bluuebunny/crossref_metadata_2025 huggingface dataset:
Orthodontic plate for management of obstructive sleep apnoea in infants with Pierre Robin sequence: experience and protocol in Hong Kong
Authors: Ho Angus CH , Wong Ricky WK , Cheung Tania , Ng Daniel K , Siu KK , Fung SC
Published: October 2019

Objective:

To present the application of the pre-epiglottic baton plate (PEBP) in infants with Pierre Robin sequence (PRS) in the Southern Chinese population (Hong Kong) and to present the diagnosis and management protocol of these infants in our centre.

Design:

Retrospective case series of three patients with PRS.

Setting:

Neonatal Intensive Care Unit in Kwong Wah Hospital and Craniofacial Orthodontic Centre in United Christian Hospital, Hong Kong.

Participants:

Three new-born infants (two girls, one boy) with PRS and upper airway obstruction due to glossoptosis.

Methods:

A protocol for the diagnosis and management of these infants in the Southern Chinese population (Hong Kong) was presented. The three patients received nasal high-flow oxygen and/or continuous positive airway pressure (CPAP) as first-line respiratory support, followed by PEBP for 3–5 months. A two-stage approach was undertaken to ensure accurate positioning of the PEBP.

Results:

All three infants had improvement in clinical signs, symptoms and polysomnography upon discharge. PEBP and other respiratory aids were weaned off at 3–6 months.

Conclusions:

The PEBP, combined with other respiratory support, is a useful modality in the treatment of obstructive sleep apnoea in infants with PRS.
Outlier analysis of nonlinear solitary waves for health monitoring applications
Authors: Zheng Bowen , Rizzo Piervincenzo , Nasrollahi Amir
Published: October 2019

The structural health monitoring/nondestructive evaluation method based on the generation and detection of highly nonlinear solitary waves is emerging as a cost-effective technique to monitor or inspect a variety of structures and materials. These waves possess unique characteristics not seen in conventional ultrasounds. Outlier analysis is a statistic tool able to identify anomalies in data that diverge from a set of baseline data. Although outlier analysis has received considerable attention for defect detection using modal data, guided ultrasonic waves, or other nondestructive approaches, its application for the analysis of solitary waves has never been explored. In the study presented in this article, the use of outlier analysis in terms of discordancy test and Mahalanobis squared distance was investigated to enhance the damage detection capability of a monitoring system based on highly nonlinear solitary waves. Two experiments were performed to demonstrate the procedure. In the first experiment, a thick steel plate was probed with a solitary wave transducer placed above the plate, and damage was simulated in terms of a foreign object magnetically attached to the bottom of the plate, at different distances from the transducer. In the second experiment, two aluminum plates were placed above each other in dry contact with the top plate subjected to localized, mostly hidden, defects. The transducer used in the first experiment was in this second test encased in a small cart with wheels to scan the sample at discrete positions. For both experiments, a few features were extracted from the time waveforms and fed to a univariate and a multivariate analysis that compared the testing data to a set of baseline data. The results show that the outlier analysis significantly improves the ability to detect damage using solitary waves.
Targeted Issue Messages and Voting Behavior
Authors: Endres Kyle
Published: October 2019

In today’s data-driven campaigns, presidential targeting strategies rely on detailed perceptions about the political leanings and policy positions of Americans to decide which registered voters to contact and which messages to emphasize in their outreach. However, identifying supporters and opponents of a candidate’s policy positions is far from foolproof. This reality results in some citizens encountering political message(s) on congruent issues, where their issue stance aligns with the messaging candidate, and others encountering incongruent issue message(s), where the candidate and message recipient do not share the same position. Examining official contact records from the 2012 presidential campaign of Republican Mitt Romney, I find evidence that Romney’s campaign had some success when targeting Democrats with congruent issues. Messaging Democrats with an issue where they and Romney share common ground is associated with decreased support for Obama, increased abstention, and increased support for Romney. Contacting Democrats with an incongruent message and contacting Republicans with either an incongruent or congruent issue message had minimal effects on the voting behavior of the recipient.
Accurate diagnosis and treatment of isolated mesenteric artery dissections
Authors: Gang Chen , Xiujuan Gao , Yingjiang Xu , Xun Cui , Dan Shang , Jianyong Liu , Bi Jin
Published: October 2019

Objectives

Diagnosis and treatment of isolated mesenteric artery dissections (IMAD) are overlooked. The purpose of this study was to assess the clinical feature, possible diagnostic errors and treatment methods.

Methods

From January 2010 to December 2017, 99 consecutive patients who were diagnosed with IMAD on computed tomography angiography were enrolled retrospectively. Thirty-nine misdiagnosed patients, false negative, and 60 accurate diagnosis patients with revealed IMAD were compared. In addition, therapeutic schemes were evaluated.

