bluuebunny/crossref_metadata_2025 huggingface dataset:
Product and Process Analysis of Machine Translation into the Inflectional Language
Authors: Munkova Dasa , Munk Michal , Welnitzova Katarina , Jakabovicova Johanna
Published: November 2021

This study focuses on the influence of quality of Machine Translation (MT) output on a translator’s performance. We analyze the translator’s effort by product analysis and process analysis. The product analysis consists of MT quality evaluation according to the Dynamic Quality Framework; using error typology and the criteria such as fluency and adequacy. We examine translator’s effort from the point of view of typing time, in the context of MT quality—focusing on error rate in language, accuracy, terminology, and style, and also in fluency and adequacy to the source text. We have found that the translator’s performance is influenced by MT quality. The typing time is very closely related to errors in language, accuracy, terminology, and style as well as to fluency and adequacy. We used the Mann-Whitney test to compare the productivity of post-editing of MT with human translation. The results of the study have shown that post-editing—compared to human translation of journalistic text from English into the inflectional Slovak language is more effective.
Health Conditions, Substance Use, Physical Activity, and Quality of Life in Current and Former Baseball Players
Authors: Bullock Garrett S. , Nicholson Kristen F. , Waterman Brian R. , Niesen Eric , Salamh Paul , Thigpen Charles A. , Shanley Ellen , Devaney Laurie , Collins Gary S. , Arden Nigel K. , Filbay Stephanie R.
Published: November 2021

Background:

A comprehensive understanding of lifestyle (health conditions and substance use), health-related quality of life (HRQoL), flourishing (holistic representation of health), and physical activity can inform stakeholders (players, coaches, and clinicians) and help improve long-term health across the life span.

Purpose:

To describe health conditions (comorbidities or diagnoses), substance use, physical activity, HRQoL, and flourishing in current and former collegiate and professional baseball players and to assess the relationship between playing position and HRQoL/flourishing in former baseball players.

Study Design:

Descriptive epidemiology study.

Methods:

Eligible participants were those ≥18 years old with ≥1 season of collegiate or professional baseball experience. Participants completed a survey on health conditions (asthma, diabetes, hypertension, hypercholesterolemia, and depression), substance use (tobacco, alcohol, and energy drinks), physical activity (International Physical Activity Questionnaire–Short Form), HRQoL (Veterans Rand 12-Item Health Survey [VR-12] physical and mental component scores), and flourishing (Flourishing Scale). Adjusted multivariable regressions were performed for HRQoL and flourishing.

Results:

Overall, 260 baseball players opened the survey, and 214 (current players, 97; former players, 117) participated for an 82% response rate. Of the former players, 32% had hypertension or hypercholesterolemia. In addition, 26% of current players had used smokeless tobacco (median, 3 years; interquartile range [IQR], 1-5 years) as compared with 34% of former players (median, 15 years; IQR, 5-25 years). In addition, 14% of current players had used electronic cigarettes (median, 2 years; IQR, 0-4 years) as opposed to 3% of former (median, 3 years; IQR, 2-4 years). Energy drinks were consumed by 31% and 14%, respectively, of current and former players on at least a weekly basis. Current baseball players performed 8667 metabolic equivalents per week of physical activity as opposed to 3931 in former players. Pitching was associated with worse VR-12 Mental Component Scores (–5.0; 95% confidence interval, –9.0 to –1.0). Playing position was not related to VR-12 Physical Component Scores or flourishing in former baseball players.

