bluuebunny/crossref_metadata_2025 huggingface dataset:
Women and Public Organization: An Examination of Mentorship and Its Effect on Reporting Workplace Discrimination
Authors: Yu Helen H. , Lee David
Published: October 2019

A number of studies have focused on mentorship as a variable often associated with career advancement; however, there is little to no research on the impact mentors have with women reporting workplace discrimination, specifically sex-based discrimination to include sexual harassment. Using a survey dataset of 1,113 female officers from a large federal law enforcement agency, this research employs coarsened exact matching to examine mentorship and to include mentor’s gender and its effect on women’s reporting behaviors. This study finds that the probability of reporting sexual harassment increases when women have mentors; however, the existence of mentors did not lead to a significant difference in reporting sex discrimination. In addition, there is no significance on the mentor’s gender with women’s reporting behaviors.
Visibility graphs and blindspots: Wajdi Mouawad’s Incendies and its mathematical poetics
Authors: Khordoc Catherine
Published: October 2019

This article examines the use of mathematics in the 2003 play Incendies by the Lebanese–Québécois playwright Wajdi Mouawad. Mathematics functions not only as a theme in the play, but also as a mechanism that enables the main characters to decipher the mysteries surrounding their identity which are revealed in their deceased mother’s will. In their reluctant quest to find a father and a brother that are unknown to them, the twins Jeanne and Simon discover the unsettling truth that the two are actually one person, in part by turning to number theory and visibility graphs. This article argues that the mathematical dimensions of the play serve as a mise en abyme of its narrative structure and its Oedipian conclusion.
In vivo hepatotoxicity of chemically modified nanocellulose in rats
Authors: Otuechere CA , Adewuyi A , Adebayo OL , Ebigwei IA
Published: October 2019

Chemical modification of cellulose is currently attracting attention as researchers attempt to take advantage of the abundance of hydroxyl groups on its surface to introduce extra biological functionality. However, the possible deleterious effect of exposure to functionalized nanocellulose (CSN) remains a concern. Therefore, this study aims to explore the potential mechanisms of hepatotoxicity of CSN modified with oxalate ester (NCD) in rats. A 7-day repeated oral toxicity study of NCD at the doses of 50 and 100 mg kg−1 body weight was conducted, and plasma and liver tissue samples were assayed using biochemical analysis, liver histopathology, and protein expression. NCD, at both doses, did not significantly ( p > 0.05) alter the relative weight of liver, alkaline phosphatase activity, and lipid peroxidation levels of the animals. However, NCD at the dose of 100 mg kg−1 body weight significantly elevated aspartate aminotransferase, alanine aminotransferase, and myeloperoxidase activities. NCD also enhanced the immunohistochemical expression of inducible nitric oxide synthase and Bcl-2-associated X protein in the liver of rats. Histological observations revealed necrosis and severe cellular infiltration at the high-dose treatment. Our study provides an experimental basis for the safe application of NCDs.
Does Integration of Business Processes and ERP Improves Supply Chain Performances? Evidence from Indian Capital Goods Industry
Authors: Pattanayak Santosh Kumar , Roy Supriyo , Satpathy Biswajit
Published: October 2019

In today’s competitive market environment coupled with post effect of globalization, managing supply chains is critical to any business. Rather than becoming function-oriented, firms are now selectively deploying valuable resources on automated processes operated through technology-enabled ‘information communication’ platforms to improve performance. However, there are visible gaps in integrating business processes with information-enabled domain like enterprise resource planning (ERP), which has the potential to bring in the radical improvement in firm’s performance. Again, integration always does not come with positive results, specifically to Indian capital goods sector. Under this consideration, an attempt has been made to explore this unknown domain with conceptualization of a hypothesized model. Data for validation of this study were collected through questionnaire from 25 different units under Indian capital goods industry and relationship proposed in the hypothesized framework is tested by using structural equation modelling. Analysis of result indicates a favourable disposition of the model framework wherein synergy between business processes and ERP, on an integrated mode, can fetch higher level of performance. Considering multiple performance-related issues deterring growth of India’s capital goods industry, it is strongly recommended to synergize business processes under information system domain in order to make business sustainable.
Examining Children’s Indoor and Outdoor Nature Exposures and Nature-related Pedagogic Approaches of Teachers at Two Reggio-Emilia Preschools in Halifax, Canada
Authors: Omidvar Nazanin , Wright Tarah , Beazley Karen , Seguin Daniel
Published: October 2019

Early childhood environmental education focusses on expanding children’s bio-affinity, developing their environmental attitudes and encouraging them to behave in a more environmentally friendly manner. One example of the educational method that is based on high-quality practices of both early childhood education and environmental education is the Reggio-Emilia pedagogical approach, which provides children with various nature-related experiences. This study examines the frequency and variety of indoor and outdoor nature experiences for children and the preschool teachers’ educational approaches and goals for children’s development in nature in two Reggio-Emilia preschools located in Halifax, Canada. To do this, first-hand observations and semi-structured teacher interviews were used. Results suggest that the Reggio-Emilia curriculum followed at the preschools provided various opportunities for children to be exposed to nature. However, the teachers have emphasized more on anthropocentric than nature-related educational goals.
Plasma cell leukemia with plasmablastic morphology in a dog
Authors: Dagher Elie , Soetart Nicolas , Chocteau Florian , Dequéant Bérengère , Piccirillo Esther , Ibisch Catherine , Abadie Jérôme , Jaillardon Laëtitia
Published: October 2019

