bluuebunny/crossref_metadata_2025 huggingface dataset:
Ottoman transcultural memories: Introduction
Authors: Koureas Gabriel , Prosser Jay , Wilson Colette , Hakim-Dowek Leslie
Published: October 2019

This introduction lays out the context and aims for the special issue’s focus on Ottoman transcultural memories. We explain the pertinence of transcultural memories for the Ottoman Empire, and we discuss contemporary politicizations of Ottoman nostalgia, or neo-Ottomanism. We define the key terms in our analyses, rooting our approach in memory studies, and distinguishing a transcultural approach to memory from comparable approaches in postcolonial studies. The introduction further sets out how the special issue refigures memory studies, transcultural and Ottoman studies. The issue’s contents are outlined, with the interdisciplinary and transmedial contributions necessarily driven by the diverse archives of Ottoman transcultural memories. Creative selections are informed by the affective resonance of Ottoman transcultural memories, in turn refiguring postmemory.
Parallelotopia: Ottoman transcultural memory assemblages in contemporary art practices from the Middle East
Authors: Koureas Gabriel
Published: October 2019

This article engages with the conversations taking place in the photographic space between then and now, memory and photography, and with the symbiosis and ethnic violence between different ethnic communities in the ex-Ottoman Empire. It questions the role of photography and contemporary art in creating possibilities for coexistence within the mosaic formed by the various groups that made up the Ottoman Empire. The essay aims to create parallelotopia, spaces in the present that work in parallel with the past and which enable the dynamic exchange of transcultural memories. Drawing on memory theory, the article shifts these debates forward by adopting the concept of ‘assemblage’. The article concentrates on the aesthetics of photographs produced by Armenian photographic studios in Istanbul during the late nineteenth century and their relationship to the present through the work of contemporary artists Klitsa Antoniou, Joanna Hadjithomas, Khalil Joreige and Etel Adnan as well as photographic exhibitions organised by the Centre for Asia Minor Studies, Athens, Greece.
Remembering Armenian music in Bolis: Komitas Vardapet in transcultural perspective
Authors: Olley Jacob
Published: October 2019

This article explores the relationship between music, memory and transcultural processes in late Ottoman Istanbul by studying the writings of the Armenian composer and musicologist Komitas Vardapet (1869–1935). It describes the changing political and intellectual landscape in which Komitas and his contemporaries redefined the collective musical memory of the Armenian people through a process of secularisation and internationalisation. I argue that there was a shift from local transculturalism, in which musical memories were to some extent shared between different ethnic and confessional groups in the Ottoman Empire, to a more global and modern transculturalism, in which consciously differentiated and often antagonistic national musical memories were constructed and disseminated across non-local spaces through new media and discursive strategies. In the process, rural music practices were appropriated from their local and unofficial contexts by urban, cosmopolitan elites and purposefully inscribed as monuments of Armenian cultural memory which have endured to the present.
A nomogram for predicting the response to exclusive enteral nutrition in adult patients with isolated colonic Crohn’s disease
Authors: Xu Yihan , Guo Zhen , Huang Liangyu , Gong Jianfeng , Li Yi , Gu Lili , Shen Weisong , Zhu Weiming
Published: October 2019

Background:

Isolated colonic Crohn’s disease (cCD) responds less well to induction therapy with exclusive enteral nutrition (EEN) compared with ileal or ileocolonic disease in adult patients; therefore, we aimed to identify the factors that influence the response to EEN and develop a predictive nomogram model to optimize the use of EEN in cCD patients.

Materials and methods:

Eighty-five cCD patients treated with EEN as first-line therapy at our center between 1 June 2012 and 30 June 2018 were retrospectively analyzed as the primary cohort. The primary endpoint was clinical remission after EEN therapy. Potential predictive factors for the efficacy of EEN were assessed by univariate and multivariate analyses, and a nomogram to predict the response to EEN therapy in cCD patients was designed. Another 19 cCD patients were retrospectively included in the validation cohort to verify the accuracy of the nomogram model.

Results:

The clinical remission rates for the primary cohort and validation cohort were 52.9% and 47.4%, respectively. Pancolitis was the greatest contributor to the risk of failure to respond to EEN [odds ratio (OR) = 4.896; 95% confidence interval (CI) = 1.223–19.607; p = 0.025], lean body mass index (LBMI), colonic lesion features, simple endoscopic scores for Crohn’s disease, C-reactive protein before treatment and ∆prealbumin were also related to the efficacy of EEN in cCD. The nomogram model showed robust discrimination, with an area under the receiving operating characteristic curve of 0.906.

Conclusion:

Several predictive factors for response to EEN therapy in cCD adult patients were identified, and a promising nomogram that can predict the effect of EEN in cCD was developed.
Rediscovering the Transition in China’s National Interest: A Neoclassical Realist Approach
Authors: Ye Xiaodi
Published: October 2019

Recently, China’s core national interest proposal has drawn significant attention from scholars, triggering a wide range of discussions on this interesting phenomenon. However, the existing literature remains largely limited to single-case studies and has neglected several crucial questions: What is the major difference between China’s national interest and core national interest? What factors may cause a transition from a national interest to a core interest? How can we understand this long-term transition? Based on these questions, this article constructs a neoclassical-based analytical framework to trace that transition, arguing that the major difference between these two concepts is the scope of their application. Meanwhile, the transition in China’s national interest can be categorised as “defensive national interest,” “constructive national interest,” and “adversary core interest” from the beginning of the 1980s to 2017 – with the scope expanded accordingly from the domestic and regional levels to the inter-regional one.
Determination of (+)-Dihydrorobinetin as An Active Constituent of the Radical-Scavenging Activity of Asana (Pterocarpus marsupium) Heartwood
Authors: Deguchi Takahiro , Miyamoto Akane , Miyamoto Kana , Kawata-Tominaga Takuya , Yoshioka Yuri , Iwaki Masahiro , Murata Kazuya
Published: October 2019

