Towards third generation matrix metalloproteinase inhibitors for cancer therapy

The failure of matrix metalloproteinase (MMP) inhibitor drug clinical trials in cancer was partly due to the inadvertent inhibition of MMP antitargets that counterbalanced the benefits of MMP target inhibition. We explore how MMP inhibitor drugs might be developed to achieve potent selectivity for validated MMP targets yet therapeutically spare MMP antitargets that are critical in host protection

Treatment plan comparison of proton vs photon radiotherapy for lower-grade gliomas

Background and purpose: Patients with lower-grade gliomas are long-term survivors after radiotherapy and may benefit from the reduced dose to normal tissue achievable with proton therapy. Here, we aimed to quantify differences in dose to the uninvolved brain and contralateral hippocampus and compare the risk of radiation-induced secondary cancer for photon and proton plans for lower-grade glioma patients. Materials and methods: Twenty-three patients were included in this in-silico planning comparative study and had photon and proton plans calculated (50.4 Gy(RBE = 1.1), 28 Fx) applying similar dose constraints to the target and organs at risk. Automatically calculated photon plans were generated with a 3 mm margin from clinical target volume (CTV) to planning target volume. Manual proton plans were generated using robust optimisation on the CTV. Dose metrics of organs at risk were compared using population mean dose-volume histograms and Wilcoxon signed-rank test. Secondary cancer risk per 10,000 persons per year (PPY) was estimated using dose-volume data and a risk model for secondary cancer induction. Results: CTV coverage (V95%>98%) was similar for the two treatment modalities. Mean dose (D-mean) to the uninvolved brain was significantly reduced from 21.5 Gy (median, IQR 17.1-24.4 Gy) with photons compared to 10.3 Gy(RBE) (8.1-13.9 Gy(RBE)) with protons. D-mean to the contralateral hippocampus was significantly reduced from 6.5 Gy (5.4-11.7 Gy) with photons to 1.5 Gy(RBE) (0.4-6.8 Gy(RBE)) with protons. The estimated secondary cancer risk was reduced from 6.7 PPY (median, range 3.3-10.4 PPY) with photons to 3.0 PPY (1.3-7.5 PPY) with protons. Conclusion: A significant reduction in mean dose to uninvolved brain and contralateral hippocampus was found with proton planning. The estimated secondary cancer risk was reduced with proton therapy

Is there a role for TNF-alpha antagonists in the treatment of SSc? EUSTAR expert consensus development using the Delphi technique

Objective: To obtain experiences and expert opinion on treatment of SSc patients with TNF-alpha antagonists. Methods: An investigation was carried out among the EUSTAR centres into their expertise on use of TNF-alpha antagonists. Assessment forms on the frequency of TNF-alpha inhibitor use were distributed to EULAR Scleroderma Trials and Research Group (EUSTAR) centres. Afterwards, a three round Delphi exercise was performed to obtain expert consensus on the use of TNF-alpha inhibitors in SSc. Results: Seventy-nine centres returned information on use of TNF-alpha antagonists in SSc patients. A total of 65 patients were treated with TNF-alpha inhibitors in 14 different centres. Forty-eight of the 65 patients treated with TNF-alpha inhibitors improved. Improvement was mainly seen in patients with arthritis, whereas the effects on fibrosis varied. In the first round of the subsequent Delphi approach, 71 out of 79 experts stated that they would use TNF-alpha antagonists in SSc. Arthritis was suggested as an indication for TNF alpha antagonists by 75% of the experts. However; after the third stage of the Delphi exercise, the acceptance for the off-label use of TNF-alpha antagonists decreased and 59% recommended that TNF-alpha antagonists should not be used or only used in clinical trials in SSc patients, while 38% of the experts suggested the use of TNF-alpha antagonists for arthritis associated with SSc. Conclusions: Most of the experts do not recommend the routine use of TNF-alpha antagonists in systemic sclerosis. Arthritis might be a potential indication in SSc, although controlled clinical trials with TNF-alpha antagonists are needed before general recommendations can be given.29265S40S45NovartisBayer Schering PharmaCell Gen TherapeuticsNicOxArray BioPharmaBristol-Myers SquibbErgonex Pharma GmbHActelion PharmaceuticalsPfizerGlaxoSmithKlineMerckAmgenAbbottRocheEUSTAR/EULARSanofi-AventisUnited BioSource CorporationMedacBiovitriumActive BiotechErgone

Is There A Role For Tnf-α Antagonists In The Treatment Of Ssc? Eustar Expert Consensus Development Using The Delphi Technique

Objective: To obtain experiences and expert opinion on treatment of SSc patients with TNF-α antagonists. Methods: An investigation was carried out among the EUSTAR centres into their expertise on use of TNF-α antagonists. Assessment forms on the frequency of TNF-α inhibitor use were distributed to EULAR Scleroderma Trials and Research Group (EUSTAR) centres. Afterwards, a three round Delphi exercise was performed to obtain expert consensus on the use of TNF-α inhibitors in SSc. Results: Seventy-nine centres returned information on use of TNF-α antagonists in SSc patients. A total of 65 patients were treated with TNF-a inhibitors in 14 different centres. Forty-eight of the 65 patients treated with TNF-α inhibitors improved. Improvement was mainly seen in patients with arthritis, whereas the effects on fibrosis varied. In the first round of the subsequent Delphi approach, 71 out of 79 experts stated that they would use TNF-α antagonists in SSc. Arthritis was suggested as an indication for TNFa antagonists by 75% of the experts. However, after the third stage of the Delphi exercise, the acceptance for the off-label use of TNF-a antagonists decreased and 59% recommended that TNF-α antagonists should not be used or only used in clinical trials in SSc patients, while 38% of the experts suggested the use of TNF-a antagonists for arthritis associated with SSc. Conclusions: Most of the experts do not recommend the routine use of TNF-a antagonists in systemic sclerosis. 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