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As advanced non-small cell lung cancer (aNSCLC) is being increasingly divided into rare oncogene-driven subsets, conducting randomised trials becomes challenging. Using real-world data (RWD) to construct control arms for single-arm trials provides an option for comparative data. However, non-randomised treatment comparisons have the potential to be biased and cause concern for decision-makers. Using the example of pralsetinib from a RET fusion-positive aNSCLC single-arm trial (NCT03037385), we demonstrate a relative survival benefit when compared to pembrolizumab monotherapy and pembrolizumab with chemotherapy RWD cohorts. Quantitative bias analyses show that results for the RWD-trial comparisons are robust to data missingness, potential poorer outcomes in RWD and residual confounding. Overall, the study provides evidence in favour of pralsetinib as a first-line treatment for RET fusion-positive aNSCLC. The quantification of potential bias performed in this study can be used as a template for future studies of this nature. Real-world data (RWD) based control arms provide an option to compare the effectiveness of single-arm trials. By performing multiple quantitative bias analyses to alleviate concerns about trial-RWD comparability, here the authors show that the RET inhibitor pralsetinib provides survival benefit in patients with RET fusion-positive non-small cell lung cancer from the ARROW single-arm trial, (NCT03037385) when compared to pembrolizumab monotherapy and pembrolizumab with chemotherapy RWD cohorts. [ABSTRACT FROM AUTHOR]

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the preferred first-line (1L) therapy for EGFR mutation-positive (EGFRm) advanced/metastatic non-small cell lung cancer (NSCLC). Objective: Our objective was to describe real-world treatment patterns and T790M testing practices in patients with 1L disease progression (Europe/USA) following treatment with first- or second-generation EGFR-TKIs. Methods: This was a retrospective, non-interventional medical record review of patients with EGFRm locally advanced/metastatic NSCLC from routine clinical practice (EGFR-TKI initiation: 1 January 2015 to 31 December 2017; follow-up: last available medical record). Endpoints were demographic/clinical characteristics, incidence of central nervous system (CNS) metastases/leptomeningeal disease, second-line (2L) treatment, T790M mutation testing, and osimertinib treatment prevalence. Results: Among 469 patients, 73% (n = 341/469) progressed on 1L EGFR-TKI treatment. Of those who progressed, 74% (n = 252/341) were tested for T790M, with 50% (n = 126/252) testing positive; 75% (n = 94/126) of T790M-positive patients received osimertinib (mostly 2L). Of the patients with progression, 24% (n = 83/341) did not receive 2L treatment, and 88% (n = 73/83) of these patients died. At diagnosis of advanced disease, 9% of patients (n = 41) had CNS metastases; at EGFR-TKI initiation, 14% of patients (n = 68) had CNS metastases. Over the study period, 11% of patients (n = 42) developed CNS metastases not detected at NSCLC diagnosis. Conclusions: Rates of resistance mutation testing and subsequent utilization of recommended 2L therapies could be improved. As more targeted therapies are developed, it will be crucial to improve the molecular testing rates to ensure patients receive appropriate, effective, and timely treatment. [ABSTRACT FROM AUTHOR]

Background: The cancer vaccine Vx-001, which targets the universal tumour antigen TElomerase Reverse Transcriptase (TERT), can mount specific Vx-001/TERT572 CD8 + cytotoxic T cells; this immune response is associated with improved overall survival (OS) in patients with advanced/metastatic non-small cell lung cancer (NSCLC).Methods: A randomised, double blind, phase 2b trial, in HLA-A*201-positive patients with metastatic, TERT-expressing NSCLC, who did not progress after first-line platinum-based chemotherapy were randomised to receive either Vx-001 or placebo. The primary endpoint of the trial was OS.Results: Two hundred and twenty-one patients were randomised and 190 (101 and 89 patients in the placebo and the Vx-001 arm, respectively) were analysed for efficacy. There was not treatment-related toxicity >grade 2. The study did not meet its primary endpoint (median OS 11.3 and 14.3 months for the placebo and the Vx-001, respectively; p = 0.86) whereas the median Time to Treatment Failure (TTF) was 3.5 and 3.6 months, respectively. Disease control for >6months was observed in 30 (33.7%) and 26 (25.7%) patients treated with Vx-001 and placebo, respectively. There was no documented objective CR or PR. Long lasting TERT-specific immune response was observed in 29.2% of vaccinated patients who experienced a significantly longer OS compared to non-responders (21.3 and 13.4 months, respectively; p = 0.004).Conclusion: Vx-001 could induce specific CD8+ immune response but failed to meet its primary endpoint. Subsequent studies have to be focused on the identification and treatment of subgroups of patients able to mount an effective immunological response to Vx-001.Clinical Trial Registration: NCT01935154. [ABSTRACT FROM AUTHOR]