Asana used in Ayurveda medicine originates from the heartwood of Fabaceae Pterocarpus marsupium. In our previous report, we demonstrated that a 50% ethanolic extract (PM-ext) of Asana was a promising candidate as a skin-whitening agent based on its anti-tyrosinase and antioxidative activities. Moreover, the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activity of PM-ext was demonstrated and one of the active constituents was identified as oxyresveratrol. However, the potency of oxyresveratrol was low and the other active constituent has not yet been investigated. Activity-guided purification led us to isolate (+)-dihydrorobinetin (DHR). DHR had a potent DPPH radical-scavenging activity (half-maximal inhibitory concentration [IC50] = 1.3 µM) and also showed suppressive activity of advanced glycation end products (AGEs) production (IC50 =132 µM), as well as superoxide dismutase (SOD)-like activity (half-maximal effective concentration=27 µM). In a PM-ext, this is the first report to identify DHR and to demonstrate the suppressive activity of AGEs production and SOD-like activity of DHR. From these results, PM-ext containing DHR is a promising candidate as a multifunctional material with multiple anti-oxidant activities.
Management of Athletes With G6PD Deficiency: Does Missing an Enzyme Mean Missing More Games?
Authors: Stone Shane N. , Reisig Karl V. , Saffel Heather L. , Miles Christopher M.
Published: October 2019

Context:

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is likely the most prevalent enzyme deficiency on the planet, with an estimated 4.9% of people, or approximately 330 million individuals, across the globe affected by the disease. In the United States, 4% to 7% of the population is likely affected, but each year our nation’s major sport leagues become more international. It is important for medical professionals who treat athletes to understand how this genetic condition can affect the athletes we are working with, especially because exercise in itself results in oxidative stress.

Evidence Acquisition:

PubMed was searched for relevant articles published from 1980 to 2018. The search terms G6PD, athletes, military, and sports were used.

Study Design:

Clinical review.

Level of Evidence:

Level 4.

Results:

Though some case reports suggest a potential impact on athlete safety and performance, controlled studies demonstrate limited impact of exercise on oxidative stress in G6PD-deficient individuals. The care of athletes with G6PD deficiency does not drastically differ from the care of athletes without this condition. Most of the medications and supplements that are regularly given to athletes should not negatively affect their health.

Conclusion:

Although the care of athletes with G6PD deficiency is for the most part no different from the care of other athletes, there are certain situations (visiting areas where malaria is endemic) and medications for which it is important to recognize how your management should change. G6PD deficiency is not regularly screened for but could be considered if an athlete has known sickle cell disease or when traveling to areas where malaria is prevalent. Expanding our knowledge of G6PD deficiency will allow for better care of athletes.
Concha Bullosa Affects Baseline and Postoperative Quality-of-Life Measures in Surgically Managed Chronic Rhinosinusitis
Authors: Qualliotine Jesse R. , Jafari Aria , Shen Sarek , Bernstein Jeffrey D. , DeConde Adam S.
Published: October 2019

Background

Concha bullosa (CB) is a prevalent anatomic variant and frequent surgical target in endoscopic sinus surgery (ESS). However, whether CB impacts quality-of-life (QOL) in chronic rhinosinusitis (CRS) is not well established. The purpose of this study was to investigate baseline and post-ESS QOL differences in patients with medically recalcitrant CRS with and without CB.

Methods

Demographic and surgical characteristics, baseline and postoperative 22-item Sino-Nasal Outcome Test (SNOT-22) scores for 137 patients with CRS who underwent primary ESS at our institution were recorded. Computed tomography (CT) scans were reviewed for Lund–Mackay score and presence of CB. Multiplanar CT was used to measure CB dimensions and estimate volume. Multivariable analysis was performed to identify differences in SNOT-22 overall and symptom-domain scores between patients with upper quartile (≥0.8 mL) CB and without CB.

Results

CB was found in 37% of patients with mean volume of 0.67 mL. There were no significant differences in distribution of clinicodemographic variables by large CB status. At baseline, large CB was associated with higher SNOT-22 extranasal-rhinologic domain score (9.8 vs 6.0, P < .01). Following ESS, patients with large CB reported greater improvement in SNOT-22 extranasal-rhinologic domain score (multivariable mean absolute improvement 3.8, P = .01; relative 56% vs 30%).

Conclusion

Patients with medically recalcitrant CRS and concomitant large CB have higher SNOT-22 extranasal-rhinologic domain scores at baseline, but also report greater intradomain improvement exceeding the subdomain’s mean clinically important difference. To our knowledge, this is the first demonstration that CB has a clinically significant impact on QOL in CRS, and surgical intervention may be helpful to address these symptoms.
Symptom and cost evaluation of ureteric stent extraction using strings versus flexible cystoscopy at a single high-volume centre
Authors: Bates Anthony Simon , Jameson Molly , Nkwam Nkwam Michael , Khan Masood Ahmed
Published: October 2019

Background:

This study evaluated ureteric stent symptoms using a modified ureteric stent symptom questionnaire (USSQ) for patients undergoing stent removal by either flexible cystoscopy, or manual, healthcare worker lead string extraction.

Methods:

Patients completed a stent symptom questionnaire derived from the USSQ. Mean data were compared between groups using paired Student’s t-tests. Data are presented as mean ± SD with associated p-values. A departmental cost analysis was undertaken.