A 5-y-old female Golden Retriever was presented with a 2-wk history of hyporexia, vomiting, diarrhea, lethargy, weight loss, polyuria, and polydipsia. Clinical examination and ultrasonography revealed multiple organ enlargement with gallbladder and kidney nodules suggestive of disseminated neoplasia. Hematologic and biochemical analyses revealed pancytopenia, hypercalcemia, and monoclonal IgA gammopathy suspicious for a plasma cell neoplasm. Bone marrow and blood smear examination revealed neoplastic atypical cells highly suggestive of lymphoid origin. Autopsy confirmed the presence of homogeneous white masses and multifocal pale infiltrates in the spleen, kidney, small intestine, gallbladder, and urinary tract. Histologic features were consistent with a multicentric atypical plasma cell tumor. Tumor cells were negative for CD204, IBA-1, E-cadherin, CD3, CD5, CD79a, CD20, and PAX5, and positive for MUM1, consistent with plasma cell origin. The presence of > 20% of circulating blastic plasma cells was consistent with primary plasma cell leukemia with plasmablastic morphology, a disease rarely described in veterinary medicine.
Living beings as autopoietic bodies
Authors: Villalobos Mario
Published: October 2019

In the target article, it was claimed that the enactive extended interpretation of the autopoietic theory (AT) of living beings is incorrect, and an embodied reformulation of AT (EAT) was put forward to remedy and prevent such an interpretation. In this general reply, I want to clarify the motivation, reach, philosophical commitments, and theoretical status of EAT. I do this, mainly, by explicating the notions of body and autopoiesis, and by reconstructing EAT, not as a conceptual definition of life but as a theoretical identity statement of living beings as a natural kind.
Teacher-Reported Priorities and Practices for Students With Autism: Characterizing the Research-to-Practice Gap
Authors: Brock Matthew E. , Dynia Jaclyn M. , Dueker Scott A. , Barczak Mary A.
Published: October 2019

Despite broad consensus that a research-to-practice gap exists in the education of students with autism, the extent of this gap has not been well studied. We surveyed 99 teachers in Ohio about their highest priority goals for students with autism spectrum disorder (ASD), their approach for addressing these goals, the degree to which students had made progress, and barriers to student progress. Only half of all teachers described an approach that included any evidence-based practice (EBP). Teachers often reported inadequate progress on Individualized Education Program (IEP) goals, and that identifying and implementing effective intervention practices were barriers to progress. We found some alignment between the outcomes prioritized by teachers and those measured by researchers in the literature, although teachers more highly prioritized academic and cognitive outcomes.
Does surgical approach affect early outcomes following primary total hip replacement in obese patients?
Authors: Zhang John , Wyatt Michael C , Frampton Chris M , Anderson Geoffrey
Published: October 2019

Aim:

The aim of this study was to assess whether obese patients undergoing primary total hip replacement (THR) via a posterior approach had superior revision rates and Oxford Hip Scores (OHS) compared to those via a lateral approach.

Patients and methods:

This is a retrospective cohort study using prospective data from the New Zealand Joint Registry applying STROBE and RECORD guidelines. Patients undergoing THR since 2010 were stratified by body mass index (BMI) into obese (BMI 30–39 kg/m2), and morbidly obese (BMI ⩾40 kg/m2) groups. All-cause revision rates, and 6-month OHS post-surgery were compared between groups. Multivariate analysis was performed.

Results:

12,109 unilateral THRs in obese patients were identified. The mean follow-up was 2.8 years (range 0.01–6.95 years). Univariate analysis in the BMI ⩾ 40 group showed the posterior approach had a significantly lower all-cause revision rate (0.99/100 observed component years (ocys); 95% CI, 0.65–1.44/100 ocys) than the lateral approach (1.71/100 ocys (95% CI, 0.98–2.77/100 ocys), p < 0.05). There was no significant difference in dislocation rates between the surgical approaches. OHS was statistically higher in the posterior approach group in BMI 30–39 patients ( p < 0.001) but not clinically significant. Multivariate analysis showed femoral head size significantly influenced all-cause revision rates and mitigated against the increased risk associated with the surgical approach.

Conclusion:

The choice of surgical approach in obese patients conveys no advantage in overall revision rates in the short-term. Choosing an appropriate size of femoral head may be of greater importance than choice of surgical approach for obese patients in primary THR.
Cripping criminology
Authors: Thorneycroft Ryan , Asquith Nicole L
Published: October 2019

The position of disabled people within criminal justice frameworks and scholarship is one of ambivalence, which leaves disabled people in the simultaneous and contradictory position of centrality and marginality. While disabled people are over-represented within the criminal justice system (as offenders, victims, and witnesses), their voices are often marginalized or silenced. So too, while disabled people are over-represented within the criminal justice system, they remain under-explored in policy, practice, research, and scholarship. Aligning with the shift to queer and queering criminology, in this article we deploy the lens of ‘crip’ and ‘cripping’ to facilitate a more critical engagement with the concerns of disabled people, along with the mechanisms by which abledness informs criminal justice encounters.
The production and characterization of microbial cellulose–electrospun membrane hybrid nano-fabrics
Authors: Naeem Muhammad A , Siddiqui Qasim , Leroy Adélaïde , Khan Muhammad R , Wei Qufu
Published: October 2019