Conclusion:

The similar smokeless tobacco prevalence between current and former baseball players suggests that they may start using tobacco products during baseball participation and continue after retirement. Similar reported HRQoL as compared with the general US population and high flourishing and physical activity levels suggest that baseball players may present with good musculoskeletal and psychological health.
Pediatric Inflammatory Bowel Disease Associated With Celiac Disease: A Retrospective Study in a Tertiary Care Hospital in Saudi Arabia
Authors: Qadi Mamdouh , Hasosah Mohammed , Alamoudi Anas , AlMansour Abdullah , Alghamdi Mohammed , Alzahrani Faisal , Alzahrani Sultan , Khawaji Bader
Published: November 2021

Background. Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn’s disease (CD), is a chronic relapsing disease indicated by inflammation of the gastrointestinal tract. Celiac disease (CeD) is a chronic autoimmune disease of the small bowel. The prevalence of CeD in IBD patients is unknown. Some studies have described the coexistence of the 2 diseases in the same patient. This study aimed to investigate the prevalence of CeD in Saudi Arabian children with IBD. Methods. We used a retrospective study design because data can be collected immediately and is easier to analyze afterward. The study was conducted on IBD patients in the Pediatric Gastroenterology Department at National Guard Hospital, Jeddah, Saudi Arabia. We enrolled Saudi patients aged between 1 and 18 years who had been diagnosed with IBD and CeD based on positive biochemical serology and histology from January 2011 to January 2020. We excluded patients with immunodeficiency disorders. Results. Among the 46 enrolled patients with IBD, CeD was identified in 4, and they did not develop any relapses. We discovered that the weight at IBD diagnosis improved significantly compared to current weight ( P-value < .0001). We also discovered that the height at diagnosis of IBD improved significantly compared to the current height ( P-value < .0001). Additionally, we found no significant associations between UC and CeD ( P-value = 1), or CD and CeD ( P-value = .625). Conclusion. No significant associations were evident between the prevalence of CeD and IBD. More prospective multicenter studies are needed to clarify the prevalence of CeD in children with IBD.
Basic Biomechanics for Craniofacial Surgeons: The Responses of Alloplastic Materials and Living Tissues to Mechanical Forces
Authors: Yu Jack C. , Buchman Steven R. , Gosain Arun K. , Havlik Robert J. , Wang Tien-Hsiang , Lam Po-Sang , Masoumy Mohamad
Published: November 2021

Many terms such as twist, compress, bend, and stretch, describe how materials behave when subjected to mechanical stresses. Subjective adjectives to describe the property of materials such as hard or brittle are imprecise and impedes proper understanding of important principles needed in planning and performing surgical treatments. The viability of tissue and time dependent variables effect healing and compound the issue. Some parameters are time dependent (strain rate), while others are nearly independent of time (Young’s modulus). The craniofacial skeleton and enveloping soft tissues are viscoelastic composite materials which undergo time-dependent changes upon loading. The ability to remodel and respond to environmental changes makes them “smart,” reenforcing where needed and removing where not required based on a set of predetermined upper and lower thresholds. This mini review has 7 sections on engineering principles that underpin craniofacial surgery: (1) The general concept of mechanics: load, force, stress, strain, compression, tension, shear, stress-strain curves and values derived from them such as Young’s modulus, fatigue damage, and load- shearing. (2) Material properties of bone and suture and structural engineering of the craniofacial skeleton in normal and pathological conditions. (3) Fixation using wires, screws, and plates: anatomy and function of screws and plates, locking plates, lag screws, internal and external fixators. (4) Biomechanics of distraction osteogenesis and the effects of radiation. (5) Finite element analysis and other computational biomechanical tools. (6) Virtual surgical planning, cutting guides, and intra-operative navigation. (7) Tissue engineering: design goals, criteria, and constraints. An appreciation and understanding of these biomechanical principles will help craniofacial surgeons to facilitate intrinsic optimization and better treat complex morphological problems, helping one achieve the most favorable and durable results. The biological responses to mechanical stress are extremely important as well, but due to space constraints, they will be the subject of a separate dedicated review.
Survival Determinants in Primary Intestinal NK/T-Cell Lymphoma (PINKTCL): Analysis of a Pooled Database
Authors: Haddad Philip A , Graham Christopher
Published: November 2021

Introduction: PINKTCL is a less common presentation of extranodal, extranasal NK/T-cell lymphoma which arises along any segment of the gastrointestinal tract. PINKTCL is a rare and rapidly progressive disease with a poor prognosis. It is commonly associated with EBV infection and displays angiotropism and necrosis. PINKTCL affects younger adults and is not associated with pre-existing enteropathy. We conducted this exploratory analysis to delineate key disease characteristics and clinicopathologic determinants of survival in this rare NK/T-cell entity.