Results

Ninety-nine patients participated in this study; 39 patients (34 men, 5 women; median age, 51.41 years, range 38–64 years) were included in group A who were misdiagnosed initial visit; the remaining 60 patients (52 men, 8 women; median age, 52.07 years, range 38–68 years) with IMAD who were diagnosed accurately initial visit were included in group B. Significant differences were observed between the two groups with respect to dissection length (55.26 ± 3.88 mm vs. 43.37 ± 2.75 mm; p = 0.01), and branch involvement (14 and 9, respectively; p = 0.04). Ultimately, 33 patients (group A 14 patients and group B 19 patients) underwent invasive interventional therapy, and 66 patients with conservative treatment with antithrombotic agents (group A 25 patients and group B 41 patients). A total of 86 (86.87%) had follow-up computed tomography angiography with a median duration of 24.51 months (range 2–71 months). Three patients died during follow-up. The remaining patients recovered smoothly.

Conclusion

Physicians should raise the awareness of IMAD and use the optimal treatment time frame. Diagnosis of IMAD depends on imaging examinations, especially computed tomography angiography. Additionally, conservative management is the most common initial treatment. For patients in whom conservative treatment fails, endovascular and/or surgery may be necessary.
Improving the modeling and forecasting of fuel selling price using the radial basis function technique: A case study
Authors: Aman Zineb , Ezzine Latifa , El Bahi Younes Fakhradine , EL Moussami Haj
Published: October 2019

Recently, the petroleum sector in Morocco has been liberalized which has a significant effect for petroleum product distributors. Since the beginning of December 2015, fuel prices are freely determined. This event presents many constraints affecting the balance of the sector plus the competition between its economic players. The lack of accompanying measures by the State makes this vital reform for public finances that stop subsidizing the price of gasoline vulnerable. As all fuel products are imported, we will be interested in the evolution by making forecasts of the price of fuels in the Moroccan market. In this context, our paper aims mainly to study the selling price of diesel and gasoline in order to provide precise forecasts to the company and to respect the permissible error margin of 3%. To this end, we worked with a widely used approach for price forecasting: artificial neural networks technique (radial basis function). Recently, it is suggested to work with artificial neural networks in forecasting field as an alternative to the traditional linear methods. We developed a radial basis function network to come up with conclusions in terms of the superiority in forecasting performance. Consequently, the radial basis function technique proved its strength manifested in the error that was further minimized: 1.95% instead of 2.85% for autoregressive integrated moving average (ARIMA) model used in our previous work. The error is further minimized by applying radial basis function technique.
European arrest warrants and the independence of the issuing judicial authority – How much independence is required? (Case note on joined cases C-508/18 and C-82/19 PPU OG and PI)
Authors: Heimrich Chad
Published: October 2019

This case note examines the Court of Justice of the European Union (CJEU)’s decision in OG (C-508/18) and PI (C-82/19 PPU) concerning the interpretation of the notion of ‘issuing judicial authority’ within the meaning of Article 6(1) Framework Decision 2002/584/JHA. It assesses whether the German Public Prosecutor’s Office can be considered to be sufficiently independent to issue European Arrest Warrants. In this context, the CJEU’s previous case law on Article 6(1) will be taken into consideration and briefly outlined. The case note, then, summarises the Opinion of the Advocate General and the Court’s line of reasoning and closes with a commentary on the decision.
Clinical implications of partial anomalous pulmonary venous connection: a rare cause of severe pulmonary arterial hypertension
Authors: Pizzini Alex , Sonnweber Thomas , Frank Renate , Theurl Markus , Weiss Günter , Tancevski Ivan , Löffler‐Ragg Judith
Published: October 2019

Isolated partial anomalous pulmonary venous connection (PAPVC) is an uncommon congenital heart anomaly that is sporadically associated with pulmonary arterial hypertension in the adult population. The diagnosis and therapy for this condition are challenging. We report on three cases of patients with unexpected severe precapillary pulmonary hypertension in single PAPVC treated with an upfront pulmonary arterial hypertension‐specific combination therapy. Our cases indicate that the combination of PAPVC and pulmonary comorbidities may trigger the development of severe pulmonary arterial hypertension. The initiation of pulmonary arterial hypertension‐targeted combination therapy revealed to be a safe and efficacious strategy for patients with PAPVC‐associated severe pulmonary arterial hypertension.
Exploring a physiotherapy well‐being review to deliver community‐based rehabilitation in patients with pulmonary hypertension
Authors: Keen Carol , Hashmi‐Greenwood Molly , York Janelle , Armstrong Iain J , Sage Karen , Kiely David
Published: October 2019

Background

Highly structured, supervised exercise training has been shown to be beneficial in patients with pulmonary hypertension. Despite evidence of the effectiveness of community‐based rehabilitation in other cardiopulmonary diseases, there are limited data in patients with pulmonary hypertension.

Methods

This prospective study evaluated the intervention of a physiotherapist well‐being review in patients with pulmonary hypertension who had been established on targeted drug therapy for between 3 and 12 months. The intervention included a detailed consultation assessing functional, social and motivational status to identify individual patient rehabilitation goals and facilitate tailored referrals to community‐based services.

Results

One hundred and thirty‐eight patients (79% pulmonary arterial hypertension, 17% chronic thromboembolic disease), age 67 ± 14 years, diagnosed over a one year period were evaluated between July 2017 and January 2018. Fifty‐two per cent of patients were referred to community‐based pulmonary rehabilitation programmes, 19% received other forms of community rehabilitation, 17% were given exercise advice, 5% had an assessment of social support and 7% declined any intervention. At the end of the study, 32% of patients were undertaking independent exercise.