This study investigates the biosynthesis of microbial cellulose–electrospun nano-fibrous membrane hybrid nano-fabric via the use of a modified bioreactor. Microbial cellulose is known for its high liquid absorbency and hygienic nature. Electrospun nano-fibrous membranes, on the other hand, exhibit excessive surface hydrophobicity in typical conditions. As such, this research intends to improve the hydrophilic property of electrospun membranes through in situ self-assembly of microbial cellulose nano-fibrils on membrane’s surface. Scanning electron microscopy showed successful growth of microbial cellulose nano-fibrils on the surface and within the structure of electrospun membranes which could possibly contribute toward improved tensile properties. Some functional properties of hybrid nano-fabric, including water absorbency, drying time, and amount of vertical wicking, were determined and compared with pure electrospun membrane samples. Results showed that water absorbency, wicking ability, and drying time increased, as a result of microbial cellulose reinforcement. The average increase in water absorption capability and water-holding time was 72.8 and 32.65%, respectively, whereas wicking ability increased up to 16.5%. In conclusion, the results demonstrate that microbial cellulose contribution has importance for hybrid nano-fabric in terms of key material characteristics that are appropriate for wound dressing and related applications.
MicroRNA-215-3p Suppresses the Growth, Migration, and Invasion of Colorectal Cancer by Targeting FOXM1
Authors: Tang Xiaowei , Shi Xianfeng , Wang Nianfei , Peng Wanren , Cheng Zhendong
Published: October 2019

Previous investigations have indicated that microRNA-215-3p is dysregulated in many kinds of cancers and functions as oncogene or tumor suppressor. However, the potential role of microRNA-215-3p in the progression of colorectal cancer remains not well known. Herein, we demonstrated that microRNA-215-3p was downregulated in human colorectal cancer tissues and was reversely correlated to the lymph node metastasis of colorectal cancer. Overexpression of microRNA-215-3p inhibited the clonogenic abilities and metastasis-relevant traits of colorectal cancer cell in vitro. Consistently, upregulation of microRNA-215-3p inhibited the growth and metastasis of colorectal cancer cell in vivo. Forkhead box protein M1 was identified as a direct target of microRNA-215-3p and reexpression of forkhead box protein M1 reversed the suppressive impacts of microRNA-215-3p on the growth, mobility, and invasion abilities of colorectal cancer cell. Altogether, these results revealed the vital role of microRNA-215-3p in the tumorigenesis and metastasis of colorectal cancer.
The Bio-inspired Artificial Pancreas for Type 1 Diabetes Control in the Home: System Architecture and Preliminary Results
Authors: Herrero Pau , El-Sharkawy Mohamed , Daniels John , Jugnee Narvada , Uduku Chukwuma N. , Reddy Monika , Oliver Nick , Georgiou Pantelis
Published: October 2019

Background:

Artificial pancreas (AP) technology has been proven to improve glucose and patient-centered outcomes for people with type 1 diabetes (T1D). Several approaches to implement the AP have been described, clinically evaluated, and in one case, commercialized. However, none of these approaches has shown a clear superiority with respect to others. In addition, several challenges still need to be solved before achieving a fully automated AP that fulfills the users’ expectations. We have introduced the Bio-inspired Artificial Pancreas (BiAP), a hybrid adaptive closed-loop control system based on beta-cell physiology and implemented directly in hardware to provide an embedded low-power solution in a dedicated handheld device. In coordination with the closed-loop controller, the BiAP system incorporates a novel adaptive bolus calculator which aims at improving postprandial glycemic control. This paper focuses on the latest developments of the BiAP system for its utilization in the home environment.

Methods:

The hardware and software architectures of the BiAP system designed to be used in the home environment are described. Then, the clinical trial design proposed to evaluate the BiAP system in an ambulatory setting is introduced. Finally, preliminary results corresponding to two participants enrolled in the trial are presented.

Results:

Apart from minor technical issues, mainly due to wireless communications between devices, the BiAP system performed well (~88% of the time in closed-loop) during the clinical trials conducted so far. Preliminary results show that the BiAP system might achieve comparable glycemic outcomes to the existing AP systems (~73% time in target range 70-180 mg/dL).

Conclusion:

The BiAP system is a viable platform to conduct ambulatory clinical trials and a potential solution for people with T1D to control their glucose control in a home environment.
The initiation, design, and establishment of the Desmoid Tumor Research Foundation Patient Registry and Natural History Study
Authors: Mercier Kelly A , Walsh Darragh M
Published: October 2019