Methods: To study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 126 cases. Kaplan-Meier survival curves were constructed. Cox proportional-hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on overall survival (OS).

Results: A total of 126 patients with confirmed PINKTCL were identified and analyzed. The median age of the sample was 39 years, with a peak incidence occurring between ages 34 and 48. Males were predominantly afflicted with an M:F ratio of 2.7. The colorectum and ileocecum were the most involved sites. The median overall survival (OS) of the whole group was 6 months. PINKTCL commonly presented with abdominal pain, GI bleeding, and perforation. The majority of cases were at stages I&IE (56%). The median duration of symptoms prior to diagnosis was 6 months. The median OS of surgery alone, chemotherapy alone, and surgery and chemotherapy were 2, 6, and 10 months respectively (p=0.002). OS was not impacted by age, sex, presentation with obstruction, anatomic site involvement, or stage. While constitutional symptoms, perforation, non-ileocecal GI involvement, EBER+, and CD56+ seemed to impact OS negatively, they did not reach statistical significance. Surprisingly, CD4 expression despite CD56+ conferred a significantly longer overall survival (18 vs. 6 months), raising the possibility of a separate and less aggressive entity.

Conclusions: This study presents an updated clinicopathologic data from a pooled cohort of patients with PINKTCL. It identifies CD4+ status and surgical resection in conjunction with chemotherapy as major determinants of OS in this rare disease.

Disclosures

No relevant conflicts of interest to declare.
Efficacy and Safety of Decitabine Combined with IA Regimen in the Treatment of Newly Diagnosed Acute Myeloid Leukemia
Authors: Kuang Lifen , Li Juan
Published: November 2021

Objective: To evaluate the efficacy and safety of decitabine combined with IA regimen in the treatment of newly diagnosed acute myeloid leukemia.

Methods: From September 1, 2013 to October 18, 2019, 164 newly diagnosed acute myeloid leukemia patients who received IA or decitabine combined with IA induction chemotherapy who were hospitalized in the Department of Hematology of the First Affiliated Hospital of Sun Yat-sen University were enrolled. The efficacy and side effects of treatment were analyzed.

Results: The complete remission rate of decitabine combined with IA regimen chemotherapy group (n=88) and IA regimen chemotherapy group (n=76) was 83.0% vs. 68.4% (P=0.029, Fig 1). Subgroup analysis (table 1) showed that age ≥40 years old, WBC＜10*10^9/L, Hb＞85g/L, PLT≥50*10^9/L, MCV≥98fL, ratio of bone marrow immature cells ≤45%, NCCN intermediate-risk or high-risk group, patients with FLT3ITD mutation had a higher CR rate in the decitabine combined with IA regimen group. Multivariate analysis showed that combined decitabine was an independent favorable factor affecting the CR rate (OR 3.559, 95% CI: 1.554-8.151, P=0.003). Compared with the IA group, patients in the decitabine combined with IA group took longer to rebuild the granule system (20 days vs 19 days, P=0.026), and the incidence of infection was higher (93.2% vs 78.8%, P=0.028) (table 2).

Conclusion: Compared with the IA regimen, the decitabine combined with the IA regimen significantly improves the induction chemotherapy response rate of newly diagnosed non-M3 AML patients, especially for patients with the following characteristics: age ≥ 40 years old, WBC <10*10^ 9/L, Hb＞85g/L, PLT≥50*10^9/L, MCV≥98fL, bone marrow immature cell proportion ≤45%, NCCN risk stratification medium-risk or high-risk group, FLT3ITD mutation. After combining with decitabine, the patient's granular bone marrow suppression increased.

Figure 1 Figure 1.

