Cancer therapy shapes the fitness landscape of clonal hematopoiesis.

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies

Cancer therapy shapes the fitness landscape of clonal hematopoiesis.

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies

Unidentifiable Thrombophilia

The term “thrombophilia” is generally used to designate states of hypercoagulability caused by an inherent abnormality of the coagulation system, resulting in an increased risk of thrombosis. Abnormalities of blood flow or the blood vessel wall, the other two components of Virchow’s triad that increase the risk of thrombosis, are not considered a thrombophilia

What's new in the pathogenesis of the coagulopathy in acute promyelocytic leukemia?

Purpose of reviewAcute promyelocytic leukemia (APL) is associated with a complex coagulopathy. In spite of substantial recent improvements in treatment regimens, hemorrhagic death remains the main cause of induction failure. In this review, we delineate recent understanding of the pathophysiology and management of the hemorrhagic diathesis of APL.Recent findingsLaboratory and clinical data suggest that the malignant leukocytes mediate the hemorrhagic diathesis associated with APL through multiple mechanisms which lead to a combination of consumptive coagulopathy and primary hyperfibrinolysis. Exposure of tissue factor and Annexin II by the leukemic blasts is the main determinants of these processes. Promyelocyte-derived microparticles have recently been implicated in the coagulopathy as well. Total white cell count and platelet count have emerged as good general predictors of hemorrhagic death, along with the different routine hemostatic parameters. Prompt treatment with all-trans retinoic acid, with or without arsenic trioxide, is the most important step in preventing bleeding complications. Repletion of coagulation factors and platelets with blood products remains the mainstay of supportive treatment, whereas the role of recombinant soluble thrombomodulin is currently being investigated.SummaryThe coagulopathy of APL is multifactorial, with both disseminated intravascular coagulation and primary hyperfibrinolysis mediated largely by the malignant leukocytes

Enoxaparin dose reduction for thrombocytopenia in patients with cancer: a quality assessment study

The development of thrombocytopenia in the setting of therapeutic anticoagulation for venous thromboembolic disease (VTE) is common in cancer patients, but guidelines for management are based on limited past data and have not been validated. In 2011, Memorial Sloan Kettering Cancer Center (MSKCC) implemented the following guidelines in this setting: administer full dose enoxaparin for a platelet count > 50,000/mcL, half-dose enoxaparin for a platelet count of 25,000-50,000/mcL, and hold anticoagulation for a platelet count < 25,000/mcL. We now report validation of safety and efficacy of these guidelines. As a Quality Assessment Initiative, we evaluated our guidelines for adult cancer patients at MSKCC who were on therapeutic-dose enoxaparin for VTE during the years 2011 through 2013 and experienced at least one 7-day period of thrombocytopenia (platelet count ≤ 50,000/mcL). We assessed adherence to the enoxaparin dose modification guidelines, major bleeding, clinically relevant non-major bleeding, recurrent VTE, and mortality during the thrombocytopenic episodes. We identified 99 patients with 140 episodes of thrombocytopenia of 7 or more days. The median duration of these thrombocytopenic episodes was 12 days. The enoxaparin dose was modified in 133 of the 140 episodes (95%), reflecting satisfactory adherence to our institutional guidelines. There were no recurrent VTE events or major bleeding episodes when the anticoagulant dose was reduced or held. In this cohort, there was only one major bleeding episode, a trauma-associated retroperitoneal hemorrhage that occurred on the third day of a thrombocytopenic episode, prior to enoxaparin dose modification. There were 13 clinically relevant non-major bleeding episodes. Lastly, 10 patients died of cancer-related causes during an episode of thrombocytopenia. This Quality Assessment Initiative supports the safety and efficacy of our guidelines for therapeutic enoxaparin dose modification