Conclusion

This study has identified that the majority of patients with pulmonary hypertension who are optimised on targeted drug therapy have rehabilitation needs. The use of a physiotherapy well‐being review can identify this need and facilitate access to community‐based rehabilitation. Further research is required to evaluate the efficacy of such interventions in pulmonary hypertension.
Ununited accessory caudal glenoid ossification centre and associated joint mouse as a cause of lameness in a cat
Authors: Serck Boris MA , Wouters Erik EG
Published: October 2019

Case summary

A 16-year-old neutered female domestic shorthair cat was evaluated for chronic lameness of the right thoracic limb. On clinical examination, pain was localised to the right glenohumeral joint. Radiography and arthrography of the right glenohumeral joint revealed an ununited accessory caudal glenoid ossification centre, abbreviated here to ununited caudal glenoid (UCG), and a joint mouse. The UCG and attached joint mouse were removed via arthroscopy and this resulted in complete resolution of the clinical signs. The cat was euthanased 3 years later, for an unrelated cause, having shown no recurrence of lameness.

Relevance and novel information

UCG should be considered as a differential diagnosis for cats with lameness of the thoracic limb. The clinical implications of a UCG have been described in dogs, but to our knowledge have not yet been described in cats. Excision of the UCG, as described in dogs, may be an effective treatment for this condition.
Cerebral gliosarcoma with perivascular involvement in a cat
Authors: Álvarez Patricia , Wessmann Annette , Pascual Mireia , Comas Oriol , Pi Dolors , Pumarola Martí
Published: October 2019

Case summary

A 5-year-old neutered male domestic shorthair cat presented with an 18-month history of facial tics, and progressive general ataxia, weakness, lethargy and anorexia of 2 weeks’ duration. MRI of the brain showed a well-defined heterogeneous hyperintense mass on T1-weighted and T2-weighted images, with central hypointensity in the rostral commissure and septum pellucidum, and perilesional hyperintensity in fluid-attenuated inversion recovery, suggestive of perilesional oedema. Gross examination in a transverse section of the brain at the level of the septum pellucidum revealed a 0.2 cm brown soft mass. Histopathological examination identified a biphasic neoplastic proliferation of mesenchymal and neuroepithelial cell populations. Fusiform cells were predominately distributed in bundles showing a high degree of anisocytosis and marked immune-positive reaction to vimentin immunochemistry, confirming a sarcomatous origin. Additionally, high numbers of astrocytic cells were identified by an intense immunopositive reaction to glial fibrillary acidic protein and negative reaction to oligodendrocyte transcription factor 2 immunochemistry. Vascular invasion of the neoplasia into the wall of a medium branch of the rostral cerebral artery was present (secondary Scherer structures). Based on these characteristics, the tumour was defined as a gliosarcoma. Gliosarcoma is a recognised astrocytoma grade IV anaplastic glial cell tumour with sarcomatous differentiation.

Relevance and novel information

To our knowledge, this is the first report describing a cerebral gliosarcoma in a cat including clinical, MRI, macroscopic and histopathological features and immunolabelling characteristics.
Information-Sharing Behaviors Among Sports Fans Using #Hashtags
Authors: Kim Han Soo , Cho Kwang Min , Kim Minjung
Published: October 2019

The purpose of this study was to explore sports fans’ hashtags usage for information sharing over social media on the basis of the theory of interpersonal behavior. We collected data from 323 social media users who have employed hashtags to exchange sports-related information during the past 12 months. The structural equation modeling confirmed affect, perceived usefulness, perceived reciprocity, and social factors as motivators of the intention to share information. Other motivators, including habit and facilitating conditions, function as predictors of actual hashtags posting among sport fans. In deriving empirical evidence and novel insights into the role of hashtags, this research elevated our understanding of information circulation among sport fans over social media and serves as a foundation for inquiries into hashtag adoption in sport domains.
FDA Reported Use of Patient Experience Data in 2018 Drug Approvals
Authors: Kieffer Cameron M. , Miller Alexis Reisin , Chacko Benjamin , Robertson Andrew S.
Published: October 2019

Background:

“Patient experience data” (PED) refers to the systematic collection of meaningful data relating to the experiences, perspectives, needs, and priorities of patients. PED can augment traditional clinical trial data in the FDA’s review of product applications. Section 3001 of the 2016 21st Century Cures Act requires the FDA to make a public statement about the PED considered in the approval of a drug application. Here, we present one of the first assessments of PED consideration during drug application approval, as reported by the FDA under Sec. 3001 of the Cures Act.

Methods:

FDA reported use of PED in the Review Documentation of the 59 new molecular entities (NMEs) approved in 2018 were collected, indexed, and cross-referenced against information regarding FDA review and product regulatory designation. The data reported in the PED tables were quantitatively described and visualized.