Disclosures

No relevant conflicts of interest to declare.
A Novel Asymmetrical Anti-CLL-1×CD3 Bispecific Antibody, ABL602, Induces Potent CLL1-Specific Antitumor Activity with Minimized Sensitization of Pro-Inflammatory Cytokines
Authors: Lim Yangmi , Lee Eunhee , Lee Shinai , Park Sumyeong , Park Hyeyoung , Won Jonghwa
Published: November 2021

Acute myeloid leukemia (AML) is a disease with high incidence of relapse that is originated and maintained from leukemia stem cells (LSCs). Expression of C-type lectin-like molecule-1 (CLL-1; also known as CLEC12A, c-type lectin domain family 12 member A) is mainly restricted to LSCs but absent in normal hematopoietic stem cells (HSCs), suggesting CLL-1 as an excellent therapeutic target for AML. This unique expression pattern paves the way to develop therapies that potentially eliminate CLL1-positive LSC while preserving CLL1-negative HSC.

To re-direct T cells to AML cells, we generated IgG-based asymmetric (2+1, ABL602) bispecific antibody (BsAb) targeting CLL-1 and CD3. As a 2+1 format BsAb, ABL602 has bivalent binding to CLL-1 for target arm and monovalent binding to CD3. ABL602 exhibited higher binding activity to CLL-1-expressing AML cell lines and greater tumor-killing efficacy than 1+1 format BsAb and benchmark antibody MCLA-117 (Merus; CLEC12AxCD3 bispecific antibody). ABL602 induced potent cytotoxic activities on CLL1-expressing AML cell lines (EC 50 of 0.04~3.05pM and 0.97~16.64pM for U937 and HL-60, respectively) with concomitant T cell activation (EC 50 of 0.10~3.54pM and 0.94~4.92pM for U937 and HL-60, respectively) and cytokine/granzyme B release. Despite strong tumor-killing activity, ABL602 did not kill CLL1-negative cancer cell lines, suggesting that ABL602 induces CLL-1-dependent cytotoxicity. Moreover, ABL602 did not or minimally induce TNF-α and IL-6 in PBMC in the absence of AML cell lines, while MCLA-117 triggered high level of expression of those cytokines. In established orthotopic AML mouse model using HL-60 Luc, ABL602 demonstrated statistically significant anti-tumor activity in a dose-dependent manner. Proportions of bone marrow CD33 + AML blasts diminished in a dose-dependent manner, while CD3 + T cells more infiltrated to the bone marrow.

Overall, our results indicate that ABL602, appropriately engineered 2+1 asymmetric BsAb, promotes T-cell activity specifically against CLL1-expressing AML cells and is a promising treatment strategy for AML patients by achieving the desired balance between antitumor activity and safety.

Disclosures

No relevant conflicts of interest to declare.
Bivalent Histone Modifications By Reiibp Leads to Transcriptional Reprogramming and TLR7-BTK Driven IL-6 Pro-Inflammatory Response in t(4;14) Myelomagenesis
Authors: Chong Phyllis SY , Lim Julia , Chooi Jing Yuan , Chng Wee-Joo
Published: November 2021

Multiple Myeloma (MM) is characterized by the uncontrolled proliferation of malignant plasma cells that are incapable of producing functional antibodies. Current treatment regime involves novel drug classes such as proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies, which have significantly improved survival outcomes in patients. Patients with t(4;14) translocation represents ~15% of MM cases, and displays a dysregulation of the MMSET locus. It has one of the worst prognosis when compared to other subgroups, but represents an intermediate-risk group given its response towards bortezomib. REIIBP is a t(4;14)-deregulated isoform arising from alternative promoter usage within the MMSET locus. Despite sharing identical sequence with the C-terminus of MMSET II, we found that REIIBP displayed mutually exclusive expression with the full-length MMSET II arising from MB4-1 breakpoint. Additionally, the expression of REIIBP can be regulated through microRNAs by another histone methyltransferase, EZH2 in a Dicer-dependent manner. We generated a stable cell line that overexpresses REIIBP in the t(4;14)-negative human myeloma cells, RPMI8226, and revealed REIIBP as an epigenetic regulator of repressive H3K27me3 and active H3K4me3 modifications. Transcriptome profiling and ChIP-sequencing identified an upregulation of Toll-like receptor 7 (TLR7) by REIIBP through the enrichment of H3K4me3 on its promoter coupled with decrease in intragenic H3K27me3. This led to a BCR-independent activation of Bruton's tyrosine kinase (BTK) and NF-ĸB signaling in t(4;14) myeloma cells. Using Cancer Cell Line Encyclopedia and DepMap portal (Broad Institute) to compare the expression of BTK and BTK dependency scores across lineages revealed that BTK is an important target in MM, and REIIBP expression correlated with BTK in the CoMMpass dataset. Activation of TLR7-BTK by REIIBP conferred bortezomib resistance through the dysregulation of pro-inflammatory cytokine expression such as IL-6. Importantly, cells with REIIBP overexpression displayed enhanced lethality towards BTK inhibitor Ibrutinib, and combination with Bortezomib potentiated inhibition in myeloma cell lines and mice engrafted with RPMI8226-REIIBP tumors. Altogether, our results indicated that blockade of REIIBP in t(4;14) cells through combining proteasome and BTK inhibitors is a therapeutic strategy in the clinic for further evaluation.

