ORCID Profile
0000-0002-6557-895X
Current Organisations
Hospital for Sick Children
,
Aarhus University
,
University of Toronto
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Publisher: Springer Science and Business Media LLC
Date: 31-05-2019
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-10-2016
Abstract: Vinblastine monotherapy has shown promising activity and a low-toxicity profile in patients with pediatric low-grade glioma (PLGG) who experienced treatment failure after initial treatment with chemotherapy and/or radiation. The aim of this study was to assess the activity of vinblastine in therapy-naïve children. Patients 18 years old with unresectable and/or progressive therapy-naïve PLGG were eligible. Vinblastine was administered once per week at a dose of 6 mg/m 2 intravenously over a period of 70 weeks. Vision, quality of life, neurofibromatosis type 1 (NF1) status, and BRAF mutation/fusion status were also determined and correlated with outcome. Fifty-four patients were enrolled onto the study, with a median age of 8 years (range, 0.7 to 17.2 years). Most patients had chiasmatic/hypothalamic tumors (55.5%), and 13 patients (24.1%) had NF1. The most common histology was pilocytic astrocytoma (46.3%). Seventeen patients were diagnosed using radiologic criteria alone. Best response to chemotherapy was centrally reviewed with a response rate (complete, partial, or minor response) of 25.9%. Disease stabilization (complete, partial, or minor response or stable disease) was achieved in 47 patients (87.0%). Visual improvement was observed in 20% of patients with optic pathway glioma. Five-year overall survival and progression-free survival (PFS) rates were 94.4% (95% CI, 88.5% to 100%) and 53.2% (95% CI, 41.3% to 68.5%), respectively, for the entire cohort. Patients with NF1 had a significantly better PFS (85.1% 95% CI, 68.0% to 100%) when compared with patients without NF1 (42.0% 95% CI, 29.1% to 60.7% P = .012). Age 3 years or 10 years was not associated with poor outcome. Treatment was well tolerated, and quality of life was not affected during treatment. In this trial, there was no correlation between BRAF alterations and outcome. Vinblastine administered once per week is well tolerated in children with treatment naïve PLGG. Overall survival and PFS are comparable to current therapies, with a favorable toxicity profile and a maintained quality of life.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-07-2016
Abstract: Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known. Four independent nonoverlapping retrospective cohorts of posterior fossa ependymomas (n = 820) were profiled using genome-wide methylation arrays. Risk stratification models were designed based on known clinical and newly described molecular biomarkers identified by multivariable Cox proportional hazards analyses. Molecular subgroup is a powerful independent predictor of outcome even when accounting for age or treatment regimen. Incompletely resected EPN_PFA ependymomas have a dismal prognosis, with a 5-year progression-free survival ranging from 26.1% to 56.8% across all four cohorts. Although first-line (adjuvant) radiation is clearly beneficial for completely resected EPN_PFA, a substantial proportion of patients with EPN_PFB can be cured with surgery alone, and patients with relapsed EPN_PFB can often be treated successfully with delayed external-beam irradiation. The most impactful biomarker for posterior fossa ependymoma is molecular subgroup affiliation, independent of other demographic or treatment variables. However, both EPN_PFA and EPN_PFB still benefit from increased extent of resection, with the survival rates being particularly poor for subtotally resected EPN_PFA, even with adjuvant radiation therapy. Patients with EPN_PFB who undergo gross total resection are at lower risk for relapse and should be considered for inclusion in a randomized clinical trial of observation alone with radiation reserved for those who experience recurrence.
Publisher: Elsevier BV
Date: 11-2017
Publisher: Springer Science and Business Media LLC
Date: 27-04-2020
Publisher: Wiley
Date: 22-09-2020
DOI: 10.1002/PBC.28627
Publisher: SAGE Publications
Date: 27-01-2011
Abstract: Abnormal copper metabolism has been linked with neurological disorders, such as Wilson and Menkes disease. Another disorder causing symptoms similar to copper metabolism disorder is Niemann-Pick type C. However, a definite pathophysiological connection between Niemann-Pick type C and copper metabolism disorders has never been established. The authors present an adolescent with an unusual presentation of copper deficiency—dysarthria, ataxia, and vertical gaze paresis, without significant cognitive degeneration or pathological magnetic resonance imaging (MRI). The patient was found to carry 2 mutations in the NPC1 gene. A possible link, explaining how copper deficiency might induce the Niemann-Pick phenotype might involve overproduction of cholesterol and inhibition of acid sphingomyelinase. We suggest that copper metabolism disorders be included in the differential diagnosis for ataxia and dysarthria, even in cases with unusual presentations. Moreover, should the connection between copper and Niemann-Pick be validated, screening for copper metabolism disorders may be advisable in Niemann-Pick type C patients and vice-versa.