Results:

Ninety patients completed questionnaires, 30 undergoing flexible cystoscopy and 60 string extraction. Six stents with strings were removed early (days 1–5, 6.67%, four female and two male). There were no adverse events recorded for this group. Men undergoing string extraction had significantly less pain (2.47 ± 1.88) compared to men undergoing flexible cystoscopic removal (5.67 ± 2.27, p < 0.001). There was no significant difference in pain scores for women undergoing string and flexible cystoscopic stent removal (3.56 ± 2.56 versus 3.66 ± 3.14, p > 0.90). The mean duration of stents left in situ was significantly less in the string group (10.1 ± 5.3 versus 26.5 ± 14.1 days, p < 0.001). Urinary tract infection rates did not differ between the string and the cystoscopy groups (3.7% ± 0.19 versus 2.78% ± 0.46, p > 0.90). The haematuria rates were 32.14% ± 0.47 and 66.67% ± 0.5, respectively ( p < 0.001). In our study, 60 flexible cystoscopies were avoided, saving over £67,000 at the institution within our study period.

Conclusions:

In our small study, stents removed with strings reduced pain scores in men, the duration of an indwelling ureteric stent, and cost to the health service.

Level of evidence:

2b
A review of surgery and new technology procedures for the management of benign prostatic obstruction
Authors: Morton Simon , McGuiness Luke , Harding Christopher , Thorpe Andrew
Published: October 2019

Level of evidence: Not applicable for this review article.
Use of mobile health applications for health-promoting behavior among individuals with chronic medical conditions
Authors: Mahmood Asos , Kedia Satish , Wyant David K , Ahn SangNam , Bhuyan Soumitra S
Published: October 2019

Background

Chronic medical conditions (CCs) are leading causes of morbidity and mortality in the United States. Strategies to control CCs include targeting unhealthy behaviors, often through the use of patient empowerment tools, such as mobile health (mHealth) technology. However, no conclusive evidence exists that mHealth applications (apps) are effective among individuals with CCs for chronic disease self-management.

Methods

We used data from the Health Information National Trends Survey (HINTS 5, Cycle 1, 2017). A sample of 1864 non-institutionalized US adults (≥18 years) who had a smartphone and/or a tablet computer and at least one CC was analyzed. Using multivariable logistic regressions, we assessed predisposing, enabling, and need predictors of three health-promoting behaviors (HPBs): tracking progress on a health-related goal, making a health-related decision, and health-related discussions with a care provider among smart device and mHealth apps owners.

Results

Compared to those without mHealth apps, individuals with mHealth apps had significantly higher odds of using their smart devices to track progress on a health-related goal (adjusted odds ratio (aOR) 8.74, 95% confidence interval (CI): 5.66–13.50, P <  .001), to make a health-related decision (aOR 1.77, 95% CI: 1.16–2.71, P <  .01) and in health-related discussions with care providers (aOR 2.0, 95% CI: 1.26–3.19, P <  .01). Other significant factors of at least one type of HPB among smart device and mHealth apps users were age, gender, education, occupational status, having a regular provider, and self-rated general health.

Conclusion

mHealth apps are associated with increased rates of HPB among individuals with CCs. However, certain groups, like older adults, are most affected by a digital divide where they have lower access to mHealth apps and thus are not able to take advantage of these tools. Rigorous randomized clinical trials among various segments of the population and different health conditions are needed to establish the effectiveness of these mHealth apps. Healthcare providers should encourage validated mHealth apps for patients with CCs.
Does a modifiable risk factor score predict disability worsening in people with multiple sclerosis?
Authors: Marck Claudia H , Aitken Zoe , Simpson Steve , Weiland Tracey J , Jelinek George A
Published: October 2019

Background

Risk factors for chronic disease include smoking, hazardous alcohol consumption, physical inactivity, unhealthy body mass index and poor diet (SNAP factors). In multiple sclerosis (MS) SNAP factors are associated with health outcomes such as disability in cross-sectional studies, but longitudinal data are lacking.

Objective

The objective of this study was to assess whether a combined SNAP risk score predicts disability worsening.

Methods

Longitudinal self-reported data from two time-points 2.5 years apart from an international survey of 1225 people with MS were used in linear regression models adjusted for potential confounding. Disability worsening was measured using the patient-derived Multiple Sclerosis Severity Score.

Results

The majority (62%) had two or more risk factors, with insufficient fruit and vegetable intake (83%), unhealthy body mass index (42%) and physical inactivity (33%) most common. Some SNAP factors at follow-up were associated with disability at follow-up (cross-sectionally), and in addition there was some evidence that increasing risk factors was associated with disability worsening over the 2.5 year study period. Baseline SNAP score was not predictive of disability worsening at follow-up, however.

Conclusion

Known risk factors for morbidity and mortality were common and associated with disability cross-sectionally, but not prospectively. Further studies using longer time frames, objective measures and interventions may elucidate potential benefits from changes in risk factors on MS outcomes.
Central Symptoms Predict Posttreatment Outcomes and Clinical Impairment in Anorexia Nervosa: A Network Analysis
Authors: Elliott Haley , Jones Payton J. , Schmidt Ulrike
Published: October 2019