Disclosures

Chng: Novartis: Honoraria, Research Funding; Antengene: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; AbbVie: Honoraria; Amgen: Honoraria; BMS/Celgene: Honoraria, Research Funding; Johnson & Johnson: Honoraria, Research Funding; Takeda: Honoraria; Aslan: Research Funding.
Fc-Modified Kko: A Novel Therapeutic for Heparin-Induced Thrombocytopenia (HIT), Reversing Both the Thrombocytopenia and Thrombosis
Authors: Sarkar Amrita , Khandelwal Sanjay , Yarovoi Serge , Arepally Gowthami M. , Cines Douglas B. , Poncz Mortimer , Rauova Lubica
Published: November 2021

Heparin induced thrombocytopenia (HIT) is an immunogenic prothrombotic disorder caused by antibodies that recognize human platelet factor 4 (PF4) complexed to polyanions. We had previously shown using chimeric constructs of hPF4 and mouse (m) PF4 and chimeras with the related chemokine, neutrophil-activating peptide-2 that there is a single antigenic locus on hPF4 in these complexes to which most HIT antibodies bind. KKO is a mouse monoclonal IgG2b k anti-hPF4/polyanion monoclonal antibody that mimics pathogenic antibodies that induce HIT and provokes thrombosis in a murine model of HIT. We previously established that specific hydrolysis of N-linked glycans in the Fc-region of KKO by endoglycosidase from Streptococcus pyogenes EndoS (Genovis) yields >97% deglycosylation on LC-MS/MS generating DGKKO. This modification has no significant effect on binding to PF4-heparin complexes as shown by ELISA and by dynamic light scattering, but abrogates FcgRIIA-mediated binding and platelet activation, and decreases complement activation as evaluated by flow cytometry. To examine if DGKKO reduces prothrombotic effects, we compared DGKKO with KKO in human microfluidic system lined with human umbilical vein cells (HUVECs) that are then photochemically injured and a murine model involving "HIT mice" (mice that express FcgRIIA and human PF4 and lack mouse PF4). Using the microfluidic system described above and infusing blood from healthy donors with added human PF4 (25 µg/ml) and KKO (50 µg/ml) or HIT IgG from three individuals with SRA-positive HIT (1mg/ml) resulted in increased platelet adherence to the injured endothelium (Figure 1). Addition of DGKKO (50 µg/ml) 15 minutes after addition of HIT antibodies eliminated platelet accumulation (Figure 1). In the HIT murine model, we found that intraperitoneal (IP, 200 µg/mice) or intravenous (IV, 20 µg/mice) DGKKO did not induce thrombocytopenia in HIT mice, but reversed the thrombocytopenia induced by either IP KKO (200 µg/mice) or HIT IgG (1 mg/mice) even when the DGKKO is given 6 hrs after HIT induction (Figure 2A). We used an intravital cremaster laser arteriole injury model in HIT mice to study the efficacy of DGKKO as an antithrombotic agent. We found that unlike KKO that enhances growth of established thrombi in these mice, DGKKO significantly reversed the size of the observed thrombi (Figure 2B). These studies suggest that DGKKO obstructs the HIT antigenic site recognized by HIT antibodies and leads to a reversal of thrombocytopenia and thrombus size. Additional studies are underway to examine if DGKKO can be used as a monotherapy or adjunctive therapy in the murine model of HIT thrombosis.

