Abstract

Axillary surgery for patients with breast cancer (BC) in 2024 is becoming increasingly specific, moving away from the previous ‘one size fits all’ radical approach. The goal is to spare morbidity whilst maintaining oncologic safety. In the upfront surgery setting, a first landmark randomized controlled trial (RCT) on the omission of any surgical axillary staging in patients with unremarkable clinical examination and axillary ultrasound showed non-inferiority to sentinel lymph node (SLN) biopsy (SLNB). The study population consisted of 87.8% postmenopausal patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative BC. Patients with clinically node-negative breast cancer and up to two positive SLNs can safely be spared axillary dissection (ALND) even in the context of mastectomy or extranodal extension. In patients enrolled in the TAXIS trial, adjuvant systemic treatment was shown to be similar with or without ALND despite the loss of staging information. After neoadjuvant chemotherapy (NACT), targeted lymph node removal with or without SLNB showed a lower false-negative rate to determine nodal pathological complete response (pCR) compared to SLNB alone. However, oncologic outcomes do not appear to differ in patients with nodal pCR determined by either one of the two concepts, according to a recently published global, retrospective, real-world study. Real-world studies generally have a lower level of evidence than RCTs, but they are feasible quickly and with a large sample size. Another global real-world study provides evidence that even patients with residual isolated tumor cells can be safely spared from ALND. In general, few indications for ALND remain. Three randomized controlled trials are ongoing for patients with clinically node-positive BC in the upfront surgery setting and residual disease after NACT. Pending the results of these trials, ALND remains indicated in these patients.

Introduction

Axillary surgery for breast cancer (BC) has evolved significantly from a previous “one size fits all” approach that involved radical surgery, including lymph node dissection extending from the axilla to the neck, to an increasingly granular and individualized surgical treatment. Axillary lymph node dissection (ALND) was the standard of care for all patients with BC until the nineties, which was considered to be a therapeutic procedure. The rationale behind it was that a complete surgical removal of locoregional tumor residues would result in improved survival, a hypothesis that has never been proven and was already questioned by the NSABP-04 trial [1,2,3]. In this landmark study, patients with clinically node-negative and node-positive BC were shown to have similar 10-year overall survival outcomes, no matter whether ALND or axillary radiotherapy (ART) were performed [3]. These results could be confirmed in clinically node-negative patients, who underwent breast-conserving surgery (BCS) and adjuvant radiotherapy of the breast [4]. Therefore, radical surgery and its associated morbidity was increasingly questioned. Axillary staging information was still deemed necessary, leading to the development of the sentinel lymph node (SLN) biopsy (SLNB). Whilst showing a false-negative rate of around 10%, excellent oncologic outcomes were achieved [5,6,7,8]. Notably, SLNB dramatically reduced surgical morbidity and improved quality of life [5,9,10,11,12,13,14,15,16,17]. Nevertheless, approximately 5% of patients still experience surgery-related morbidity [9]. Therefore, studies to identify patients in whom surgical axillary staging can be altogether abandoned have been initiated.

Conclusions

Efforts to de-escalate axillary surgery in BC have led to major changes in treatment paradigms, sparing thousands of women the associated morbidity of ALND whilst remaining oncologically safe, as shown in randomized controlled trials with a high level of evidence. Few indications for ALND remain, with real-world studies being indicative of safe omission possibilities even if ITCs are found after NACT. Such studies generally have a lower level of evidence. However, they can address clinically relevant questions in a global manner, quickly, with the largest number of participants, and therefore the strongest statistical power available. For patients with clinically node-positive BC, the results of three randomized controlled trials—namely, the Alliance A011202 trial, the ADARNAT trial, and the OPBC-03/TAXIS trial—are eagerly awaited.

Abstract

One in eight women will develop breast cancer in the US. For women with moderate (15–20%) to average (12.5%) risk of breast cancer, there are few options available for risk reduction. For high-risk (>20%) women, such as BRCA mutation carriers, primary prevention strategies are limited to evidence-based surgical removal of breasts and/or ovaries and anti-estrogen treatment. Despite their effectiveness in risk reduction, not many high-risk individuals opt for surgical or hormonal interventions due to severe side effects and potentially life-changing outcomes as key deterrents. Thus, better communication about the benefits of existing strategies and the development of new strategies with minimal side effects are needed to offer women adequate risk-reducing interventions. We extensively review and discuss innovative investigational strategies for primary prevention. Most of these investigational strategies are at the pre-clinical stage, but some are already being evaluated in clinical trials and others are expected to lead to first-in-human clinical trials within 5 years. Likely, these strategies would be initially tested in high-risk individuals but may be applicable to lower-risk women, if shown to decrease risk at a similar rate to existing strategies, but with minimal side effects.

