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- Mourikis, TP, et al.
(författare)
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Patient-specific cancer genes contribute to recurrently perturbed pathways and establish therapeutic vulnerabilities in esophageal adenocarcinoma
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3101-
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Tidskriftsartikel (refereegranskat)abstract
- The identification of cancer-promoting genetic alterations is challenging particularly in highly unstable and heterogeneous cancers, such as esophageal adenocarcinoma (EAC). Here we describe a machine learning algorithm to identify cancer genes in individual patients considering all types of damaging alterations simultaneously. Analysing 261 EACs from the OCCAMS Consortium, we discover helper genes that, alongside well-known drivers, promote cancer. We confirm the robustness of our approach in 107 additional EACs. Unlike recurrent alterations of known drivers, these cancer helper genes are rare or patient-specific. However, they converge towards perturbations of well-known cancer processes. Recurrence of the same process perturbations, rather than individual genes, divides EACs into six clusters differing in their molecular and clinical features. Experimentally mimicking the alterations of predicted helper genes in cancer and pre-cancer cells validates their contribution to disease progression, while reverting their alterations reveals EAC acquired dependencies that can be exploited in therapy.
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- Turkington, RC, et al.
(författare)
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Immune activation by DNA damage predicts response to chemotherapy and survival in oesophageal adenocarcinoma
- 2019
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Ingår i: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 68:11, s. 1918-1927
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Tidskriftsartikel (refereegranskat)abstract
- Current strategies to guide selection of neoadjuvant therapy in oesophageal adenocarcinoma (OAC) are inadequate. We assessed the ability of a DNA damage immune response (DDIR) assay to predict response following neoadjuvant chemotherapy in OAC.DesignTranscriptional profiling of 273 formalin-fixed paraffin-embedded prechemotherapy endoscopic OAC biopsies was performed. All patients were treated with platinum-based neoadjuvant chemotherapy and resection between 2003 and 2014 at four centres in the Oesophageal Cancer Clinical and Molecular Stratification consortium. CD8 and programmed death ligand 1 (PD-L1) immunohistochemical staining was assessed in matched resection specimens from 126 cases. Kaplan-Meier and Cox proportional hazards regression analysis were applied according to DDIR status for recurrence-free survival (RFS) and overall survival (OS).ResultsA total of 66 OAC samples (24%) were DDIR positive with the remaining 207 samples (76%) being DDIR negative. DDIR assay positivity was associated with improved RFS (HR: 0.61; 95% CI 0.38 to 0.98; p=0.042) and OS (HR: 0.52; 95% CI 0.31 to 0.88; p=0.015) following multivariate analysis. DDIR-positive patients had a higher pathological response rate (p=0.033), lower nodal burden (p=0.026) and reduced circumferential margin involvement (p=0.007). No difference in OS was observed according to DDIR status in an independent surgery-alone dataset.DDIR-positive OAC tumours were also associated with the presence of CD8+ lymphocytes (intratumoural: p<0.001; stromal: p=0.026) as well as PD-L1 expression (intratumoural: p=0.047; stromal: p=0.025).ConclusionThe DDIR assay is strongly predictive of benefit from DNA-damaging neoadjuvant chemotherapy followed by surgical resection and is associated with a proinflammatory microenvironment in OAC.
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- Browaeys, Hilde, et al.
(författare)
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A Retrospective Analysis of Early and Immediately Loaded Osseotite Implants in Cross-Arch Rehabilitations in Edentulous Maxillas and Mandibles Up to 7 Years
- 2013
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Ingår i: Clinical Implant Dentistry and Related Research. - : John Wiley & Sons. - 1523-0899 .- 1708-8208. ; 15:3, s. 380-389
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Tidskriftsartikel (refereegranskat)abstract
- Background: Immediate loading of full-arch restorations yields good results in selected cases, but long-term follow-up and the outcome in compromised bone are scarcely evaluated. Purpose: To evaluate immediately loaded Osseotite implants (Biomet 3i, Palm Beach, FL, USA) installed in healed or grafted bone, with regard to implant survival and peri-implant bone loss up to 7 years in function. Materials and Methods: Information was retrospectively retrieved from 83 patients' records with 749 Osseotite implants supporting immediately loaded semipermanent full-arch acrylic restorations. Five hundred sixty-eight (75.8%) implants were placed in healed bone and 181 (24.2%) in augmented bone, regenerated with sinus lifting and/or onlay/inlay grafts with/without biomaterials and membranes. Implant survival and success based on radiological peri-implant bone loss were registered. Wilcoxon rank sum tests evaluated peri-implant bone loss in compromised versus healed bone or between jaws or time intervals with p < .05 as statistically significant. Results: Sixteen of 749 implants failed (2.1%), 11/343 in maxilla (3.2%) and 5/406 (1.2%) in mandible. After 7 years, the cumulative failure rate was 9%. Mean peri-implant bone loss increased to 1.2 mm (SD 1.0) during the first 2 years but remained unchanged thereafter. Around implants in grafted bone, on average, 0.3 mm more bone loss was found. Conclusion: The Osseotite implants offer a predictable long-term outcome in terms of implant survival and stable peri-implant bone under immediate loading even in grafted bone. However, the high incidence of technical repair because of fractures of the semipermanent provisionals requires attention because it may be negative from a cost-benefit perspective. Implants in grafted bone show a tendency to a more pronounced initial bone remodeling without clinical consequence in the long term.
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