Network analysis can be used to identify central symptoms of eating disorders such as anorexia nervosa (AN), but the validity of this approach has been questioned. Using network analysis, in the present study we identify central symptoms of adult AN, identify key bridge symptoms between AN and anxiety/depression, and examine whether central symptoms at baseline are important predictors of treatment outcomes. We conducted network analyses for AN and comorbid depression and anxiety using longitudinal data (N = 142) with measurements at baseline, and at 6-month, 12-month, and 24-month postrandomization follow-ups. We identified central symptoms and bridge symptoms and tested whether centrality values calculated at baseline were related to the prognostic utility of symptoms longitudinally. Feeling fat and fear of weight gain were among the most central symptoms of AN. Feelings of worthlessness had the highest bridge centrality connecting depression to AN. Symptom centrality at baseline was strongly related to prognostic utility ( r2 = .52, .55). The finding that symptom centrality was strongly related to prognostic utility supports the validity of network theory in that central symptoms may have a particularly strong influence on clinical impairment and recovery. These analyses generate useful hypotheses about the etiology and maintenance of AN and related comorbidities and may inform future treatment development.
Impact of Cirrhosis on Morbidity and Mortality After Spinal Fusion
Authors: Lu Young , Lin Charles C. , Stepanyan Hayk , Alvarez Andrew P. , Bhatia Nitin N. , Kiester P. Douglas , Rosen Charles D. , Lee Yu-Po
Published: October 2019

Study Design:

Retrospective large database study.

Objective:

To determine the impact of cirrhosis on perioperative outcomes and resource utilization in elective spinal fusion surgery.

Methods:

Elective spinal fusion hospitalizations in patients with and without cirrhosis were identified using ICD-9-CM codes between the years of 2009 and 2011 using the Nationwide Inpatient Sample database. Main outcome measures were in-hospital neurologic, respiratory, cardiac, gastrointestinal, renal and urinary, pulmonary embolism, wound-related complications, and mortality. Length of stay and inpatient costs were also collected. Multivariable logistic regressions were conducted to compare the in-hospital outcomes of patients with and without cirrhosis undergoing spinal fusion.

Results:

A total of 1 214 694 patients underwent elective spinal fusions from 2009 to 2011. Oh these, 6739 were cirrhotic. Cirrhosis was a significant independent predictor for respiratory (odds ratio [OR] = 1.43, confidence interval [CI] 1.29-1.58; P < .001), gastrointestinal (OR = 1.72, CI 1.48-2.00; P < .001), urinary and renal (OR = 1.90, CI 1.70-2.12; P < 0.001), wound (OR = 1.36, CI 1.17-1.58; P < 0.001), and overall inpatient postoperative complications (OR = 1.43, CI 1.33-1.53; P < .001). Cirrhosis was also independently associated with significantly greater inpatient mortality (OR = 2.32, CI 1.72-3.14; P < .001). Cirrhotic patients also had significantly longer lengths of stay (5.35 vs 3.35 days; P < .001) and inpatient costs ($36 738 vs $29 068; P < .001).

Conclusions:

Cirrhosis is associated with increased risk of perioperative complications, mortality and greater resource utilization. Cirrhotic patients undergoing spinal fusion surgeries should be counseled on these increased risks. Current strategies for perioperative management of cirrhotic patients undergoing spinal fusion surgery need improvement.
Effect of Output Quality and Result Demonstrability on Generation Y’s Behavioural Intention in Adopting Mobile Health Applications
Authors: Gow Chen Xian , Wong Siew Chin , Lim Chui Seong
Published: October 2019

The aim of this study is to investigate the relationships between image, output quality, perceived self-efficacy, result demonstrability and Generation Y’s behavioural intention to use mobile health applications. Research data are gathered from a sample of 120 Generation Y participants in Malaysia. Partial least squares structural equation modelling (PLS-SEM) is employed to examine the influences of image, output quality, perceived self-efficacy and result demonstrability on behavioural intention to use mobile health applications. The results demonstrate that output quality and result demonstrability are potential predictors of behavioural intention to use mobile health applications. However, there is no significant relationship between image, perceived self-efficacy and behavioural intention. This study contributes to the body of knowledge focused on a better understanding of the behavioural intention of younger generations to adopt and use mobile health applications. Current research provides developers of mobile health applications and healthcare professionals with useful insights into how the adoption rate of mobile health applications can be enhanced.
Human megakaryocytes: finding the root
Authors: Laurenti Elisa
Published: October 2019

In this issue of Blood, Miyawaki et al identify the most primitive progenitor cell population that makes only megakaryocytes and platelets in adult humans and show it is expanded in myeloproliferative neoplasms such as essential thrombocythemia (ET).1 Approximately 1011 platelets are produced on a daily basis in humans, but their exact journey from undifferentiated hematopoietic stem cells (HSCs) is still highly debated. Platelets have the shortest half-life of all blood components and are rapidly recruited when injury occurs, yet have long been thought to be among the cell types to be specified as the furthest from the HSCs in the hematopoietic hierarchy. For several decades, it was understood that differentiation proceeds by a series of binary fates choices, in particular with a common myeloid progenitor (CMP) downstream of HSCs that would give rise to a restricted myeloid progenitor (granulocyte-macrophage progenitor) and to a megakaryocyte-erythrocyte progenitor (MEP). Only downstream of MEPs would unilineage megakaryocyte and unilineage erythrocyte progenitors arise. Recently though, several groups have reported that megakaryocyte and platelet production may not follow this strict hierarchical branching path. Instead, committed megakaryocyte precursors could be found much earlier, either within the HSC2-4 or the multipotent progenitor compartment.5 An early precursor that exclusively produces human megakaryocytes in humans, however, had not been described.
LEDGF: a leukemia-specific target
Authors: Milne Thomas A.
Published: October 2019