Anticoagulation in the Patient with Cancer

The association between malignant neoplasms and venous thromboembolism (VTE) is well recognized, and anticoagulation therapy is commonly administered in the oncological setting. The treatment approach to cancer-associated VTE differs substantially compared to the general population, as chronic low-molecular-weight heparin (LMWH) has been shown to be more effective than vitamin K antagonist (VKA). There are also several challenges specific to the cancer patient. These include an increased risk of bleeding, higher rates of anticoagulation failure, drug interactions, decreased oral intake, chemotherapy-induced thrombocytopenia, and cerebral metastases. Most of the literature in the field concerns the use of LMWH for cancer-associated VTE. Data is accumulating about the use of direct oral anticoagulants (DOACs) in this setting. DOACs offer improved patient quality of life and reduced cost compared to LMWH, although no published randomized trial has directly compared these two classes of anticoagulants in patients with cancer. Even though atrial fibrillation is by far the most common indication for anticoagulation in developed countries, there are little data about the best choice of agent when this arrhythmia occurs in cancer patients. It is unclear if the risk of ischemic stroke or systemic embolization is increased in the presence of malignancy, although the risk of bleeding is likely higher. Notably, VKA are still administered for the treatment of AF despite the difficulties inherent to cancer patients

MOOC "Discovering Greek & Roman Cities"

MOOCThe Massive Open Online Course (MOOC) "Discovering Greek & Roman Cities" is aimed at people interested in archaeology, art and cultural history, architecture and history. The participation does not require prerequisites such as possession of a qualification or a level of performance in earlier studies The course can be accessed online free of charge. Over a period of eight weeks, experts from five different European countries will impart basic knowledge about ancient cities and methods of urban archaeology. In this way, participants learn about the complexity of the ancient cultural heritage. The project is committed to the European idea, so the course will be available in German, English and French. The course is divided into eight modules. After an introduction, life, religion, death, politics, infrastructure and the economy of ancient cities will be discussed. The last module focuses on the legacy of ancient cities and the role of the ancient heritage in our cities today. Each module consists of three 10-minute videos. Following these clips, the participants can work on further assignments, answer quiz questions and go deeper into the subject matter on the basis of selected literature references. An online forum is available for virtual discussions and exchange with the teachers. Once a week, one of the lecturers gives insight into their own research area in a video conference and is also available to answer questions. Once the participants have watched all the videos and completed the corresponding assignments, they can finally receive an official certificate confirming their successful participation in the course

Der MOOC Discovering Greek & Roman Cities. Lebenslanges Lernen im digitalen Zeitalter

International audienceDer Kommentar reflektiert anhand des vorgestellten MOOC 'Discovering Greek & Roman Cities' Herausforderungen und Perspektiven des digitalen historischen Lernens auf Ebene der wissenschaftlichen Auseinandersetzung, der Ausbildung von Lehrenden und der schulischen Umsetzung. Dafür werden Facetten des geschichtsdidaktischen Diskurses zum digitalen historischen Lernen mit dem Aufbau und den Erfahrungen des MOOC verknüpft, um so Impulse für für die Gestaltung digitalen Lehre, als auch die Ziele und Prozesse einer digitalen wie analogen Lehre im Hinblick auf digitale geschichtskulturelle Angebote abzuleiten. Im Fokus stehen dabei die Aspekte der Lerngruppendifferenzierung, der veränderten Kommunikation und der Mehrsprachigkeit sowie einer historischen und geschichtsdidaktischen Medienkompetenz und die Einbindung von Sachquellen.Based on the MOOC 'Discovering Greek & Roman Cities', the commentary reflects the challenges and perspectives of digital historical learning on the level of academic discussion, the education of teachers and the implementation in schools. For this purpose, facets of the academic historical education discourse on digital historical learning are linked with the structure and experiences of the MOOC in order to derive impulses for the design of digital teaching and the goals and processes of digital and analog teaching with regard to digital historical-cultural offers. The focus is on the aspects of learning group differentiation, changed communication and multilingualism as well as historical and historical-didactic media competence and the integration of factual source