Introduction

For women in the US, breast cancer (BC) is the most prevalent cancer and the second-leading cause of cancer-related deaths. Projections for 2023 estimate that 55,720 women will be diagnosed with carcinoma in situ, 297,790 with invasive carcinoma, and 43,170 women will die from BC [1]. With the number of new diagnoses still on the rise, one in eight women will develop BC within their lifetime, but all women are at risk. Therefore, there is a need to develop new strategies for primary prevention with a focus on high-risk (>20%) individuals, but that can also be applied to moderate- (15–20%) and average (12.5%)-risk individuals.

There are well-established risk factors that contribute to the absolute risk of developing BC [2,3]. There are modifiable risk factors such as having a healthy diet, regular exercise, and limiting alcohol consumption [2,4]. Cumulative exposure of breast tissue to estrogen is an important risk factor for BC. This risk can be minimized by various actions such as having their first-born before age 30, limiting the use of hormonal birth control medications, and avoiding hormone replacement therapy. Non-modifiable risk factors that increase cumulative exposure to estrogen include younger age at menarche and older age at natural menopause [2]. There are non-modifiable genetic risk factors that include known mutations in a high-penetrant BC gene such as BRCA1 and BRCA2, cumulative interaction of risk-associated alleles of BC susceptible SNPs, and/or family history with multiple incidences of BC [5]. There are also non-modifiable risk factors related to the personal history of radiation therapy to the chest, and the number of breast biopsies [4].

Conclusions and Future Directions

BC is the leading cause of new cancer cases and is the second leading cause of cancer-related deaths in women. The limited, approved prevention interventions available for high-risk individuals can have severe and long-term side effects that deter many women from making proactive choices. Regrettably, BC prevention is an area of translational research that is currently underfunded by federal agencies [182]. Therefore, emerging and novel approaches for the primary prevention of BC that provide the same or superior protection while minimizing the side effects of current interventions should be pursued and prioritized. These approaches seek to eradicate BC and align well with NIH’s All of US Research Program—a nationwide initiative for precision health interventions that proactively prevent rather than treat disease in high-risk individuals. We provide a comprehensive review of emerging approaches for BC prevention based on non-modifiable risk factors that put women at a higher risk of developing BC. Virtually all of these studies were performed in rodent models of BC, which have some limitations and challenges for direct translation to at-risk individuals. Additional scalability and validation studies in larger animal models will be an important step in bridging the gap between discovery and clinical evaluation. Although currently underutilized, rabbit studies should be considered as an appropriate intermediate model. Evolutionarily, anatomically, and physiologically, rabbit mammary glands are more similar to humans than those of rodent models or other large animals such as cows and sheep [183,184]. Female rabbits have four pairs of mammary glands each containing four ductal trees [177], which can be cannulated for ID injection [177,185,186,187,188,189] using a procedure very similar to ID administration of contrast agents in clinical ductography [190,191] and chemotherapeutic agents in first-in-human clinical research [92,145]. Alternatively, or complementary to validation studies in larger animals, judicious determination based on the scientific rigor and clinical feasibility of these emerging approaches should be applied to prioritize those interventions more likely to have an impact on primary prevention of BC.

Abstract

Breast cancer affected more than 2.3 million women in 2022 and is the most diagnosed cancer among women worldwide. The incidence rates are greater in developed regions and are significantly higher among women with higher education and socioeconomic status. Therefore, it is reasonable to assume that the way women live their lives may impact their risk of being diagnosed with breast cancer. This systematic review aimed to identify what is known about the causes and risk factors of breast cancer, excluding genetic causes. A comprehensive systematic search identified 2387 systematic reviews, 122 were included and six overall themes identified. In our “top list” with the 36 most important findings, a study of breast density had the highest effect size for increasing the risk of breast cancer, and a high sex-hormone-binding globulin level was the most protective factor. Many of the included studies investigating the same topics had conflicting results. The conclusion from this evidence synthesis reveals a lack of consensus of factors associated with the causes and risk of breast cancer. These findings suggest that recommendations about lifestyle and breast cancer should be made with caution.

Introduction

Breast cancer affected more than 2.3 million women in 2022 and is the most diagnosed cancer among women worldwide [1,2]. Breast cancer is also the number one cause of death from cancer in women; 670,000 women died from this disease in 2022 [2]. That is approximately 7% of all cancer deaths worldwide. The incidence rates are greater than 80 per 100,000 in developed regions of the world, such as Europe and North America, Australia, and New Zealand, and less than 40 per 100,000 in developing countries [3,4]. However, statistics from some developing countries may be attributed to underreporting [5]. The differences in incidence between countries could be due to changes in exposure to environmental risk factors, behavior, and lifestyle factors of different population groups [6]. These facts provide good reasons to study the causes and risk factors of breast cancer.

