bluuebunny/crossref_metadata_2025 huggingface dataset:
Introduction: Poland’s Wars of Symbols
Authors: Lewis Simon , Waligórska Magdalena
Published: April 2019

This introduction to the special section on Poland’s wars of symbols analyzes the symbolic contestation that has characterized the country in recent years, studying a range of phenomena including nation, gender, memory, and religious symbolism within the overall framework of political conflict. In doing so, it offers a multidisciplinary view on political fractures that have resonated throughout Europe and the “West.” Overall, the four case studies in this section study ways in which national symbols, topoi, and narratives have been deployed as tools in drawing and redrawing boundaries within society, polarizing and mobilizing the political camps as well as contesting and resisting power. These studies enable us to situate recent political events in a historical perspective, mapping the rise of populism in Poland against the background of legacies specific to the East-Central European region.
Fuzzy logic feedforward active noise control with distance ratio and acoustic feedback using Takagi–Sugeon–Kang inference
Authors: Peng Tongrui , Zhu Quanmin , Tokhi M. Osman , Yao Yufeng
Published: April 2019

Noise, as undesired sound, severely affects the quality of human life. Currently, active noise control method has demonstrated its capability in low-frequency noise cancellation and the advance in saving money and reducing weight and volume of related materials used in the passive noise control technology. The widespread configuration for active noise control technology is finite impulse response filter with filtered-x least mean squares (FxLMS) algorithm. However, the nonlinearities in the secondary path, which mainly arise from sensors, actuators and amplifiers used in the active noise control system, will cause instability and degrade the performance while using the FxLMS algorithm. In order to cope with this challenge, many new approaches have been proposed and fuzzy logic control is one of these. In this paper, a Takagi–Sugeon–Kang-type fuzzy logic control-based feedforward active noise control system with focus on the geometry configuration is introduced. In contrast to previous work, all physical paths are modelled by pure time delay transfer function and the acoustic feedback is added as part of inputs for the fuzzy logic control. Computational experiments are implemented within the Matlab/Simulink platform, and several case studies are presented with time and frequency domain analyses to demonstrate the cancellation ability of the proposed feedforward active noise control system and investigate the influence of distance ratio on the overall noise cancellation performance.
MicroRNA-7a ameliorates neuropathic pain in a rat model of spinal nerve ligation via the neurofilament light polypeptide-dependent signal transducer and activator of transcription signaling pathway
Authors: Yang Feng-Rui , Chen Ji , Yi Han , Peng Liang-Yu , Hu Xiao-Ling , Guo Qu-Lian
Published: April 2019

Neuropathic pain is a type of chronic pain induced by either central or peripheral nerve injury. MicroRNAs have been recently linked to many diseases, including neuropathic pain. However, the role of miR-7a in neuropathic pain still remains elusive. Thus, we aim to investigate the effects of miR-7a on neuropathic pain based on the spinal nerve ligation rat model. After establishment of spinal nerve ligation rat models, rats were infected with adeno-associated virus-neurofilament light polypeptide, adeno-associated virus-miR-7a or treated with metformin. The paw withdrawal threshold and paw withdrawal latency were assessed afterward, and the expression of miR-7a and neurofilament light polypeptide as well as their interaction was determined. Subsequently, miR-7a was overexpressed or silenced in dorsal root ganglion cells to investigate the role of miR-7a in neuropathic pain. Furthermore, the regulatory effect of neurofilament light polypeptide on neuropathic pain was detected using plasmid overexpressing neurofilament light polypeptide. Spinal nerve ligation rat model exhibited upregulation of neurofilament light polypeptide but downregulation of miR-7a. In addition, neurofilament light polypeptide accumulation or miR-7a inhibition decreased paw withdrawal threshold and paw withdrawal latency. Then, neurofilament light polypeptide accumulation or miR-7a inhibition was observed to increase the phosphorylation level of signal transducer and activator of transcription. miR-7a was found to directly target neurofilament light polypeptide and downregulate neurofilament light polypeptide. In addition, inhibiting the signal transducer and activator of transcription signaling pathway was also revealed to increase paw withdrawal threshold and paw withdrawal latency. Collectively, our study demonstrated that miR-7a ameliorated neuropathic pain via blocking the signal transducer and activator of transcription signaling pathway by repressing neurofilament light polypeptide. These findings, if taken further, can be of important clinical significance in treating patients with neuropathic pain.
Monitoring blood biomarkers to predict nivolumab effectiveness in NSCLC patients
Authors: Passiglia Francesco , Galvano Antonio , Castiglia Marta , Incorvaia Lorena , Calò Valentina , Listì Angela , Mazzarisi Salvatore , Perez Alessandro , Gallina Giuseppe , Rizzo Sergio , Soto Parra Hector , Bazan Viviana , Russo Antonio
Published: April 2019

Background:

We investigated whether early dynamic changes of circulating free (cfDNA) levels as well as the neutrophil to lymphocyte ratio (NLR) could predict nivolumab effectiveness in pretreated patients with advanced non-small cell lung cancer (NSCLC).