Figure 1 Figure 1.

Disclosures

Cines: Rigel: Consultancy; Dova: Consultancy; Treeline: Consultancy; Arch Oncol: Consultancy; Jannsen: Consultancy; Taventa: Consultancy; Principia: Other: Data Safety Monitoring Board.
The Potential Roles of Mucosa-Associated Invariant T Cells in the Pathogenesis of Gut Graft-Versus-Host Disease after Hematopoietic Stem Cell Transplantation
Authors: Mengge Gao , Hong Yan , Xiangyu Zhao , Sun Yuqian , Kong Jun , Wang Zhidong , Wang Fengrong , Wang Jingzhi , Yan Chenhua , Wang Yu , Huang Xiaojun , Zhao Xiaosu
Published: November 2021

Background & Purpose: Gut acute graft-versus-host disease (aGVHD) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is associated with high mortality. Mucosal-associated invariant T cells (MAITs) are a group of innate-like T cells enriched in the intestine that can be activated by riboflavin metabolites from various microorganisms. However, little is known about the function or mechanism of action of MAIT in the occurrence of gut aGVHD in the human body.

Methods & Cases: In our study, multiparameter flow cytometry (FCM) was used to evaluate the number of MAIT cells (MAITs) and functional cytokines. 16S V34 region amplicon sequencing analysis was used to analyse the intestinal flora of transplant patients. In vitro stimulation and coculture assays were used to study the activation and function of MAITs. The number and distribution of MAITs in intestinal tissues were analysed by immunofluorescence technology. We prospectively studied the enrolled 150 consecutive patients who underwent allo-HSCT in our institute.

Results: The number and frequency of MAITs in infused grafts in gut aGVHD patients were lower than those in non-gut aGVHD patients (Figure). Recipients with a high number of MAITs in infused grafts had a higher abundance of intestinal flora in the early post-transplantation period (+14 days). At the onset of gut aGVHD, the number of MAITs decreased in peripheral blood, and the activation marker CD69, chemokines CXCR3 and CXCR4 and transcription factors Rorγt and T-bet tended to increase. Furthermore, when gut aGVHD occurred, the proportion of MAIT17 was higher than that of MAIT1. The abundance of intestinal flora with non-riboflavin metabolic pathways tended to increase in gut aGVHD patients. MAITs secreted more granzyme B, TNF-α and IFN-γ under the stimulation of IL-12/IL-18 (non-TCR signal) and secreted most of the IL-17 under the stimulation of CD3/CD28 (TCR signal). MAITs inhibited the proliferation of CD4+ T cells in vitro.

Conclusions: In conclusion, the lower number of MAITs in infused grafts was related to the higher incidence of gut aGVHD, and the number of MAITs in grafts may affect the composition of the intestinal flora of recipients early after transplantation. The flora of the riboflavin metabolism pathway activated MAITs and promoted the secretion of intestinal protective factors to affect the occurrence of gut aGVHD in humans.

Figure 1 Figure 1.

Disclosures

No relevant conflicts of interest to declare.
Development of a Prognostic Nomogram for PCNSL Based on the SEER Database and External Validation
Authors: Wang Hua , Fu Bibo , Chen Guanjun
Published: November 2021

Background: Significant difference existed in survival outcomes of primary central nervous system lymphoma (PCNSL) patients. The aim of this study was to establish a prognostic nomogram to access personalized survival rate of PCNSL patients.

Methods: 2947 patients were extracted from the Surveillance, Epidemiology, and End Results database as the training cohort. 177 patients diagnosed from 2006-2020 in Sun Yat-Sen University cancer center were identified as the external validation cohort. Cox proportional hazards model was performed to identify independent factors for establishing the nomogram. Concordance index (C-index) and calibration curves were used to test the accuracy of the model.