Publisher: Scholar Publishing
Date: 13-01-2020
Abstract: Migration, the movement of people from one geographical location to another is an indispensable component of globalisation which has impacted the latter with visible effects. Neo-Pentecostal Christian movements from different parts of Africa have seized the advantage of both migration and globalization to advance their missionary causes. This has resulted in planting new churches and organization of para-church ministries and outreaches in different parts of Europe and elsewhere. Using the Critical Integrated Analysis (CIA) method, which seeks to generate data from the existing body of knowledge, the article explored the trajectories of African migration vis-à-vis the penetration of African-led Pentecostal churches in some part of Europe. This process has stemmed encounters between the European and African cultures plus the hurdle of navigating the cultural nuances of the Europeans. The article discovered that although there are shreds of evidence of growth among African-led migrant churches, more grounds need to be covered. It suggested that migrant churches need to structure their ministries and organisations in ways that propel appropriate cultural engagement with their host communities to enable them to influence and transform their immediate social realities.
Publisher: Wiley
Date: 10-03-2016
DOI: 10.1002/CNCR.29907
Abstract: The determinants of outcomes for adult survivors of pediatric low-grade glioma (PLGG) are largely unknown. This study collected population-based follow-up information for all PLGG patients diagnosed in Ontario, Canada from 1985 to 2012 (n = 1202) and determined factors affecting survival. The impact of upfront radiation treatment on overall survival (OS) was determined for a cohort of Ontario patients and an independent reference cohort from the Surveillance, Epidemiology, and End Results database. At a median follow-up of 12.73 years (range, 0.02-33 years), only 93 deaths (7.7%) were recorded, and the 20-year OS rate was 90.1% ± 1.1%. Children with neurofibromatosis type 1 had excellent survival and no tumor-related deaths during adulthood. Adverse risk factors included pleomorphic xanthoastrocytoma (P < .001) and a thalamic location (P < .001). For patients with unresectable tumors surviving more than 5 years after the diagnosis, upfront radiotherapy was associated with an approximately 3-fold increased risk of overall late deaths (hazard ratio [HR], 3.3 95% confidence interval [CI], 1.6-6.6 P = .001) and an approximately 4-fold increased risk of tumor-related deaths (HR, 4.4 95% CI, 1.3-14.6 P = .013). In a multivariate analysis, radiotherapy was the most significant factor associated with late all-cause deaths (HR, 3.0 95% CI, 1.3-7.0 P = .012) and tumor-related deaths (HR, 4.4 95% CI, 1.3-14.6 P = 0.014). A similar association between radiotherapy and late deaths was observed in the independent reference cohort (P < .001). In contrast to early deaths, late mortality was associated not with PLGG progression but rather with tumor transformation and non-oncological causes. The course of PLGG is associated with excellent long-term survival, but this is h ered by increased delayed mortality in patients receiving upfront radiotherapy. These observations should be considered when treatment options are being weighed for these patients.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 14-08-2021
Publisher: Oxford University Press (OUP)
Date: 2023
Abstract: ZFTA-RELA (formerly known as c11orf-RELA) fused supratentorial ependymoma (ZFTAfus ST-EPN) has been recognized as a novel entity in the 2016 WHO classification of CNS tumors and further defined in the recent 2021 edition. ZFTAfus ST-EPN was reported to portend poorer prognosis when compared to its counterpart, YAP1 ST-EPN in some previously published series. The aim of this study was to determine the treatment outcome of molecularly confirmed and conventionally treated ZFTAfus ST-EPN patients treated in multiple institutions. We conducted a retrospective analysis of all pediatric patients with molecularly confirmed ZFTAfus ST-EPN patients treated in multiple institutions in 5 different countries (Australia, Canada, Germany, Switzerland, and Czechia). Survival outcomes were analyzed and correlated with clinical characteristics and treatment approaches. A total of 108 patients were collated from multiple institutions in 5 different countries across three continents. We found across the entire cohort that the 5- and 10-year PFS were 65% and 63%, respectively. The 5- and 10-year OS of this cohort of patients were 87% and 73%. The rates of gross total resection (GTR) were high with 84 out of 108 (77.8%) patients achieving GTR. The vast majority of patients also received post-operative radiotherapy, 98 out of 108 (90.7%). Chemotherapy did not appear to provide any survival benefit in our patient cohort. This is the largest study to date of contemporaneously treated molecularly confirmed ZFTAfus ST-EPN patients which identified markedly improved survival outcomes compared to previously published series. This study also re-emphasizes the importance of maximal surgical resection in achieving optimal outcomes in pediatric patients with supratentorial ependymoma.