The causes of breast cancer in women are still unclear, and nonhereditary causes and risk factors predominate [7]. These include early menarche, hormone intake, nutrition, alcohol consumption, smoking, and obesity, all of which are commonly reported as risk factors [6]. Heredity accounts for only 5–10% of breast cancer cases, with germline mutations in BRCA1 or BRCA2 accounting for 30% of inheritable breast cancer cases [7]. Several researchers are working on the identification of specific genes as a cause of breast cancer, while others are conducting studies on the combinations of genes and other factors [8]. A study published in the Lancet in 2005 concluded that 21% of all breast cancer deaths worldwide were attributable to physical inactivity, overweight and obesity, and alcohol use [9]. An update from 2017 examined the connection between breast cancer incidence and environmental factors such as chemicals and radiation and found that exposure to these substances may lead to an increased risk of developing breast cancer [10]. However, numerous studies have identified late age of first full-term (if any) pregnancy, short periods of breast-feeding, dietary habits, quality and composition of meals, physiologic factors, lower age at menarche, and later menopause as causes and risk factors of breast cancer in women [11].

Conclusions

Six overall themes and more than 27 topics were identified. In our “top list” of the 36 most important findings, high breast density had the highest effect size for increasing the risk of breast cancer, and a high sex-hormone-binding globulin level was identified as the most protective factor in decreasing breast cancer risk. Notwithstanding the comprehensive work in performing these studies, there is still a large degree of uncertainty with respect to what exactly triggers or may influence or cause breast cancer. Unfortunately, this extensive work has not provided a clear and convincing answer as to why women develop breast cancer. Based on our review, however, it is important to point out this lack of consensus because the recommendations from some health authorities use several uncertain consensus statements to guide us to a healthy lifestyle. We therefore argue that this review of systematic reviews provides a valuable contribution to the research portfolio regarding breast cancer in women. We also argue that it highlights that health professionals should be careful because there still remains a great deal of uncertainty regarding the risk factors and causes of breast cancer in women.

Abstract

     Low hemoglobin (Hb) level or anemia is associated with osteoporosis and bone fracture. Cadmium (Cd) and lead (Pb) exposure are also risk factors of osteoporosis and anemia. However, the role of anemia in Cd/Pb related bone loss remains unclear. The aim of present study was to investigate the association between Hb level and bone loss in a population with environmental lead and cadmium exposure. One hundred and ninety-four women and 108 men with different levels of Cd/Pb exposure were included in our study. The Cd/Pb exposure was determined using graphite-furnace atomic absorption spectrometry. Forearm bone mineral density (BMD) was determined by peripheral dual-energy X-ray absortiometry. Hb concentration was determined using an automatic blood cellcounter. A logistic model was established to predict the risk of osteoporosis. The BMDs of women that had the highest quartile BCd and BPb were markedly lower than that with the lowest quartile (p < 0.05). The BMD and the prevalence of osteoporosis in men with anemia were lower and higher than that with normal Hb (p < 0.05), respectively. In men, age, BPb and anemia were independent risk factors for osteoporosis. The odds ratio (OR) of men with anemia was 11.28 (95%confidence interval (CI):1.94-65.54) and 19.56 (95%CI: 2.98-128.78) compared to those with normal Hb after adjusting for potential cofounders. No such association was found in women. The area under the curve was 0.88 (95%CI: 0.82-0.96) in predicting osteoporosis using the logistic model in men. Linear discriminant analysis also showed that 90.7% of osteoporosis was correctly classified. Our data show that anemia is associated with incident of osteoporosis in men but not in women that environmentally exposed to Pb and Cd.

Introduction

     Cadmium (Cd) and lead (Pb) are both distributed in the environment and used in industrial field. Both Cd and Pb can enter the human body via digestive tract. Bone is an important target organ for Cd and Pb toxicity. Cd and Pb exposure are associated with low bone mass or osteoporosis (A˚ kesson et al., 2014; Jalili et al., 2020; Li et al., 2016). Moreover, both animal and population studies indicated that Cd and Pb exposure can affect hemoglobin (Hb) level, in particular to Pb exposure. Chronic Pb exposure is a risk factor of hematologic impairments that can decrease the Hb content (Dobrakowski et al. 2015; Li et al., 2018; Nakhaee et al. 2018) and hematocrit (Chwalba et al. 2019; Nakhaee et al. 2018). However, the association and interplay between those outcomes has not been completely clarified (Zhang et al., 2020).