Results:

Of the 59 approved NMEs in 2018, 48 include a table that summarized whether PED was or was not used during the FDA drug review. Thirty-four of those 48 approvals (70.8%) reported using PED in the drug review. Patient-reported outcomes (PROs) represented the most significant source of PED and were used in 60.4% of approved drug reviews. Additional findings, including PED use by FDA review division and by FDA regulatory designation, are described.

Conclusions:

This assessment is a first step to better understanding how FDA considers PED in regulatory decision making. This analysis should help develop a baseline regarding FDA use of PED and may inform decisions to ensure patients’ experiences are adequately heard in future drug development.
A Qualitative Exploration of Facilitators for Health Service Use among Aging Gay Men Living with HIV
Authors: Green Daniel Colton , Wheeler Elizabeth Mirizio
Published: October 2019

Using Anderson’s Health Behavioral Model of Health Service Use, this study explores factors facilitating health service use among aging gay men living with HIV. Qualitative data from 10 participants recruited from a federally qualified health center were analyzed using theoretical thematic analysis. Results shown to facilitate health service use include an existing need for services in the form of HIV management; predisposing factors of age and the development of resilience in the face of stigmatizing experiences related to their sexual identity and health status; and enabling influences including comfort with medical providers, providers knowledgeable in lesbian, gay, bisexual, transgender, and queer issues, and sexual concordant providers. Need for services, predisposing factors, and enabling factors are discussed in relation, as well as each factor’s unique implications for this population. Results from this study may be used to improve service use and provides tangible clinical recommendations.
Mentoring in Research-Practice Partnerships: Toward Democratizing Expertise
Authors: Ghiso María Paula , Campano Gerald , Schwab Emily R. , Asaah Dee , Rusoja Alicia
Published: October 2019

Reconceiving relationships between universities, schools, and community organizations through research-practice partnerships, and building capacity for partnership work, necessarily entails rethinking the mentorship of graduate students. In this article, we describe our findings on what mentorship looks like in a now 9-year RPP focusing on educational equity through participatory approaches. The authors include the two project principal investigators and three doctoral students who participated at different stages of the project, one of whom is now a faculty member. In our analysis, we identify dimensions of a more horizontal form of mentorship, involving qualities and skills that extend beyond traditional practices of academic apprenticeship: universalizing who is an intellectual, cultivating community responsiveness, implementing collective structures and protocols, and constructing a shared vision. Our findings shift conceptions of mentorship from individual apprenticeship into a narrowly defined discipline to a collective undertaking that aims to democratize expertise and enact a new vision of the public scholar.
Iron Sharpens Iron: Lessons Learned from a Songwriting Workshop in Mozambique
Authors: Hansen Antoinette , Meyers Megan
Published: October 2019

Mozambique, a nation that boasts the longest coastline in Sub-Saharan Africa, has long weathered encounters with the global economy, from Muslim traders to Portuguese colonists. The resultant cultures are incredibly diverse and complex. What ethnodoxology “best practices” will both preserve the present culture and promote Christ? This article outlines some of the unique challenges and surprising results of a recent songwriting workshop among the Makhuwa-Nahara people in northern Mozambique, suggests strategies for future workshops, and explores missiological implications for such efforts in Muslim contexts.
Atypical Lymphoproliferative Diseases
Authors: Greiner Timothy , Armitage James O. , Gross Thomas G.
Published: October 2019

This review addresses the clinical presentation, pathology, and therapy of several uncommon lymphoid proliferations. Because these lymphoproliferations span the characteristics of reactive polymorphous proliferations to clonal malignant neoplasms, they are often difficult to diagnose and treat effectively.

In Section I, Dr. Greiner describes the pathology of the spectrum of atypical lymphoid disorders including Castleman's disease, angioimmunoblastic lymphadenopathy, lymphadenopathy in autoimmune diseases, posttransplant lymphoproliferative disorders, and X-linked lymphoproliferative disorder. The relationship to Epstein-Barr virus (EBV) and human herpsesvirus-8 (HHV-8) is discussed, and molecular diagnostic assays and principles for obtaining proper diagnostic evaluation are emphasized.

In Section II, Dr. Armitage presents a practical approach to the management of Castleman's disease. The discussion includes the importance of confirmation of the histological diagnosis and careful staging evaluation, therapeutic options, and the increased risks for infection and lymphoma. The appropriate roles of surgical excision, corticosteroids, and combination chemotherapy are addressed along with alternative strategies such as anti-interleukin-6 and bone marrow transplantation.

In Section III, Dr. Gross reviews the treatment of EBV-associated lymphoproliferative disorders in primary immunodeficiencies and in post-transplant patients. He gives an update on the recent molecular discoveries in X-linked lymphoproliferative disorder. Preliminary results of a phase II trial of low-dose cyclophosphamide in posttransplant lymphoproliferative disorders and the use of GM-CSF as preemptive therapy are presented.
Chronic Lymphocytic Leukemia (CLL): First-Line Treatment
Authors: Hallek Michael ,   On Behalf Of The German CLL Study Group
Published: October 2019

