A one-year cost–utility analysis of resuscitative endovascular balloon occlusion of the aorta versus resuscitative thoracotomy with aortic cross-clamping for non-compressible torso haemorrhage

Introduction Major trauma is a leading cause of death and disability in young adults, especially from massive non- compressible torso haemorrhage. The standard technique to control distal haemorrhage and maximise central perfusion is resuscitative thoracotomy with aortic cross-clamping (RTACC). More recently, the minimally invasive technique of resuscitative endovascular balloon occlusion of the aorta (REBOA) has been developed to similarly limit distal haemor- rhage without the morbidity of thoracotomy; cost–utility studies on this intervention, however, are still lacking. The aim of this study was to perform a one-year cost–utility analysis of REBOA as an intervention for patients with major traumatic non-compressible abdominal haemorrhage, compared to RTACC within the U.K.’s National Health Service. Methods A retrospective analysis of the outcomes following REBOA and RTACC was conducted based on the published literature of survival and complication rates after intervention. Utility was obtained from studies that used the EQ- 5D index and from self-conducted surveys. Costs were calculated using 2016/2017 National Health Service tariff data and supplemented from further literature. A cost–utility analysis was then conducted. Results A total of 12 studies for REBOA and 20 studies for RTACC were included. The mean injury severity scores for RTACC and REBOA were 34 and 39, and mean probability of death was 9.7 and 54%, respectively. The incremental cost- effectiveness ratio of REBOA when compared to RTACC was £44,617.44 per quality-adjusted life year. The incremental cost-effectiveness ratio, by exceeding the National Institute for Health and Clinical Effectiveness’s willingness-to-pay threshold of £30,000/quality-adjusted life year, suggests that this intervention is not cost-effective in comparison to RTACC. However, REBOA yielded a 157% improvement in utility with a comparatively small cost increase of 31.5%. Conclusion Although REBOA has not been found to be cost-effective when compared to RTACC, ultimately, clinical experience and expertise should be the main factor in driving the decision over which intervention to prioritise in the emergency context

Effects of the Tankyrase inhibition in Human Medulloblastoma cell lines

Tanchirasi (TNKS) è un membro della superfamiglia delle PARP (Poli ADP-Ribosio Polimerasi). TNKS è coinvolta nella stabilizzazione della subunità catalitca del complesso proteico DNA-PK (protein chinasi DNA-dipendente), la DNA-PKcs. Questa proteina è fondamentale per il corretto funzionamento del meccanismo di riparo del DNA chiamato "Saldatura Non Omologa delle Estremità" (NHEJ). La deplezione di TNKS induce una degradazione della DNA-PKcs e una maggiore sensibilità alle radiazioni ionizzanti (RI). TNKS è inoltre un regolatore negativo di axina e di conseguenza un attivatore del pathway di WNT; l'inibizione quindi di TNKS induce anche una inibizione del pathway di WNT. Alterazioni in questo signalling si riscontrano frequentemente nel Medulloblastoma (MB), il tumore cerebrale embrionale più comune dell'infanzia. La radioterapia post-operatoria risulta essere molto efficacia in questa neoplasia, ma causa gravi effetti collaterali e un terzo dei pazienti presenta radioresistenza intrinseca. Un'importante sfida per la ricerca è quindi l'aumento della radiosensibilità tumorale. In questo lavoro, abbiamo studiato gli effetti dell'inibizione farmacologica di TNKS in linee cellulari di MB umano, mediante la small molecule XAV939, potente e specifico inibitore di TNKS. Il trattamento con XAV939 induce una consistente inibizione della capacità proliferativa e clonogenica, non correlata ad un aumento della mortalità cellulare, indicando una bassa tossicità legata alla molecola. Il co-trattamento di XAV939 e RI (γ-ray, dose 2 Gy) causa una ulteriore inibizione della proliferazione cellulare e della capacità di formare colonie. Abbiamo inoltre constatato, mediante Neutral Comet Assay, una minore efficacia nel riparo del DNA in cellule irradiate trattate con XAV939, indicando un effettivo aumento della radiosensibilità in cellule di MB trattate con l'inibitore di TNKS. L'aumentata mortalità cellulare in cellule tumorali trattate con XAV939 e RI ha confermato la nostra ipotesi. Il nostro studio in vitro indica come TNKS possa essere un utile target terapeutico per rendere più efficace l'attuale terapia contro il MB.Tankyrase (TNKS) is a member of the poly-ADP-ribose polymerase (PARP) family. TNKS is involving in the stabilization of the “non-homologous end-joining” (NHEJ) proteins complex, referred as “DNA-dependent protein kinase” (DNA-PK). TNKS depletion resulted in degradation of catalytic subunit of DNA-PK (DNA-PKcs) causing increased sensitivity to ionizing radiation (IR). Moreover, TNKS interacts with Axin, stimulating its degradation and arising in a WNT/β-catenin pathway activation; thus, a TNKS protein reduction induces a WNT pathway inhibition. Alterations in this pathway often occur in Medulloblastoma (MB), the most common pediatric malignant brain tumor. Furthermore, post-operative radiotherapy is very effective for MB, but survivors have severe long-terms side effects and radiotherapy response sometimes is limited by intrinsic radioresistance. Hence, an important challenge is to improve radio-sensitivity. In this study we showed the consequences of pharmacological TNKS inhibition on human MB cell lines using the small molecule XAV939, a potent and specific TNKS-PARP activity inhibitor. XAV939 treatment on MB cell lines resulted in a consistent proliferative and clonogenic capability decrease, not related to cell mortality increase, showing the low toxicity of the small molecule. The co-administration of XAV939 and IR (γ-ray, dose 2 Gy) induced a massive inhibition of the clonogenic and proliferative capacity compared to controls. Moreover, we observed, by Neutral Comet Assay, a minor efficacy of the DNA repair in XAV939 and IR treated cells related to IR treated cells, indicating an enhanced MB cells radiosensitivity mediated by TNKS inhibition. The cell mortality increase in XAV939 and IR treated cells, compared to controls, confirmed our thesis. Our in vitro results suggested TNKS as a possible therapeutic target to improve current therapy in MB