Desmoid tumors are locally invasive sarcoma, affecting 5–6 individuals out of 1,000,000 per year. The desmoid tumors have high rates of recurrence after resection and can lead to significant deterioration of the quality of life of patients. There is a need for a better understanding of the desmoid tumors’ patient experience from first symptoms through diagnosis, disease monitoring, and clinical treatment options. With the National Organization of Rare Disorders, the Desmoid Tumor Research Foundation Natural History Study was designed to be collected through the registry. This article describes the protocol for the Desmoid Tumor Research Foundation Natural History Study and some initial findings. The Desmoid Tumor Research Foundation Natural History Study Advisory Committee developed a series of questionnaires and longitudinal surveys, in addition to those from the National Organization of Rare Disorders for all of the rare diseases. These 13 surveys are designed to uncover initial symptoms, diagnosis process, disease monitoring, quality of life, treatments, as well as socioeconomic information. Since launching the Desmoid Tumor Research Foundation Registry and Natural History Study ( https://dtrf.iamrare.org ), more than 300 desmoid tumor patients have consented to the Desmoid Tumor Research Foundation Natural History Study and completed the Participant Profile. The majority of the respondents are between the ages of 21 and 50 years (76%), female (81.2%), White (91.5%), and live in the United States (47.1%). The majority of tumors are in the lower or upper extremity, (22.9%) followed closely by abdominal desmoid tumors (21.5%). Most are willing to donate specimens (89.9%) and participate in trials (97.2%). Ongoing efforts are addressing the demographic differences between the respondents and non-respondents and any selection bias based on access to the registry and study. The Desmoid Tumor Research Foundation Natural History Study is built on the largest desmoid tumors registry and has recruited more desmoid tumors participants since launching in September 2017. It will serve to fill desmoid tumors knowledge gaps and assist other researchers in their recruitment efforts for additional studies.
Prevalence of and Risk Factors for Heterotopic Ossification After Cervical Total Disc Replacement: A Systematic Review and Meta-Analysis
Authors: Hui Nicholas , Phan Kevin , Kerferd Jack , Lee Meiyi , Mobbs Ralph J.
Published: October 2019

Study Design:

A systematic review and meta-analysis.

Objectives:

The results from previous meta-analyses are limited by the small number of included studies. Moreover, the risk factors of heterotopic ossification (HO) have not been well studied. Therefore, this study aims to estimate the prevalence of HO after cervical total disc replacement (CTDR) at different follow-up time points and explore potential risk factors for HO.

Methods:

We searched databases to identify eligible studies that reported the rate of HO after CTDR. The pooled prevalence of HO, according to different grades of HO, length of follow-up and types of prosthesis, and 95% confidence intervals (CIs) were calculated. Multivariable meta-regression analyses were performed to identify factors that may contribute to the heterogeneity between estimates.

Results:

Of the 94 studies included, 82 studies reported an overall rate of HO, encompassing a total of 5861 cervical spinal levels that underwent CTDR. The overall pooled prevalence of HO was 32.5% (95% CI 26.7% to 38.4%). Single-level CTDR was associated with a higher overall rate of HO. When the rate of HO was stratified by McAfee/Mehren classification, the pooled prevalence of range of motion (ROM)–limiting HO was 11.0% (95% CI 9.2% to 12.8%). Latest publication, single-level CTDR, longer follow-up period, and studies published outside were associated with a higher rate of ROM-limiting HO.

Conclusions:

We provide a comprehensive overview of the prevalence of different grades of HO. This meta-analysis also identifies and rules out some risk factors for HO after CTDR.
HIT the price point with fondaparinux
Authors: Connell Nathan T.
Published: October 2019

In this issue of Blood, Aljabri and colleagues report on their analysis of the cost-effectiveness of fondaparinux for the treatment of heparin-induced thrombocytopenia (HIT) in the United States.1 HIT is a relatively uncommon but serious complication of the use of heparin-containing products.2 Treatment of HIT requires use of an alternate anticoagulant such as the direct thrombin inhibitors argatroban and bivalirudin.3
Metabolic Dysregulation in Normal and Malignant Hematopoiesis
Authors: Mak Tak Wah
Published: October 2019

Over the past decade, the metabolic alterations that occur during tumorigenesis have been recognized as a key feature required for the transformation and maintenance of malignant cells. In order to meet the demands of unrestrained growth, tumor cells must adopt metabolic phenotypes that provide sufficient energy generation, biosynthetic precursor molecules, maintenance of redox/oxidative stress balance and intracellular biochemical homeostasis for growth and survival. Many of these deregulated pathways may predispose premalignant cells to genomic instability resulting to aneuploidy. These phenotypes allow tumor cells to cease functioning as part of an integrated tissue, and evolve independently along a trajectory ultimately leading to malignant disease. During this process, cells must adapt to abnormal microenvironmental conditions that develop after tissue architecture and homeostatic regulation are disrupted. Based on recent work, we will provide an overview of the metabolic alterations, such as mutations in isocitrate dehydrogenase genes that occur in malignancies of the myeloid an lymphoid system. Although the importance of these metabolic alterations to specific disease states, including Acute Myeloid Leukemia and T cell lymphomas, remains to be determined, there may be opportunities for novel therapeutic intervention. Recent advances based on these molecular changes will be discussed.

Disclosures

No relevant conflicts of interest to declare.
Targeting Autophagy as a Therapeutic Pathway in Diamond-Blackfan Anemia
Authors: Doulatov Sergei
Published: October 2019