Conclusion

     In conclusion, we observe that anemia is a negative and independent risk of osteoporosis in men but not in women that environmentally exposed to Cd and Pb. Age, BPb and anemia are important factors that are related to osteoporosis in men. A model based on the three factors showed acceptable performance in predicting osteoporosis. Hb level or anemia should be considered when aim to show the association between Pb or Cd exposure and bone loss, in particular to men population

1.Introduction

2.Sepsis

3.Catheter-related bloodstream infection

4.Supplementary data

References

1. Introduction

Sepsis is one of the most serious conditions among all infectious diseases. To establish a sepsis treatment system as the basis of bacterial infection treatment, knowledge regarding infectious disease medicine/chemotherapeutics must be collected. Due to the recent appearance of various antimicrobial-drug-resistant bacteria, it is necessary to flexibly switch strategies to treat bacterial infection. This is not exceptional in the field of sepsis. It is also necessary to manage such infection, considering the involvement of antimicrobial-drug-resistant bacteria, including MRSA(methicillin resistant Staphylococcus aureus) and ESBL(extended spectrum β-lactamase)-producing bacteria. Antimicrobial-drug-resistant bacteria have been routinely detected in patients not only with nosocomial but also with community-acquired infection.

Sepsis is defined as a severe condition derived from a primary infection site. On the other hand, we often encounter patients with narrow-sense blood stream infection caused by intravascularly inserted catheters in clinical practice. Although there is a dissociation as a condition to be described in the “Sepsis” section, it was included in this section for convenience. In patients with sepsis, as a rule, a primary infected focus should be investigated, and treatment must be performed in accordance with the site of infection and condition. However, in the present guidelines, antimicrobial chemotherapy as empiric therapy is described, focusing on initial treatment with antimicrobial drugs for sepsis at a time point when a primary focus is unclear or inaccurate. In the “Catheter-related bloodstream infection” section, definitive therapy after the identification of causative bacteria is concretely described.

1- Introduction

2- Materials and methods

3- Results

4- Discussion

References

Abstract

Introduction: Long non-coding RNAs (lncRNAs) are RNA molecules that structurally resemble mRNA but do not encode proteins. Studies have been associated this class of non-coding RNA with the development of several disease, among them the different types of leukemia. However, the results are contradictory. Thus, we performed a systematic review of the literature available in order to better understand the involvement of lncRNAs in the development of leukemia. Materials and Methods: Pubmed and Embase databases were used to identify all studies that evaluated the expression of one or more lncRNA between human samples (peripheral blood, bone marrow) with leukemia (cases) and without leukemia (controls). Results: A total of 3675 articles were found in the databases, and after exclusion of articles that did not meet the eligibility criteria, 86 articles were included in this systematic review. In the 86 included studies, 3927 lncRNAs were differentially expressed between cases and controls. Among these, 110 lncRNAs were reported as being altered in samples from at least 2 studies and only 16 of them in ≥ 3 studies, which were selected for further evaluation. Of these, 12 lncRNAs were consistently dysregulated between cases and controls (CCAT1, CCDC26, CRNDE, HOTAIR, KCNQ5IT1, LINC00265, MALAT1, PVT1, SNHG5,TUG1: increased in cases, MEG3 and NEAT1: decreased in cases) in human samples of patients with some type of leukemia. Conclusion: Our data demonstrate that 12 lncRNAs are dysregulated in leukemia.

Introduction

Leukemia is a type of cancer that affects the blood and bone marrow and is characterized by the uncontrolled production and accumulation of blood cells (1). According to American Cancer Society (2), cancer the second leading cause of deaths among children, adolescents and young adults younger than 20 years, and leukemia is the main type of cancer that affect children. In addition, 381,774 people are living with or in remission from leukemia in the US (2). Radiation exposure, viral infections, ethnicity, gender and genetic mutations are some of the risk factors of leukemia (1). However, more studies are necessary to better understand the development and the pathogenesis of the different types of leukemia. In this context, epigenetic factors, such as non-coding RNAs (ncRNA), have been associated with leukemia development. NcRNAs are a group of regulatory RNAs that are not translated into protein (3). NcRNAs longer than 200 nucleotides are classified as long non-coding RNAs (lncRNAs). LncRNAs are located in nucleus, where they can act as molecular scaffolds, help in alternative splicing or modify chromatin structures. In addition, there are some lncRNAs that have functions in cytoplasm, such as modulating translation, promoting or inhibiting mRNA degradation, and acting as miRNAs sponges (4).