Methods:

A total of 45 patients receiving nivolumab 3 mg/kg every 2 weeks were enrolled. Patients underwent a computed tomography scan and responses were evaluated by the response evaluation criteria in solid tumors. Peripheral blood samples were obtained from the patients and the cfDNA level as well as the NLR were assessed. Time to progression (TTP) and overall survival (OS) were determined.

Results:

Patients with increased cfDNA >20% at the sixth week reported significantly worse survival outcomes (median OS: 5.7 versus 14.2 months, p < 0.001; median TTP: 3.3 versus 10.2 months, p < 0.001), as well as patients with increased NLR >20% (median OS: 8.7 versus 14.6 months, p = 0.035; median TTP: 5.2 versus 10.3 months, p = 0.039). The combined increase of cfDNA and NLR >20% was associated with significantly worse survival outcomes as compared with the remained population (median OS: 5.8 versus 15.5 months, p = 0.012; median TTP: 3.2 versus 11.9 months, p = 0.028). Multivariable analysis identified three significant factors associated with worse OS: combined cfDNA/NLR increase >20% [hazard ratio (HR): 5.16; 95% confidence interval (CI), 1.09–24.29; p = 0.038], liver metastasis (HR: 0.44; 95% CI, 0.20–0.96; p = 0.038), and extra-thoracic disease (HR: 0.33; 95% CI, 0.12–0.89; p = 0.029).

Conclusion:

An early combined increase of both cfDNA and NLR over the course of the first 6 weeks of nivolumab therapy predicted worse survival in pretreated patients with advanced NSCLC, suggesting a potential role in the real-time monitoring of immunotherapy resistance.
Pancreas‐specific plasma amylase for assessment and diagnosis of chronic pancreatitis: New insights on an old topic
Authors: Olesen Søren Schou , Krarup Henrik , Poulsen Jakob Lykke , Christensen Jeppe Hagstrup , Sheel Andrea Rhiannon Glynne , Sutton Robert , Greenhalf William , Halloran Christopher , Drewes Asbjørn Mohr
Published: April 2019

Background

Pancreatic function testing and imaging are used to inform the diagnosis of chronic pancreatitis, but most of these methods are time‐ and cost‐consuming or lack diagnostic accuracy.

Objective

We investigated the utility of pancreas‐specific plasma amylase for assessment and diagnosis of chronic pancreatitis.

Design

This was a prospective study of 121 consecutive patients with chronic pancreatitis and a reference population of 94 healthy controls. Pancreas‐specific plasma amylase level was determined and analysed for its association with exocrine pancreatic insufficiency, diabetes and other clinical variables. Receiver operating characteristic curve analyses were performed to determine the diagnostic utility of plasma amylase for diagnosing chronic pancreatitis and to study associations with disease severity. The findings were validated in a further cohort of 57 patients with chronic pancreatitis.

Results

Significant and independent associations between plasma amylase level and duration of chronic pancreatitis as well as the presence of exocrine pancreatic insufficiency and diabetes were observed (all p < 0.001). An amylase level below 17.3 U/l had a high specificity (94%) and moderate sensitivity (59%) for the diagnosis of chronic pancreatitis. Diagnostic performance was influenced by disease stage with the best performance observed for advanced disease. The findings were replicated in the validation cohort.

Conclusion

Pancreas‐specific plasma amylase may provide a clinically useful mean for assessment and diagnosis of chronic pancreatitis.
Minimal residual disease in adult ALL: technical aspects and implications for correct clinical interpretation
Authors: Brüggemann Monika , Kotrova Michaela
Published: April 2019

Nowadays, minimal residual disease (MRD) is accepted as the strongest independent prognostic factor in acute lymphoblastic leukemia (ALL). It can be detected by molecular methods that use leukemia-specific or patient-specific molecular markers (fusion gene transcripts, or immunoglobulin/T-cell receptor [IG/TR] gene rearrangements), and by multi-parametric flow cytometry. The sensitivity and specificity of these methods can vary across treatment time points and therapeutic settings. Thus, knowledge of the principles and limitations of each technology is of the utmost importance for correct interpretation of MRD results. Time will tell whether new molecular and flow cytometric high-throughput technologies can overcome the limitations of current standard methods and eventually bring additional benefits. MRD during standard ALL chemotherapy is the strongest overall prognostic indicator and has therefore been used for refining initial treatment stratification. Moreover, MRD positivity after the maintenance phase of treatment may point to an impending relapse and thus enable salvage treatment to be initiated earlier, which could possibly improve treatment results. The prognostic relevance of pretransplantation MRD was shown by several studies, and MRD high-risk patients were shown to benefit from stem cell transplantation (SCT). Also, MRD positivity after SCT correlates with worse outcomes. In addition, MRD information is very instructive in current clinical trials that test novel agents to evaluate their treatment efficacy. Although conventional clinical risk factors lose their independent prognostic significance when combined with MRD information, recently identified genetic markers may further improve the treatment stratification in ALL.
Direct oral anticoagulants: now also for prevention and treatment of cancer-associated venous thromboembolism?
Authors: Pabinger Ingrid , Riedl Julia
Published: April 2019

