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تهدف هذه الدراسة إلى قياس أثر التكنولوجيا في انتقال البلدان من مسارات منخفضة ومتوسطة للدخل إلى مسارات أعلى للدخل، والخروج من فخ الدخل المتوسط والدخل المنخفض وإحداث عملية التقارب الاقتصادي، ولتحقيق هدف الدراسة تم اختيار عينة تضم 105 بلدا متباينة اقتصاديا، ومن ثم بناء نموذج لوجيستي خلال الفترة (1990- 2018). ومن أهم ما توصلت إليه الدراسة وجود أثر معنوي للتكنولوجيا في زيادة احتمال انتقال البلدان منخفضة ومتوسطة الدخل إلى مسارات عليا للدخل وإحداث عملية التقارب الاقتصادي فيما بين هذه الدول.

The EUROPE phase 2 trial investigated the predictive value of biomarkers on the clinical efficacy of single agent romiplostim (ROM) treatment in patients with lower-risk myelodysplastic neoplasms (LR-MDS) and thrombocytopenia within the ‘European Myelodysplastic Neoplasms Cooperative Group‘ (EMSCO) network. A total of 77 patients with LR-MDS and a median platelet count of 25/nl were included, all patients received ROM at a starting dose of 750 μg by SC injection weekly. Thirty-two patients (42%) achieved a hematologic improvement of platelets (HI-P) with a median duration of 340 days. Neutrophil (HI-N) and erythroid (HI-E) responses were observed in three (4%) and seven (9%) patients, respectively. We could not confirm previous reports that HI-P correlated with baseline endogenous thrombopoietin levels and platelet transfusion history, but SRSF2 mutation status and hemoglobin levels at baseline were significantly linked to HI-P. Sequential analysis of variant allelic frequency of mutations like SRSF2 did not reveal an impact of ROM on clonal evolution in both responders and non-responders. In summary, our study confirms the safety and efficacy of ROM in LR-MDS patients and may allow to better define subgroups of patients with a high likelihood of response.

PURPOSE TP53-mutated ( TP53m) myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) have very poor outcome irrespective of the treatment received, including 40% responses (20% complete remission [CR]) with azacitidine (AZA) alone, short response duration, and a median overall survival (OS) of approximately 6 months. Eprenetapopt (APR-246), a novel first-in-class drug, leads to p53 protein reconformation and reactivates its proapoptotic and cell-cycle arrest functions. PATIENTS AND METHODS This phase II study assessed the safety and efficacy of eprenetapopt in combination with AZA in untreated high or very high International Prognostic Scoring System-R TP53m MDS and AML patients. RESULTS Fifty-two TP53m patients (34 MDS, 18 AML [including seven with more than 30% blasts]) were enrolled. In MDS, we observed an overall response rate (ORR) of 62%, including 47% CR, with a median duration of response at 10.4 months. In AML, the ORR was 33% including 17% CR (27% and 0% CR in AML with less than and more than 30% marrow blasts, respectively). Seventy-three percent of responders achieved TP53 next-generation sequencing negativity (ie, variant allele frequency < 5%). The main treatment-related adverse events were febrile neutropenia (36%) and neurologic adverse events (40%), the latter correlating with a lower glomerular filtration rate at treatment onset ( P < .01) and higher age ( P = .05), and resolving with temporary drug interruption without recurrence after adequate eprenetapopt dose reduction. With a median follow-up of 9.7 months, median OS was 12.1 months in MDS, and 13.9 and 3.0 months in AML with less than and more than 30% marrow blasts, respectively. CONCLUSION In this very high-risk population of TP53m MDS and AML patients, eprenetapopt combined with AZA was safe and showed potentially higher ORR and CR rate, and longer OS than reported with AZA alone.

Key Points Systematically developed set of core PROs in MDS, involving patients and hematologists in a 2-round Delphi survey.Core PROs will support unified outcome measurement and facilitate inclusion of reliable patient information in MDS disease care., Visual Abstract, Patient-reported outcomes (PROs) are relevant and valuable end points in the care of patients with myelodysplastic syndromes (MDS). However, a consensus-based selection of PROs for MDS, derived by both patients and hematologists, is lacking. We aimed to develop a core set of PROs for patients with MDS as part of the prospective European LeukemiaNet MDS (EUMDS) Registry. According to international guidelines, candidate PROs were identified from a comprehensive literature search of MDS studies. Overall, 40 PROs were selected and evaluated in a two-round Delphi survey by 40 patients with MDS and 38 hematologists in the first round and 38 patients and 32 hematologists in the second round. Based on an agreement scale and predefined inclusion criteria, both patients and hematologists selected “general quality of life” as a core PRO. Hematologists also selected “transfusion-dependency burden” and “ability to work/activities of daily living” as core PROs. The second Delphi round increased PRO rating agreements. Statistically significant rating differences between patients and hematologists were observed for 28 PROs (Mann-Whitney U test; P < .05) in the first round and for 19 PROs in the second round, with “disease knowledge” and “confidence in health care services” rated notably higher by patients. The overall mean PRO ratings correlation between the 2 groups was moderate (Spearman’s rank correlation coefficient = 0.5; P < .05). This first consensus on a core set of PROs jointly developed by patients and hematologists forms the basis for patient-centered care in daily practice and clinical research.