1- Introduction

2- Experimental

3- Results and discussion

4- Conclusions

References

Abstract

For the first time the method DI-SPME/LC-TOFMS was used and developed in order to determine the large antidepressant drugs in real forensic cases. The aim of the study was to optimize the new DI-SPME/LC-TOFMS method for the quantification of the large group of psychotropic drugs such as benzodiazepines, selective serotonin reuptake inhibitors, selective serotonin and noradrenaline reuptake inhibitors, tricyclic antidepressants and sleeping pills “Z”. The volume of the sample, adsorption time, post-adsorption purification and desorption time were precisely optimized. The validation parameters such as limit of detection and quantification, linearity, precision during and between days and the matrix effect were determined. All obtained values are within the acceptable range for toxicological analyses. The usefulness of the method was confirmed by analyzing the post-mortem samples. Drug concentrations were determined in real samples with high precision, which gives perspectives for the DI-SPME/LC-TOFMS routine application in toxicological and forensic analyses in the future.

Introduction

Due to complicated post-mortem processes that occur in the body after intake of drugs or poisons like redistribution, degradation, and contamination, it is necessary to provide a complex analysis of available body fluids like urine, blood or other alternative materials such as bone marrow. Material which can be helpful in post-mortem investigation is bone marrow aspirate (BMA), which is a semi-liquid form (it can be handled with a pipette) of bone marrow, placed inside the bones [1–3]. However, analysis of alternative materials often carried out with various limitations and compared to that analysis of BMA appears to have few practical advantages. It is a well-preserved post-mortem material, because of the physical barrier provided by cortical bone, which can be easily collected in large amounts and may be used as an alternative material to peripheral venous blood [4–6]. Due to high fat level and blood supply, it is possible to determine psychotropic drugs in bone marrow, which has been confirmed by Snamina et al. [7] with very satisfying results. On the other hand Cartiser et al. [2] provided a comprehensive summary on correlation studies between blood or plasma and bone marrow levels of different xenobiotics. The correlations varied from very low to almost absolute, depending on the drug. The success and application of the method often depend on its capabilities, trueness and also time of whole analysis. Considering extraction of analytes as the most demanding, time-consuming and multistep process it is regarded as a critical process to carry out in the whole analysis. The technique which may facilitate and simplify the extraction of analytes from complex samples like biological materials may be Direct Immersion Solid-Phase Micro Extraction (DI-SPME) [8–10]. It is an extraction technique based on the sorption of analytes on the stationary phase of fused silica, placed on the solid support. The DI-SPME procedure is based on the exposure of the fiber to the sample for sufficient time. This technique integrates extraction, concentration and analyte desorption into a single procedure [11,12]. As the technique is reducing sample handling, solvent use, time and cost it is prosperous for toxicological and forensic analysis. Due to the wide selection of fiber coatings and its sorption capabilities DI-SPME extraction is also used in food and environmental analyses, as well as studies for its in vivo application are carried out. The initial application of the DI-SPME technique in drug analysis was for psychotropic substances. Moreover, in recent years the increase of DI-SPME applications was observed with connection of liquid chromatography and capillary electrophoresis [13,14].

1- Acute leukemias — Novel therapeutics are urgently required

2- cAMP-dependent pathway – A meaningful target in hematological malignancies

3- Targeting cAMP transporters/efflux – an unexplored approach to modulation of the cyclic nucleotide pathway

4- Conclusions

References

Abstract

While current treatment regimens for acute leukemia can dramatically improve patient survival, there remains room for improvement. Due to its roles in cell differentiation, cell survival, and apoptotic signaling, modulation of the cyclic AMP (cAMP) pathway has provided a meaningful target in hematological malignancies. Several studies have demonstrated that gene expression profiles associated with increased pro-survival cAMP activity or downregulation of various pro-apoptotic factors associated with the cAMP pathway are apparent in acute leukemia patients. Previous work to increase leukemia cell intracellular cAMP focused on the use of cAMP analogs, stimulating cAMP production via transmembrane-associated adenylyl cyclases, or decreasing cAMP degradation by inhibiting phosphodiesterase activity. However, targeting cyclic nucleotide efflux by ATP-binding cassette (ABC) transporters represents an unexplored approach for modulation of intracellular cyclic nucleotide levels. Preliminary studies have shown that inhibition of cAMP efflux can stimulate leukemia cell differentiation, cell growth arrest, and apoptosis, indicating that targeting cAMP efflux may show promise for future therapeutic development. Furthermore, inhibition of cyclic nucleotide transporter activity may also contribute multiple anticancer benefits by reducing extracellular pro-survival signaling in malignant cells. Hence, several opportunities for drug repurposing may exist for targeting cyclic nucleotide transporters.

