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Background: The anti-programmed cell death-1 (PD-1) inhibitors pembrolizumab and nivolumab alone or in combination with ipilimumab have shown improved objective response rates and progression-free survival compared to ipilimumab only in advanced melanoma patients. Anti-PD-1 therapy demonstrated nearly equal clinical efficacy in patients who had progressed after ipilimumab or were treatment-nave. However, only limited evidence exists regarding the efficacy of ipilimumab alone or in combination with nivolumab after treatment failure to anti-PD-therapy.
Patients and methods: A multicenter retrospective study in advanced melanoma patients who were treated with nivolumab (1 or 3 mg/kg) and ipilimumab (1 mg or 3 mg/kg) or ipilimumab (3 mg/kg) alone after treatment failure to anti-PD-1 therapy was performed. Patient, tumour, pre- and post-treatment characteristics were analysed.
Conclusions: Ipilimumab should be considered as a viable treatment option for patients with failure to prior anti-PD-1 therapy, including those with progressive disease as best response to prior anti-PD-1. In contrast, the combination of ipilimumab and nivolumab appears significantly less effective in this setting compared to treatment-nave patients.
The combination of Sono and Stim allows unparalleled flexibility and variety of treatment programs. In addition to ultrasound therapy and electrotherapy, SonoStim offers outstanding specific combined treatments. An undeniable therapeutic bonus.
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Synchronized, Alternate, Separate, Sequential Current Types Monophasic, Biphasic, TENS, Medium Frequency, Inferential, High Volt, Micro Current, Premodulated IFC Channels 2 independent channels (programs, intensities, parameters) Programs More than 50 specific programs Specific Modules Muscle rehabilitation / Sports rehabilitation
SD memory card 1GB SD memory card / 120 memory entries + favorites entries Accessory Support 2 supports supplied with all versions Dimensions Width 13 in / Height 5.1 in / Depth 8.7 in / Weight 4.4 lb Optional Accessories Move Carts, designed for Soleoline with a special magnetic holder for improved cable management
On February 26, the agency approved the targeted therapy as an initial, or first-line, treatment in postmenopausal women with advanced or metastatic breast cancer whose tumors are hormone receptor (HR)-positive and HER2-negative.
Abemaciclib is one of a class of targeted cancer therapies that block the activity of CDK4 and CDK6 proteins (CDK4/6). These proteins can serve as dual threats, fueling the progression of breast tumors and helping to make them resistant to commonly used treatments like aromatase inhibitors.
Two other CDK4/6 inhibitors, ribociclib (Kisqali) and palbociclib (Ibrance), were previously approved as first-line treatments in postmenopausal women with HR-positive, HER2-negative metastatic breast cancer.
In the phase 3 clinical trial that led to the approval of abemaciclib, called MONARCH 3, the drug substantially increased how long women lived without their disease progressing (progression-free survival).
FDA initially approved abemaciclib in October 2017 for women with HR-positive, HER2-negative advanced breast cancer whose disease had returned after treatment with aromatase inhibitors or other hormone therapies.
MONARCH 3 enrolled nearly 500 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had not previously received treatment for advanced cancer. Trial participants were randomly assigned to receive abemaciclib or a placebo, together with one of two aromatase inhibitors, anastrozole (Arimidex) or letrozole (Femara). The trial was funded by Eli Lilly, which manufactures abemaciclib.
In addition to experiencing improved progression-free survival, more women treated with abemaciclib and an aromatase inhibitor experienced at least some reduction in the size of their tumors than women treated only with an aromatase inhibitor: 59% versus 44%.
As with other studies involving abemaciclib, the most frequent serious side effect for those receiving the drug was diarrhea, which occurred in approximately 80% of patients. This side effect was usually manageable, the trial leaders reported, with most cases of diarrhea treated with commonly used medications and/or reductions in the abemaciclib dose.
Despite sharing the same molecular target in cancer cells, each of the three drugs has different side effects, Dr. Zimmer said. And those differences may help to identify which patients might be best off receiving which drug.
For example, serious diarrhea is more common with abemaciclib than either palbociclib or ribociclib, she noted. Meanwhile, a substantial drop in white blood cells (neutropenia) is more common in patients treated with palbociclib, and patients treated with ribociclib are more likely to experience a type of change in heart rhythm called QT prolongation.