Chest wall resections for lung cancer treatment remain difficult to plan using standard 2-dimensional computed tomography. Although virtual reality headsets have been used in many medical contexts, they have not been used in chest wall resection planning.We compared preoperative planning of a chest wall surgical resection for lung cancer treatment between senior and resident surgeons who used an immersive virtual reality device and a 2-dimensional computed tomography.Chest wall resection planning was more accurate when surgeons used virtual reality vs computed tomography analysis (28.6% vs 18.3%, P = .018), and this was particularly true in the resident surgeon group (27.4% vs 8.3%, P = .0025). Predictions regarding the need for chest wall substitutes were also more accurate when they were made using virtual reality vs computed tomography analysis in all groups (96% vs 68.5%, P.0001). Other studied parameters were not affected by the use of the virtual reality tool.Virtual reality may offer enhanced accuracy for chest wall resection and reconstruction planning for lung cancer treatment.

Context: Hypoxia is found in at least 47% of soft-tissue sarcoma (STS) patients and is known to be a major contributor to treatment resistance, metastasis progression and associated with poor prognosis. Indeed, expression of hypoxic proteins (HIF1-α, CAIX) in STS is associated with a shorter overall survival, and a shorter progression-free survival in patients. Specifically, Yang et al. demonstrated in 2017 that patients stratified by a 24-gene hypoxia signature had a poorer distant metastasis free survival. Nevertheless, hypoxia is seldom considered during treatment development due to the lack of a user-friendly way to culture naturally hypoxic 3D tumor models. Therefore, we developed a user-friendly in vitro preclinical tool allowing the study of natural chronic hypoxia and its effect on treatment response. Methods: Microfabrication technologies were used to design a microfluidic chip allowing culture, maintenance, treatment, and analysis of 240 STS naturally hypoxic spheroids (750µm of diameter). SK-LMS-1 Human leiomyosarcoma and STS117 (human primary undifferentiated pleomorphic sarcoma cells) spheroids were formed 48h after seeding. Gold-standard hypoxic protein Hypoxia Inducible Factor 1 alpha (HIF1- α) and Carbonic Anhydrase IX (CAIX) expression was assessed by Western Blot (WB). Spatial distribution of CAIX was assessed by immunofluorescence (IF). Based on the IF, an in silico model of the oxygen consumption of the spheroids was built using COMSOL. As a proof of concept, the spheroids were treated using two oxygen-dependent treatment: RT and hypoxia prodrug Tirapazamine (TPZ). DNA-damages were quantified using yH2AX in IF to assess treatment efficacy. Results: These spheroids on-a-chip are the largest to date (>750µm), and express gold-standard hypoxic protein CAIX in their core only, a feature absent in spheroids of 450µm of diameter of the same cell lines. HIF1-α expression patterns were cell line dependent. CAIX expression in SK-LMS-1 and STS117 large spheroids was respectively 7.8 and 24 times higher than in 450µm spheroids. Quantification of DNA damages (count of yH2AX foci/nuclei area in mm²) demonstrated that TPZ preferentially targets the hypoxic core. However, the response (DNA damages) to RT alone showed no evidence of radioresistance of the hypoxic regions, on samples fixed 24h after irradiation. A possible explanation could be that, in 24h, the oxygen-dependent DNA repair and the accumulation of DNA damages in hypoxic regions hide the oxygen-dependent radioresistance. Therefore, quantification of DNA damages with yH2AX 30min after irradiation is currently being investigated, as maximum DNA damage response has been shown to be observed at this time point. Our 750µm spheroids naturally display a hypoxic core expressing gold-standard hypoxic protein CAIX at 120µm of depth, a feature absent in smaller spheroids. Together, these results cement our microfluidic device and our spheroids as a potent fundamental and pre-clinical tool to explore the biology of hypoxia on 3D tumor model, its effects on treatment response. Citation Format: Elena Refet-Mollof, Ouafa Najyb, Rodin Chermat, Audrey Glory, Julie Lafontaine, Philip Wong, Thomas Gervais. Hypoxic sarcoma spheroid on a chip: Insights into treatment response [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr B005.