Biology and etiology of acute leukemias

While not the most prevalent malignancy in the United States, acute leukemia ranks among the top ten cancers in terms of both morbidity and mortality [1]. These hematological malignancies involve aberrant proliferation of blood cells with immature phenotypes. Acute leukemias are typically identified by the presence of > 20% blast cells in the peripheral blood or bone marrow [2]. Due to inherent characteristics related to a reduced differentiation state, and the ability to rapidly propagate, acute leukemias may have worse prognoses than chronic leukemias. Acute myelogenous leukemia (AML) is most prominent in elderly adults over 65 years of age. Annually, 21,450 cases are diagnosed in the United States, and 10,920 cases succumb to the disease [1]. The five year overall survival for this disease is a disheartening 28.3% for adults [1] and about 60% for children [3]. T-cell lineage and B-cell precursor acute lymphoblastic leukemia (T-ALL and B-ALL) primarily affects children, adolescents and young adults, with about 6,000 new cases diagnosed and 1,500 deaths each year [4, 5]. This disease is considered > 80% curable, however there is much room for improvement, specifically for high-risk subtypes such as Ph-like ALL, leukemias harboring rearrangements of KMT2A gene at 11q23 or BCR-ABL1 translocations, etc. [6-8] Therefore, there is a strong need for the development of novel approaches to treat these malignancies and improve patient outcome. The primary classification of acute leukemia is based on the presence of chromosomal abnormalities and translocations along with immunophenotyping. For example, 25-30% of B-ALL have hyperdiploidy [9], while a surprising 40-50% of AML are cytogenetically normal [2]. An analysis of primary AML samples determined an average of 13 mutated genes per sample [10]. It has also been reported that > 80% of B-ALL cases contain deletions within genes related to B cell development [11]. De novo B-ALL genomes also contain 10-20 gene coding mutations [12]. Most commonly, the etiology of acute leukemias is attributed to the combination of mutations that govern pro-survival signaling and reduce tumor suppressor genes [13]. Many factors are potentially implicated in leukemogenesis, and most include aberrancies that increase cell proliferation and induce differential arrest. Due to potential mutations, rapid growth, and deviant signaling, leukemia cells have the capacity to overcome normal mechanisms that would typically result in cell death.

The full impact of the Coronavirus Disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2 virus, on the field of hematopoietic cell transplantation (HCT) is unknown. This perspective paper reviews the following: current COVID-19 epidemiology, diagnosis and potential therapies; care considerations unique to HCT patients; and the concept of a learning network to assimilate emerging guidelines and best practices and to optimize patient outcomes through facilitating shared learning and experience across transplant centers.

Introduction

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel single strand (ss) RNA beta-coronavirus, has caused the current Coronavirus Disease 2019 (COVID-19) pandemic. As of April 13, 2020, the World Health Organization (WHO) reported 1,773,084 laboratory confirmed cases and 111,652 deaths globally. 1 What ultimate impact COVID-19 will have on the field of hematopoietic cell transplantation (HCT) is currently unknown. This perspectives paper anticipates the significant influence of COVID-19 on HCT patients given their immune compromise, presence of other medical co-morbidities, and concerns for higher infection-related severity and mortality and also reviews the substantial impact of COVID-19 on the HCT-related healthcare system. To address these challenges, novel care approaches and ways to assimilate and share information in the background of rapid change are critically needed. Therefore, the concept of learning networks as interactive platforms for effectively assimilating and distributing evolving information to transplant centers is introduced.

Graphical abstract

1. Introduction

2. Materials and methods

3. Results and discussion

4. Conclusions

Acknowledgments

References

Abstract

The interest in bioactive compounds from natural sources, such as marine organisms, has increased considerably in recent years. Among these compounds, sulfated polysaccharides from seaweed exhibit a broad spectrum of biological activities. Sulfated polysaccharides from green algae are still poorly investigated. For this reason, in this study, using unusual methodologies, such as extraction conditions, FACE, and RAMAN, we investigated the structural features of F50UL and F70UL sulfated polysaccharides from Ulva lactuca L. and their distinct in vitro anticoagulant and in vivo antithrombotic activities. Sulfated polysaccharides of U. lactuca were obtained by enzymatic proteolysis with ALCALASE® and fractionated by acetone precipitation. F50Ul and F70Ul sulfated polysaccharides with higher yield were partially chemically characterized by Fluorophore-assisted carbohydrate electrophoresis (FACE) and RAMAN spectroscopy analysis and submitted to an in vitro screening by APTT, PT, TT, and anti-factor Xa and IIa tests. The venae cavae ligature experimental model for the analysis of in vivo antithrombotic activity of F50Ul and F70Ul sulfated polysaccharides were also performed. The U. lactuca L. sulfated polysaccharides characterization by FACE and RAMAN showed a typical ulvans structure that contains as principal component rhamnose, but other monosaccharides (uronic acid, glucose, and galactose) are present. F50Ul (0.1–1.0 μg/μl) showed anticoagulant activity in vitro. However, F70Ul that has a similar composition did not present these effects. Also, only F50Ul sulfated polysaccharides (≥5 μg/g) showed a great in vivo antithrombotic concentration-dependent and time-dependent activity. In summary, we demonstrate the use of unusual extraction and characterization analysis procedures for U. lactuca L. sulfated polysaccharides and the ability of F50Ul to reduce the weight of thrombus in rats probably by the association with factors Xa and IIa inhibition. These results provide strong evidence of the anticoagulant potential of these sulfated polysaccharides isolated from Ulva lactuca L.

