 54) assessed user (RA patients, caregivers, health care providers) ability to administer tocilizumab effectively by AI.
Results: Bioequivalence criteria for tocilizumab AI versus PFS were met for key pharmacokinetic parameters. Safety was comparable between devices and consistent with the established tocilizumab profile. In the real-life human factors study, the proportion of users who successfully performed all essential tasks required to operate the AI to deliver the full dose was 92.3% at first assessment and 98.1% at second assessment, with no safety concerns.
Conclusions: Tocilizumab administration by AI was bioequivalent to administration by PFS. Intended users were successful in performing the tasks required to administer tocilizumab by AI. No new safety signals were observed in either study.
Clinical Trial Registration: NCT02678988, NCT02682823 相似文献