Diamond-Blackfan anemia (DBA) is a congenital disorder characterized by the failure of erythroid progenitor differentiation, severely curtailing red blood cell production. Because many DBA patients fail to respond to corticosteroid therapy, there is considerable need for therapeutics for this disorder. We previously used unbiased drug screens in induced pluripotent stem cells (iPSCs) which identified SMER28 as a potential therpauetic for DBA. SMER28 acts by selectively modulating autophagy, but has distinct effects from the mTOR inhibitor rapamycin, highlighting the need for further study. Autophagy and mitophagy are critical metabolic pathways that mediate turnover of damaged organelles and mitochondria. Autophagy has been linked to regulation of hematopoietic stem cell function and terminal erythroid differentiation. However, the mechanisms by which autophagy regulates hematopoiesis are still poorly understood. We utilize primary cord blood and adult human progenitors and iPSCs to circumvent the paucity of primary patient blood stem and progenitor cells. To understand the role of autophagy, we have developed a lentiviral LC3-based reporter which allows real-time quantitation of autophagic flux. Using this reporter, we show that autophagy is dynamically regulated during erythroid differentiation and closely parallels mitochondrial mass and levels of reactive oxygen species. In our model, oxidative stress in erythroid precursors drives a stress response which involves activation of autophagy and mitophagy pathways. The interplay between oxidative stress and autophagy regulates erythropoiesis in normal and multiple disease contexts, including DBA and myelodysplastic syndromes (MDS). SMER28 and mitochondrial uncouplers promote homeostasis by facilitating mitochondrial clearance. In summary, therpauetic modulation of autophagy may be a broadly applicable therpauetic strategy in both inherited and acquired anemias.

Disclosures

No relevant conflicts of interest to declare.
Epigenetic Heterogeneity in Non-Hodgkin Lymphoma
Authors: Landau Dan A.
Published: October 2019

In chronic lymphocytic leukemia (CLL) genetically distinct subpopulations are commonly observed and predict future evolutionary and clinical trajectories. Similar to the case of intra-tumoral genetic diversity, intra-tumoral epigenetic diversity occurs at the level of DNA methylation, leading to massive stochastic diversification in methylation patterns. Importantly, stochastic "epimutations" impact transcription, clonal evolution and clinical outcome.

To robustly differentiate "epidrivers" from the majority of random passenger DNA methylation changes, a novel statistical inference framework has been developed that accounts for the varying epimutation rate across the genome. This framework can also include histone modifications revealing a decrease in the coherence between different epigenetic marks in CLL and consistent with intra-leukemic epigenetic diversity. Finally, multi-omic single-cell sequencing techniques further allow for tracking of epimutations and inferring high-resolution lineage trees.

Disclosures

Landau: Pharmacylcics: Honoraria.
Mitochondrial Morphology Controls Hematopoietic Stem Cell (HSC) Self-Renewal and Confers HSC Divisional Memory
Authors: Filippi Marie-Dominique
Published: October 2019

Adult hematopoietic stem cell (HSC) have extensive regenerative capacity; but recent evidence strongly indicate that their actual capacity for self-renewal is limited. HSC attrition occurs with cumulative divisions and after acute stress, causing reduction in regenerative capacity of the progeny. The principal mechanism driving the loss of HSC potency with stress hematopoiesis is not completely understood. We will show and discuss the concept that regulatory programs that are activated with HSC activation and cell cycle entry cause a permanent remodeling of mitochondria. Mitochondria do not return to homeostasis after replicative stress despite HSC re-entry into quiescence and termination of the metabolic programs that were activated with HSC cell cycle entry. HSC keep dysfunctional mitochondria after replicative stress and this loss in mitochondrial fidelity drives the decline of the HSC pool after regenerative stress. The mitochondrial remodeling with replicative stress is at least in part due to a loss in mitochondrial quality control, notably Drp1-mediated mitochondrial dynamics. Further, single cell RNA-seq data indicate that HSC carrying dysfunctional mitochondria fail to synchronize the transcriptional control of core cell cycle and metabolic components in subsequent division providing unexpected mechanism of why HSC that have divided are less potent than HSC that have never divided in similar microenvironment. Thus, the loss of fidelity of mitochondria homeostasis drives HSC attrition and serves as one source of cellular memory of hematopoietic stem cell replicative history.

Disclosures

No relevant conflicts of interest to declare.
Long-Term Follow-up of Myeloablative Haploidentical (HID) Peripheral Blood Stem Cell Transplantation and Post-Transplant Cyclophosphamide (PTCy) Following Fludarabine and Total Body Irradiation (TBI)
Authors: Solomon Scott R , Zhang Xu , Solh Melhem , Morris Lawrence E , Holland H. Kent , Bashey Asad
Published: October 2019

Haploidentical donor (HID) transplant with post-transplant cyclophosphamide (PTCy) is being increasingly utilized worldwide. Although the original "Baltimore" protocol employed nonmyeloablative conditioning, there has been increasing interest in the use of myeloablative conditioning (MAC) in an attempt to decrease the risk of disease recurrence and graft failure. We present the long-term follow-up results of 82 consecutive patients receiving a MAC HID transplant at a single institution between 2011-2017, following a uniform protocol of Fludarabine/total body irradiation (TBI) 1200cGy conditioning, PTCy, tacrolimus and mycophenolate mofetil. PBSC was utilized as the graft source for all transplants and graft CD34 dose was capped at 5 x 106/kg. Median patient age was 42 (range 19-61) years. The most common diagnoses were AML (51%) and ALL (33%), and 39% were high/very high disease risk index (DRI). Donor was a child, sibling or parent in 35%, 43% and 22% respectively. Median follow-up time for surviving patients was 37 months. Primary engraftment occurred in all patients, with all patients achieving complete donor T cell and myeloid chimerism by day +30. There were no cases of late graft failure. The cumulative incidence of grade 3-4 acute graft-versus-host disease (GVHD) and moderate-to-severe chronic GVHD was 17% and 22%, respectively. Non-relapse mortality (NRM) was 7% at one year and 12% at three years post-transplant. Overall survival at 1, 2, and 3 years post-transplant was 85%, 72% and 66% respectively (figure 1). Estimated 3-year DFS, current GVHD-, relapse-free survival (CGRFS), conventional GRFS, and relapse was 67%, 62%, 43%, and 21% respectively. DFS at 3-yr was significantly improved in patients with low/intermediate vs high/very high DRI (79% vs. 48%, figure 2) due to a lower risk of relapse (12% vs. 36%). Infectious complications included CMV reactivation in 55% of patients (CMV disease - 2%) and BK virus infection in 38% (severe - 2%). There were no reported cases of EBV lymphoproliferative disease. This large single institution analysis with long-term follow-up confirms the feasibility of Fludarabine/TBI-based MAC HID transplant with PBSC/PTCy in younger adult patients. This is supported by both the high rate of engraftment, low NRM and a 3-yr CGRFS of 62% (suggesting freedom from relapse and need for long-term systemic immunosuppression for GVHD). The achievement of long term DFS in approximately 80% of low/intermediate DRI and half of high/very high DRI patients is promising.

