Evaluating preclinical evidence for clinical translation in childhood brain tumours: Guidelines from the CONNECT, PNOC, and ITCC brain networks

Clinical outcomes for many childhood brain tumours remain poor, despite our increasing understanding of the underlying disease biology. Advances in molecular diagnostics have refined our ability to classify tumour types and subtypes, and efforts are underway across multiple international paediatric neuro-oncology consortia to take novel biological insights in the worst prognosis entities into innovative clinical trials. Whilst for the first time we are designing such studies on the basis of disease-specific biological data, the levels of preclincial evidence in appropriate model systems on which these trials are initiated is still widely variable. We have considered these issues between CONNECT, PNOC and ITCC-Brain, and developed a framework in which we can assess novel concepts being brought forward for possible clinical translation. Whilst not intended to be proscriptive for every possible circumstance, these criteria provide a basis for self-assessment of evidence by laboratory scientists, and a platform for discussion and rational decision-making prior to moving forward clinically

Larotrectinib efficacy and safety in TRK fusion cancer: An expanded clinical dataset showing consistency in an age and tumor agnostic approach

Background: TRK fusion cancer results from gene fusions involving NTRK1, NTRK2 or NTRK3. Larotrectinib, the first selective TRK inhibitor, has demonstrated an overall response rate (ORR) of 75% with a favorable safety profile in the first 55 consecutively enrolled adult and pediatric patients with TRK fusion cancer (Drilon et al.,NEJM2018). Here, we report the clinical activity of larotrectinib in an additional 35 TRK fusion cancer patients and provide updated follow-up of the primary analysis set (PAS) of 55 patients as of 19thFeb 2018. Methods: Patients with TRK fusion cancer detected by molecular profiling from 3 larotrectinib clinical trials (NCT02122913, NCT02637687, and NCT02576431) were eligible.Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Disease status was assessed using RECIST version 1.1. Results: As of Feb 2018, by independent review, 6 PRs in the PAS deepened to CRs. The median duration of response (DoR) and progression-free survival in the PAS had still not been reached, with 12.9 months median follow-up. At 1 year, 69% of responses were ongoing, 58% of patients remained progression-free and 90% of patients were alive. An additional 19 children and 25 adults (age range, 0.1-78 years) with TRK fusion cancer were enrolled after the PAS, and included cancers of the salivary gland, thyroid, lung, colon, melanoma, sarcoma, GIST and congenital mesoblastic nephroma. In 35 evaluable patients, the ORR by investigator assessment was 74% (5 CR, 21 PR, 6 SD, 2 PD, 1 not determined). In these patients, with median follow-up of 5.5 months, median DoR had not yet been reached, and 88% of responses were ongoing at 6 months, consistent with the PAS. Adverse events (AEs) were predominantly grade 1, with dizziness, increased AST/ALT, fatigue, nausea and constipation the most common AEs reported in ≥ 10% of patients. No AE of grade 3 or 4 related to larotrectinib occurred in more than 5% of patients. Conclusions: TRK fusions are detected in a broad range of tumor types. Larotrectinib is an effective age- and tumor-agnostic treatment for TRK fusion cancer with a positive safety profile. Screening patients for NTRK gene fusions in solid- and brain tumors should be actively considered

Current Indications of Secondary Enucleation in Retinoblastoma Management: A Position Paper on Behalf of the European Retinoblastoma Group (EURbG).

Secondary enucleation (SE) puts an irreversible end to eye-preserving therapies, whenever their prolongation is expected to violate the presumed state of metastatic grace. At present, it must be acknowledged that clear criteria for SE are missing, leading to empiric and subjective indications commonly related to disease progression or relapse, disease persistence masking the optic nerve head or treatment-related complications obscuring the fundus view. This absence of evidence-based consensus regarding SE is explained by the continuously moving frontiers of the conservative management as a result of diagnostic and therapeutic advances, as well as by the lack of studies sufficiently powered to accurately stratify the risk of metastasis in conservatively treated patients. In this position paper of the European Retinoblastoma Group (EURbG), we give an overview of the progressive shift in the indications for SE over the past decades and propose guidelines to assist decision-making with respect to when SE becomes imperative or recommended, with corresponding absolute and relative SE indications. Further studies and validation of biologic markers correlated with the risk of metastasis are expected to set more precisely the frontiers of conservative management and thus consensual criteria for SE in the future

