Anti-inflammatory agents and monoHER protect against DOX-induced cardiotoxicity and accumulation of CML in mice

Cardiac damage is the major limiting factor for the clinical use of doxorubicin (DOX). Preclinical studies indicate that inflammatory effects may be involved in DOX-induced cardiotoxicity. Nɛ-(carboxymethyl) lysine (CML) is suggested to be generated subsequent to oxidative stress, including inflammation. Therefore, the aim of this study was to investigate whether CML increased in the heart after DOX and whether anti-inflammatory agents reduced this effect in addition to their possible protection on DOX-induced cardiotoxicity. These effects were compared with those of the potential cardioprotector 7-monohydroxyethylrutoside (monoHER)

Caspase-dependent and -independent suppression of apoptosis by monoHER in Doxorubicin treated cells

Doxorubicin (DOX) is an antitumour agent for different types of cancer, but the dose-related cardiotoxicity limits its clinical use. To prevent this side effect we have developed the flavonoid monohydroxyethylrutoside (monoHER), a promising protective agent, which did not interfere with the antitumour activity of DOX. To obtain more insight in the mechanism underlying the selective protective effects of monoHER, we investigated whether monoHER (1 mM) affects DOX-induced apoptosis in neonatal rat cardiac myocytes (NeRCaMs), human endothelial cells (HUVECs) and the ovarian cancer cell lines A2780 and OVCAR-3. DOX-induced cell death was effectively reduced by monoHER in heart, endothelial and A2780 cells. OVCAR-3 cells were highly resistant to DOX-induced apoptosis. Experiments with the caspase-inhibitor zVAD-fmk showed that DOX-induced apoptosis was caspase-dependent in HUVECs and A2780 cells, whereas caspase-independent mechanisms seem to be important in NeRCaMs. MonoHER suppressed DOX-dependent activation of the mitochondrial apoptotic pathway in normal and A2780 cells as illustrated by p53 accumulation and activation of caspase-9 and -3 cleavage. Thus, monoHER acts by suppressing the activation of molecular mechanisms that mediate either caspase-dependent or -independent cell death. In light of the current work and our previous studies, the use of clinically achievable concentrations of monoHER has no influence on the antitumour activity of DOX whereas higher concentrations as used in the present study could influence the antitumour activity of DOX

An Essential Difference between the Flavonoids MonoHER and Quercetin in Their Interplay with the Endogenous Antioxidant Network

Antioxidants can scavenge highly reactive radicals. As a result the antioxidants are converted into oxidation products that might cause damage to vital cellular components. To prevent this damage, the human body possesses an intricate network of antioxidants that pass over the reactivity from one antioxidant to another in a controlled way. The aim of the present study was to investigate how the semi-synthetic flavonoid 7-mono-O-(β-hydroxyethyl)-rutoside (monoHER), a potential protective agent against doxorubicin-induced cardiotoxicity, fits into this antioxidant network. This position was compared with that of the well-known flavonoid quercetin. The present study shows that the oxidation products of both monoHER and quercetin are reactive towards thiol groups of both GSH and proteins. However, in human blood plasma, oxidized quercetin easily reacts with protein thiols, whereas oxidized monoHER does not react with plasma protein thiols. Our results indicate that this can be explained by the presence of ascorbate in plasma; ascorbate is able to reduce oxidized monoHER to the parent compound monoHER before oxidized monoHER can react with thiols. This is a major difference with oxidized quercetin that preferentially reacts with thiols rather than ascorbate. The difference in selectivity between monoHER and quercetin originates from an intrinsic difference in the chemical nature of their oxidation products, which was corroborated by molecular quantum chemical calculations. These findings point towards an essential difference between structurally closely related flavonoids in their interplay with the endogenous antioxidant network. The advantage of monoHER is that it can safely channel the reactivity of radicals into the antioxidant network where the reactivity is completely neutralized

Resectability and Ablatability Criteria for the Treatment of Liver Only Colorectal Metastases:Multidisciplinary Consensus Document from the COLLISION Trial Group