Disclosures

Solh: ADC Therapeutics: Research Funding; Celgene: Speakers Bureau; Amgen: Speakers Bureau.
The Role of Hydroxyurea to Prevent Silent Stroke in Sickle Cell Disease: Systematic Review and Meta-Analysis
Authors: Hasson Carla , Veling Lisa , Rico Juan Felipe , Mhaskar Rahul
Published: October 2019

Chronic blood transfusions are standard of care for stroke prevention in sickle cell disease. We evaluated hydroxyurea's efficacy in preventing silent stroke. We searched for randomized controlled trials (RCTs) and observational studies on Pubmed, CENTRAL, Embase, and Web of Science without using language/time limits. Eligible studies compared hydroxyurea with transfusions or observation to prevent silent stroke. This systematic review adheres to the Cochrane guidelines. Data were pooled using random effects model using STATA to perform meta-analysis. Methodological quality of RCTs was investigated using the Cochrane risk of bias assessment tool, while observational studies were assessed using the Downs & Black Checklist for Study Quality. One RCT enrolling 121 participants was included. There were no strokes, silent strokes, or deaths reported in either arm. There was no difference between hydroxyurea versus chronic blood transfusions (RR 1.52, 95% CI 0.57 to 4.02, P = 0.39) for adverse events. We included 10 observational studies, with 361 participants receiving hydroxyurea. There were no deaths attributed to hydroxyurea. Approximately 1% (I2 = 48.67%, 95% CI 0.0 to 0.05, 314 participants, seven comparisons) of patients receiving hydroxyurea had stroke. Approximately 18% (I2 = 91.37%, 95% CI 0.03 to 0.4, 266 participants, six comparisons) of the hydroxyurea patients had silent stroke. Approximately 24% (I2 = 88.54%, 95% CI 0.02 to 0.57, 91 participants, four comparisons) of the hydroxyurea patients had adverse events attributed to hydroxyurea. Our findings suggest that hydroxyurea is safe and may prevent silent stroke and stroke. More high-quality studies are needed.

Disclosures

No relevant conflicts of interest to declare.
Predictors Factors of Death during Induction Therapy of Acute Myeloblastic Leukemias (Western Algeria, multicenter experience)
Authors: Benzineb Brahim , Naima Mesli , Ahmed Fouad Bendahmane , Ismahane Chekkaf , Bensmail Faiza , Nadjia Benkhira , Krim Amina , Bekadja Mohammed Amine , Zouani Samira , Saidi Djamel , Touhami Hadj , Aberkane Mohamed , Bachiri Aissa , Hadjeb Asma , Zahia Zouaoui , Mehalhal Nemra , Ibraheem Othman
Published: October 2019

Introduction:

Death during induction therapy remains a problem in the management of acute myeloid leukemia (AML). An estimated 6.1% in adult patients and between 19.3% and 27% in subjects of all ages have died of AML during induction therapy. The purpose of this study is to identify the factors that can lead to death during induction therapy.

Patient and methods:

In this multicenter retrospective study, including the Hematology Services of CHU Tlemcen, EHU of Oran, CHU of Oran, CHU of SBA, EPH of Mascara and HMRU of Oran, from 01/01/2007 to 31/12 / 2017. We have included de novo and secondary AML adult patients and have benefited from conventional chemotherapy (regardless of the type and doses of anthracyclin). However, we have excluded patients with a contraindication to treatment, acute promyelocytic leukemias. The evaluation criterion was the death or the survival during the induction therapy (3 + 7 or 3 + 10 regimens).

A variable was considerated statistically significant if the p value was ≤ 0.05. The measurement of a relationship between a possible variable and the occurrence of death was estimated by the Odds-ratio. The associations were evaluated first by a bi-variate analysis followed by a multivariate analysis using logistic regression, including statistically significant variables at the value ≤ 0.1 in bi-variate analysis. If a continuous variable was statistically significant, the receiver operating characteristic curve ROC was constructed.