Ergebnisse zur saisonalen Low-Input Vollweidehaltung von Milchkühen im österreichischen Berggebiet

In a research project six dairy farms (5 organic, 1 low input) in mountainous regions of Austria were supervised in converting to a seasonal low-input dairy production system based on grazing. Within an observation period of three years (October 1st, 2004 – September 30th, 2007) a strict annual cycle in milk production and reproduction could be implemented on two farms only. In average a pasture proportion of 42 % (26–61 %) of the total feeding ration per year could be determined, depending on the farm specific conditions and the implementation level of this low input strategy. On four farms, which fed low amounts of supplemental feeds, a pasture proportion of 50 % of the total feeding ration was realized. With an input of only 470 kg DM concentrate (8 % of DM intake) per cow and year a milk performance of 5.837 kg with 4.1 % fat and 3.3 % protein was achieved. The results clearly indicate that the full grazing strategy with seasonal calving is feasible in Austria for animal health reasons. The project farms realized an average value of 0.29 Euro of payments free of direct charge per kg milk and 1.640 Euro per cow

How do banks assess entrepreneurial competence? The role of voluntary information disclosure

This research adds to the literature on relationship lending in the small business context by discussing the roles of entrepreneurial competence and voluntarily disclosed information as determinants of credit access. More specifically, we propose that the loan manager’s evaluation of the information voluntarily disclosed by the entrepreneur is an important complement to publicly available financial data and soft information collected through observation and third parties in framing the loan manager’s perception of the entrepreneur’s competence. Further, we argue that banks charge lower interest rates if the loan manager perceives the entrepreneur to be competent. Econometric analysis based on 433 bank-firm relationships supports these hypothesised relationships. The results imply that entrepreneurs need to communicate their competence effectively to loan managers, and that banks should utilise their loan managers’ personal evaluations as inputs to lending decisions

An evolutionary stage model of outsourcing and competence destruction : a Triad comparison of the consumer electronics industry

Outsourcing has gained much prominence in managerial practice and academic discussions in the last two decades or so. Yet, we still do not understand the full implications of outsourcing strategy for corporate performance. Traditionally outsourcing across borders is explained as a cost-cutting exercise, but more recently the core competency argument states that outsourcing also leads to an increased focus, thereby improving effectiveness. However, no general explanation has so far been provided for how outsourcing could lead to deterioration in a firm‟s competence base. We longitudinally analyze three cases of major consumer electronics manufacturers, Emerson Radio from the U.S., Japan‟s Sony and Philips from the Netherlands to understand the dynamic process related to their sourcing strategies. We develop an evolutionary stage model that relates outsourcing to competence development inside the firm and shows that a vicious cycle may emerge. Thus it is appropriate to look not only at how outsourcing is influenced by an organization‟s current set of competences, but also how it alters that set over time. The four stages of the model are offshore sourcing, phasing out, increasing dependence on foreign suppliers, and finally industry exit or outsourcing reduction. The evolutionary stage model helps managers understand for which activities and under which conditions outsourcing across borders is not a viable option. Results suggest that each of these firms had faced a loss of manufacturing competitiveness in its home country, to which it responded by offshoring and then outsourcing production. When a loss of competences occurred, some outsourcing decisions were reversed