Introduction

According to the World Health Organization, cardiovascular diseases are the major cause of death worldwide. An approximate calculation has shown that over 23.6 million people will die due to cardiovascular diseases until 2030. It is associated with heart and blood vessels disorders and includes coronary heart disease, hypertension, stroke (cerebrovascular), rheumatic heart and peripheral vascular diseases [1]. Arterial thrombosis is one of the most common causes of death in the world due to either instability or rupture of an atherosclerotic plaque resulting in localized clot formation and blockage of blood flow with subsequent myocardial infarction (heart attack) or stroke [2].

The physiologic action of the hemostatic system removes fibrin deposits from vessels and maintains the circulating blood in a fluidic state. In cases of vessel injury, the tissue factor on adventitial cells, such as adventitial fibroblasts and smooth muscle cells activates the clotting system with a complex series of enzymatic reactions involving coagulation proteins, culminating in the activation of thrombin, which converts fibrinogen to fibrin. Thus, it forms a stable clot and prevents excessive blood loss. While hemostatic clots are localized to the vessel wall and do not impair blood flow, the thrombotic clots result in impairment of blood flow and even complete occlusion of the vessel [2]. In this case, anticoagulation therapy is required for inhibition of blood clotting using appropriate drugs, i.e., warfarin or heparin [3].

Coronavirus disease 2019 (COVID-19) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus strain disease, has recently emerged in China and rapidly spread worldwide. This novel strain is highly transmittable and severe disease has been reported in up to 16% of hospitalized cases. More than 600,000 cases have been confirmed and the number of deaths is constantly increasing. COVID-19 hospitalized patients, especially those suffering from severe respiratory or systemic manifestations, fall under the spectrum of the acutely ill medical population, which is at increased venous thromboembolism risk. Thrombotic complications seem to emerge as an important issue in patients infected with COVID-19. Preliminary reports on COVID-19 patients’ clinical and laboratory findings include thrombocytopenia, elevated D-dimer, prolonged prothrombin time, and disseminated intravascular coagulation. As the pandemic is spreading and the whole picture is yet unknown, we highlight the importance of coagulation disorders in COVID-19 infected patients and review relevant data of previous coronavirus epidemics caused by the severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and the Middle East Respiratory Syndrome coronavirus (MERS-CoV).

COVID-19 and coagulation disorders

A novel coronavirus strain disease, Coronavirus disease 2019 (COVID-19) or severe acute respiratory syndrome coronavirus 2 (SARSCoV-2), has recently emerged in Wuhan, China and rapidly spread throughout China and subsequently worldwide [1,2]. Currently, more than 600,000 cases have been diagnosed and over 25,000 infected people have died [3]. Patients usually present with fever (> 80%), cough (> 60%), and myalgia or fatigue (> 40%) [1,4]. Males are more commonly affected (∼60% of cases) with a median age of approximately 50 years [1,4,5]. The complete spectrum of presentations and complications associated with COVID-19 is not fully elucidated. Clinical manifestations range from asymptomatic or very mild to severe illness, sepsis and death. While the current state of evidence suggests that most COVID-19 illness is mild, the study by Guan et al. suggests severe illness occurs in 16% of cases [4,6]. As the pandemic is still in progression, with an incomplete picture and potential treatments in preliminary stages only, we sought to review the available literature relevant to coagulation disorders in patients infected by the severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and the Middle East Respiratory Syndrome coronavirus (MERS-CoV) to raise awareness about these potential complications in patients with COVID-19. Thrombotic complications seem to emerge as an important issue in patients with COVID-19. Preliminary reports on COVID-19 pandemic outcomes have shown that infected patients commonly develop thrombocytopenia (36.2%) and may have elevated D-dimer (46.4%) [4], while these rates are even higher in patients with severe COVID-19 disease (57.7% and 59.6%, respectively) [4]. Emerging data support that patients infected by this novel coronavirus are at risk of developing disseminated intravascular coagulation (DIC) [4,7,8].

