Neuroinflammation is the response of the central nervous system to events that interfere with tissue homeostasis and represents a common denominator in virtually all neurological diseases. Activation ...of microglia, the principal immune effector cells of the brain, contributes to neuronal injury by release of neurotoxic products. Toll-like receptor 4 (TLR4), expressed on the surface of microglia, plays an important role in mediating lipopolysaccharide (LPS)-induced microglia activation and inflammatory responses. We have previously shown that curcumin and some of its analogues harboring an α,β-unsaturated 1,3-diketone moiety, able to coordinate the magnesium ion, can interfere with LPS-mediated TLR4-myeloid differentiation protein-2 (MD-2) signaling. Fluoroquinolone (FQ) antibiotics are compounds that contain a keto-carbonyl group that binds divalent ions, including magnesium. In addition to their antimicrobial activity, FQs are endowed with immunomodulatory properties, but the mechanism underlying their anti-inflammatory activity remains to be defined. The aim of the current study was to elucidate the molecular mechanism of these compounds in the TLR4/NF-κB inflammatory signaling pathway.
The putative binding mode of five FQs ciprofloxacin (CPFX), levofloxacin (LVFX), moxifloxacin, ofloxacin, and delafloxacin to TLR4-MD-2 was determined using molecular docking simulations. The effect of CPFX and LVFX on LPS-induced release of IL-1β and TNF-α and NF-κB activation was investigated in primary microglia by ELISA and fluorescence staining. The interaction of CPFX and LVFX with TLR4-MD-2 complex was assessed by immunoprecipitation followed by Western blotting using Ba/F3 cells.
CPFX and LVFX bound to the hydrophobic region of the MD-2 pocket and inhibited LPS-induced secretion of pro-inflammatory cytokines and activation of NF-κB in primary microglia. Furthermore, these FQs diminished the binding of LPS to TLR4-MD-2 complex and decreased the resulting TLR4-MD-2 dimerization in Ba/F3 cells.
These results provide new insight into the mechanism of the anti-inflammatory activity of CPFX and LVFX, which involves, at least in part, the activation of TLR4/NF-κB signaling pathway. Our findings might facilitate the development of new molecules directed at the TLR4-MD-2 complex, a potential key target for controlling neuroinflammation.
Persistent and/or recurrent inflammatory processes are the main factor leading to multiple sclerosis (MS) lesions. The composite ultramicronized palmitoylethanolamide, an endogenous ...N-acylethanolamine, combined with the flavonoid luteolin, PEALut, have been found to exert neuroprotective activities in experimental models of spinal and brain injury and Alzheimer disease, as well as a clinical improvement in human stroke patients. Furthermore, PEALut enhances the expression of different myelin proteins in oligodendrocyte progenitor cells suggesting that this composite might have protective effects in MS experimental models.
The mouse model of experimental autoimmune encephalomyelitis (EAE) based on active immunization with a fragment of myelin oligodendrocyte glycoprotein (MOG
) was used. The daily assessment of clinical score and the expression of serum amyloid A (SAA1), proinflammatory cytokines TNF-α, IL-1β, IFN-γ, and NLRP3 inflammasome, as well as TLR2, Fpr2, CD137, CD3-γ, and TCR-ζ chain, heterodimers that form T cell surface glycoprotein (TCR), and cannabinoid receptors CB
, CB
, and MBP, were evaluated in the brainstem and cerebellum at different postimmunization days (PIDs).
Vehicle-MOG
-immunized (MOG
) mice developed ascending paralysis which peaked several days later and persisted until the end of the experiment. PEALut, given intraperitoneally daily starting on day 11 post-immunization, dose-dependently improved clinical score over the range 0.1-5 mg/kg. The mRNA expression of SAA1, TNF-α, IL-1β, IFN-γ, and NLRP3 were significantly increased in MOG
mice at 14 PID. In MOG
mice treated with 5 mg /kg PEALut, the increase of SAA1, TNF- α, IL-1β, and IFN-γ transcripts at 14 PID was statistically downregulated as compared to vehicle-MOG
mice (p < 0.05). The expression of TLR2, Fpr2, CD137, CD3-γ, TCR-ζ chain, and CB
receptors showed a significant upregulation in vehicle-MOG
mice at 14 PID. Instead, CB
and MBP transcripts have not changed in expression at any time. In MOG/PEALut-treated mice, TLR2, Fpr2, CD137, CD3-γ, TCR-ζ chain, and CB
mRNAs were significantly downregulated as compared to vehicle MOG
mice.