For the past ten years, there has been a dynamic development of new therapeutic compounds and prognostic parameters for chronic lymphocytic leukemia (CLL). Hematologists and oncologists are challenged to use these new possibilities for an optimized, risk- and fitness-adapted treatment strategy, with the goal of achieving long-term remissions and preserving a good quality of life. This review is intended to summarize the current knowledge on first-line treatment of CLL.
Platelets and Thrombosis in Myeloproliferative Diseases
Authors: Harrison Claire N.
Published: October 2019

The myeloproliferative disorders have been the “poor cousins” in the family of hematological malignancies for some time. Recently this field has advanced considerably with the description of a mutation in the JAK2 kinase detectable in the majority of patients and the publication of two landmark clinical trials—ECLAP and MRC PT1. But although both ECLAP and MRC PT1 inform clinical management and allude to the complexities of thrombosis we still lack fundamental knowledge, and our understanding of thrombosis in these conditions has not paralleled advances in the field of thrombosis and vascular biology. The predominant clinical complications of essential thrombocythemia and polycythemia vera are thrombotic and hemorrhagic; these significantly impact upon prognosis and quality of life. Here the current status of our knowledge is reviewed with specific emphasis upon the role of the platelet in the pathogenesis of thrombosis as well as the impact of recent data from ECLAP and MRC PT1.
Bleeding scores: are they really useful?
Authors: O'Brien Sarah H.
Published: October 2019

Given the commonality of bleeding symptoms in the general population and the diagnostic limitations of available laboratory testing for mild bleeding disorders, there has been increasing interest in a more precise quantification of bleeding symptoms. The Vicenza bleeding score (and its successor, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand disease [MCMDM-1 VWD]) and its pediatric counterpart, the Pediatric Bleeding Questionnaire, are validated research tools that have demonstrated their ability to discriminate between healthy subjects and those with VWD. These instruments collect data regarding both the presence and severity of a variety of bleeding symptoms and generate a bleeding score by summing the severity of all symptoms reported by a subject. More recent work demonstrates the promise of these tools as a diagnostic aid in the evaluation of patients with a suspected inherited mild bleeding disorder, as well as the development of a condensed score with increased clinical applicability. This review focuses on the development of these bleeding assessment tools, recent publications applying and refining these instruments, and current limitations of bleeding scores. Needed research studies and potential clinical applications of bleeding scores are also discussed. The ultimate goal would be for bleeding scores to be integrated with the results of standardized laboratory testing to allow for a universal diagnostic approach to patients with suspected bleeding disorders.
How to approach chronic anemia
Authors: Koury Mark J. , Rhodes Melissa
Published: October 2019

We present herein an approach to diagnosing the cause of chronic anemia based on a patient's history and complete blood cell count (CBC). Four patterns that are encountered frequently in CBCs associated with chronic anemias are considered: (1) anemia with abnormal platelet and/or leukocyte counts, (2) anemia with increased reticulocyte counts, (3) life-long history of chronic anemia, and (4) anemia with inappropriately low reticulocytes. The pathophysiologic bases for some chronic anemias with low reticulocyte production are reviewed in terms of the bone marrow (BM) events that reduce normal rates of erythropoiesis. These events include: apoptosis of erythroid progenitor and precursor cells by intrinsic and extrinsic factors, development of macrocytosis when erythroblast DNA replication is impaired, and development of microcytosis due to heme-regulated eIF2α kinase inhibition of protein synthesis in iron-deficient or thalassemic erythroblasts.
Thrombosis in pregnancy: updates in diagnosis and management
Authors: Greer Ian A.
Published: October 2019

Acute venous thromboembolism poses significant problems in pregnancy, a time when objective diagnosis and prompt treatment are essential. Events can occur at any stage in pregnancy, but the period of greatest risk is in the weeks after delivery. Ultrasound venography remains the diagnostic technique of choice for deep venous thrombosis. For pulmonary thromboembolism, ventilation perfusion lung scan is usually preferred more than computerized tomography pulmonary angiography because of the lower maternal radiation dose and the lower prevalence of coexisting pulmonary problems. Low-molecular-weight heparin is the agent of choice for treatment of venous thromboembolism in pregnancy, and treatment should be provided for a minimum of 3 months and for at least 6 weeks after delivery. New anticoagulant agents such as dabigatran, rivaroxaban, or apixaban are not recommended for use in pregnancy.
Baby on board: what you need to know about pregnancy in the hemoglobinopathies
Authors: Naik Rakhi P. , Lanzkron Sophie
Published: October 2019

Pregnancy poses a unique challenge to patients with sickle cell disease and β-thalassemia, who often have exacerbations of hemolysis or anemia during the gestational period, experience higher rates of obstetric and fetal complications, and may have distinct underlying comorbidities related to vasculopathy and iron overload that can endanger maternal health. Optimal management of pregnant women with hemoglobinopathies requires both an understanding of the physiologic demands of pregnancy and the pathophysiology of disease-specific complications of inherited blood disorders. A multidisciplinary team of expert hematologists and high-risk obstetricians is therefore essential to ensuring appropriate antenatal maternal screening, adequate fetal surveillance, and early recognition of complications. Fortunately, with integrated and targeted care, most women with sickle cell disease and β-thalassemia can achieve successful pregnancy outcomes.
Haploidentical transplantation for hematologic malignancies: where do we stand?
Authors: Fuchs Ephraim J.
Published: October 2019

