| 1. |
- Das, A., et al.
(författare)
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Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency
- 2022
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 28:1, s. 125-135
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Tidskriftsartikel (refereegranskat)abstract
- Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion–deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10–100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in ‘immunologically cold’ tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy. © 2022, The Author(s).
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| 2. |
- Von Lensa, W., et al.
(författare)
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Red-impact : A European research programme to assess the impact of partitioning and transmutation on final nuclear waste disposal
- 2008
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Ingår i: Int. Congr. Adv. Nucl. Power Plants - ICAPP, "Nucl. Renaiss. Work". - 9781604238716 ; , s. 2564-2573
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Konferensbidrag (refereegranskat)abstract
- It is the objective of the EU-funded 'Red-Impact' project to analyse the impact of partitioning, transmutation and waste reduction technologies on the final nuclear waste disposal. The partnership of 25 organisations is originating from European nuclear industry, waste agencies, research centres and universities. The system studies focus on a realistic evolution of P&T technologies and advanced fuel cycles which can be deployed incrementally on an industrial scale as well as on future developments such as reactors of the third and fourth generation (Gen III & Gen IV) and Accelerator Driven Systems (ADS). A comprehensive inventory of all existing and foreseen nuclear fuel cycle facilities in Europe has been performed including a review on worldwide ongoing R&D programs on P&T. Thus, it was possible to select a set of three so-called "industrial scenarios", taking into account industrial feasibility of alternate strategies leading to increased actiniae burning and reduced actinide generation based on direct disposal (reference case) or MOXfuel for LWR and plutonium recycle in Sodium Fast Reactors (SFR). R&D needs for the development of processes and technologies have also been addressed. In addition, three 'innovative scenarios ' have been identified allowing multi-recycling of plutonium and minor actinides in SFR and Accelerator-Driven Systems (ADS) as well as GANEX or COEXprocess and PYRO reprocessing technologies. Waste streams have been calculated for all of these scenarios including the transition from the present situation towards new fuel cycle options. These data provide the input to specific analyses on the impact on geological disposal in different host formations such as granite, clay and salt. The results show that advanced fuel cycles influence the required size of the geological repository in case of disposal in clay, salt or hard rock formations. Recycling of all the actinides results in a reduction of the necessary gallery length (depending on geology and design) at least by a factor 3. If additionally cesium and strontium are extracted from the high-level waste for separate decay, the reduction factor will become 10 or more. In the frame of the project, the feasibility and the impact of the Cs or Sr separated management were not assessed or evaluated. Transmutation of the actinides fast neutron spectrum reactors (FR or ADS) results in a limited reduction of the maximum dose because the dose is essentially due to long-lived fission and activation products. On the other hand, reprocessing the spent fuel decreases the maximum dose at the storage with a factor 5 because a considerable fraction of the iodine is separated from the high level waste during reprocessing. The radiotoxicity in the high level waste or spent fuel as well as human intrusion doses after 500 years are drastically reduced by the transmutation of the actinides. Evaluating actinide minimization systems and industrialised P&T in general requires an assessment of relevant nuclear fuel cycles especially with regard to the economic, environmental and societal advantages/disadvantages (i.e. the sustainability of the fuel cycles). Thus, a set of indicators has been derived for each of these areas. The results are analysed using the multi-criterion analysis approach which allows the importance of each of the indicators to be specified.
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