| 1. |
- Torchia, Jonathon, et al.
(författare)
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Molecular subgroups of atypical teratoid rhabdoid tumours in children : an integrated genomic and clinicopathological analysis
- 2015
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Ingår i: The Lancet Oncology. - 1470-2045 .- 1474-5488. ; 16:5, s. 569-582
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Tidskriftsartikel (refereegranskat)abstract
- Background Rhabdoid brain tumours, also called atypical teratoid rhabdoid tumours, are lethal childhood cancers with characteristic genetic alterations of SMARCB1/hSNF5. Lack of biological understanding of the substantial clinical heterogeneity of these tumours restricts therapeutic advances. We integrated genomic and clinicopathological analyses of a cohort of patients with atypical teratoid rhabdoid tumours to find out the molecular basis for clinical heterogeneity in these tumours. Methods We obtained 259 rhabdoid tumours from 37 international institutions and assessed transcriptional profiles in 43 primary tumours and copy number profiles in 38 primary tumours to discover molecular subgroups of atypical teratoid rhabdoid tumours. We used gene and pathway enrichment analyses to discover group-specific molecular markers and did immunohistochemical analyses on 125 primary tumours to evaluate clinicopathological significance of molecular subgroup and ASCL1-NOTCH signalling. Findings Transcriptional analyses identified two atypical teratoid rhabdoid tumour subgroups with differential enrichment of genetic pathways, and distinct clinicopathological and survival features. Expression of ASCL1, a regulator of NOTCH signalling, correlated with supratentorial location (p=0.004) and superior 5-year overall survival (35%, 95% CI 13-57, and 20%, 6-34, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0.033) in 70 patients who received multimodal treatment. ASCL1 expression also correlated with superior 5-year overall survival (34%, 7-61, and 9%, 0-21, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0.001) in 39 patients who received only chemotherapy without radiation. Cox hazard ratios for overall survival in patients with differential ASCL1 enrichment treated with chemotherapy with or without radiation were 2.02 (95% CI 1.04-3.85; p=0.038) and 3.98 (1.71-9.26; p=0.001). Integrated analyses of molecular subgroupings with clinical prognostic factors showed three distinct clinical risk groups of tumours with different therapeutic outcomes. Interpretation An integration of clinical risk factors and tumour molecular groups can be used to identify patients who are likely to have improved long-term radiation-free survival and might help therapeutic stratification of patients with atypical teratoid rhabdoid tumours.
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| 2. |
- Nobre, Liana, et al.
(författare)
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Outcomes of BRAF V600E pediatric gliomas treated with targeted BRAF inhibition
- 2020
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Ingår i: JCO Precision Oncology. - 2473-4284. ; 3, s. 561-571
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Tidskriftsartikel (refereegranskat)abstract
- © 2020 by American Society of Clinical Oncology PURPOSE Children with pediatric gliomas harboring a BRAF V600E mutation have poor outcomes with current chemoradiotherapy strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors. PATIENTS AND METHODS We collected clinical, imaging, molecular, and outcome information from patients with BRAF V600E–mutated glioma treated with BRAF inhibition across 29 centers from multiple countries. RESULTS Sixty-seven patients were treated with BRAF inhibition (pediatric low-grade gliomas [PLGGs], n = 56; pediatric high-grade gliomas [PHGGs], n = 11) for up to 5.6 years. Objective responses were observed in 80% of PLGGs, compared with 28% observed with conventional chemotherapy (P, .001). These responses were rapid (median, 4 months) and sustained in 86% of tumors up to 5 years while receiving therapy. After discontinuation of BRAF inhibition, 76.5% (13 of 17) of patients with PLGG experienced rapid progression (median, 2.3 months). However, upon rechallenge with BRAF inhibition, 90% achieved an objective response. Poor prognostic factors in conventional therapies, such as concomitant homozygous deletion of CDKN2A, were not associated with lack of response to BRAF inhibition. In contrast, only 36% of those with PHGG responded to BRAF inhibition, with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95% CI, 35.3% to 69.5%) versus 29.8% (95% CI, 20% to 44.4%) for BRAF inhibition versus chemotherapy, respectively (P = .02). CONCLUSION Use of BRAF inhibition results in robust and durable responses in BRAF V600E–mutated PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAF inhibitor therapy in childhood gliomas.
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| 3. |
- Eisenstat, R. A., et al.
(författare)
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The uncompromising leader
- 2008
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Ingår i: Harvard Business Review. - 0017-8012. ; 86:7-8, s. 50-
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Tidskriftsartikel (refereegranskat)abstract
- Managing the tension between performance and people is at the heart of the CEO's job. But CEOs under fierce pressure from capital markets often focus solely on the shareholder, which can lead to employee disenchantment. Others put so much stock in their firms' heritage that they don't notice as their organizations slide into complacency. Some leaders, though, manage to avoid those traps and create high-commitment, high-performance (HCHP) companies. The authors' in-depth research of HCHP CEOs reveals several shared traits: These CEOs earn the trust of their organizations through their openness to the unvarnished truth. They are deeply engaged with their people, and their exchanges are direct and personal. They mobilize employees around a focused agenda, concentrating on only one or two initiatives. And they work to build collective leadership capabilities. These leaders also forge an emotionally resonant shared purpose across their companies. That consists of a three-part promise: The company will help employees build a better world and deliver performance they can be proud of, and will provide an environment in which they can grow. HCHP CEOs approach finding a firm's moral and strategic center in a competitive market as a calling, not an engineering problem. They drive their firms to be strongly market focused while at the same time reinforcing their firms' core values. They are committed to short-term performance while also investing in long-term leadership and organizational capabilities. By refusing to compromise on any of these terms, they build great companies.
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| 4. |
- Foote, N., et al.
(författare)
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The Higher Ambition Leader
- 2011
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Ingår i: Harvard Business Review. - 0017-8012. ; 89:9, s. 94-
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- In 2009, as financial institutions faced plummeting profits and public scorn, the star of Standard Chartered Bank was on the rise. The bank posted its seventh straight year of income growth (with no help from government funding) and increased its Lending by 13%. Why was it thriving in such a difficult time? Because a different approach to leadership had taken hold there, say the authors, a team from the TruePoint consultancy. Mervyn Davies, who took Standard Chartered's reins in 2001, and his successor, Peter Sands, represent a new breed of CEO. Not content with achieving only strong economic returns, these CEOs drive their companies toward high performance on three fronts at once: creating tong-term value, producing benefits for the wider community, and building strong social capital within the organization. Many CEOs do well in one of these areas, but what sets these "higher-ambition leaders" apart is their ability to excel in all three. In pursuing their aggressive agendas, higher-ambition leaders do three things: They draw on a much broader view of their companies' organizational and cultural assets to forge more-powerful strategic visions. They build widespread commitment to achieve those visions by turning their companies into communities of shared purpose. And they demonstrate the grit to commit to their visions over the long term. As each of these activities reinforces the others, the full human and business potential of the organization is unlocked, allowing these CEOs to lead their companies to remarkable success, even in the face of daunting challenges.
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