Hypoxia is a key characteristic of the tumor microenvironment, too rarely considered during drug development due to the lack of a user-friendly method to culture naturally hypoxic 3D tumor models. In this study, we used soft lithography to engineer a microfluidic platform allowing the culture of up to 240 naturally hypoxic tumor spheroids within an 80 mm by 82.5 mm chip. These jumbo spheroids on a chip are the largest to date (&gt, 750 µm), and express gold-standard hypoxic protein CAIX at their core only, a feature absent from smaller spheroids of the same cell lines. Using histopathology, we investigated response to combined radiotherapy (RT) and hypoxic prodrug Tirapazamine (TPZ) on our jumbo spheroids produced using two sarcoma cell lines (STS117 and SK-LMS-1). Our results demonstrate that TPZ preferentially targets the hypoxic core (STS117: p = 0.0009, SK-LMS-1: p = 0.0038), but the spheroids’ hypoxic core harbored as much DNA damage 24 h after irradiation as normoxic spheroid cells. These results validate our microfluidic device and jumbo spheroids as potent fundamental and pre-clinical tools for the study of hypoxia and its effects on treatment response.

High-risk myelodysplastic syndrome/acute myeloid leukemia patients have a very poor survival after azacitidine failure. Guadecitabine (SGI-110) is a novel subcutaneous hypomethylating agent which results in extended decitabine exposure. This multicenter phase II study evaluated the efficacy and safety of guadecitabine in high-risk myelodysplastic syndrome and low blast count acute myeloid leukemia patients refractory or relapsing after azacitidine. We included 56 patients with a median age of 75 years [Interquartile Range (IQR) 69-76]. Fifty-five patients received at least one cycle of guadecitabine (60 mg/m2/d subcutaneously days 1-5 per 28-day treatment cycles), with a median of 3 cycles (range, 0-27). Eight (14.3%) patients responded, including two complete responses; median response duration was 11.5 months. Having no or few identified somatic mutations was the only factor predicting response (P=0.035). None of the 11 patients with TP53 mutation responded. Median overall survival was 7.1 months, and 17.9 months in responders (3 of whom had overall survival >2 years). In multivariate analysis, IPSS-R (revised International Prognostic Scoring System) score other than very high (P=0.03) primary versus secondary azacitidine failure (P=0.01) and a high rate of demethylation in blood during the first cycle of treatment (P=0.03) were associated with longer survival. Thus, guadecitabine can be effective, sometimes yielding relatively prolonged survival, in a small proportion of high-risk myelodysplastic syndrome/low blast count acute myeloid leukemia patients who failed azacitidine. (Trial registered at clinicaltrials.gov identifier: 02197676).

Patient-reported outcomes (PROs) are relevant and valuable endpoints in the care of patients with myelodysplastic syndromes (MDS). However, a consensus-based selection of PROs for MDS, derived by both patients and hematologists, is lacking. We aimed to develop a core set of PROs for patients with MDS as part of the prospective European LeukemiaNet MDS (EUMDS) Registry. Following international guidelines, candidate PROs were identified from a comprehensive literature search in MDS studies. Overall, 40 PROs were selected and evaluated in a two-round Delphi survey by 40 patients with MDS and 38 hematologists in the first, and 38 and 32 in the second round, respectively. Based on an agreement scale and predefined inclusion criteria, both patients and hematologists selected "general quality of life" as a core PRO. Hematologists also selected "transfusion-dependency burden" and "ability to work/activities of daily living" as core PROs. The second Delphi round increased PRO rating agreements. Statistically significant rating differences between patients and hematologists were observed for 28 PROs (Mann-Whitney U test; p-value

The ecodendrological study, on 35 plots were sampled in the Alep pine formation of the Ain Hamda Tizi N’bechar forest at the rate of one plot per station and in each plot a Phytoecological floristic survey was carried out. Concerning the species of the floral procession of the pine forest, there are 19 medicinal species, belonging to 13 families and 20 genera. This medicinal potential must be protected and preserved; it is in this context that this study is based on the knowledge of the factors which influence the distribution and the distribution of these species within the framework of a good rational management in support of the local and sustainable development of the local population through valuation.