Cloud computing offers a flexible pay-as-you-go model for provisioning application resources, which enables applications to scale on-demand based on the current workload. In many cases, though, users face the single vendor lock-in effect, missing opportunities for optimal and adaptive application deployment across multiple clouds. Several cloud modelling languages have been developed to support multi-cloud resource management, but still they lack holistic cloud management of all aspects and phases. This work defines the Cloud Application Modelling and Execution Language (CAMEL), which (i) allows users to specify the full set of design time aspects for multi-cloud applications, and (ii) supports the models@runtime paradigm that enables capturing an application's current state facilitating its adaptive provisioning. CAMEL has been already used in many projects, domains and use cases due to its wide coverage of cloud management features. Finally, CAMEL has been positively evaluated in this work in terms of its usability and applicability in several domains (e.g., data farming, flight scheduling, financial services) based on the technology acceptance model (TAM). [ABSTRACT FROM AUTHOR]

Derivative chromosomes of 40 patients diagnosed with t(4;11) acute lymphoblastic leukemia (ALL) were analysed on the genomic DNA level. Chromosomal breakpoints were identified in most cases within the known breakpoint cluster regions of the involved MLL and AF4 genes. Due to our current knowledge of the primary DNA sequences of both breakpoint cluster regions, specific features were identified at the chromosomal fusion sites, including deletions, inversions and duplications of parental DNA sequences. After separation of all t(4;11) leukemia patients into two age classes (below and above 1 year of age), the analysis of chromosomal fusion sites revealed significant differences in the distribution of chromosomal breakpoints and led to the definition of two hotspot areas within the MLL breakpoint cluster region. This may point to the possibility of different age-linked mechanisms that were leading to t(4;11) chromosomal translocations. Oncogene (2001) 20, 2900–2907. [ABSTRACT FROM AUTHOR]

Some chromosomal translocations involved in the origin of leukemias and lymphomas are due to malfunctions of the recombinatorial machinery of immunoglobulin and T-cell receptor-genes. This mechanism has also been proposed for translocations t(4;11)(q21;q23), which are regularly associated with acute pro-B cell leukemias in early childhood. Here, reciprocal chromosomal breakpoints in primary biopsy material of fourteen t(4;11)-leukemia patients were analysed. In all cases, duplications, deletions and inversions of less than a few hundred nucleotides indicative of malfunctioning DNA repair mechanisms were observed. We concluded that these translocation events were initiated by several DNA strand breaks on both participating chromosomes and subsequent DNA repair by `error-prone-repair' mechanisms, but not by the action of recombinases of the immune system. [ABSTRACT FROM AUTHOR]

In vivo and in vitro humoral and cell-mediated immunological defects have been described in untreated patients with Hodgkin's disease (HD). The cellular basis of the recently described in vitro reduction of mitogen-induced immunoglobulin synthesis has not been elucidated so far. In this study, we attempted to dissect T and B lymphocyte function in untreated HD patients. Mitogen-induced in vitro immunoglobulin synthesis was assessed in the presence of pokeweed mitogen, the mitogenic anti-CD3 monoclonal antibody OKT3 and the relatively T-cell-independent B cell mitogen Nocardia opaca delipidated mitogen (NDCM). Mitogen-induced Ig synthesis by HD peripheral blood mononuclear cells was significantly reduced compared to that in control peripheral blood mononuclear cells. In coculture assays, T cells of HD patients exerted an adequate helper function to control B cells. However, normal donor T cells did not restore Ig synthesis by B cells of HD patients. Finally, B cells of HD patients were unresponsive to NDCM, which is able to induce Ig synthesis in control B cells even in the absence of T cells. These data provide evidence for an intrinsic functional B lymphocyte defect in HD patients, and suggest that increased activation of suppressor HD T lymphocytes may not play a significant role in the suppression of in vitro Ig synthesis [ABSTRACT FROM AUTHOR]

The Cloud offers enhanced flexibility in the management of resources for any kind of application while it promises the reduction of its cost as well as its infinite scalability. In this way, due to these advantages, there is a recent move towards migrating business processes (BPs) in the Cloud. Such a move is currently performed in a manual manner and only in the context of one Cloud. However, a multi- & cross-Cloud configuration of a BP can be beneficial as it can allow exploiting the best possible offers from multiple Clouds and enable to avoid the lock-in effect by also having the ability to deploy different instances of the BP in different Clouds close to the locations of BP customers. In this respect, this article presents a novel architecture of an environment which realises the vision of multi-Cloud BP provisioning. This environment involves innovative components which support the cross-level orchestration of cloud services as well as the cross-level monitoring and adaptation of BPs. It also relies on a certain language called CAMEL which has been extended to support the adaptive provisioning of multi-Cloud BPs. [ABSTRACT FROM AUTHOR]