Results:

Over the past 11 years, 316 patients were included. These patients received either the 3 + 7 or 3 + 10 regimens. The death rate has been estimated at 11.4% (36 patients). We found that age (p: 0.17), PS ≥2 (p: 0.36), clinical symptoms at diagnosis, secondary AML (p: 0.86), FAB classification, white blood cell count (p: 0.34), anthracyclines doses (Daunorubicin 90 mg / m2 and Doxorubicin 45 mg / m2 VS Daunorubicin 60 mg / m2) and antibiotic prophylaxis (p: 0, 95) do not affect the mortality rate Table 1. In contrast, the creatinin level ≥ 12 mg / dL (p: 0.02), the LDH level> 700 U / L (p: 0.038) and the albumin level ≤ 35 g / L (p: 0.046), increase the risk of death during induction therapy. Table 1

Conclusion:

Conventional induction therapy can be used in patients over 60 years of age. On the other hand, renal failure, hypoalbuminemia and elevated LDH levels increase the risk of mortality during induction therapy.

Disclosures

No relevant conflicts of interest to declare.
Patient Adherence and Persistence to Oral Targeted Therapies for Hematologic Malignancies: A Retrospective Cohort Study Among Managed Care Enrollees
Authors: Patel Krish , Sudhir Vinjamuri Sai , Kabadi Shaum , Huang Joanna C , Porwal Sanchita , Thakkar Kushan , Pagel John M.
Published: October 2019

Existing studies evaluating patient adherence to oral targeted therapies such as tyrosine kinase inhibitors focus on small populations with single malignancies. This study evaluated patterns of use of oral agents in a larger population across multiple hematologic malignancies.

Adult patients diagnosed with a hematologic malignancy and prescribed oral targeted therapy between 2011 and 2016 (N = 18,976) were identified from the MarketScan Commercial Claims and Encounters, and Medicare Supplemental databases. Eligible patients were enrolled in monthly prescription plans 6 months before and 12 months after index date (date of first prescription claim) (n = 2,442). Multivariable logistic regressions were used to determine predictors of adherence using the medication possession ratio (MPR), and persistence through prescription refill gaps.

The overall median adherence was 0.9 (MPR ≥ 80%) and was comparable between once-daily (QD) and twice-daily (BID) groups (Table). Overall, 59% of patients were persistent at 12 months (Table). Patients on QD and BID products did not have significant differences in adherence (fixed interval MPR, odds ratio, 0.94; 95% CI, 0.75 to 1.18) or persistence (odds ratio, 0.93; 95% CI, 0.75 to 1.17) 12 months from index (Figure). Significant predictors of adherence and persistence included patient age, total inpatient admissions, number of adverse events and total hospital visits (Figure).

Patient-specific clinical factors, rather than regimen-specific factors, were the main predictors of oral targeted therapy adherence and persistence. Adherence to oral targeted therapies appears to be similar for patients on QD and BID regimens in the real-world setting.

Disclosures

Patel: Sunesis Pharmaceuticals: Consultancy; Pharmacyclics/Janssen: Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Juno Therapeutics: Consultancy; Celgene: Consultancy. Sudhir:ZS Associates: Employment. Kabadi:AstraZeneca: Employment. Huang:ZS Associates: Employment; Novo Nordisk Inc: Equity Ownership; AstraZeneca: Research Funding. Porwal:ZS Associates: Employment. Thakkar:ZS Associates: Employment. Pagel:Gilead: Consultancy; Pharmacyclics, an AbbVie Company: Consultancy.
Allogeneic Stem Cell Transplantation Overcomes the Negative Prognostic Impact of TP53 Alterations in Mantle Cell Lymphoma
Authors: Lin Richard J , Ho Caleb , Hilden Patrick , Barker Juliet , Giralt Sergio , Hamlin Paul A. , Jakubowski Ann A. , Castro-Malaspina H.R. , Papadopoulos Esperanza B. , Perales Miguel-Angel , Sauter Craig S.
Published: October 2019

TP53 alterations detected by chromosome 17p deletion, oncogenic mutation, or p53 protein overexpression portend extremely poor prognosis for patients with mantle cell lymphoma (MCL), despite aggressive upfront therapy including consolidative high-dose therapy autologous stem cell transplant and; more recently, novel agents such as ibrutinib or lenalidomide. We reviewed outcomes of 42 patients with available TP53 status who had received reduced-intensity/non-myeloablative conditioning (RIC/NMA) allogeneic hematopoietic cell transplant (allo-HCT) for MCL at our institution and examined the impact of TP53 alteration and other clinical factors on outcomes.

Nineteen patients had TP53 alterations including 17p deletion (n=3), oncogenic mutation (n=7), and strong p53 protein overexpression by immunohistochemistry (n=9). There were no differences in demographic or clinical characteristics among patients with and without TP53 alterations (Table 1). With a median follow-up for survivors of 23 months (range 4-119), the one-year overall survival (OS) and progression-free survival (PFS) is 87% (95% CI 72-94) and 74% (95% CI 57-85), respectively (Figure 1A). The one-year cumulative incidence of relapse and non-relapse mortality is 16% (95% CI 6-29) and 10% (95% CI 3-22), respectively (Figure 1B). The cumulative incidences of grade II-IV acute GVHD is 38% at 180 days (95% CI 24-53), and of any chronic GVHD is 33% at three-year (95% CI 17-49).