Publisher: Wiley
Date: 25-01-2018
DOI: 10.1002/PBC.26988
Abstract: Clinical trials have failed to demonstrate a survival benefit of adjuvant chemotherapy in diffuse intrinsic pontine gliomas (DIPG). Radiation therapy (RT) is the only effective treatment thus far and reirradiation (rRT) has become an option at the time of progression. The aim of this study was to review the Canadian experience of DIPG rRT with a focus on the safety and possible efficacy of this approach. We retrospectively reviewed the demographic, clinical, and RT data of patients with DIPG treated in Canada with rRT. Since January 2011, we identified 16 patients with progressive DIPG who received rRT. Median time from diagnosis to progression was 10.5 months (range, 4-37 months). rRT was given focally in 14 patients at a dose ranging from 21.6 to 36 Gy. rRT was well tolerated by all children but one. All but three patients showed neurological improvement. With a median follow-up from original diagnosis of 19.2 months, all patients died, with a median time from rRT to death of 6.48 months (range, 3.83-13.26 months). When compared to a historic cohort of 46 consecutive patients, the median time from progression to death was 92 days in the non-reirradiated patients versus 218 days in the reirradiated ones (P = 0.0001). In this limited experience, rRT was safe and feasible in patients with progressive DIPG, providing neurological improvement and a prolonged life span in most patients. Prospective Canadian rRT protocols are ongoing to further assess the benefit of this approach, including quality of life assessment.
Publisher: Springer Science and Business Media LLC
Date: 10-08-2015
DOI: 10.1038/NN.4088
Publisher: Springer Science and Business Media LLC
Date: 25-09-2019
DOI: 10.1038/S41467-019-12187-5
Abstract: Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK , ROS1 , NTRK and MET . These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.
Publisher: American Association for Cancer Research (AACR)
Date: 12-10-2023
Publisher: Springer Science and Business Media LLC
Date: 10-04-2017
DOI: 10.1038/NG.3838
Publisher: Springer Science and Business Media LLC
Date: 17-07-2018
Publisher: American Society of Clinical Oncology (ASCO)
Date: 07-2016
Abstract: Recurrent glioblastoma multiforme (GBM) is incurable with current therapies. Biallelic mismatch repair deficiency (bMMRD) is a highly penetrant childhood cancer syndrome often resulting in GBM characterized by a high mutational burden. Evidence suggests that high mutation and neoantigen loads are associated with response to immune checkpoint inhibition. We performed exome sequencing and neoantigen prediction on 37 bMMRD cancers and compared them with childhood and adult brain neoplasms. Neoantigen prediction bMMRD GBM was compared with responsive adult cancers from multiple tissues. Two siblings with recurrent multifocal bMMRD GBM were treated with the immune checkpoint inhibitor nivolumab. All malignant tumors (n = 32) were hypermutant. Although bMMRD brain tumors had the highest mutational load because of secondary polymerase mutations (mean, 17,740 ± standard deviation, 7,703), all other high-grade tumors were hypermutant (mean, 1,589 ± standard deviation, 1,043), similar to other cancers that responded favorably to immune checkpoint inhibitors. bMMRD GBM had a significantly higher mutational load than sporadic pediatric and adult gliomas and all other brain tumors (P .001). bMMRD GBM harbored mean neoantigen loads seven to 16 times higher than those in immunoresponsive melanomas, lung cancers, or microsatellite-unstable GI cancers (P .001). On the basis of these preclinical data, we treated two bMMRD siblings with recurrent multifocal GBM with the anti–programmed death-1 inhibitor nivolumab, which resulted in clinically significant responses and a profound radiologic response. This report of initial and durable responses of recurrent GBM to immune checkpoint inhibition may have implications for GBM in general and other hypermutant cancers arising from primary (genetic predisposition) or secondary MMRD.
