The prognosis of adult acute myeloid leukemia (AML) remains poor, with the long-term survival rate less than 50%. However, the current paradigms of treatment are changing through a better ...understanding of the disease genetics and pathophysiology. Since 2017, eight new drugs have been approved by the U.S. Food and Drug Administration for the treatment of AML, including the FLT3 inhibitors midostaurin and gilteritinib, the IDH inhibitors ivosidenib and enasidenib, the anti-CD33 monoclonal antibody gemtuzumab ozogamicin, liposomal daunorubicin and cytarabine, the hedgehog pathway inhibitor glasdegib and the BCL-2 inhibitor venetoclax. Preclinical data demonstrated the anti-leukemic efficacy of venetoclax in AML and its synergy when combined with hypomethylating agents or chemotherapy agents. Clinical trials have demonstrated the clinical benefit of venetoclax-based therapies in newly diagnosed AML, leading to the recent FDA approval of venetoclax in combination with hypomethylating agents or low-dose cytarabine for older adults with newly diagnosed AML. Herein, we focus on the role of single-agent BCL-2 inhibition in AML and review the clinical studies of venetoclax-based combination regimens and the evolving mechanisms of resistance.
•Exposure to thalidomide analogs, particularly lenalidomide, is associated with increased risk of TP53-mutated myeloid neoplasms.•Treatment with lenalidomide but not pomalidomide leads to expansion ...of preleukemic Trp53-mutant HSPCs due to selective degradation of Ck1α.
Display omitted
There is a growing body of evidence that therapy-related myeloid neoplasms (t-MNs) with driver gene mutations arise in the background of clonal hematopoiesis (CH) under the positive selective pressure of chemo- and radiation therapies. Uncovering the exposure relationships that provide selective advantage to specific CH mutations is critical to understanding the pathogenesis and etiology of t-MNs. In a systematic analysis of 416 patients with t-MN and detailed prior exposure history, we found that TP53 mutations were significantly associated with prior treatment with thalidomide analogs, specifically lenalidomide. We demonstrated experimentally that lenalidomide treatment provides a selective advantage to Trp53-mutant hematopoietic stem and progenitor cells (HSPCs) in vitro and in vivo, the effect of which was specific to Trp53-mutant HSPCs and was not observed in HSPCs with other CH mutations. Because of the differences in CK1α degradation, pomalidomide treatment did not provide an equivalent level of selective advantage to Trp53-mutant HSPCs, providing a biological rationale for its use in patients at high risk for t-MN. These findings highlight the role of lenalidomide treatment in promoting TP53-mutated t-MNs and offer a potential alternative strategy to mitigate the risk of t-MN development.
Studying fluvial dynamics and environments, GIS-based analyses are of fundamental importance to evaluate the network geometry and possible anomalies, and can be particularly useful to estimate ...modifications in processes and erosion rates. The aim of this paper is to estimate short-term erosion rates attributable to fluvial processes in two sample catchment sub-basins of the Marecchia river valley, by conducting quantitative morphometric analyses in order to calculate various descriptive parameters of the hierarchisation of the river networks and the mean turbid transport of streams (Tu). Sediment yield transported by streams can in fact partially express the amount of erosional processes acting within the drainage basin. The study area includes two sub-basins of the Marecchia valley (Senatello river, 49 km2 and Mazzocco river, 47 km2), chosen because of their similar extent and of the different location in the major catchment basin. Starting from geomorphological maps of the two river basins, the Tu parameter has been calculated and converted in short-term rate (average value 0.21 mm/year). Moreover, the comparison of these short-term mean data with the uplift rates calculated on a regional scale (0.41 ± 0.26 mm/year) in the Marecchia valley confirms that the northern Apennines may represent a non-steady state system.
Geoheritage is a geotourism resource that could lead to the sustainable development of society, and could contribute to information on geological and geomorphological characteristics, education, ...public awareness on geoconservation, and landscape protection. Understanding this cultural wealth is still limited, since the information available is often specialized. Communication addressed to the emotional sphere can profoundly engage people, and technical information can be transmitted more effectively. For several years, our research group dealt with geoheritage and geotourism in central Italy. This work aimed to investigate different communication methods, such as publications, announcements through social media, conferences, live performances, and field excursions aimed at the emotional involvement of the public. Furthermore, the emotional response of the public was explored through a digital survey. These communication methodologies enabled a broad public reach, without any distinction based on social origin, cultural background, or age. Narrating the landscape through different forms of art creates a personal relationship with the audience. The emotional participation of the people demonstrates the effectiveness of the method in transmitting scientific and cultural themes, such as the origin of the geological landforms, the culture and the traditions that the site generated, and the problems pertaining to its protection and conservation.
Rimini is located at the southernmost end of the Po Plain, in Emilia-Romagna region. The geomorphology of the site mainly depends on the actions of the Marecchia River, coupled with marine processes ...in Holocene times. By creating a geomorphological map of the area, we highlight the factors that influenced the historical evolution of the town, relating them to anthropic features, with acmes in natural changes probably matching periods of climate deterioration. Many clues suggest that the Marecchia river pattern changed frequently and drastically during the climate deterioration of the Early Middle Ages, when the river's name changed from Ariminus to Maricula ('little sea'). The river frequently aggraded and overflowed during the climate deterioration of the Little Ice Age and until the early twentieth century. The urban geomorphological map, implemented according to the official ISPRA cartography criteria, has enabled us to highlight valuable elements for reconstructing the evolution of the town, that are now almost completely hidden by urbanisation.
FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation in acute myeloid leukemia (AML) is associated with poor prognosis. We hypothesized that quizartinib, a selective and potent ...FLT3 inhibitor, with azacitidine (AZA) or low-dose cytarabine (LDAC) might improve the outcomes in patients with FLT3-ITD-mutated AML. In this open-label phase I/II trial, patients of any age receiving first-salvage treatment for FLT3-ITD AML or age >60 years with untreated myelodysplastic syndrome or AML were treated with quizartinib plus AZA or LDAC. Seventy-three patients were treated (34 frontline, 39 first-salvage). Among previously untreated patients, composite response (CRc) was achieved in 13/15 (87%, 8 CR, 4 Cri, 1 CRp) treated with quizartinib/AZA and 14/19 (74%, 1 CR, 8 CRi, 5 CRp) in quizartinib/LDAC. The median OS was 19.2 months for quizartinib/AZA and 8.5 months for quizartinib/LDAC cohort; RFS was 10.5 and 6.4 months, respectively. Among previously treated patients, 16 (64%) achieved CRc in quizartinib/AZA and 4 (29%) in quizartinib/LDAC. The median OS for patients treated with quizartinib/AZA and quizartinib/LDAC was 12.8 vs. 4 months, respectively. QTc prolongation grade 3 occurred in only 1 patient in each cohort. Quizartinib-based combinations, particularly with AZA, appear effective in both frontline and first-salvage for patients with FLT3-ITD-mutated AML and are well tolerated.
Adult acute lymphoblastic leukemia (ALL) has a poor overall survival compared with pediatric ALL where cure rates are observed in more than 90% of patients. The recent development of novel monoclonal ...antibodies targeting CD20, CD19, and CD22 has changed the long-term outcome of this disease, both in the frontline setting (e.g. rituximab) and for patients with relapsed/refractory disease (e.g. inotuzumab ozogamicin and blinatumomab). The CD3-CD19 bispecific T-cell-engaging antibody blinatumomab is also the first drug approved in ALL for patients with persistent or recurrent measurable residual disease, providing a new treatment paradigm for these patients. Several new agents are also in development that use novel constructs or target alternative surface epitopes such as CD123, CD25, and CD38. Herein, we review the role of monoclonal antibodies in adult ALL and summarize the current and future approaches in ALL, including novel combination therapies and the possibility of early incorporation of these agents into treatment regimens.
SYNOPSIS Worldwide, breast cancer is the most common disease in women and constitutes the second leading cause of cancer death in this population. The factors that contribute to the risk of ...occurrence are divided into nonmodifiable and modifiable factors. Although there are interventions in primary care to prevent the disease, these measures have not produced the desired changes in women's health. This article reviews the major modifiable risk factors for breast cancer and describes how these factors can affect the incidence of cancer in women. This information shows that modifiable risk factors (such as physical activity, diet, obesity, and use of alcohol and tobacco) can influence the occurrence of breast cancer, in part depending on the life stage of a woman, including menopausal status. Timely prevention at the primary care level is one of the most important areas on which health professionals need to focus in order to help reduce the incidence of breast cancer.
The aim of this paper is to present the geomorphological map of the right side of the middle Marecchia valley, in the northern Apennines (Italy), as a basis to enhance the geotouristic potential of ...the area. This area has been chosen because it is representative of the geological, geomorphological and geodynamic context characterizing the whole Marecchia basin, where a massive allochthonous body (known as Valmarecchia Nappe) widely outcrops. This area consists of Ligurian and Epiligurian formations that overthrust the Umbro-Marchean autochthonous units, drawing a peculiar landscape characterized by high geodiversity and marked above all by landforms developing into various formations. In order to map the main geomorphological features, multi-temporal aerial photos analysis, field survey and bibliographical research, concerning both the geomorphological and cultural values, have been carried out. The landforms highlighted in the map include stream terraces, vertical cliffs, alluvial fans, badlands and landslides; additional geomorphological points of interest have been described and mapped as they represent the most distinctive events in the area. The geomorphological features have been integrated with the additional (ecological, aesthetic, cultural) values to quantify the value of each geosite using an adapted version of Reynard et al. (2016)’s method, from which it emerged that the sites have high scores both in terms of scientific and additional values, making the study area an ideal territory in which implement actions and proposals for geotouristic fruition.
The geomorphological analysis of historically urbanized areas is the best scientific way to understand how the extant geomorphological factors conditioned urbanization. It also provides a baseline to ...enable comparisons to be made with the modern environment. This paper considers four urbanized historical sites on the Adriatic coast (Italy) that owe their urban development to particular geomorphological and environmental conditions that were modified over the centuries from the Roman age to the present day. The focus here is on the evolution of the shoreline and associated geomorphic variables (streambeds and river mouths migration). These factors are fundamental for determining the development of a city, both as basic boundary elements – therefore including defence and protection – and also for the development of harbours.
PDF