The fundamental obstacle to the successful application of partially HLA-mismatched related donor, or HLA-haploidentical stem cell transplantation, is the strength of the host and donor T-cell response to allogeneic HLA molecules, which results in increased incidences of graft failure, GVHD, and nonrelapse mortality. The holy grail of haplo-SCT is to mitigate host-versus-graft and graft-versus-host responses while preserving immune responses to infection and the patient's malignancy. Two strategies have been taken to achieve this goal. The first strategy is to supplement a T cell–depleted graft with pathogen-specific T cells or populations of T cells in which alloreactivity can be controlled. The second strategy is to eliminate alloreactive T cells selectively from a T cell–replete graft. Substantial progress has been made with both approaches so that the safety of haplo-SCT now approaches that of SCT using grafts of umbilical cord blood or from HLA-matched donors. In light of the rapid and near universal availability of HLA-haploidentical related donors, it should now be possible to identify and mobilize a donor for every patient referred for allogeneic SCT. Prospective comparisons between haploidentical SCT and unrelated donor SCT should be performed to identify the most efficacious approach to alternative donor transplantation.
Do different conditioning regimens really make a difference?
Authors: Blaise Didier , Castagna Luca
Published: October 2019

Over the past 15 years, the use of reduced-intensity/nonmyeloablative conditioning regimens before allogeneic hematopoietic stem cell transplantation has been increasing. Despite major disparities in the level of myeloablation, intensity of immunosuppression (including great diversity of in vivo T-cell depletion), and postgraft immunomodulation, the different approaches have contributed jointly to a modification of the stage of allogeneic stem cell transplantation: transplantation-related procedure mortality has been decreased dramatically, allowing allogeneic immunotherapy to be used in previously excluded populations, including elderly patients, young but clinically unsuitable patients, patients with lymphoid malignancies or solid tumors, and patients without an HLA-identical related or unrelated donor. Together, these diverse regimens have provided one of the biggest breakthroughs since the birth of allogeneic BM transplantation. However, consensus on how to reach the optimal goal of minimal transplantation-related mortality with maximum graft-versus-tumor effect is far from being reached, and further studies are needed to define optimal conditioning and immunomodulatory regimens that can be integrated to reach this goal. These developments, which will most likely vary according to different clinical situations, have to be compared continuously with advances achieved in traditional allogeneic transplantation and nontransplantation treatments. However, the lack of prospective comparative trials is and will continue to make this task challenging.
Does antithymocyte globulin have a place in reduced-intensity conditioning for allogeneic hematopoietic stem cell transplantation?
Authors: Siddiqi Tanya , Blaise Didier
Published: October 2019

A 63-year-old male patient without siblings is treated for acute myeloid leukemia with poor prognostic cytogenetics. Despite achieving a first complete remission, he relapsed within the first year of diagnosis. He then achieved a second complete remission. A search for an HLA-identical unrelated donor identified a 10/10 possible match. The patient has several comorbidities (hematopoietic stem cell comorbidity index = 3) and it is recommended that he undergo a reduced-intensity conditioning regimen for allogeneic peripheral blood stem cell transplantation. The patient is well-read on allogeneic stem cell transplantation and asks you the merits of antithymocyte globulin that you propose to include in the conditioning regimen.
Delayed opportunistic infections in hematopoietic stem cell transplantation patients: a surmountable challenge
Authors: Marr Kieren A.
Published: October 2019

Changes in the transplantation procedure and the implementation of effective supportive care strategies have decreased the incidence of infectious complications early after conditioning therapy for allogeneic hematopoietic stem cell transplantation (HCT) and have extended the duration of risks later. Therefore, the types of infections that cause significant morbidity and the timing of risks have changed. These late infections are caused by all types of organisms, bacterial, viral, and fungal, but risks are predictable and surmountable with the use of tailored prevention strategies. Specifically, recent studies document prolonged risks for bacterial infections in the setting of GVHD, especially those caused by encapsulated organisms and those secondary to impaired Ab responses. Both prophylaxis and vaccination strategies can be used as a means to prevent infections, which typically manifest in the respiratory tract. Multiple viruses cause infection later after HCT, including several herpesviruses (eg, CMV and varicella zoster virus) and other respiratory viruses such as influenza and adenovirus. These infections can cause severe disease with diagnostic challenges, but prevention strategies using enhanced monitoring and/or prophylaxis may be effective. Finally, fungi also cause disease late after HCT, especially filamentous fungi (eg, Aspergillus species and Mucormycoses) and Pneumocystis jiroveci; prophylactic strategies may be used successfully to prevent invasive infection. Late infections and methods to prevent them are reviewed herein.
New insights in the biology of Hodgkin lymphoma
Authors: Küppers Ralf
Published: October 2019