The guidelines for metastatic colorectal cancer crudely state that the best local treatment should be selected from a 'toolbox' of techniques according to patient- and treatment-related factors. We created an interdisciplinary, consensus-based algorithm with specific resectability and ablatability criteria for the treatment of colorectal liver metastases (CRLM). To pursue consensus, members of the multidisciplinary COLLISION and COLDFIRE trial expert panel employed the RAND appropriateness method (RAM). Statements regarding patient, disease, tumor and treatment characteristics were categorized as appropriate, equipoise or inappropriate. Patients with ECOG≤2, ASA≤3 and Charlson comorbidity index ≤8 should be considered fit for curative-intent local therapy. When easily resectable and/or ablatable (stage IVa), (neo)adjuvant systemic therapy is not indicated. When requiring major hepatectomy (stage IVb), neo-adjuvant systemic therapy is appropriate for early metachronous disease and to reduce procedural risk. To downstage patients (stage IVc), downsizing induction systemic therapy and/or future remnant augmentation is advised. Disease can only be deemed permanently unsuitable for local therapy if downstaging failed (stage IVd). Liver resection remains the gold standard. Thermal ablation is reserved for unresectable CRLM, deep-seated resectable CRLM and can be considered when patients are in poor health. Irreversible electroporation and stereotactic body radiotherapy can be considered for unresectable perihilar and perivascular CRLM 0-5cm. This consensus document provides per-patient and per-tumor resectability and ablatability criteria for the treatment of CRLM. These criteria are intended to aid tumor board discussions, improve consistency when designing prospective trials and advance intersociety communications. Areas where consensus is lacking warrant future comparative studies.</p

The clinical introduction of MR-guided radiation therapy from a RTT perspective

The latest development in radiation oncology departments towards high precision and adaptive radiation therapy is the clinical introduction of magnetic resonance image guided radiation therapy (MRgRT). Early 2016, patient treatment using MRgRT was started at Amsterdam UMC, location VU University Medical Center. Introducing this novel technique in clinical practice requires thorough preparation with regard to important topics, such as MR-safety and training, equipping the treatment vault and console room, development of MRgRT workflow and logistical issues. Certainly when MRgRT is combined with daily plan adaptation, this indicates adjusting existing workflows and protocols. The MRgRT workflow requires a multidisciplinary process, and while each discipline has had its own tasks and responsibilities, with growing clinical experience there has been a shift towards RTT responsibilities. In this overview we discuss preclinical training and preparation for the implementation of (adaptive) MRgRT, with a particular focus on the perspective of RTTs. Although the reviewed logistics are partly the result of the decision to perform daily plan re-optimization, our experience can be extrapolated to implementation of alternative approaches for MRgRT

MR-guided Gated Stereotactic Radiation Therapy Delivery for Lung, Adrenal, and Pancreatic Tumors: A Geometric Analysis

PURPOSE: We implemented magnetic resonance-guided breath-hold stereotactic body radiation therapy in combination with visual feedback using the MRIdian system. Both accuracy of gated delivery and reproducibility of tumor positions were studied. METHODS AND MATERIALS: Tumor tracking is realized through repeated magnetic resonance imaging in a single sagittal plane at 4 frames per second with deformable image registration. An in-room monitor allowed visualization of the tracked gross tumor volume (GTV) contour and the planning target volume (PTV) (GTV + 3 mm), which was the gating boundary. For each delivery, a predefined threshold-region of interest percentage (ROI%) allows a percentage of GTV area to be outside the gating boundary before a beam-hold is triggered. Accuracy of gated delivery and tumor position reproducibility during breath-holds was analyzed for 15 patients (87 fractions) with lung, adrenal, and pancreas tumors. For each fraction, we analyzed (1) reproducibility of system-tracked GTV centroid position within the PTV; (2) geometric coverage of GTV area within the PTV; (3) treatment duty cycle efficiency; (4) effects of threshold ROI% settings on treatment duty cycle efficiency and GTV area coverage; and (5) beam-off latency effect on mean GTV coverage. RESULTS: For lung, adrenal, and pancreatic tumors, grouped 5th to 95th percentile distributions of GTV centroid positions in the dorsoventral direction, relative to PTV-center of mass (COM), were, respectively, -3.3 mm to 2.8 mm, -2.5 mm to 3.7 mm, and -4.4 mm to 2.9 mm. Corresponding distributions in the craniocaudal direction were -2.6 mm to 4.6 mm, -4.1 mm to 4.4 mm, and -4.4 mm to 4.5 mm, respectively. Mean GTV areas encompassed during beam-on for all fractions were 94.6%, 94.3%, and 95.3% for lung, adrenal, and pancreas tumors, respectively. Mean treatment duty cycle efficiency ranged from 67% to 87% for these tumors. Use of higher threshold-ROI% resulted in increased duty cycle efficiency, at the cost of a small decrease in GTV area coverage. The beam-off latency had a marginal impact on the GTV coverage. CONCLUSIONS: Gated stereotactic body radiation therapy delivery during breath-hold, real-time magnetic resonance guidance resulted in at least 95% geometric GTV coverage in lung, adrenal, and pancreatic tumors