1. Diversity of Coronaviruses

2. SARS-CoV

3. MERS-CoV

4. SARS-CoV-2

5. Inactivation of Coronavirus in Blood Products

6. Conclusions

Declarations of interest

References

Abstract

With the outbreak of unknown pneumonia in Wuhan, China, in December 2019, a new coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), aroused the attention of the entire world. The current outbreak of infections with SARS-CoV-2 is termed Coronavirus Disease 2019 (COVID-19). The World Health Organization declared COVID-19 in China as a Public Health Emergency of International Concern. Two other coronavirus infections—SARS in 2002-2003 and Middle East Respiratory Syndrome (MERS) in 2012—both caused severe respiratory syndrome in humans. All 3 of these emerging infectious diseases leading to a global spread are caused by β-coronaviruses. Although coronaviruses usually infect the upper or lower respiratory tract, viral shedding in plasma or serum is common. Therefore, there is still a theoretical risk of transmission of coronaviruses through the transfusion of labile blood products. Because more and more asymptomatic infections are being found among COVID-19 cases, considerations of blood safety and coronaviruses have arisen especially in endemic areas. In this review, we detail current evidence and understanding of the transmission of SARS-CoV, MERS– CoV, and SARS-CoV-2 through blood products as of February 10, 2020, and also discuss pathogen inactivation methods on coronaviruses.

Diversity of Coronaviruses

As the largest known RNA viruses, CoVs are further divided into four genera: α-CoVs, β-CoVs, γ-CoVs, and δ-CoVs [11], among which α- and β-CoVs are able to infect mammals, whereas the other two genera can infect birds and could also infect mammals [12]. So far, seven coronaviruses have been found to infect humans and cause respiratory diseases. Four of seven are common human CoVs (HCoVs) usually leading to common self-limited upper respiratory disease: HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1. These viruses can occasionally cause more serious disease in young, elderly, or immunocompromised individuals.

The first two HCoVs, HCoV-229E and HCoV-OC43, have been known since the 1960s. With the emergence of SARS in 2002, a novel βcoronavirus came to attention; and subsequently, HCoV-NL63 and HCoV-HKU1 were identified in 2004 and 2005, respectively [13]. MERS-CoV, which was isolated in 2012, is similar to SARS-CoV—both can infect the lower respiratory tract and usually cause a severe respiratory syndrome in humans [14] with a case fatality rate of 35.5% and 10%, respectively [15]. SARS-CoV-2 was recently isolated from human airway epithelial cells, characterized by next-generation sequencing in January 2020, and identified to be a new member of β-CoVs [16]. SARS-CoV-2 can also infect the lower respiratory tract, but the clinical symptoms are milder than SARS and MERS according to current limited evidence and reports [1].

Diagnosis and classification

Pathophysiology

Epidemiology and prognosis

Treatment

Summary

References

INTRODUCTION

Acute myeloid leukemia (AML) is a heterogenous, aggressive myeloid malignancy. In 2018, an estimated 19,520 new cases and 10,670 deaths occurred in the United States. Although strides have been made in AML treatment using novel therapies and small molecule inhibitors, the 5-year overall survival (OS) is only approximately 27%. Contributing to this dismal prognosis is the increasing rates of secondary AML (sAML), which describe a subset of AML that arises from either an antecedent hematologic disorder (AHD) such as myelodysplastic syndrome (MDS), or are related to prior exposure to cytotoxic chemotherapy agents or radiation therapy. The incidence of sAML ranges from 10% to 35% of AML cases. This article focuses on the epidemiology, diagnosis, pathogenesis, molecular, and treatment of sAML.

DIAGNOSIS AND CLASSIFICATION

Secondary AML occurs by 2 separate mechanisms, either through an antecedent hematologic disorder (AHD) or prior chemotherapy or radiation therapy, and the classification of AML has begun to reflect this etiology. In a study evaluating the ontogeny of AML, distinct somatic mutations differentiated AML subtypes between de novo AML, AML-AHD (labeled as s-AML), and therapy-related AML (t-AML). Multiple analyses have been studied to determine the transformational cause for the change from AHD to AML. Clonal evolution in AML is common, with many of the mutations occurring as random events, then acquiring a cooperating mutation leading to proliferation of the malignant clone. In 2008, the World Health Organization (WHO) introduced the diagnosis of AML with myelodysplasia-related changes (AML-MRC), which was later expanded to specific criteria in the 2016 WHO classification system. This newer classification requires a prior history of MDS, MDS-associated cytogenetic abnormalities, or multilineage dysplasia, but specifically excludes prior cytotoxic chemotherapy or radiation therapy and entity-defining recurring cytogenetic abnormalities. The classification of AML-MRC has a high frequency of mutations in ASXL1 mutations, and a low rating of NPM1, FLT3, and DNMT3A mutations. Patients with AMLMRC who have either the ASXL1 mutation or TP53 mutations are associated with shorter OS. In a retrospective study of Chinese patients with AML-MRC, patients had significantly shortened complete response (CR) rates, disease-free survival (DFS), and OS compared with AML-NOS patients.