Data on specific studies in cancer patients using direct oral anticoagulants (DOACs) for the prevention and treatment of venous thromboembolism (VTE) are still scarce. For preventing VTE with DOACs, current experience is still very limited, so definite conclusions cannot yet be drawn. However, DOACs have so far been compared with vitamin K antagonists (VKAs) in patients with acute VTE in 5 studies, and several hundreds of patients included in these studies had either active cancer, a history of cancer, or a new occurrence of cancer during the course of disease. Meta-analyses have revealed an at least similar efficacy and safety profile of DOACs compared with VKAs. A number of studies of cancer patients investigating primary prevention and treatment are underway, and some will be finalized soon. Nevertheless, we might need further trials, specifically on the prevention of VTE in patients who are at particularly high risk. This article also includes a personal opinion on the use of DOACs in cancer patients. In conclusion, the currently available data show that DOACs might be safe and efficacious in the treatment of VTE, however, this has yet to be proven in specifically designed trials in patients with cancer. With regard to prevention, thus far, even less data exist, and the outcomes of the ongoing studies have to be evaluated before DOACs may be used for primary prevention.
Fixed duration vs continuous therapy in multiple myeloma
Authors: Ludwig Heinz , Zojer Niklas
Published: April 2019

The introduction of new drugs with less severe toxicity profiles than those of conventional antimyeloma agents allowed the evaluation of continuous therapy compared with fixed duration therapy. In transplant-eligible patients, consolidation therapy with bortezomib or bortezomib-based regimens showed significant progression-free survival (PFS) benefit in cytogenetic standard-risk patients and to a lesser extent, high-risk patients. Continuous therapy with lenalidomide maintenance treatment after autologous stem cell transplantation resulted in a significant survival gain. In transplant noneligible patients, continuous lenalidomide-dexamethasone therapy improved survival over fixed duration melphalan-prednisone-thalidomide. The concept of prolonged treatment in elderly patients is supported by some other studies, but most of them revealed a gain in PFS only. Young patients with unfavorable prognosis show a greater willingness to accept long-term treatment, whereas the readiness to undergo such treatments and the benefits therefrom decline with increasing age and decreasing fitness, rendering fixed duration therapy a suitable option in elderly frail patients.
Controversies in venous thromboembolism: to treat or not to treat superficial vein thrombosis
Authors: Beyer-Westendorf Jan
Published: April 2019

The management of superficial vein thrombosis (SVT) is poorly defined and remains controversial overall. SVT has long been considered a benign, self-limited disease, but recent studies show that SVT carries a nonnegligible risk for recurrence, deep vein thrombosis, or pulmonary embolism. Current guidelines recommend the use of low-molecular-weight heparin or fondaparinux, but results of several surveys indicate that the majority of patients with SVT receive nonanticoagulant therapy only, which includes compression stockings or bandages, nonsteroidal anti-inflammatory drugs, topical application of heparin gel, or surgical interventions. However, several recent observational and interventional studies provide better insight into the optimal treatment of patients with SVT who are at different risks for thromboembolic complications. This educational review summarizes the available evidence and aims to provide practical guidance based on a clinical decision pathway.
Symptomatic subsegmental pulmonary embolism: to treat or not to treat?
Authors: Carrier Marc , Klok Fredrikus A.
Published: April 2019

The introduction of computed tomographic pulmonary angiography and its recent increasing availability has led to a significant rise in its use to help clinicians diagnose acute pulmonary embolism (PE). This has led to a significant increase in the incidence of PE diagnoses. Simultaneously, the case fatality rate of acute PE has been decreasing and no significant change in its mortality has been noted, suggesting that the additional PE diagnoses are less severe and these patients might not benefit from anticoagulation therapy. This also seems to be correlated with an increase in the diagnosis of PE localized in the subsegmental pulmonary arteries (subsegmental pulmonary embolism [SSPE]). The clinical importance of SSPE is unclear. Whereas some studies have shown that it might be reasonable to manage patients with SSPE without anticoagulation, others have not. Although the current medical literature is limited, it suggests that a subgroup of patients with SSPE might be safely managed without the use of anticoagulant therapy. Current clinical practice guidelines suggest that clinicians take an individualized approach after carefully assessing the risk/benefit ratio for patients with SSPE and negative leg limb ultrasonography results. Prospective studies are ongoing and results are eagerly awaited to help tailor the management of this patient population.
Primary mediastinal B-cell lymphoma: biology and evolving therapeutic strategies
Authors: Dunleavy Kieron
Published: April 2019

Primary mediastinal B-cell lymphoma (PMBCL) is recognized as a distinct clinicopathologic entity that predominantly affects adolescents and young adults and is more common in female subjects. Although PMBCL is considered to be a subtype of diffuse large B-cell lymphoma, its clinical, morphologic, and biological characteristics overlap significantly with those of nodular sclerosing Hodgkin lymphoma (NSHL). Over the past few years, the shared biology of these 2 entities has been highlighted in several studies, and mediastinal gray zone lymphoma, with features intermediate between PMBCL and NSHL, has been recognized as a unique molecular entity. Although there is a lack of consensus about the optimal therapeutic strategy for adolescent and young adult patients newly diagnosed with PMCBL, highly curative strategies that obviate the need for mediastinal radiation are favored by most. Progress in understanding the biology of PMBCL and its close relationship to NSHL have helped pave the way for the investigation of novel approaches such as immune checkpoint inhibition. Other strategies such as adoptive T-cell therapy and targeting CD30 are also being studied.
Rigorous and practical quality indicators in sickle cell disease care
Authors: Oyeku Suzette O. , Faro Elissa Z.
Published: April 2019