In this issue of Blood, El Ashkar et al1 reveal that the lens epithelium-derived growth factor (LEDGF) protein is a key therapeutic target by showing that it is essential for leukemia, but not normal hematopoiesis. Such context-dependent information is important for the development of new targeted therapies.
Multivariate analysis of prognostic factors in CLL: clinical stage, IGVH gene mutational status, and loss or mutation of the p53 gene are independent prognostic factors
Authors: Oscier David G. , Gardiner Anne C. , Mould Sarah J. , Glide Sharron , Davis Zadie A. , Ibbotson Rachel E. , Corcoran Martin M. , Chapman Robert M. , Thomas Peter W. , Copplestone J. Adrian , Orchard Jenny A. , Hamblin Terry J.
Published: October 2019

This study evaluates the prognostic significance of genetic abnormalities (detected at or shortly after presentation), clinical stage, lymphocyte morphology, CD38 expression, and IGVHgene status in 205 patients with chronic lymphocytic leukemia (B-CLL). Deletion of chromosome 11q23, absence of a deletion of chromosome 13q14, atypical lymphocyte morphology, and more than 30% CD38 expression are significantly associated with the presence of unmutatedIGVH genes. Advanced stage, male sex, atypical morphology, more than 30% CD38 expression, trisomy 12, deletion of chromosome 11q23, loss or mutation of the p53 gene, and unmutatedIGVH genes are all poor prognostic factors in a univariate analysis. However, only 98% or more homology of IGVH genes to the germline sequence, loss or mutation of the p53 gene, and clinical stage retain prognostic significance in a multivariate analysis. The median survival of patients with mutated IGVHgenes, unmutated IGVH genes, and loss or mutation of thep53 gene regardless of IGVH gene status is 310, 119, and 47 months, respectively. These data should facilitate the design of new trials for the management of patients presenting with advanced disease or poor prognosis early stage disease.
Zinc-finger transcription factor Slug contributes to the function of the stem cell factor c-kit signaling pathway
Authors: Pérez-Losada Jesus , Sánchez-Martı́n Manuel , Rodrı́guez-Garcı́a Arancha , Sánchez Maria Luz , Orfao Alberto , Flores Teresa , Sánchez-Garcı́a Isidro
Published: October 2019

The stem cell factor c-kit signaling pathway (SCF/c-kit) has been previously implicated in normal hematopoiesis, melanogenesis, and gametogenesis through the formation and migration of c-kit+ cells. These biologic functions are also determinants in epithelial–mesenchymal transitions during embryonic development governed by the Snail family of transcription factors. Here we show that the activation of c-kit by SCF specifically induces the expression of Slug, a Snail family member. Slug mutant mice have a cell-intrinsic defect with pigment deficiency, gonadal defect, and impairment of hematopoiesis. Kit+ cells derived from Slug mutant mice exhibit migratory defects similar to those of c-kit+ cells derived from SCF and c-kit mutant mice. Endogenous Slug is expressed in migratory c-kit+ cells purified from control mice but is not present in c-kit+cells derived from SCF mutant mice or in bone marrow cells from W/Wv mice, though Slug is present in spleen c-kit+ cells of W/Wv (mutants expressing c-kit with reduced surface expression and activity). SCF-induced migration was affected in primary c-kit+ cells purified from Slug−/− mice, providing evidence for a role of Slug in the acquisition of c-kit+ cells with ability to migrate. Slug may thus be considered a molecular target that contributes to the biologic specificity to the SCF/c-kit signaling pathway, opening up new avenues for stem cell mobilization.
Genomic abnormalities in monoclonal gammopathy of undetermined significance
Authors: Fonseca Rafael , Bailey Richard J. , Ahmann Gregory J. , Rajkumar S. Vincent , Hoyer James D. , Lust John A. , Kyle Robert A. , Gertz Morie A. , Greipp Philip R. , Dewald Gordon W.
Published: October 2019

Translocations involving immunoglobulin (Ig) loci and chromosome 13 monosomy (Δ13) are frequent cytogenetic findings in multiple myeloma (MM). Similar chromosomal aberrations have been identified in the monoclonal gammopathy of undetermined significance (MGUS), but their prevalence and significance remain uncertain. Bone marrow from 72 patients with MGUS (n = 62) and smoldering MM (n = 10) was evaluated for translocations between the Ig heavy chain (IgH) and chromosomes 4, 11, and 16, translocations involving Ig light chain–lambda (IgL-λ, and Δ13. Fluorescence in situ hybridization (FISH) analysis was done on clonal plasma cells (PCs) detected by immunofluorescence (cIg-FISH) of the cytoplasmic light chain. We also studied cells for cyclin D1 and FGFR3 up-regulation by immunohistochemistry and immunofluorescence, respectively. Twenty-seven (46%) of 59 patients had IgH translocations, and 4 (11%) of 37 had an IgL-λ translocation. A t(11;14)(q13;q32) was found in 15 (25%) of 59 patients, a t(4;14)(p16.3;q32) in 9% of patients, and a t(14;16)(q32;q23) in 5% of patients. All patients with t(4;14)(p16.3;q32) tested (n = 3) had intense cytoplasmic fluorescence with an anti-FGFR3 antibody. PC nuclear staining of cyclin D1 was only observed in patients with t(11;14)(q13;q32); Δ13 was detected in the clonal PCs in 50% of patients. The percentage of abnormal PCs varied with any given abnormality. No obvious clinical or biologic correlations were associated with these chromosome abnormalities. Similar translocations are found in both MGUS and MM, including t(4;14)(p16.3;q32) and t(14;16)(q32;q23). Moreover, Δ13 is common in MGUS and unlikely to play a predominant role in the evolution of MGUS to MM.
Typical Waldenstrom macroglobulinemia is derived from a B-cell arrested after cessation of somatic mutation but prior to isotype switch events
Authors: Sahota Surinder S. , Forconi Francesco , Ottensmeier Christian H. , Provan Drew , Oscier David G. , Hamblin Terry J. , Stevenson Freda K.
Published: October 2019