Importantly, there is no statistically significant difference in OS (p=0.582, Figure 1C), and cumulative incidence of relapse (p=0.715, Figure 1D) among patients with and without TP53 alterations. In univariate and multivariate analyses, we find that only Ki67 >30% is a significant predictor of PFS (HR 4.1, 95% CI 1.1-15.5, p=0.024), and that only Karnofsky Performance Status (KPS) <90 is a significant predictor of OS (HR 4.9, 95% CI 1.4-17, p=0.01). This is the first report that RIC/NMA allo-HCT could overcome the negative prognostic impact of TP53 alterations in MCL with relatively low incidence of transplant-related mortality. While requiring prospective evaluation, our data supports the consideration of RIC/NMA allo-HCT for MCL patients with TP53 alterations.

Disclosures

Ho: Invivoscribe, Inc.: Honoraria. Hamlin:Portola: Consultancy. Perales:Novartis: Other: Personal fees; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Merck: Other: Personal fees; Takeda: Other: Personal fees; Abbvie: Other: Personal fees. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy.
Varicella Zoster Virus Reactivation Can be Prevented Very Well By Valacyclovir in Patients with Multiple Myeloma Treated with Bortezomib
Authors: Wei Qi , Wei Yongqiang , Feng Ru , Wei Xiaolei
Published: October 2019

BACKGROUND:

Bortezomib is associated with a significant risk of Varicella zoster virus (VZV) reactivation in patients with multiple myeloma (MM). There are some reports that acyclovir or valacycclovir reduces the risk of VZV reactivation. We assessed whether VZV reactivation could be prevented by valacyclovir at a dose of 300 mg bid.

PATIENTS AND METHODS:

We retrospectively evaluated 108 patients with MM who received bortezomib and valacyclovir prophylaxis at the Nanfang Hospital from 2015 to 2017. Patients received valacyclovir prophylaxis orally at a dose of 300 mg bid, without cessation until finishing the whole course of bortezomib treatment.

RESULTS:

The median age was 56 years (range=37-84 years). 57 patients were male and 51 were female. The median bortezomib dose was 31.2 mg/m2(range=5.2-83.2 mg/m2). All patients also received corticosteroids. The median duration of valacyclovir prophylaxis was 333 days (range=38-724 days) and the median valacyclovir dose was 199.8 g (range=22.8-434.4 g). VZV reactivation did not develop in any patient during valacyclovir prophylaxis. Adverse events over grade 3 associated with valacyclovir were not observed.

CONCLUSION:

Valacyclovir at a dose of 300 mg bid appears to be effective at preventing VZV reactivation and was well-tolerated by patients with MM treated with bortezomib.

Disclosures

No relevant conflicts of interest to declare.
Intestinal Microbiota at Neutrophil Engraftment Can Predict Acute Graft-Versus-Host Disease in the Recipients of Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Han Lijie , Fan Zhiping , Jin Hua , Xuan Li , Dai Min , Huang Fen , Lin Ren , Sun Jing , Liu Qifa
Published: October 2019

Backgrounds: An increasing of researches have demonstrated that intestinal microbiome plays an important role in the development of acute graft-versus-host disease (aGVHD), and loss of microbiota diversity is associated with aGVHD. But whether microbiota might be as a biomarker to predict aGVHD is undetermined. This study investigates the prediction of intestinal microbiota at neutrophil engraftment for occurrence of aGVHD.

Methods: We prospectively collected stool and blood samples from 166 patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) at pre-conditioning, day 0 and day 15 post-transplantation. The microbiota in stool were detected by 16S rRNA gene sequencing; the inflammatory factors (TNF-α, IL-6, IL-17A, IL-1β and Lipopolysaccharide (LPS)) in blood by multiplex immunoassays and dynamic turbidimetric methods; and T lymphocyte subsets were tested by flow cytometry. AGVHD was determined by retrospective review of the clinical charts.

Results: 141 patients were enrolled into analysis, including 83 in grade 0-I aGVHD (non-aGVHD group) and 58 in grades II-IV aGVHD (aGVHD group). The microbiota diversity was lower in aGVHD group than that in non-aGVHD both at day 0 and day 15 post-transplantation (P = 0.018, 0.009, respectively). The diversity was associated with conditioning (Intensified vs. Standard: medain, 3.39 vs. 3.04 (P = 0.017, day 0); medain, 3.17 vs.1.89 (P = 0.045, day 15)) and β-lactam antibiotics (β-lactam vs. No β-lactam: medain, 3.33 vs. 2.48, P = 0.004 (day 15)). At day 15 post-transplantation, Treg/Th17 cells ratio in blood positively correlated with the microbial diversity(r = 0.217, P = 0.010), but negatively correlated with the levels of TNF-α, IL-17A and LPS (r = -0.226, -0.216, -0.291; P = 0.007, 0.010, < 0.001, respectively). Based on the accumulated microbiota Score of the diversity and the special discriminated constitution (Enterobacteriaceae, Lachnospiraceae, Peptostreptococcaceae and Erysipelotrichaceae) between aGVHD and non-aGVHD groups at day 15, the area under the receiver operator characteristic curve (AUC) of the Score could be used to predict aGVHD (II-IV aGVHD: AUC = 0.75, P < 0.001; III-IV aGVHD: AUC = 0.84, p < 0.001). The Score also correlated with the grades of aGVHD (r = 0.481, P < 0.001).

Conclusions: The intestinal microbiota diversity is affected by both conditioning and antibiotics. The constitution of microbiota at neutrophil engraftment was a predictive marker for the subsequent development and grades of aGVHD.

Keywords: intestinal microbiota, marker, acute graft-versus-host disease, hematopoietic stem cell transplantation

Disclosures

No relevant conflicts of interest to declare.