Beyond the lessons learned from the COVID-19 pandemic: opportunities to optimize clinical trial implementation in oncology

COVID-19 pandemic; OncologyPandemia de COVID-19; OncologíaPandèmia de COVID-19; OncologiaIn this paper, we aim to capitalize on the lessons learnt from the impact of the COVID-19 pandemic on clinical trials and use them as a catalyst to launch a discussion over a framework of broader adaptations needed in the design and implementation of oncology clinical trialsNone declared

Challenges and Knowledge Gaps with Immune Checkpoint Inhibitors Monotherapy in the Management of Patients with Non-Small-Cell Lung Cancer: a Survey of Oncologist Perceptions

Background: Immune checkpoint-inhibitors (ICIs) are changing outcomes in different cancer settings, notably for patients with non-small-cell lung cancer (NSCLC). There are, however, still important gaps of evidence for clinical practice when using these novel treatments. In this study, we assessed physicians' opinion and experience on challenges for clinical practice with ICIs monotherapy in NSCLC. Methods: A survey was conducted on experienced physicians treating patients with NSCLC with ICIs. Two rounds of pilot tests were carried out for validation among a group of experts. Topics under analysis were in relation to treatment of elderly populations, performance status, brain metastases, use of steroids or antibiotics, the effects of gut microbiome, autoimmune diseases, human immunodeficiency virus infection, solid organ transplants, use of anti-programmed cell death protein 1 versus anti-programmed death-ligand 1 drugs, atypical tumour responses, predictors of response, duration of treatment and a final open question on additional relevant challenges. Results: Two hundred and twenty-one answers were collected, including 106 (48%) valid answers from experts for final analysis (physicians who have treated at least 20 patients with NSCLC with ICIs). The vast majority agreed that the selected topics in this study are important challenges ahead and more evidence is needed. Moreover, predictors of response, treating brain metastasis, shorter duration of treatment, the effects of gut microbiome and concomitant use of steroids were voted the most important topics to be further addressed in prospective clinical research. Conclusions: This survey contributed to understanding which are the main challenges for clinical practice with ICIs monotherapy in NSCLC. It can also contribute to guide further clinical research, considering the opinions and experience of those who regularly treat NSCLC patients with ICIs.info:eu-repo/semantics/publishedVersio

Subgroup analyses from a phase 3, open-label, randomized study of eribulin mesylate versus capecitabine in pretreated patients with advanced or metastatic breast cancer

Purpose and methods: Our secondary analyses compared survival with eribulin versus capecitabine in various patient subgroups from a phase 3, open-label, randomized study. Eligible women aged ≥18 years with advanced/metastatic breast cancer and ≤3 prior chemotherapies (≤2 for advanced/metastatic disease), including an anthracycline and taxane, were randomized 1:1 to intravenous eribulin mesylate 1.4 mg/m² on days 1 and 8 or twice-daily oral capecitabine 1250 mg/m² on days 1–14 (21-day cycles). Results: In the intent-to-treat population (eribulin 554 and capecitabine 548), overall survival appeared longer with eribulin than capecitabine in various subgroups, including patients with human epidermal growth factor receptor 2-negative (15.9 versus 13.5 months, respectively), estrogen receptor-negative (14.4 versus 10.5 months, respectively), and triple-negative (14.4 versus 9.4 months, respectively) disease. Progression-free survival was similar between the treatment arms. Conclusions: Patients with advanced/metastatic breast cancer and human epidermal growth factor receptor 2-, estrogen receptor-, or triple-negative disease may gain particular benefit from eribulin as first-, second-, and third-line chemotherapies

Supersymmetric AdS vacua and separation of scales

The moduli space of the supersymmetric massive IIA AdS4xS2(B4) vacua, where S2(B4) is a two-sphere bundle over a four-dimensional Kaehler-Einstein base B4, includes three independent parameters which can be thought of as corresponding to the sizes of AdS4, B4 and the S2 fiber. It might therefore be expected that these vacua do not suffer from the absence of scale separation. We show that the independence of the geometric moduli survives flux quantization. However, we uncover an attractor behavior whereby all sizes flow to equality in some neighborhood of spacetime independently of the initial conditions set by the parameters of the solution. This is further confirmed by the study of the ratio of internal to external scalar curvatures. We also show that the asymptotic Kaluza-Klein spectrum of a ten-dimensional massive scalar is governed by a scale of the order of the AdS4 radius. Furthermore we point out that the curvature ratio in supersymmetric IIA AdS4 vacua with rigid SU(3) structure is of order one, indicating the absence of scale separation in this large class of vacua.Comment: 21 pages, 2 figures; v2 typos correcte

Study protocol for THINK : a multinational open-label phase I study to assess the safety and clinical activity of multiple administrations of NKR-2 in patients with different metastatic tumour types