In recent years, several sickle cell–specific quality indicators have been developed using rigorous approaches. A review of the history and current status of the development of sickle cell–specific indicators highlights opportunities for future refinement. Despite efforts at alignment, lack of strong evidence hinders the adoption of current quality indicators across stakeholder groups. There are many directions in which to take the current existing quality indicators, including expanding to different age groups, aims of care such as safety and equity, and better understanding of contextual and environmental factors.
Chronic organ failure in adult sickle cell disease
Authors: Vichinsky Elliott
Published: April 2019

Sickle cell disease is now a chronic adult illness characterized by progressive multiorgan failure, particularly involving the brain and kidney. The etiology is multifactorial; it includes hemolysis and nitric oxide deficiency. As patients age, most experience neurologic insult. Twenty-five percent of older adults have had a clinical stroke and at least half of the population have had a silent infarct, cortical atrophy, and neurocognitive impairment. Periodic screening with neuroimaging and neurocognitive testing is recommended. Identification and correction of modifiable risk factors such as nocturnal hypoxemia, obstructive sleep apnea, and physical exercise programs should be implemented. Patients with neurocognitive impairment require cognitive remediation and educational accommodations. Chronic renal disease occurs in 25% of older adults and results in 50% of their deaths. Renal failure often develops insidiously. It can be prevented or minimized by early screening and treatment of modifiable risk factors including hypertension and microalbuminuria. There is an increasing number of therapeutic options, including inhibitors of the renin angiotensin system, angiotensin-II receptor blockers, endothelin-1 receptor antagonist, and haptoglobin therapy. Patients with sickle cell disease have increased mortality rates from renal failure compared with nonsickle cell patients, in part from a lack of access to early multidisciplinary care, including timely initiation of dialysis and renal transplantation.
How and when to decide between epigenetic therapy and chemotherapy in patients with AML
Authors: Dombret Hervé , Itzykson Raphael
Published: April 2019

Remission induction with chemotherapy has long been the frontline treatment of acute myeloid leukemia (AML). However, intensive therapy is limited in frail patients by its associated toxicity and higher rates of failure or relapse in patients with chemoresistant disease, such as secondary AML or poor-risk cytogenetics. Frailty and chemoresistance are more frequent in older adults with AML. In recent years, epigenetic therapies with the hypomethylating agents decitabine and azacitidine have been thoroughly explored in AML. The results of two pivotal studies carried out with these agents in older adults with newly diagnosed AML have challenged the role of intensive chemotherapy as the frontline treatment option in this high-risk population. Here, we review the results of treatment with intensive chemotherapy and hypomethylating agents in older patients with AML; discuss the patient- and disease-specific criteria to integrate into treatment decision making; and also, highlight the methodological limitations of cross-study comparison in this population.
Myeloproliferative neoplasms: from origins to outcomes
Authors: Nangalia Jyoti , Green Anthony R.
Published: April 2019

Substantial progress has been made in our understanding of the pathogenetic basis of myeloproliferative neoplasms. The discovery of mutations in JAK2 over a decade ago heralded a new age for patient care as a consequence of improved diagnosis and the development of therapeutic JAK inhibitors. The more recent identification of mutations in calreticulin brought with it a sense of completeness, with most patients with myeloproliferative neoplasm now having a biological basis for their excessive myeloproliferation. We are also beginning to understand the processes that lead to acquisition of somatic mutations and the factors that influence subsequent clonal expansion and emergence of disease. Extended genomic profiling has established a multitude of additional acquired mutations, particularly prevalent in myelofibrosis, where their presence carries prognostic implications. A major goal is to integrate genetic, clinical, and laboratory features to identify patients who share disease biology and clinical outcome, such that therapies, both existing and novel, can be better targeted.
Emerging options in multiple myeloma: targeted, immune, and epigenetic therapies
Authors: Kumar Shaji
Published: April 2019

Considerable progress has been made in the treatment of multiple myeloma in the past decade with median survival for the disease improving significantly. This has come through a combination of better understanding of the disease biology and coordinated research into new treatment approaches including better supportive care. However, patients eventually become refractory to available treatments and succumb to the disease, highlighting the need to develop new treatment approaches. The genetic heterogeneity in the disease and clonal evolution under treatment pressure underlie the development of resistance, underscoring the need to develop more effective therapies that can eradicate the disease at initial treatment as well as the need for new classes of drugs with varying mechanisms of action. To this end, there has been intense focus on exploring novel approaches to therapy including small-molecule inhibitors targeting specific abnormalities, immune therapies including monoclonal antibodies and adaptive T-cell therapy, as well as epigenetic approaches. Although many of these drugs are in the early stages of clinical development, the early data appear to be very promising. Many of these drugs can be safely and effectively combined with the current treatment classes such as proteasome inhibitors and immunomodulatory drugs, further enhancing the treatment options for myeloma.
Biology of CNS lymphoma and the potential of novel agents
Authors: Rubenstein James L.
Published: April 2019