Among the larger questions now, Dr. Zimmer said, is whether women being treated with a CDK4/6 inhibitor whose cancer begins to progress should continue the treatment along with the addition of another therapy.
Another question is whether CDK4/6 inhibitors might improve outcomes in women with early-stage cancer. All three FDA-approved CDK4/6 inhibitors, in fact, are being tested in large phase 3 clinical trials of women with early-stage HR-positive, HER2-negative breast cancer, both as a presurgical (neoadjuvant) and a post-surgical (adjuvant) treatment.
Other trials are also testing CDK4/6 inhibitors in women with HER2-positive breast cancer, using the drugs in combination with HER2-targeted therapies like trastuzumab (Herceptin) and lapatinib (Tykerb), Dr. Forero noted.
Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system. However, studies of MS and the animal model, experimental autoimmune encephalomyelitis (EAE), indicate that neuronal pathology is the principle cause of clinical disability. Thus, there is need to develop new therapeutic strategies that not only address immunomodulation but also neuroprotection. Here we show that the combination therapy of Glatiramer acetate (GA), an immunomodulatory MS therapeutic, and the neuroprotectant epigallocatechin-3-gallate (EGCG), the main phenol in green tea, have synergistic protective effects in vitro and in the EAE model. EGCG and GA together led to increased protection from glutamate- and TRAIL-induced neuronal cell death in vitro. EGCG combined with GA induced regeneration of hippocampal axons in an outgrowth assay. The combined application of EGCG and GA did not result in unexpected adverse events in vivo. Neuroprotective and neuroregenerative effects could be translated in the in vivo model, where combination treatment with EGCG and GA significantly delayed disease onset, strongly reduced clinical severity, even after onset of symptoms and reduced inflammatory infiltrates. These results illustrate the promise of combining neuroprotective and anti-inflammatory treatments and strengthen the prospects of EGCG as an adjunct therapy for neuroinflammatory and neurodegenerative diseases.
Copyright: 2011 Herges et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by the Deutsche Forschungsgemeinschaft (DFG) with SFB-TRR 43 to F.Z. and by the Will Foundation. K.H. received a fellowship from the German academic exchange program (DAAD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Multiple Sclerosis (MS) is a common inflammatory autoimmune disease of the central nervous system (CNS) in which myelin-specific CD4+Th1 and Th17 cells are thought to orchestrate effector processes resulting in the destruction of the myelin sheath [1]. Recent studies in MS and the animal model, experimental autoimmune encephalomyelitis (EAE) suggest that already during the early phase of disease, neuronal pathology involving axonal transection and loss of parental cell bodies play a pivotal role in clinical severity and correlate better with long-term disability than the degree of demyelination [2], [3], [4]. Regarding the underlying mechanisms, we showed that tumor necrosis factor related apoptosis inducing ligand (TRAIL) contributes to inflammatory neurodegeneration [5]. Activated T cells and microglia secrete TRAIL, which acts as a death signal on neurons and susceptible oligodendrocytes [5], [6], [7]. Furthermore, excitotoxicity and oxidative stress play a major role as mediators of axonal damage [8]. However, currently approved treatments focus primarily on immunomodulation, and are only partially effective. Thus, new therapeutic strategies that include neuroprotective as well as neuroregenerative aspects are required. One promising strategy is the use of combination therapies based on drugs that may complement one another in order to provide additive benefit [9].
Glatiramer acetate (GA, Copaxone, Copolymer 1) is an immunomodulatory agent for treatment of relapsing-remitting MS. GA is a synthetic basic random copolymer composed of tyrosine, glutamate, alanine and lysine that induces GA-specific Th2 cells which secrete anti-inflammatory cytokines in the CNS through cross-recognition with myelin autoantigens [10]. Recently, it has been shown that GA promotes neurogenesis, neuroprotection and remyelination in MS lesions mediated by neurotrophic factors such as brain-derived neurotrophic factor (BDNF), Neurotrophin 3 and Neurotrophin 4 produced by GA-specific Th2 cells [11], [12], [13]. New studies also indicate that GA can induce anti-inflammatory type II monocytes, that are characterized by increased secretion of interleukin (IL)-10 and decreased production of IL-12 and that can direct differentiation of Th2 cells and CD4+CD25+FoxP3+ regulatory T cells [14].
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