There exists a wide spectrum of IgM-secreting B-cell tumors with different clinical behavior. Knowledge of the VH gene status can reveal their origin and clonal history. For Waldenstrom macroglobulinemia (WM), a distinct subtype of lymphoplasmacytic lymphoma, early data on limited sequences showed evidence for somatic mutation. A recent report of one case demonstrated intraclonal mutational activity occurring after transformation, a characteristic of germinal center lymphomas. To extend the investigation, we have analyzed 7 cases of WM. VH genes were somatically mutated with no evidence of intraclonal variation in all cases. In contrast to IgM-secreting multiple myeloma, there was no evidence for isotype switch transcripts in any of the cases. These data support the concept that typical WM is derived from a B cell that has undergone somatic mutation prior to transformation, at a point where isotype switch events have not been initiated.
Imatinib mesylate therapy for relapse after allogeneic stem cell transplantation for chronic myelogenous leukemia
Authors: Kantarjian Hagop M. , O'Brien Susan , Cortes Jorge E. , Giralt Sergio A. , Rios Mary Beth , Shan Jianqin , Giles Francis J. , Thomas Deborah A. , Faderl Stefan , De Lima Marcos , Garcia-Manero Guillermo , Champlin Richard , Arlinghaus Ralph , Talpaz Moshe
Published: October 2019

Twenty-eight adults with chronic myelogenous leukemia (CML) that had relapsed after allogeneic stem cell transplantation (SCT) received imatinib mesylate (400-1000 mg/d). Disease was in chronic phase in 5 patients, accelerated in 15, and blastic in 8 (7 medullary, 1 extramedullary); median time from transplantation to relapse was 9 months (range, 1-137 months). Thirteen patients had undergone salvage donor lymphocyte infusion (DLI) (median time from DLI to imatinib mesylate therapy, 4 months [range, 2-39 months]). The overall response rate was 79% (22 of 28 patients); the complete hematologic response (CHR) rate was 74% (17 of 23 patients), and the cytogenetic response rate was 58% (15 of 26 patients; complete response in 9 [35%] patients). CHR rates were 100% for chronic phase, 83% for accelerated phase, and 43% for blastic phase. The patient with extramedullary blastic disease achieved complete response. Cytogenetic response rates were 63% (12 of 19 patients) for chronic or accelerated phases (complete cytogenetic response in 8) and 43% for blastic phase (3 of 7 patients). At median follow-up of 15 months, 19 patients were alive, 9 with no evidence of disease. The 1-year estimated survival rate was 74%. Five patients had recurrence of grade 3 (3 patients) or grades 1 to 2 (2 patients) graft-versus-host disease (GVHD). Severe granulocytopenia developed in 43% of patients and thrombocytopenia in 27%; both conditions reversed with dose adjustments of imatinib mesylate. We conclude that imatinib mesylate effectively controlled CML that recurred after allogeneic SCT, but it was associated with side effects including myelosuppression and recurrence of severe GVHD.
Splenic marginal zone lymphoma: clinical characteristics and prognostic factors in a series of 60 patients
Authors: Chacón Jose I. , Mollejo Manuela , Muñoz Enriqueta , Algara Patricia , Mateo Marisol , Lopez Luis , Andrade Jesús , Carbonero Iciar Garcı́a , Martı́nez Beatriz , Piris Miguel A. , Cruz Miguel A.
Published: October 2019

A precise description of clinical features at presentation and analysis of clinical and biologic prognostic factors in splenic marginal zone lymphoma (SMZL) are still lacking. Here we describe the clinical and biologic features of a series of 60 SMZL patients diagnosed after splenectomy. Analysis for overall survival (OS), failure-free survival (FFS), and the probability of obtaining a response was performed using univariate and multivariate tests. The median age of the patient was 63 years (range, 35-84 years). Performance status according to the Eastern Cooperative Oncology Group (ECOG scale) was 0 = 16%, 1 = 58%, and 2 = 25%. Of the 60 patients, 53 (86.6%) were at Ann Arbor stage IV. All 60 patients received splenectomies, 29 of 60 also received chemotherapy, and 2 received spleen radiotherapy. A complete response (CR) was achieved by 38.3% of patients, and a partial response (PR) was achieved by 55%. Mean OS of the series was 103 months (range, 2-164 months); mean FFS was 40 months (range, 3-164 months). At 5 years from diagnosis, 39 patients (65%) were alive. Patients dying from the disease had a relatively aggressive clinical course, with a short survival (17.5 months [range, 2-72 months]). Significant prognostic factors in multivariate analysis were (1) (for OS and FFS) lack of response to therapy (CR versus noncomplete response [nCR]) and involvement of nonhematopoietic sites, and (2) (for the probability of obtaining CR) bone marrow involvement. Chemotherapy did not influence OS or FFS. p53 overexpression predicted a shorter OS in the univariate analysis. These data confirm the relative indolence of this disease, indicating the existence of a subset of more aggressive cases, which should stimulate the search for predictive biologic factors and alternative therapies.
Homozygosity for nondeletion δ-β0 thalassemia resulting in a silent clinical phenotype
Authors: Galanello Renzo , Barella Susanna , Satta Stefania , Maccioni Liliana , Pintor Carlo , Cao Antonio
Published: October 2019