Publisher: Springer Science and Business Media LLC
Date: 11-09-2019
DOI: 10.1038/S41598-019-49411-7
Abstract: The development of artificial intelligence has led researchers to study the ethical principles that should guide machine behavior. The challenge in building machine morality based on people’s moral decisions, however, is accounting for the biases in human moral decision-making. In seven studies, this paper investigates how people’s personal perspectives and decision-making modes affect their decisions in the moral dilemmas faced by autonomous vehicles. Moreover, it determines the variations in people’s moral decisions that can be attributed to the situational factors of the dilemmas. The reported studies demonstrate that people’s moral decisions, regardless of the presented dilemma, are biased by their decision-making mode and personal perspective. Under intuitive moral decisions, participants shift more towards a deontological doctrine by sacrificing the passenger instead of the pedestrian. In addition, once the personal perspective is made salient participants preserve the lives of that perspective, i.e. the passenger shifts towards sacrificing the pedestrian, and vice versa. These biases in people’s moral decisions underline the social challenge in the design of a universal moral code for autonomous vehicles. We discuss the implications of our findings and provide directions for future research.
Publisher: Springer Science and Business Media LLC
Date: 04-04-2016
Publisher: American Society of Clinical Oncology (ASCO)
Date: 03-2021
DOI: 10.1200/JCO.20.01359
Abstract: We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors. Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing. A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup ergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving MYC, MYCN, and FBXW7. Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms. Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies.
Publisher: Springer Science and Business Media LLC
Date: 03-2023
DOI: 10.1038/S41591-023-02221-X
Abstract: The causes of pediatric cancers’ distinctiveness compared to adult-onset tumors of the same type are not completely clear and not fully explained by their genomes. In this study, we used an optimized multilevel RNA clustering approach to derive molecular definitions for most childhood cancers. Applying this method to 13,313 transcriptomes, we constructed a pediatric cancer atlas to explore age-associated changes. Tumor entities were sometimes unexpectedly grouped due to common lineages, drivers or stemness profiles. Some established entities were ided into subgroups that predicted outcome better than current diagnostic approaches. These definitions account for inter-tumoral and intra-tumoral heterogeneity and have the potential of enabling reproducible, quantifiable diagnostics. As a whole, childhood tumors had more transcriptional ersity than adult tumors, maintaining greater expression flexibility. To apply these insights, we designed an ensemble convolutional neural network classifier. We show that this tool was able to match or clarify the diagnosis for 85% of childhood tumors in a prospective cohort. If further validated, this framework could be extended to derive molecular definitions for all cancer types.
Publisher: American Association for Cancer Research (AACR)
Date: 14-11-2013
DOI: 10.1158/0008-5472.CAN-12-4331
Abstract: Medulloblastoma is the most common malignant brain tumor in children. This disease is heterogeneous and is composed of four subtypes of medulloblastoma [WNT, Sonic Hedgehog (SHH), Group 3, and Group 4]. An immediate goal is to identify novel molecular targets for the most aggressive forms of medulloblastoma. Polo-like kinase 1 (PLK1) is an oncogenic kinase that controls cell cycle and proliferation, making it a strong candidate for medulloblastoma treatment. In this study, pediatric medulloblastomas were subtyped in two patient cohorts (discovery cohort, n = 63 patients validation cohort, n = 57 patients) using NanoString nCounter analysis and PLK1 mRNA was assessed. We determined that the SHH and Group 3 subtypes were independently associated with poor outcomes in children as was PLK1 using Cox regression analyses. Furthermore, we screened a library of 129 compounds in clinical trials using a model of pediatric medulloblastoma and determined that PLK1 inhibitors were the most promising class of agents against the growth of medulloblastoma. In patient-derived primary medulloblastoma isolates, the PLK1 small-molecule inhibitor BI2536 suppressed the self-renewal of cells with high PLK1 but not low PLK1 expression. PLK1 inhibition prevented medulloblastoma cell proliferation, self-renewal, cell-cycle progression, and induced apoptosis. In contrast, the growth of normal neural stem cells was unaffected by BI2536. Finally, BI2536 extended survival in medulloblastoma-bearing mice with efficacy comparable with Headstart, a standard-of-care chemotherapy regimen. We conclude that patients with medulloblastoma expressing high levels of PLK1 are at elevated risk. These preclinical studies pave the way for improving the treatment of medulloblastoma through PLK1 inhibition. Cancer Res 73(22) 6734–44. ©2013 AACR.