The present results demonstrate that the intraperitoneal administration of the composite PEALut significantly reduces the development of clinical signs in the MOG
model of EAE. The dose-dependent improvement of clinical score induced by PEALut was associated with a reduction in transcript expression of the acute-phase protein SAA1, TNF-α, IL-1β, IFN-γ, and NLRP3 proinflammatory proteins and TLR2, Fpr2, CD137, CD3-γ, TCR-ζ chain, and CB
receptors.
Purpose
For patients with oligometastatic/oligorecurrent/oligoprogressive lymph node metastases from PCa, metastases-directed therapy is an emerging strategy. The aim of this retrospective study was ...to evaluate the oncological outcome and pattern of recurrence in patients treated with stereotactic body radiation therapy (SBRT) to lymph node metastases.
Methods
In this multi-institutional analysis, patients with a maximum of five lymph node metastases from PCa treated with SBRT were included. Primary endpoints of the analysis were local control (LC), out-of-field nodal progression-free survival (NPFS), overall progression-free survival (PFS), and overall survival (OS).
Results
109 patients and 155 lymph node metastases were evaluated. Patients’ median age was 70.8 years (range 51–84) and median PSA before SBRT was 1.88 ng/ml (range 0.3–45.5 ng/ml). The dose delivered to the target ranged from 25 to 48 Gy in 4–7 fractions; median BED
1.5
Gy
was 198 Gy (range 108.3–432 Gy). With a median follow-up of 16 months, LC rates at 1 and 3 years were 93% and 86%, respectively. In-field progression of disease was observed in 11 (7%) lesions. One- and 3‑year NPFS was 59% and 29%, and median NPFS was 15 months. Rates of OS at 1 and 3 years were 100% and 95%. The median time to administration of a systemic treatment after SBRT was 7.8 months (1.7–54.8).
Conclusion
SBRT is an effective and well-tolerated treatment option in the management of lymph node metastases from PCa. Prospective trials are necessary to better select patients who benefit most from this ablative focal treatment and better define the recurrence patterns.
Purpose:
To ascertain whether a new delivery system (the Halcyon system) equipped with dual-layer stacked multileaf collimator operating in a mode, which allows independent, fully interdigitating ...motion of both layers and 6 flattening filter free energy, could generate plans of high clinical quality compared to a well-established delivery system with single layer multileaf collimator.
Methods:
Twenty patients in each of the 3 groups (advanced head and neck, breast, and high-risk prostate) were selected for an in silico planning study. For each patient, reference plans were developed for volumetric modulated arc therapy technique with 6 MV photon beams from a TrueBeam linear accelerator and compared against the corresponding plans for the Halcyon system. Plan comparison was performed in terms of dose volume histogram quantitative analysis.
Results:
Concerning the planning target volumes, with identical dose calculation and optimization algorithms and with identical planning techniques, no clinically relevant difference in coverage (D98%), hot spot (D2%), or homogeneity was observed. Similarly, for all the organs at risk, the dosimetric findings showed that (1) all planning constraints were met by the 2 delivery systems and (2) although statistical significant differences were reported for most of the parameters but none of these were judged of potential clinical relevance.
Conclusion:
The data presented confirmed that the new delivery system can generate treatment plans for volumetric modulated arc therapy with the same dosimetric quality of what is achievable with other systems routinely used in the clinics without significantly changing the current practice. Additional studies which customize the optimization parameters for each delivery device would complement the spectrum of investigations.