Primary and secondary CNS lymphomas are aggressive brain tumors that pose an immense challenge to define in terms of molecular pathogenesis, as well as to effectively treat. During the past 10 years improvements in survival have been achieved with the implementation of anti-CD20 immunotherapy and optimization of dose-intensive consolidation strategies. The applications of whole-exome sequencing, comparative genomic hybridization, transcriptional profiling, and examination of the tumor microenvironment, particularly in the context of clinical investigation, provide insights that create a roadmap for the development and implementation of novel targeted agents for this disease. A body of genetic evidence strongly suggested that primary CNS lymphomas (PCNSLs) are likely largely dependent on NF-κB prosurvival signals, with enrichment of mutations involving the B-cell receptor pathway, in particular myeloid differentiation primary response 88 and cluster of differentiation 79B. The first set of early-phase investigations that target NF-κB in PCNSL have now been completed and support the NF-κB hypothesis but at the same time reveal that much work needs to be done to translate these results into meaningful advances in survival for a large fraction of patients. Insights into secondary prosurvival pathways that mediate drug resistance is a priority for investigation. Similarly, further evaluation of the immune-suppressive mechanisms in the CNS lymphoma tumor microenvironment is requisite for progress. Combinatorial interventions that promote the antitumor immune response have significant potential. With increasing availability of targeted agents, there is also a need to develop more sensitive imaging tools, not only to detect this highly invasive brain neoplasm but also potentially to define an evolving molecular phenotype to facilitate precision medicine.
Harnessing the power of the immune system in non-Hodgkin lymphoma: immunomodulators, checkpoint inhibitors, and beyond
Authors: Ansell Stephen M.
Published: April 2019

Non-Hodgkin lymphoma is a malignancy of B lymphocytes that typically infiltrate sites of disease, including the lymph nodes, spleen, and bone marrow. Beyond the presence of malignant cells, many immune cells are also present within the tumor microenvironment. Although these immune cells have the potential to regulate the growth of malignant B cells, intratumoral immune cells are unable to eradicate lymphoma cells and most patients with lymphoma have clinical evidence of disease progression. Recent data have identified some of the mechanisms that account for the suppressed antitumor immune response and have created opportunities for treatment to overcome the deficiencies. Two general categories of immunological therapies are available. The first approach is to use agents that prevent inhibitory signals via immune checkpoint receptors that downregulate immune cell function. Blockade of suppressive programmed cell death 1 (PD-1) or CTLA-4 signaling has resulted in significant clinical activity by allowing intratumoral T cells to remain activated and target malignant cells. A second approach is to additionally activate T cells that are suboptimally active or suppressed, by providing signals through costimulatory molecules including CD27 or CD40 or by adding immunostimulatory cytokines. There has been significant heterogeneity in the responses to these treatment approaches. Clinical responses are seen in many diseases, but the most promising responses have been with PD-1 blockade in Hodgkin lymphoma. In other lymphomas, responses are seen but only in a subset of patients. Further research is needed to identify the mechanisms that account for response and to identify patients most likely to benefit from immune modulation.
JAK2 (and other genes) be nimble with MPN diagnosis, prognosis, and therapy
Authors: Ciboddo Michele , Mullally Ann
Published: April 2019

Now that the spectrum of somatic mutations that initiate, propagate, and drive the progression of myeloproliferative neoplasms (MPNs) has largely been defined, recent efforts have focused on integrating this information into clinical decision making. In this regard, the greatest progress has been made in myelofibrosis, in which high-molecular-risk mutations have been identified and incorporated into prognostic models to help guide treatment decisions. In this chapter, we focus on advances in 4 main areas: (1) What are the MPN phenotypic driver mutations? (2) What constitutes high molecular risk in MPN (focusing on ASXL1)? (3) How do we risk-stratify patients with MPN? And (4) What is the significance of molecular genetics for MPN treatment? Although substantial progress has been made, we still have an incomplete understanding of the molecular basis for phenotypic diversity in MPN, and few rationally designed therapeutic approaches to target high-risk mutations are available. Ongoing research efforts in these areas are critical to understanding the biological consequences of genetic heterogeneity in MPN and to improving outcomes for patients.
Long-term complications in adolescent and young adult leukemia survivors
Authors: Baker K. Scott , Syrjala Karen L.
Published: April 2019