Publisher: Oxford University Press (OUP)
Date: 20-01-2020
DOI: 10.1093/NOP/NPZ072
Abstract: Radiation necrosis is a frequent complication occurring after the treatment of pediatric brain tumors however, treatment options remain a challenge. Bevacizumab is an anti-VEGF monoclonal antibody that has been shown in small adult cohorts to confer a benefit, specifically a reduction in steroid usage, but its use in children has not been well described. We describe our experience with bevacizumab use for symptomatic radiation necrosis at 5 institutions including patients treated after both initial irradiation and reirradiation. We identified 26 patients treated with bevacizumab for symptomatic radiation necrosis, with a wide range of underlying diagnoses. The average age at diagnosis of radiation necrosis was 10.7 years, with a median time between the last dose of radiation and the presentation of radiation necrosis of 3.8 months (range, 0.6-110 months). Overall, we observed that 13 of 26 patients (50%) had an objective clinical improvement, with only 1 patient suffering from significant hypertension. Radiological improvement, defined as reduced T2/fluid-attenuated inversion recovery signal and mass effect, was observed in 50% of patients however, this did not completely overlap with clinical response. Both early and late radiation necrosis responded equally well to bevacizumab therapy. Overall, bevacizumab was very well tolerated, permitting a reduction of corticosteroid dose and/or duration in the majority of patients. Bevacizumab appears to be effective and well-tolerated in children as treatment for symptomatic radiation necrosis and warrants more robust study in the context of controlled clinical trials.
Publisher: Center for Open Science
Date: 15-04-2019
Abstract: Much research on moral judgment is centered on moral dilemmas in which deontological perspectives (i.e., emphasizing rules, in idual rights and duties) are in conflict with utilitarian judgements (i.e., following the greater good defined through consequences). A central finding of this field Greene et al. showed that psychological and situational factors (e.g., the intent of the agent, or physical contact between the agent and the victim) play an important role in people’s use of deontological versus utilitarian considerations when making moral decisions. As their study was conducted with US s les, our knowledge is limited concerning the universality of this effect, in general, and the impact of culture on the situational and psychological factors of moral judgments, in particular. Here, we empirically test the universality of deontological and utilitarian judgments by replicating Greene et al.’s experiments on a large (N = X,XXX) and erse (WEIRD and non-WEIRD) s le across the world to explore the influence of culture on moral judgment. The relevance of this exploration to a broad range of policy-making problems is discussed.
Publisher: Springer Science and Business Media LLC
Date: 2016
DOI: 10.1038/NATURE16478
Publisher: Springer Science and Business Media LLC
Date: 27-05-2021
Publisher: Springer Science and Business Media LLC
Date: 14-04-2022
DOI: 10.1038/S41562-022-01319-5
Abstract: The study of moral judgements often centres on moral dilemmas in which options consistent with deontological perspectives (that is, emphasizing rules, in idual rights and duties) are in conflict with options consistent with utilitarian judgements (that is, following the greater good based on consequences). Greene et al. (2009) showed that psychological and situational factors (for ex le, the intent of the agent or the presence of physical contact between the agent and the victim) can play an important role in moral dilemma judgements (for ex le, the trolley problem). Our knowledge is limited concerning both the universality of these effects outside the United States and the impact of culture on the situational and psychological factors affecting moral judgements. Thus, we empirically tested the universality of the effects of intent and personal force on moral dilemma judgements by replicating the experiments of Greene et al. in 45 countries from all inhabited continents. We found that personal force and its interaction with intention exert influence on moral judgements in the US and Western cultural clusters, replicating and expanding the original findings. Moreover, the personal force effect was present in all cultural clusters, suggesting it is culturally universal. The evidence for the cultural universality of the interaction effect was inconclusive in the Eastern and Southern cultural clusters (depending on exclusion criteria). We found no strong association between collectivism/in idualism and moral dilemma judgements.