XAV939 inhibits TNKS PARP-activity in MB cell lines.

<p>WB analysis and densitometry of total and nuclear MB cells extracts after XAV939 treatment: MB cell lines (DAOY, ONS-76) were treated with 5 μM XAV939 or with an equal volume of DMSO. <b>A.</b> Both cell lines showed an increase in total Axin protein levels at 8 h after treatment (80% and 70% respectively in ONS-76 and DAOY compared to DMSO treated control, <i>p</i> <. 05), followed by a β-catenin decrease in total (30%, <i>p</i> <. 05) and, in particular, in nuclear extracts, at 16 h after drug administration (80% reduction compared with control, <i>p</i> <. 001). <b>B.</b> XAV939 induced a DNA-PKcs protein level reduction of about 40% at 8 h and 16 h after treatment compared to non-treated control cells (<i>p</i> <. 05 in A, <i>p</i> <. 01 in B). Densitometry data (mean ± s.e.) were normalized with β-actin (for total extracts) and lamin-b (for nuclear extracts) and are representative of the results derived from three independent experiments.</p

XAV939 impairs the clonogenic and proliferative capacity and enhances MB cells radio-sensitivity.

<p><b>A.</b><i>Growth curves assay</i>. XAV939 (5 μM) treated cells and IR (2 Gy) treated cells showed a similar growth rate with about 40% (DAOY) and 30% (ONS-76) reductions compared to DMSO control cells (<i>p</i> <. 01). In both cell lines, the co-administration of XAV939 and IR induces a massive cell proliferation inhibition with a decrease of about 70% (<i>p</i> <. 001). Each point represents the mean ± s.e. of three independent assays. <b>B.</b><i>Clonogenic forming assay</i>. XAV939 alone (5 μM) inhibits a clone-forming ability in both MB cell lines as well as IR treatment (2 Gy), with a clonogenic capability reduction of about 38% (<i>p</i> <. 01). The IR and drug co-administration induces a drastic inhibition of clone-forming in both cell lines (70% reduction in DAOY cells and 81% in ONS-76 compared with control cells, <i>p</i> <. 001).</p

XAV939 affects the DNA repair efficacy of MB cell lines.

<p>Neutral Comet Assay was performed on IR treated cells (10 Gy), with or without XAV939 administration, at different time points post radiations (0, 16, and 24 h). Histograms represent mean ± s.e. of TM measured in at least three independent experiments for each treatment and time point. The greatest TM was observed immediately after IR treatment in both cell lines (A: DAOY, B: ONS-76). XAV939 induces enhanced TM values at 16 h and 24 h after IR compared to DMSO irradiated cells indicating a minor DNA repair capacity. On the right of the figure, a representative example of comets for each treatment obtained in DAOY (upper) and ONS-76 (down) cells.</p

Biological Process Analysis MB cells.

<p>Biological Process Analysis MB cells.</p

Transmission electron microscopy.

<p>MBS from DAOY (<b>A</b>), UW228 (<b>B</b>) and ONS-76 (<b>C</b>) show a uniform stem-like aspect characterized by a high N:C ratio; nucleus is irregularly shaped and cytoplasm appears sparsely organized with unspecific electron-dense organelles (<b>B</b>) and vacuoles (<b>A</b>). MB cell lines feature a low N:C ratio (<b>D, E</b>): nuclei exhibit an irregular profile and are peripherally located; the cytoplasm is populated by many organelles, such as RER, Golgi apparatus and mitochondria. On the contrary, ONS MB seem to maintain stemness appearance (<b>F</b>) as seen in the high N:C ratio with a kidney-shaped nucleus rimmed by a thin layer of cytoplasm.</p