Adolescents and young adults (AYAs) with cancer, defined by the National Cancer Institute as having been diagnosed between the ages of 15 and 39 years old, have not benefited from the same improvements in quality of outcomes and survival that have been seen for individuals diagnosed in childhood or as older adults. Although is leukemia composed of a diverse group of diagnoses, leukemia AYA survivors share unique vulnerabilities with other AYA diagnostic groups. They will spend the majority of their lives as survivors, with clear evidence of adverse medical conditions, health care requirements, and social and psychological needs that differ not only from their peers but also, from the needs of other cancer survivor populations. Furthermore, they share a developmental stage of life in which careers, finances, and family concerns are uniquely impacted by the cancer diagnosis and treatment. Leukemia in AYAs typically presents with higher-risk biologic features, and treatment requires multiagent chemotherapy, including alkylating agents, anthracyclines, high-dose steroids, frequently intrathecal chemotherapy, and sometimes, cranial radiation. Thus, AYAs have significant risks for long-term complications, subsequent malignancies, and accelerated development of usual age-related comorbid conditions, such as cardiovascular disease and dyslipidemias. AYAs require specialized health care monitoring, surveillance for late effects, and periodic evaluation of psychosocial, health behavior, and life goal outcomes.
We do still transplant CML, don’t we?
Authors: Craddock Charles F.
Published: April 2019

The remarkable clinical activity of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) has transformed patient outcome. Consequently, allogeneic stem cell transplantation (allo-SCT) is no longer the only treatment modality with the ability to deliver long-term survival. In contrast to the central position it held in the treatment algorithm 20 years ago, allografting is now largely reserved for patients with either chronic-phase disease resistant to TKI therapy or advanced-phase disease. Over the same period, progress in transplant technology, principally the introduction of reduced intensity conditioning regimens coupled with increased donor availability, has extended transplant options in patients with CML whose outcome can be predicted to be poor if they are treated with TKIs alone. Consequently, transplantation is still a vitally important, potentially curative therapeutic modality in selected patients with either chronic- or advanced-phase CML. The major causes of transplant failure in patients allografted for CML are transplant toxicity and disease relapse. A greater understanding of the distinct contributions made by various factors such as patient fitness, patient-donor HLA disparity, conditioning regimen intensity, and transplant toxicity increasingly permits personalized transplant decision making. At the same time, advances in the design of conditioning regimens coupled with the use of adjunctive posttransplant cellular and pharmacologic therapies provide opportunities for reducing the risk of disease relapse. The role of SCT in the management of CML will grow in the future because of an increase in disease prevalence and because of continued improvements in transplant outcome.
Where to start? Upfront therapy for follicular lymphoma in 2018
Authors: Leonard John P. , Nastoupil Loretta J. , Flowers Christopher R.
Published: April 2019

The initial approach to the management of follicular lymphoma (FL) is challenging for patients and physicians. Most FL patients present with minimal symptoms; given the lack of a survival benefit to early treatment in this population, a period of observation without therapy is often appropriate. Once there is disease progression beyond low-tumor-burden criteria or symptoms prompting intervention, patients may be considered for an array of potential treatment options. These range from single-agent rituximab (anti-CD20) to various forms of chemoimmunotherapy, including rituximab or the newer anti-CD20 monoclonal antibody obinutuzumab. Unfortunately, prognostic and other clinical factors are of limited value in guiding optimal selection of therapy. Once patients complete initial treatment and achieve a complete or a partial remission, the next decision relates to the pros and cons of maintenance anti-CD20 therapy. Maintenance antibody administration can improve progression-free, but not overall, survival; hence, patient preferences typically drive this decision. Monitoring after remission is achieved should generally be guided by symptoms, physical examination, and laboratory findings, with routine surveillance imaging discouraged in the absence of new clinical issues. Given the wide range of options available and the importance of optimizing quality of life in this chronic health condition, education and shared decision making are pillars in the upfront management of FL to help patients achieve the best possible outcomes.
Biology-driven developments in the therapy of acute graft-versus-host disease
Authors: Zeiser Robert
Published: April 2019

Allogeneic hematopoietic cell transplantation is a potentially curative treatment of different hematological malignancies. A major life-threatening complication is acute graft-versus-host disease (GVHD), in particular when the disease becomes steroid refractory. Based on the detection of pathogenic cytokines, chemokines, and T-cell subsets in individuals developing GVHD or experimental GVHD models, different therapeutic strategies have been developed. A potential cause why targeting individual receptors can lack efficacy could be that multiple cytokines, danger signals, and chemokine that have redundant functions are released during GVHD. To overcome this redundancy, novel strategies that do not target individual surface molecules like chemokine receptors, integrins, and cytokine receptors, but instead inhibit signaling pathways downstream of these molecules, have been tested in preclinical GVHD models and are currently being tested in clinical GVHD trials. Another important development is tissue regenerative approaches that promote healing of GVHD-related tissue damage as well as strategies that rely on microbiota modifications. These approaches are promising because they act very differently from conventional immunosuppression, instead aiming at reinstalling tissue homeostasis and microbiome diversity. This review discusses major novel developments in GVHD therapy that are based on a better understanding of GVHD biology, the repurposing of novel kinase inhibitors, microbiome modification strategies, and tissue-regenerative approaches.
Hypereosinophilic syndrome: approach to treatment in the era of precision medicine
Authors: Klion Amy
Published: April 2019