The clinical phenotype of homozygous β thalassemia varies in severity from the mild thalassemia intermedia to the severe thalassemia major. This variability depends largely on the molecular heterogeneity of β thalassemia defects. We report the first case of a homozygous state for nondeletion Sardinian δ-β0 thalassemia, which resulted in a symptomless clinical phenotype with a peculiar hemoglobin (Hb) pattern (99.8% Hb F and 0.2% Hb A2). The molecular defect was characterized by the presence of 2 nucleotide substitutions: −196C>T in the promoter of the Aγ-globin gene and β 39C>T nonsense mutation. The absence of typical β thalassemia clinical findings was due to the high Hb F output, which compensated for the absence of β chains. The near absence of Hb A2 may have resulted from either alterations in the globin gene transcriptional complex with preferential activation of γ-globin genes and suppression of δ-globin genes or preferential survival of red blood cells with the highest Hb F content and low Hb A2 level.
Impact on Transplant Outcome of Karyotyping Analysis in Apheresis Products for Autologous PBSC Transplantation in De Novo Acute Leukemias (AL).
Authors: Delannoy Bertrand , Nicolini Franck E. , Le Quoc-Hung , Clapisson Gilles , Philip Irene , Raus Nicole , Tigaud Isabelle , Charrin Christiane , Thomas Xavier , Chelghoum Youcef , Tavernier Emmanuelle , Lheritier Veronique , Michallet Mauricette
Published: October 2019

Autologous stem cell transplantation as consolidation therapy for de novo AL is able to improve long-term survival especially after second complete remission (CR). In this study, we retrospectively analyzed the karyotyping results performed in 79 out of 101 harvested autologous PBSC from 38 de novo AML patients and 8 de novo ALL in CR. We secondly, analyzed their impact on overall survival (OS) and event-free survival (EFS) post-transplant. All patients had abnormal medullar karyotype at diagnosis. We determined two groups of patients: (1) group 1 with chromosomal abnormalities in harvested PBSC included 10 AML [4 males and 6 females, median age: 53 years (45–66.5)] with at diagnosis 3 favorable, 4 intermediate and 3 unfavorable-risk karyotype ; 2 M0, 3 M2, 1 M3, 2 M4, 2 M5 according to Fab classification ; and 9 autotransplanted patients in CR1 and 1 in CR2 and (2) group 2 without any chromosomal abnormalities in harvested PBSC including 27 AML+ 9 ALL [22 males and 14 females, median age : 44 years (19–70)] ; 1 M0, 1 M1, 4 M2, 5 M3, 11 M4, 5 M5 with at diagnosis 18 favorable prognosis, 1 intermediate and 8 unfavorable-risk karyotype ; among ALL patients, 7 B ALL and 2 T ALL and at transplant, 29 autotransplant in CR1, 6 in CR2 and 1 in CR3]. Cytapheresis products collected contained a median number of 7.7x 108/Kg (5.2–17.3) and 6.79x108/Kg (1.26–16.4) mononuclear cells and 19x106/Kg (3–43) and 20.5x106/Kg (1–4O) CD34+ cells in group 1 and in group 2 respectively. All PBSC harvested were reinfused. Conditionning regimen was quite similar in the two groups and most of the patients of group 1 (60%) and group 2 (70%) received cyclophosphamide and TBI. The hematopoietic reconstitution was similar in the 2 groups [neutrophiles > 0.5 G/l: 26 days in group1 versus 19 days in group 2 (p=0,86)]. At 3 years after transplant, there was a trend for a better OS (54.7% CI 95% 40–74.8) (p=0.06) and EFS (52.5% 95%CI 39.6–74) (p=0.05) in patients who received PBSC without any chromosomal abnormalities compared to patients receiving PBSC with abnormal karyotype (OS : 30% 95% CI 11.6–77.3 ; EFS : 30% 95% CI 11.6–77.3). In conclusion, results observed from autologous harvested PBSC karyotyping are promising but a larger number of patients and a longer follow-up could enable to reach a more important significance.
Autologous Hematopoietic Stem Cell Transplantation in Patients with Severe and Refractory Crohn’s Disease.
Authors: Oyama Yu , Craig Robert M. , Traynor Ann E. , Burt Richard K. , Statkute Laisvyde
Published: October 2019

Background & Aims

Crohn’s disease (CD) is an immunologically mediated inflammatory disease of the gastrointestinal tract. In theory, immune ablation followed by autologous hematopoietic stem cell transplantation (HSCT) can induce remission by reconstituting a new immune system.

Methods

We conducted a phase I HSCT study in 12 patients with severe CD. Candidates were less than 60 years old with a Crohn’s Disease Activity Index (CDAI) of 250–400 despite conventional therapy including infliximab. Peripheral blood stem cells were mobilized with cyclophosphamide and granulocyte colony-stimulating factor and CD34+ enriched. The immune ablative conditioning regimen consisted of 200mg/kg cyclophosphamide, and 90mg/kg equine antithymocyte globulin.

Results

The procedure was well tolerated with anticipated cytopenias, neutropenic fever, and disease-related fever, diarrhea, anorexia, nausea, vomiting. The median days for neutrophil and platelet engraftment were 9.5 (range 8–11) and 9 (range 9–18), respectively. The infused CD34+ and CD3+ cell counts were 5.64 x 106/kg (range 1.73–9.93) and 0.59 x 104/kg (range 0.3–3.09), respectively. Initial median CDAI was 291 (range 250–358). Symptoms and CDAI improved dramatically (figure 1), and radiographic and colonoscopy findings improved gradually over months to years following HSCT. Ten out of twelve patients entered sustained remission defined by a CDAI ≤ 100. After median follow-up of 17.5 months (range 6–37), only one patient has developed recurrence of active CD which occurred 15 months post-HSCT.