Publisher: Springer New York
Date: 2015
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-03-2015
Abstract: To uncover the genetic events leading to transformation of pediatric low-grade glioma (PLGG) to secondary high-grade glioma (sHGG). We retrospectively identified patients with sHGG from a population-based cohort of 886 patients with PLGG with long clinical follow-up. Exome sequencing and array CGH were performed on available s les followed by detailed genetic analysis of the entire sHGG cohort. Clinical and outcome data of genetically distinct subgroups were obtained. sHGG was observed in 2.9% of PLGGs (26 of 886 patients). Patients with sHGG had a high frequency of nonsilent somatic mutations compared with patients with primary pediatric high-grade glioma (HGG median, 25 mutations per exome P = .0042). Alterations in chromatin-modifying genes and telomere-maintenance pathways were commonly observed, whereas no sHGG harbored the BRAF-KIAA1549 fusion. The most recurrent alterations were BRAF V600E and CDKN2A deletion in 39% and 57% of sHGGs, respectively. Importantly, all BRAF V600E and 80% of CDKN2A alterations could be traced back to their PLGG counterparts. BRAF V600E distinguished sHGG from primary HGG (P = .0023), whereas BRAF and CDKN2A alterations were less commonly observed in PLGG that did not transform (P .001 and P .001 respectively). PLGGs with BRAF mutations had longer latency to transformation than wild-type PLGG (median, 6.65 years [range, 3.5 to 20.3 years] v 1.59 years [range, 0.32 to 15.9 years], respectively P = .0389). Furthermore, 5-year overall survival was 75% ± 15% and 29% ± 12% for children with BRAF mutant and wild-type tumors, respectively (P = .024). BRAF V600E mutations and CDKN2A deletions constitute a clinically distinct subtype of sHGG. The prolonged course to transformation for BRAF V600E PLGGs provides an opportunity for surgical interventions, surveillance, and targeted therapies to mitigate the outcome of sHGG.
Publisher: Elsevier BV
Date: 06-2017
Publisher: Wiley
Date: 18-10-2022
DOI: 10.1002/MAR.21740
Abstract: Innovative technologies often feature inherently conflicting properties. This poses a challenge for marketers because negative properties not only weigh heavily on consumers' technology adoption decisions but potentially do more so than positive ones. To shed light on the paradox of technology and its underlying processes, the present research develops a conceptual model drawing on technology adoption and valence perception theories about the prevalence of negativity bias in consumers' technology adoption decisions with its unique effect through the serial chain of consumers' perceptions of risk and trust regarding the technology. Results of three studies ( N = 1309) demonstrate that the effect of negative valence consistently outperforms that of positive valence in consumers' technology adoption intentions (Studies 1–2) and decisions (Study 3). Furthermore, results show that the disproportionate effect of negative (vs. positive) valence can be explained by the proposed serial causal chain through consumers' perception of risk of the technology and trust in the technology (Studies 2–3) while ruling out company trust and consumer knowledge as alternative drivers of the effects (Study 3). These findings contribute to the pertinent literature on consumer psychology in decisions to adopt novel technologies in that they quantify and explain the potential outcome stemming from the ambiguous properties of novel technology. Moreover, this study finds negativity bias to be an often overlooked consumer bias with implications for marketing practice and useful for understanding and lowering resistance towards artificial intelligence technology.