Hypereosinophilic syndromes (HESs) are a heterogeneous group of rare disorders characterized by peripheral eosinophilia and eosinophilic end organ complications. Conventional therapies, including glucocorticoids and cytotoxic and immunomodulatory agents, have variable efficacy and significant toxicity. Although the recent development of agents that target eosinophils, including tyrosine kinase inhibitors and monoclonal antibodies, provides the possibility of more effective, less toxic approaches to treatment of HES, there are little available data to guide their use in these conditions. In the following review, the controversies regarding the definition and classification of HES will be discussed, and a pragmatic approach to treatment based on clinically defined HES variants will be presented. An illustrative case will be used to highlight the complexities of treatment selection in HES patients.
Optimizing quality care for the oral vitamin K antagonists (VKAs)
Authors: Pengo Vittorio , Denas Gentian
Published: April 2019

Vitamin K antagonists (VKAs) have been the only oral anticoagulants for decades. The management of anticoagulant therapy with VKA is challenging because of the intricate pharmacological properties of these agents. The success of VKA therapy depends on the quality of treatment that is ensured through continuing comprehensive communication and education. The educational program should address important issues of the VKA therapy such as beginning of treatment, pharmacological, dietary, and drug–drug interactions, as well as treatment temporary suspension during surgical interventions or invasive maneuvers. In addition, the initial and continuing patient education is of imperative importance. A major role in the educational process may be addressed by patient associations. The quality of treatment is better reached if patients are followed in anticoagulation clinics. Moreover, a federation of anticoagulation clinics may improve patient care through regular meetings to update knowledge on VKA treatment. Learning objectives of this paper is to allow readers to correctly approach patients starting VKA treatment, recognize possible pitfalls of treatment, and provide adequate solutions.
Potential new approaches to the management of the Hb Bart’s hydrops fetalis syndrome: the most severe form of α-thalassemia
Authors: King Andrew J. , Higgs Douglas R.
Published: April 2019

The α-thalassemia trait, associated with deletions removing both α-globin genes from 1 chromosome (genotype ζ αα/ζ--), is common throughout Southeast Asia. Consequently, many pregnancies in couples of Southeast Asian origin carry a 1 in 4 risk of producing a fetus inheriting no functional α-globin genes (ζ--/ζ--), leading to hemoglobin (Hb) Bart’s hydrops fetalis syndrome (BHFS). Expression of the embryonic α-globin genes (ζ-globin) is normally limited to the early stages of primitive erythropoiesis, and so when the ζ-globin genes are silenced, at ∼6 weeks of gestation, there should be no α-like globin chains to pair with the fetal γ-globin chains of Hb, which consequently form nonfunctional tetramers (γ4) known as Hb Bart’s. When deletions leave the ζ-globin gene intact, a low level of ζ-globin gene expression continues in definitive erythroid cells, producing small amounts of Hb Portland (ζ2γ2), a functional form of Hb that allows the fetus to survive up to the second or third trimester. Untreated, all affected individuals die at these stages of development. Prevention is therefore of paramount importance. With improvements in early diagnosis, intrauterine transfusion, and advanced perinatal care, there are now a small number of individuals with BHFS who have survived, with variable outcomes. A deeper understanding of the mechanism underlying the switch from ζ- to α-globin expression could enable persistence or reactivation of embryonic globin synthesis in definitive cells, thereby providing new therapeutic options for such patients.
Balancing exercise risk and benefits: lessons learned from sickle cell trait and sickle cell anemia
Authors: Liem Robert I.
Published: April 2019

Development of exercise guidelines for individuals with sickle cell trait (SCT) and sickle cell anemia (SCA) is hampered by the need to weigh the benefits against risks of exercise in these populations. In SCT, concern for exercise collapse associated with sickle cell trait has resulted in controversial screening of student athletes for SCT. In SCA, there exists unsubstantiated concerns that high-intensity exercise may result in pain and other complications. In both, finding the “right dose” of exercise remains a challenge for patients and their providers. Despite assumptions that factors predisposing to adverse events from high-intensity exercise overlap in SCT and SCA, the issues that frame our understanding of exercise-related harms in both are distinct. This review will compare issues that affect the risk-benefit balance of exercise in SCT and SCA through these key questions: (1) What is the evidence that high-intensity exercise is associated with harm? (2) What are the pathophysiologic mechanisms that could predispose to harm? (3) What are the preventive strategies that may reduce risk? and (4) Why do we need to consider the benefits of exercise in this debate? Addressing these knowledge gaps is essential for developing an evidence-based exercise prescription for these patient populations.
The current state of sickle cell trait: implications for reproductive and genetic counseling
Authors: Pecker Lydia H. , Naik Rakhi P.
Published: April 2019

Sickle cell trait (SCT) is unique among the carrier states that are identified during newborn screening. Unlike other heterozygous states for rare recessive diseases, SCT is exceedingly prevalent throughout regions of the world, making sickle cell disease one of the most common monogenetic diseases worldwide. Because of this high frequency, reproductive counseling is of paramount importance. In addition, unlike other carrier states, SCT seems to be a risk factor for several clinical complications, such as extreme exertional injury, chronic kidney disease, and venous thromboembolism. Increasing knowledge about these clinical outcomes can help inform genetic counseling recommendations. Expanding research and clinical efforts are needed to ensure that the promises of modern and precision medicine can be delivered to the millions of SCT carriers and their children.
An introduction to point-of-care testing in extracorporeal circulation and LVADs
Authors: Bercovitz Rachel Sara
Published: April 2019