Muslim Diaspora in the West and International HRM

Interest in Islam and how Muslims organise themselves within the so-called Western world has largely stemmed from the flow of Muslim immigration since the 1960s and the 1970s (Loobuyck, Debeer, & Meier, 2013). Many of these immigrants have come to these new lands in the hope of making a better life for themselves economically, or to escape the political or religious pressures of their homeland (Lebl, 2014). Initially, deeming the influx of these foreigners to be largely irrelevant, there was little interest in their presence by the different governments across many jurisdictions. Typically, scant interest was shown towards entering into dialogue with the Muslim immigrant community. Indeed, until the 1990s, it was not uncommon for Islam to be perceived as a strange, foreign religion that was best managed through outsourcing to respective consulates (Loobuyck et al., 2013). Yet, migration and work-based mobility has a significant influence on the world of work and societies in which organisations are embedded. Many individuals migrate for better employment perspectives, as well as due to chain migration, betterment in the quality of life and based on fleeing famine, war and terror zones globally (Sharma & Reimer-Kirkham, 2015; Valiūnienė, 2016). Migration could involve upward as well as downward mobility/ wages, depending on the country and organisation. For example, minimum wages differ from € 184 in Bulgaria up to € 1923 in Luxembourg (Valiūnienė, 2016). Migration also contributes to the lived religion of diasporic communities as they navigate their faith at work (Sharma & Reimer-Kirkha

We Heal as One: Interprofessional Health Collaboration During the Covid-19 Pandemic

A collaborative healthcare system enabled through multi-professional and interprofessional partnerships that pave the way to improved health outcomes has been the director of the Millennium Development Goals (World Health Organization, 2016). But the occurrence of the global COVID-19 pandemic challenged the healthcare system in unprecedented ways. This study explored the essence of interprofessional collaboration among medical and paramedical healthcare professionals. A phenomenological research study through photovoice was employed and analyzed using thematic analysis. Study corpus was gathered from a total of 15 participants, including three medical technologists, three nutritionists and dieticians, three radiologic technologists, three pharmacists, two nurses, and one physician. Four themes surfaced from the responses, namely: unity in diversity, paradigm shift, parallel dilemmas, and resilient optimism. Keywords: healthcare system, interprofessional collaboration, medical, healthcar

Enterprise agility: A Balancing Act - a local government case study

Austerity and financial constraints have been threatening the public sector in the UK for a number of years. Foreseeing the threat of continued budget cuts, and addressing the situation many local councils face, requires internal transformations for financial stability without losing the key focus on public service. Agile transformations have been undertaken by organisations wanting to learn from the software development community and bringing agile principles into the wider organisation. This paper describes and analyses an ongoing behaviour-led transformation in a district council in the UK. It presents the results of the analysis of 19 interviews with internal stakeholders at the council, of observations of meetings among senior and middle management in a five-month period. The paper explores the successes and the challenges encountered towards the end of the transformation process and reflects on balancing acts to address the challenges, be-tween: disruption and business as usual, empowerment and goal setting, autonomy and processes and procedures, and behaviours and skills. Based on our findings, we suggest that behaviours on their own cannot guarantee a sustained agile culture, and that this is equally important for enterprise agility and for large-scale agile software development transformations

Improving survival in recurrent medulloblastoma: earlier detection, better treatment or still an impasse?

Early detection of relapse has been advocated to improve survival in children with recurrent medulloblastoma. However, the prognostic factors and the longer term outcome of these patients remains unclear. Pattern of recurrences were analysed in three consecutive protocols of the Société Française d'Oncologie Pédiatrique (1985-91). A uniform surveillance programme including repeated lumbar puncture combined with computerized tomography (CT) or magnetic resonance imaging (MRI) scan was applied for all registered patients. Forty-six out of 116 patients had progressive or recurrent disease. The median time from diagnosis to recurrence was 10.5 months and 76% relapses occurred during the first 2 years. Seventeen patients had asymptomatic relapses that were detected by the surveillance protocol. Forty-one patients were treated at time of progression. Twenty-three responded to salvage therapy and 11 achieved a second complete remission. The median survival time after progression was 5 months (<1-41 months), and only two patients remained alive at time of follow-up. Length of survival is primarily related to some specific patterns of relapse (time from diagnosis to recurrence, circumstances of relapse, extent of relapse) and to the response to salvage therapy. No evidence of long-term benefit appeared from any form of treatment