Publisher: Springer Science and Business Media LLC
Date: 06-06-2022
Publisher: American Society of Clinical Oncology (ASCO)
Date: 04-2023
DOI: 10.1200/JCO.21.02968
Abstract: Infant and young childhood medulloblastoma (iMB) is usually treated without craniospinal irradiation (CSI) to avoid neurocognitive late effects. Unfortunately, many children relapse. The purpose of this study was to assess salvage strategies and prognostic features of patients with iMB who relapse after CSI-sparing therapy. We assembled a large international cohort of 380 patients with relapsed iMB, age younger than 6 years, and initially treated without CSI. Univariable and multivariable Cox models of postrelapse survival (PRS) were conducted for those treated with curative intent using propensity score analyses to account for confounding factors. The 3-year PRS, for 294 patients treated with curative intent, was 52.4% (95% CI, 46.4 to 58.3) with a median time to relapse from diagnosis of 11 months. Molecular subgrouping was available for 150 patients treated with curative intent, and 3-year PRS for sonic hedgehog (SHH), group 4, and group 3 were 60%, 84%, and 18% ( P = .0187), respectively. In multivariable analysis, localized relapse ( P = .0073), SHH molecular subgroup ( P = .0103), CSI use after relapse ( P = .0161), and age ≥ 36 months at initial diagnosis ( P = .0494) were associated with improved survival. Most patients (73%) received salvage CSI, and although salvage chemotherapy was not significant in multivariable analysis, its use might be beneficial for a subset of children receiving salvage CSI 35 Gy ( P = .007). A substantial proportion of patients with relapsed iMB are salvaged after initial CSI-sparing approaches. Patients with SHH subgroup, localized relapse, older age at initial diagnosis, and those receiving salvage CSI show improved PRS. Future prospective studies should investigate optimal CSI doses and the role of salvage chemotherapy in this population.
Publisher: Springer Science and Business Media LLC
Date: 07-02-2019
DOI: 10.1038/S41571-019-0177-5
Abstract: Despite decades of research, brain tumours remain among the deadliest of all forms of cancer. The ability of these tumours to resist almost all conventional and novel treatments relates, in part, to the unique cell-intrinsic and microenvironmental properties of neural tissues. In an attempt to encourage progress in our understanding and ability to successfully treat patients with brain tumours, Cancer Research UK convened an international panel of clinicians and laboratory-based scientists to identify challenges that must be overcome if we are to cure all patients with a brain tumour. The seven key challenges summarized in this Position Paper are intended to serve as foci for future research and investment.
Publisher: Elsevier BV
Date: 06-2020
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-10-2016
Abstract: Although the link between mutant TP53 and human cancer is unequivocal, a significant knowledge gap exists in clinically actionable molecular targets in Li-Fraumeni syndrome (LFS), a highly penetrant cancer predisposition syndrome associated with germline mutations in TP53. This study surveyed the epigenome to identify functionally and clinically relevant novel genes implicated in LFS. We performed genome-wide methylation analyses of peripheral blood leukocyte DNA in germline TP53 mutation carriers (n = 72) and in iduals with TP53 wild type in whom histologically comparable malignancies developed (n = 111). Targeted bisulfite pyrosequencing was performed on a validation cohort of 30 TP53 mutation carriers and 46 patients with TP53 wild type, and candidate sites were evaluated in primary tumors from patients with LFS across multiple histologic tumor types. In 183 patients, distinct DNA methylation signatures were associated with deleterious TP53 mutations in peripheral blood leukocytes. TP53-associated DNA methylation marks occurred in genomic regions that harbored p53 binding sites and in genes encoding p53 pathway proteins. Moreover, loss-of-function TP53 mutations were significantly associated with differential methylation at the locus encoding microRNA miR-34A, a key component of the p53 regulatory network (adjusted P .001), and validated in an independent patient cohort (n = 76, P .001). Targeted bisulfite pyrosequencing demonstrated that miR-34A was inactivated by hypermethylation across many histologic types of primary tumors from patients with LFS. Moreover, miR-34A tumor hypermethylation was associated with decreased overall survival in a cohort of 29 patients with choroid plexus carcinomas, a characteristic LFS tumor (P .05). Epigenetic dysregulation of miR-34A may comprise an important path in TP53-associated cancer predisposition and represents a therapeutically actionable target with potential clinical relevance.
Publisher: Springer Science and Business Media LLC
Date: 21-07-0001
No related grants have been discovered for Vijay Ramaswamy.