Introduction: NKR-2 are autologous T cells genetically modified to express a chimeric antigen receptor (CAR) comprising a fusion of the natural killer group 2D (NKG2D) receptor with the CD3 zeta signalling domain, which associates with the adaptor molecule DNAX-activating protein of 10 kDa (DAP10) to provide co-stimulatory signal upon ligand binding. NKG2D binds eight different ligands expressed on the cell surface of many tumour cells and which are normally absent on non-neoplastic cells. In preclinical studies, NKR-2 demonstrated long-term antitumour activity towards a breadth of tumour indications, with maximum efficacy observed after multiple NKR-2 administrations. Importantly, NKR-2 targeted tumour cells and tumour neovasculature and the local tumour immunosuppressive microenvironment and this mechanism of action of NKR-2 was established in the absence of preconditioning. Methods and analysis: This open-label phase I study will assess the safety and clinical activity of NKR-2 treatment administered three times, with a 2-week interval between each administration in different tumour types. The study will contain two consecutive segments: a dose escalation phase followed by an expansion phase. The dose escalation study involves two arms, one in solid tumours (five specific indications) and one in haematological tumours (two specific indications) and will include three dose levels in each arm: 3x10(8), 1x10(9) and 3x10(9) NKR-2 per injection. On the identification of the recommended dose in the first segment, based on dose-limiting toxicity occurrences, the study will expand to seven different cohorts examining the seven different tumour types separately. Clinical responses will be determined according to standard Response Evaluation Criteria In Solid Tumors (RECIST) criteria for solid tumours or international working group response criteria in haematological tumours. Ethics approval and dissemination: Ethical approval has been obtained at all sites. Written informed consent will be taken from all participants. The results of this study will be disseminated through presentation at international scientific conferences and reported in peer-reviewed scientific journals

Phase III Open-Label Randomized Study of Eribulin Mesylate Versus Capecitabine in Patients With Locally Advanced or Metastatic Breast Cancer Previously Treated With an Anthracycline and a Taxane

Purpose: This phase III randomized trial (ClinicalTrials.gov identifier: NCT00337103) compared eribulin with capecitabine in patients with locally advanced or metastatic breast cancer (MBC). Patients and Methods: Women with MBC who had received prior anthracycline- and taxane-based therapy were randomly assigned to receive eribulin or capecitabine as their first-, second-, or third-line chemotherapy for advanced/metastatic disease. Stratification factors were human epidermal growth factor receptor-2 (HER2) status and geographic region. Coprimary end points were overall survival (OS) and progression-free survival (PFS). Results: Median OS times for eribulin (n = 554) and capecitabine (n = 548) were 15.9 and 14.5 months, respectively (hazard ratio [HR], 0.88; 95% CI, 0.77 to 1.00; P = .056). Median PFS times for eribulin and capecitabine were 4.1 and 4.2 months, respectively (HR, 1.08; 95% CI, 0.93 to 1.25; P = .30). Objective response rates were 11.0% for eribulin and 11.5% for capecitabine. Global health status and overall quality-of-life scores over time were similar in the treatment arms. Both treatments had manageable safety profiles consistent with their known adverse effects; most adverse events were grade 1 or 2. Conclusion: In this phase III study, eribulin was not shown to be superior to capecitabine with regard to OS or PFS

M-Theory on (K3 X S^1)/Z_2

We analyze $M$-theory compactified on $(K3\times S^1)/Z_2$ where the $Z_2$ changes the sign of the three form gauge field, acts on $S^1$ as a parity transformation and on K3 as an involution with eight fixed points preserving SU(2) holonomy. At a generic point in the moduli space the resulting theory has as its low energy limit N=1 supergravity theory in six dimensions with eight vector, nine tensor and twenty hypermultiplets. The gauge symmetry can be enhanced (e.g. to $E_8$) at special points in the moduli space. At other special points in the moduli space tensionless strings appear in the theory.Comment: LaTeX file, 11 page

The Short-term Car Flow Planning Model in Rail Freight Company – Case Study

AbstractWith the promotion of the environmentally friendly transportation modes (the European Commission supports the freight transport operations in the rail sector), an increase in the diversification of the demand is observed. While most rail freight companies tend to apply fixed schedules, this approach is not effective turns out to be ineffective due to the need to meet the customer's specific requirements.The purpose of this paper is to present a case study of empty wagon flow planning over a medium term horizon and to discuss the opportunities of improvement of this plans by discrete optimization. In order to increase the utilization and availability of wagons, the planning procedure with a rolling horizon has to be implemented. Unfortunately, since the plan has to be updated ca. every 4hours, this planning approach needs effective optimization tools. Our hybrid two-stage approach is designed to be implemented in such business environment. This formulation allows us to solve real life instances even for a 7-day time horizon

The GS String Action on AdS(3)xS(3) with Ramond-Ramond Charge

We derive the classical kappa-symmetric Type IIB string action on AdS(3) x S(3) by employing the SU(1,1|2)^2 algebra. We then gauge fix kappa-symmetry in the background adapted Killing spinor gauge and present the action in a very simple form.Comment: 19 pages, LaTe