The Hodgkin and Reed/Sternberg (HRS) tumor cells of classical Hodgkin lymphoma (HL) and the lymphocyte-predominant tumor cells of nodular lymphocyte–predominant HL are both derived from germinal center B cells. HRS cells, however, have largely lost their B-cell gene-expression program and coexpress genes typical of various types of hematopoietic cells. Multiple signaling pathways show a deregulated activity in HRS cells. The genetic lesions involved in the pathogenesis of HL are only partly known, but numerous members and regulators of the NF-κB and JAK/STAT signaling pathways are affected, suggesting an important role for these pathways in HL pathogenesis. Some genetic lesions involve epigenetic regulators, and there is emerging evidence that HRS cells have undergone extensive epigenetic alterations compared with normal B cells. HRS and lymphocyte-predominant cells are usually rare in the lymphoma tissue, and interactions with other cells in the microenvironment are likely critical for HL pathophysiology. T cells represent a main population of infiltrating cells, and it appears that HRS cells both inhibit cytotoxic T cells efficiently and also receive survival signals from Th cells in direct contact with them.
How to use new biology to guide therapy in multiple myeloma
Authors: Morgan Gareth J. , Kaiser Martin F.
Published: October 2019

Recent advances in multiple myeloma (MM) therapy have led to significantly longer median survival rates and some patients being cured. At the same time, our understanding of MM biology and the molecular mechanisms driving the disease is constantly improving. Next-generation sequencing technologies now allow insights into the genetic aberrations in MM at a genome-wide scale and across different developmental stages in the course of an individual tumor. This improved knowledge about MM biology needs to be rapidly translated and transformed into diagnostic and therapeutic applications to finally achieve cure in a larger proportion of patients. As a part of these translational efforts, novel drugs that inhibit oncogenic proteins overexpressed in defined molecular subgroups of the disease, such as FGFR3 and MMSET in t(4;14) MM, are currently being developed. The potential of targeted next-generation diagnostic tests to rapidly identify clinically relevant molecular subgroups is being evaluated. The technical tools to detect and define tumor subclones may potentially become clinically relevant because intraclonal tumor heterogeneity has become apparent in many cancers. The emergence of different MM subclones under the selective pressure of treatment is important in MM, especially in the context of maintenance therapy and treatment for asymptomatic stages of the disease. Finally, novel diagnostic and therapeutic achievements have to be implemented into innovative clinical trial strategies with smaller trials for molecularly defined high-risk patients and large trials with a long follow-up for the patients most profiting from the current treatment protocols. These combined approaches will hopefully transform the current one-for-all care into a more tailored, individual therapeutic strategy for MM patients.
New challenges in hemophilia: long-term outcomes and complications
Authors: Young Guy
Published: October 2019

For the past 5 decades, the care for hemophilia patients has improved significantly to the point that a newborn with hemophilia living in a developed nation can expect to have a normal lifespan and a high quality of life. Despite this, there are several new challenges that the hemophilia community will face in the coming years. First, the hemophilia community will soon be challenged with adopting a variety of new agents into clinical practice. Second, the normalization of patients' lives as a result of improved treatment has led to new problem areas, including obese/overweight hemophiliacs and osteoporosis. In addition, although mortality rates are similar to those of the healthy population, morbidities such as hemophilic arthropathy still occur. Third, the cost of care continues to rise, both due to the development of expensive new therapies and to the costs of managing problems such as obesity and osteoporosis. Finally, most patients in the world with hemophilia receive little to no care and although this is an enormous challenge, it must be confronted. This review discusses some new challenges facing developing nations and their care for hemophilia patients. In summary, in hemophilia in the coming few years, several new challenges will need to be confronted.
Paramount prognostic factors that guide therapeutic strategies in diffuse large B-cell lymphoma
Authors: Sehn Laurie H.
Published: October 2019

Outcome in diffuse large B-cell lymphoma (DLBCL) has improved over the last decade and will likely improve further with the introduction of novel agents. At the present time, clinical prognostic factors are limited in their ability to identify patients with sufficiently poor outcome to justify deviation of therapy away from R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) outside of a clinical trial. Similarly, with the exception of the concurrent translocation of MYC and BCL2, there are no validated biologic markers that can be used to guide initial therapy in routine practice. Recognition of the molecular heterogeneity of DLBCL is of paramount importance and must be taken into consideration when investigating new therapies. It will be vital for novel targeted agents to be evaluated in patient populations enriched for those who are most likely to benefit. The identification of prognostic and predictive biomarkers should be initiated during the early phase of drug development so that these tests can be validated within phase 3 trials. Although currently available techniques such as immunohistochemistry may still be used, gene-expression profiling and whole genomic analytic techniques will likely play a major role in the evaluation of patients in the future to determine optimal personalized treatment for DLBCL.
The many faces of marginal zone lymphoma
Authors: Zinzani Pier Luigi
Published: October 2019