Introduction: Neoadjuvant radiotherapy is currently used mainly in locally advanced rectal cancer and sarcoma and in a subset of non-small cell lung cancer and esophageal cancer, whereas in other ...diseases it is under investigation. The evaluation of the efficacy of the induction strategy is made possible by performing imaging investigations before and after the neoadjuvant therapy and is usually challenging. In the last decade, texture analysis (TA) has been developed to help the radiologist to quantify and identify the parameters related to tumor heterogeneity, which cannot be appreciated by the naked eye. The aim of this narrative is to review the impact of TA on the prediction of response to neoadjuvant radiotherapy and or chemoradiotherapy. Materials and Methods: Key references were derived from a PubMed query. Hand searching and ClinicalTrials.gov were also used. Results: This paper contains a narrative report and a critical discussion of radiomics approaches in different fields of neoadjuvant radiotherapy, including esophageal cancer, lung cancer, sarcoma, and rectal cancer. Conclusions: Radiomics can shed a light on the setting of neoadjuvant therapies that can be used to tailor subsequent approaches or even to avoid surgery in the future. At the same, these results need to be validated in prospective and multicenter trials.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is not restricted to the neuronal compartment but includes important interactions with immune cells, including microglia. ...Protein aggregates, common pathological hallmarks of AD, bind to pattern recognition receptors on microglia and trigger an inflammatory response, which contributes to disease progression and severity. In this context, curcumin is emerging as a potential drug candidate able to affect multiple key pathways implicated in AD, including neuroinflammation. Therefore, we studied the effect of curcumin and its structurally related analogues
and
on amyloid-β (Aβ)-induced microglia activation and neuronal cell death, as well as their effect on the modulation of Aβ aggregation. Primary cortical microglia and neurons were exposed to two different populations of Aβ42 oligomers (Aβ42Os) where the oligomeric state had been assigned by capillary electrophoresis and ultrafiltration. When stimulated with high molecular weight Aβ42Os, microglia released proinflammatory cytokines that led to early neuronal cell death. The studied compounds exerted an anti-inflammatory effect on high molecular weight Aβ42O-stimulated microglia and possibly inhibited microglia-mediated neuronal cell toxicity. Furthermore, the tested compounds demonstrated antioligomeric activity during the process of in vitro Aβ42 aggregation. These findings could be investigated further and used for the optimization of multipotent candidate molecules for AD treatment.
Introduction
Biliary tract cancers (BTC) are rare malignancies arising from biliary system. Systemic therapy is the cornerstone for stage IV disease, with poor overall survival (OS). Evidence is ...lacking about safety and efficacy of local ablative treatments, such as surgery and stereotactic body radiotherapy (SBRT) in the context of metastatic BTC (mBTC).
Materials and methods
We retrospectively analyzed clinical outcomes for a cohort of mBTC patients treated with SBRT for oligometastatic disease. Inclusion criteria were 1–5 distant metastases; SBRT with a dose/fraction of a least 5 Gy to a biological effective dose (BED) of at least 40 Gy considering an
α
/
β
of 10 Gy. Analyzed outcomes included local control (LC), distant progression-free survival (DPFS), PFS, and OS.
Results
51 patients meeting the inclusion criteria. Primary tumor sites were intrahepatic cholangiocarcinoma (35%), extrahepatic cholangiocarcinoma (31%), ampullary adenocarcinoma (20%), gallbladder adenocarcinoma (14%). 21 patients were treated on liver lesions, 17 on nodal metastasis, 5 patients on lung lesions, 4 patients on recurrence along the extrahepatic bile duct. After a median follow-up of 14 months median OS was 13.7 months, 1- and 2-year OS were 58% and 41%, respectively. Node and lung as metastatic sites were associated with a longer OS (
p
< 0.001). Median LC was 26.8 months, and intrahepatic cholangiocarcinoma was associated with longer LC (
p
= 0.036). Median DPFS was 11 months, with 1- and 2-year DPFS of 48% and 27.8%, respectively. Ten patients reported grade 1–2 toxicity and 2 cases of acute G3 biliary obstruction.
Conclusions
Stereotactic body radiotherapy (SBRT) is feasible in the context of mBTC. OS and PFS results are promising, considering that our patients were heavily pre-treated with systemic therapy. Patients with nodal or lung relapse have better prognosis. Distant relapses remain the main pattern of failure, but treatment of all metastatic sites seems to improve DMFS.
To analyze RapidPlan knowledge-based models for DVH estimation of organs at risk from breast cancer VMAT plans presenting arc sectors en-face to the breast with zero dose rate, feature imposed during ...the optimization phase (avoidance sectors AS).
CT datasets of twenty left breast patients in deep-inspiration breath-hold were selected. Two VMAT plans, PartArc and AvoidArc, were manually generated with double arcs from ~ 300 to ~ 160°, with the second having an AS en-face to the breast to avoid contralateral breast and lung direct irradiation. Two RapidPlan models were generated from the two plan sets. The two models were evaluated in a closed loop to assess the model performance on plans where the AS were selected or not in the optimization.