There is a delicate balance between bleeding and clotting in patients on circuits such as ventricular assist devices or extracorporeal membrane oxygenation. Traditional coagulation tests, prothrombin time, activated partial thromboplastin time, and anti-factor Xa levels, are used to monitor patients on these devices. However, turnaround times and inability to assess global hemostasis, including platelets and fibrinogen have contributed to a recognition that faster, accurate, and more informative coagulation tests are needed. Activated clotting time is used to monitor heparin in patients on circuits and has the advantages of being a near-patient point-of-care test. However, its utility is limited to heparin monitoring. Viscoelastic tests (thromboelastometry and thromboelastography) are global, whole-blood coagulation tests, and whole-blood platelet aggregometry evaluates platelet function. Ideally, these tests can ensure that patients are within the therapeutic range of their antithrombotic medications, identify patients at risk for hemorrhagic or thrombotic complications, and guide management of acute bleeding complications. This ideal is currently hampered by a lack of studies that delineate clear ranges that are clinically relevant. Future research is needed to better understand the optimal use of point-of-care coagulation testing in patients on extracorporeal circuits and ventricular assist devices.
How do we diagnose immune thrombocytopenia in 2018?
Authors: Kelton John G. , Vrbensky John R. , Arnold Donald M.
Published: April 2019

In this report, we will review the various clinical and laboratory approaches to diagnosing immune thrombocytopenia (ITP), with a focus on its laboratory diagnosis. We will also summarize the results from a number of laboratories that have applied techniques to detect anti-platelet autoantibodies as diagnostic tests for ITP. Although there is considerable variability in methods among laboratories, there is general agreement that platelet autoantibody testing has a high specificity but low sensitivity. This suggests several possibilities: (1) the ideal test for ITP has yet to be developed, (2) current test methods need to be improved, or (3) ITP is the clinical expression of a variety of thrombocytopenic disorders with different underlying mechanisms. Even the clinical diagnosis of ITP is complex, and experienced clinicians do not always agree on whether a particular patient has ITP. Improvements in the diagnostic approach to ITP are necessary to improve the management of this disorder.
Treatment approach for the older, unfit patient with myeloma from diagnosis to relapse: perspectives of a European hematologist
Authors: Facon Thierry , Anderson Kenneth
Published: April 2019

Mrs. A. is a 73-year-old woman who has developed increasing fatigue and lower back pain over the past year. The pain limits her exercise tolerance such that she can now walk only 1 block. She is a retired schoolteacher who does volunteer efforts in her community but has limited her activities due to fatigue. Karnofsky performance status is 70%. She has a history of chronic hypertension treated with a diuretic, adult-onset diabetes mellitus treated with metformin, and hypothyroidism treated with levothyroxine. Initial evaluation reveals anemia, renal dysfunction, an elevated total protein, and an L2 compression fracture on lumbosacral radiographs. Results of initial and subsequent evaluation are shown below, and she is referred to a hematologist for further evaluation, which revealed the following: calcium 9.0 mg/dL, creatinine 3.2 mg/dL with estimated creatinine clearance using the Modification of Diet in Renal Disease equation of 15 mL/min, hemoglobin 9.6 g/dL, total protein 11 g/dL, albumin 3.2 g/dL, immunoglobulin A (IgA) λ M protein 6.8 g/dL, total IgA 7.2 g/dL, IgG 0.4 g/dL, IgM 0.03 g/dL, free κ <0.01 mg/L, free λ 1000 mg/L, free light chain ratio <0.01, β-2–microglobulin 4.2, viscosity 3.0, lactate dehydrogenase 200 U/L, urine protein electrophoresis: 125 mg/dL with 30% M protein, and urine immuno-electrophoresis: λ light chain. Skeletal bone survey showed lytic lesions in femurs and humeri and diffusely in ribs bilaterally as well as compression fractures at T4, T6, and L2. Bone marrow biopsy revealed λ-restricted plasma cells comprising 50% of the bone marrow core. Fluorescence in situ hybridization testing on marrow showed that del(17p) was present in 80% of the plasma cells. Mrs. A. is informed of the diagnosis of multiple myeloma and the need for therapy. She requests consultation with 2 of the leading world experts. However, she wants to be treated near her home and does not want treatment on a clinical trial.
A period without PER: understanding 24-hour rhythms without classic transcription and translation feedback loops
Authors: Millius Arthur , Ode Koji L. , Ueda Hiroki R.
Published: April 2019

Since Ronald Konopka and Seymour Benzer’s discovery of the genePeriodin the 1970s, the circadian rhythm field has diligently investigated regulatory mechanisms and intracellular transcriptional and translation feedback loops involvingPeriod, and these investigations culminated in a 2017 Nobel Prize in Physiology or Medicine for Michael W. Young, Michael Rosbash, and Jeffrey C. Hall. Although research on 24-hour behavior rhythms started withPeriod, a series of discoveries in the past decade have shown us that post-transcriptional regulation and protein modification, such as phosphorylation and oxidation, are alternatives ways to building a ticking clock.