Indolent B-cell lymphomas that are supposed to derive from the marginal zone (marginal zone lymphomas [MZLs]) include 3 specific entities: extranodal marginal zone lymphoma (EMZL) or mucosa-associated lymphatic tissue (MALT) lymphoma, splenic MZL (SMZL), and nodal MZL (NMZL). The clinical and molecular characteristics are different for each entity, with some shared phenotypic and genetic features. EMZL is the most common entity, accounting for approximately 70% of all MZLs. These neoplasms can arise at virtually any extranodal site and are commonly associated with chronic antigenic stimulation either as a result of infection (eg, Helicobacter pylori in the stomach) or autoimmune disease (eg, Sjögren syndrome and salivary glands). Several chromosomal translocations were also identified in EMZL, accounting in the aggregate for approximately one-third of all cases. SMZL accounts for approximately 20% of all MZLs. Patients typically present with an enlarged spleen and involvement of abdominal lymph nodes and BM. Approximately 40%-50% of SMZLs are associated with deletions of chromosome 7q. NMZL is the less common entity, representing approximately 10% of all MZLs. Patients with NMZL, by definition, have lymph node–based disease without involvement of the spleen or extranodal sites. The molecular pathogenesis of NMZL is still unknown.
The prevalent predicament of relapsed acute myeloid leukemia
Authors: Szer Jeffrey
Published: October 2019

A majority of patients with acute myeloid leukemia (AML) will relapse after achieving complete remission. At relapse, patients should be risk stratified and a decision made about the appropriateness of intensive therapy and whether a potentially curative allogeneic stem cell transplantation (allo-SCT) is possible. Risk factors include duration of first complete remission and adverse cytogenetics, as well as age and FLT3 mutation status. Available therapies are steadily increasing, but for the most part should be regarded as either best palliation or as a bridge to allo-SCT. Simple symptomatic therapies for patients with extreme age or the worst prognosis should also be considered. Newer therapeutic options include novel cytotoxic chemotherapies including clofarabine, immunomodulatory agents, targeted therapies against FLT3 and mTOR, and immunoconjugates. All patients with relapsed AML should be considered for an appropriate clinical trial.
Is my patient a bleeder? A diagnostic framework for mild bleeding disorders
Authors: Quiroga Teresa , Mezzano Diego
Published: October 2019

Congenital mild bleeding disorders (MBDs) are very prevalent and are the source of frequent diagnostic problems. Most MBDs are categorized as disorders of primary hemostasis (ie, type 1 VWD and platelet function disorders), but mild or moderate deficiencies of clotting factors and some rare hyperfibrinolytic disorders are also included. These patients have abnormal bleeding from the skin and mucous membranes, menorrhagia, and disproportionate hemorrhages after trauma, invasive procedures, and surgery. This review addresses the main problems that physicians and hemostasis laboratories confront with the diagnosis of these patients, including: discerning normal/appropriate from pathological bleeding, the role and yield of screening tests, the lack of distinctive bleeding pattern among the different diseases, the inherent difficulties in the diagnosis of type 1 VWD and the most common platelet functional disorders, improvements in assays to measure platelet aggregation and secretion, and the evidence that most of the patients with MBDs end up without a definite diagnosis after exhaustive and repeated laboratory testing. Much research is needed to determine the pathogenesis of bleeding in MBD patients. Better standardization of current laboratory assays, progress in the knowledge of fibrinolytic mechanisms and their laboratory evaluation, and new understanding of the factors contributing to platelet-vessel wall interaction, along with the corresponding development of laboratory tools, should improve our capacity to diagnose a greater proportion of patients with MBDs.
Malignant or benign leukocytosis
Authors: George Tracy I.
Published: October 2019

Leukocytosis, or elevated WBC count, is a commonly encountered laboratory finding. Distinguishing malignant from benign leukocytosis is a critical step in the care of a patient, which initiates a vastly different decision tree. Confirmation of the complete blood cell count and the WBC differential is the first step. Examination of the PB smear is essential to confirming the automated blood cell differential or affirming the manual differential performed on the PB smear. Next is separation of the leukocytosis into a myeloid versus a lymphoid process. Distinguishing a reactive lymphoid proliferation from a lymphoproliferative disorder requires examination of lymphocyte morphology for pleomorphic lymphocytes versus a monomorphic population, with the latter favoring a lymphoproliferative neoplasm. Samples suspicious for lymphoproliferative disorders can be confirmed and characterized by flow cytometry, with molecular studies initiated in select cases; precursor lymphoid neoplasms (lymphoblasts) should trigger a BM examination. Myeloid leukocytosis triggers a differential diagnosis of myeloid leukemoid reactions versus myeloid malignancies. The manual differential is key, along with correct enumeration of blasts and blast equivalents, immature granulocytes, basophils, and eosinophils and identifying dysplasia to identify myeloid malignancies. Confirmation and characterization of myeloid malignancies should be performed with a BM examination and the appropriate ancillary studies. Myeloid leukemoid reactions commonly result from infections and show activated neutrophil changes on morphology; these should prompt evaluation for infection. Other causes of reactive myeloid leukocytoses are also discussed herein.
Assessment and management of massive bleeding: coagulation assessment, pharmacologic strategies, and transfusion management
Authors: Callum Jeannie L. , Rizoli Sandro
Published: October 2019

This review details the current knowledge in massive hemorrhage with regard to the pathophysiology and laboratory assessment of the coagulation disturbance, the role of plasma and platelet transfusion, the role of pharmaceutical strategies, and the clinical value of having a massive transfusion protocol. The bulk of the recent medical literature on this topic stems from the study of military and civilian trauma; however, where applicable, reference to postcardiac and post-noncardiac surgery and postpartum hemorrhage will also be discussed.