Conclusion

Autologous HSCT may be peformed safely and has a marked salutary effect on CD activity. Randomized studies will be needed to confirm the efficacy of this therapy.

Figure Figure
Leukemic B Cells from Patients with Chronic Lymphocytic Leukemia Show Anomalous Lyn Tyrosine Kinase which Contributes to Defective Apoptosis.
Authors: Trentin Livio , Brunati Anna Maria , Contri Antonella , Cabrelle Anna , Miorin Marta , Cesaro Luca , Pinna Lorenzo , Semenzato Gianpietro , Donella-Deana Arianna
Published: October 2019

B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia in adults and is characterized by the accumulation of mature B lymphocytes in the G0/G1 phase of the cell cycle, expressing B-cell related (i.e. CD19, surface immunoglobulins) and unrelated molecules (CD5 and CD23). The signal transduction pathways underlying the abnormalities of these leukemic cells are poorly understood and no data are available on deregulated cell signalling in B-CLL. Since Lyn activation plays a pivotal role in the signaling cascade triggered by BCR engagement, we investigated whether this kinase may be involved in CLL pathogenesis. In this study, we investigated freshly isolated and purified malignant B cells obtained from 40 CLL patients and we observed that the Src-kinase Lyn, the switch molecule coupling B-cell-receptor to downstream signaling, displays anomalous properties. Western blot and confocal analyses demonstrated that Lyn is overexpressed at the protein level in leukemic cells as compared to normal B-lymphocytes with a substantial aliquot of the kinase anomalously present in the cytosol of leukemic cells. While in normal B lymphocytes Lyn activation is triggered by B-cell-receptor engagement with anti-IgM antibodies, in freshly isolated leukemic cells this kinase is constitutively active and accounts for high basal protein tyrosine-phosphorylation and low responsiveness to IgM-ligation. To address the question of whether the upregulation of Lyn protein and activity plays a role in the defective apoptosis of leukemic cells, we investigated the relationship between Lyn and the cell survival of malignant lymphocytes in the presence of either dexamethazone and cyclosporin A, which are known to induce apoptosis of human lymphocytes, or PP2 and SU6656, which are selective inhibitors of Lyn. When leukemic cells were cultured in the presence of cyclosporin A or dexamethazone, a marked increase in apoptosis was observed as compared to cells cultured in medium alone, and this effect correlated with a great decrease in both basal activity and protein level of Lyn. The exposure of the leukemic cells to PP2 and SU6656 caused both the inhibition of the overexpressed Lyn activity and marked cell apoptosis. These findings suggest a direct correlation between high basal Lyn activity and defects in the induction of apoptosis in leukemic cells. They also support a critical role for Lyn in B-CLL pathogenesis and identify this tyrosine kinase as a potential therapeutic target for drugs capable of inducing apoptosis in B-CLL leukemic cells.
Down Syndrome (DS) Patients with Intermediate Risk (IR) Acute Lymphoblastic Leukemia (ALL): Events and Outcome on Children’s Cancer Group (CCG) 1891 Study.
Authors: Franklin Janet , Larsen Staci , Dorey Fred , Butturini Anna , Fu Cecelia , Lange Beverly , Sather Harland , Gaynon Paul
Published: October 2019

We performed a retrospective review of the events and outcome for DS patients enrolled on CCG study 1891, a randomized clinical trial open 1990–1993 for children less than 10 years old with IR newly diagnosed ALL. Of the 1204 eligible patients enrolled, 33 (2.7%) patients had DS. DS patients were randomized in an identical manner to other enrolled patients to one of three treatment regimens: single delayed intensification (single DI), double DI, or single DI with intensified pulses of vincristine/prednisone during maintenance. This trial demonstrated an improved EFS at 6 years of 79% for the overall study group that was randomized to the double DI arm. A separate subset analysis of survivorship in the DS patients was performed using the STATA program and then compared to the Non-Downs Syndrome (NDS) study patients. 14/33 (42%) DS patients had a M1 marrow on Induction Day 7 while 19/33 (58%) DS patients had an Induction Day 7 bone marrow of M2 or M3 status. Of these 19 DS patients with slow early response, 9/19 (47%) went on to have serious events ( 3 induction failures, 3 relapses, 2 septic deaths, 1 CNS hemorrhage) compared to 2/14 (14%) rapid responders with DS that had events ( 1 relapse, 1 septic death). DS patients that had an M2 or M3 marrow response on Induction Day 7 had more adverse events than their NDS patient cohort with the same M2 or M3 bone marrow response. (p=0.02) DS patients who achieved M1 marrow status on Day 7 demonstrated a similar number of events as NDS patients with the same bone marrow response. (p=0.83) Detailed chart review demonstrated that congenital anomalies (cardiac, gatrointestinal) did not account for the greater risk of adverse events in these DS patients: 10/33 DS patients had congenital anomalies but none of these patients relapsed and only 1 died. Of all 8 patient deaths in the DS subset ( rapid and slow responders), 3 were sepsis related deaths in remission while 4 were due to relapse and 1 due to hemorrhage. Remission induction for the DS patients was 91% ( 30/33 with M1 marrow at Day 29 of Induction) compared to 98% for the overall study cohort. There was a 9% (3/33) induction failure rate; two of these three patients went into remission with an off study re-induction and have had long term disease free survival. Efficacy of the three treatment regimens in the DS patients, as measured by EFS and survival, mirrored that of the general study population. Although the DS patient numbers are small, it appears that an intensified therapy regimen provides benefit to DS patients similar to their NDS cohort. With the intensified therapy, DS patients may derive a similar improved benefit from very aggressive supportive care as a potential means of decreasing fatal sepsis and bleeding events.