The PartArc plans model estimated DVHs comparable with the original plans. The AvoidArc plans model estimated a DVH pattern with two steps for the contralateral structures when the plan does not contain the AS selected in the optimization phase. This feature produced mean doses of the contralateral breast, averaged over all patients, of 0.4 ± 0.1 Gy, 0.6 ± 0.2 Gy, and 1.1 ± 0.2 Gy for the AvoidArc plan, AvoidArc model estimation, RapidPlan generated plan, respectively. The same figures for the contralateral lung were 0.3 ± 0.1 Gy, 1.6 ± 0.6 Gy, and 1.2 ± 0.5 Gy. The reason was found in the possible incorrect information extracted from the model training plans due to the lack of knowledge about the AS. Conversely, in the case of plans with AS set in the optimization generated with the same AvoidArc model, the estimated and resulting DVHs were comparable. Whenever the AvoidArc model was used to generate DVH estimation for a plan with AS, while the optimization was made on the plan without the AS, the optimizer evidentiated the limitation of a minimum dose rate of 0.2 MU/°, resulting in an increased dose to the contralateral structures respect to the estimation.
The RapidPlan models for breast planning with VMAT can properly estimate organ at risk DVH. Attention has to be paid to the plan selection and usage for model training in the presence of avoidance sectors.
During these last years, new agents have dramatically improved the survival of the metastatic patients. Oligometastases represent a continuous field of interest in which the integration of ...metastases-directed therapy and drugs could further improve the oncologic outcomes. Herein a narrative review is performed regarding the main rationale in combining immunotherapy and target therapies with SBRT looking at the available clinical data in case of oligometastatic NSCLC, Melanoma and Kidney cancer.
Narrative Review regarding retrospective and prospective studies published between January 2009 to November 2019 with at least 20 patients analyzed.
Concerning the combination between SBRT and Immunotherapy, the correct sequence of remains uncertain, and seems to be drug-dependent. The optimal patients' selection is crucial to expect substantial benefits to SBRT/Immunotherapy combination and, among several factors. A potential field of interest is represented by the so-called oligoprogressed disease, in which SBRT could improve the long-term efficacy of the existing target therapy.
A low tumor burden seems to be the most relevant, thus making the oligometastatic disease represent the ideal setting for the use of combination therapies with immunological drugs.
Background
To investigate the role of intensity-modulated proton therapy (IMPT) compared to volumetric modulated arc therapy (VMAT) for the radiation treatment of thymoma cancer.
Methods
Twenty ...patients were retrospectively planned for IMPT with (IMPT_R1 or IMPT_R2 according to the approach adopted) and without robust optimization and VMAT. The results were compared according to dose-volume metrics on the clinical and planning target volumes (CTV and PTV) and the main organs at risk (heart, breasts, lungs, spinal cord and oesophagus). Estimates of the excess absolute risk (EAR) of secondary cancer induction were determined for the oesophagus, the breasts and the composite lungs. For the heart, the relative risk (RR) of chronic heart failure (CHF) was assessed.
Results
IMPT and VMAT plans resulted equivalent in terms of target coverage for both the CTV and the PTV. The CTV homogeneity index resulted in 0.03 ± 0.01 and 0.04 ± 0.01 for VMAT and all IMPT plans, respectively. The conformality index resulted in 1.1 ± 0.1 and 1.2 ± 0.1 for VMAT and all IMPT plans. The mean dose to the breasts resulted in 10.5 ± 5.0, 4.5 ± 3.4, 4.7 ± 3.5 and 4.6 ± 3.4 Gy for VMAT, IMPT, IMPT_R1 and IMPT_R2. For the lungs, the mean dose was 9.6 ± 2.3, 3.5 ± 1.5, 3.6 ± 1.6 and 3.8 ± 1.4 Gy; for the heart: 8.7 ± 4.4, 4.3 ± 1.9, 4.5 ± 2.0 and 4.4 ± 2.4 Gy and for the oesophagus 8.2 ± 3.5, 2.2 ± 3.4, 2.4 ± 3.6 and 2.5 ± 3.5 Gy. The RR for CHF was 1.6 ± 0.3 for VMAT and 1.3 ± 0.2 for IMPT (R1 or R2). The EAR was 3.6 ± 0.v vs 1.0 ± 0.6 or 1.2 ± 0.6 (excess cases/10,000 patients year) for the oesophagus; 17.4 ± 6.5 vs 5.7 ± 3.2 or 6.1 ± 3.8 for the breasts and 24.8 ± 4.3 vs 8.1 ± 2.7 or 8.7 ± 2.3 for the composite lungs for VMAT and IMPT_R, respectively.
Conclusion
The data from this in-silico study suggest that intensity-modulated proton therapy could be significantly advantageous in the treatment of thymoma patients with particular emphasis to a substantial reduction of the risk of cardiac failure and secondary cancer induction. Robust planning is a technical pre-requisite for the safety of the delivery.
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