Results: Age, tumor site, lymphoma subtype, surgery and chemotherapy were significant predictors included in the nomogram. C-index in the training and validation cohort were 0.701 and 0.653, respectively. Calibration curves showed favorable consistency of nomogram-predicted and actual probability of overall survival (OS). The decision curve analysis (DCA) curves exhibited great clinical application. We published a web calculator for convenient clinical practice and established a risk classification system that significantly distinguished patients into four groups. Results of the primary cohort were well confirmed in the validation cohort.

Conclusion: We developed a nomogram and a web calculator of OS prediction for PCNSL, which may assist in medical consultation, treatment decision making and clinical study design.

Figure 1 Figure 1.

Disclosures

No relevant conflicts of interest to declare.
Invasive Field Radiotherapy Combined with Rituximab Versus Rituximab Alone for Consolidation Therapy in Stage III Follicular Lymphoma Patients Response to R-CHOP Chemotherapy: A Randomized Clinical Study
Authors: Lin Tongyu , Huang He , Li Xiaoqian , Hong Huangming , Zou Liqun , Zhang Liling , Zhang Zhihui , Xia Zhongjun , Chen Yongchang , Chen Meiting , Chen Zegeng , Fang Xiaojie , Guo Hongqiang , Xie Ke , Tian Ying , Lin Suxia , Zhang Wei , Yao Yuyi , Pan Fei , Weng Huawei
Published: November 2021

Background: Stage III follicular lymphoma (FL) is currently still considered incurable after RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy and rituximab maintenance. Radiotherapy plays a vital role in early-stage FL, but the value remains unclear in stage III FL. Here, we reported the results of invasive field radiotherapy (IFRT) combined with rituximab maintenance versus rituximab maintenance alone in patients with stage III FL who achieved complete remission (CR) or partial response (PR) after induction chemotherapy.

Methods: From January 2015 and January 2020, patients aged 18-70 years with CR or PR after induction chemotherapy in stage III FL, grade 1, 2 or 3a and CD20 positive in immunohistochemical feature were randomly assigned (1:1) to receive IFRT combined rituximab maintenance or rituximab maintenance alone after induction chemotherapy in multicenter. The primary endpoint was progression-free survival at 5 years. This study is registered with Chinese ClinicalTrials.gov, number ChiCTR2000032550.

Results: 63 patients were randomly assigned to IFRT combined rituximab maintenance (IFRT+R arm) and 66 patients to rituximab maintenance alone (R arm) after induction chemotherapy. The dose of IFRT was 30Gy. After a medium follow-up of 48 months (range 7-72 months), the 5-year progression free survival (PFS) were significantly improved in patients with IFRT +R, with 87.8% versus 67.1% (HR, 0.32; 95% CI, 0.14-0.72, P=0.006). Patients with IFRT +R also have a better overall survival (OS), OS was 96.6% versus 80% (HR, 0.28; 95% CI, 0.09-0.92, P=0.036). Thirty-six (57%) patients in IFRT+R arm and twenty-four (36%) patients in R arm suffered toxic effects (P=0.02). Grade 3 and 4 adverse events were recorded in 17 patients (27%) in IFRT+R arm and 11 (16%) in R arm (P=0.200).

Conclusion: On the basis of rituximab maintenance, IFRT demonstrated promising efficacy and manageable toxicity in stage III FL, with longer PFS and OS compared with rituximab alone.

Figure 1 Figure 1.

Disclosures

No relevant conflicts of interest to declare.
Assessment of Venous Thromboembolism Risk Based on the Khorana Predictive Model and Compliance with Prophylactic Anticoagulation at a Regional Cancer Center- a Quality Improvement Study
Authors: Khan Noman Ahmed Jang , Yasin Hassaan , Nwanwene Kemnasom , Abdallah Mahmoud , Gress Todd , Tirona Maria
Published: November 2021

Background:

Malignancy is an independent risk factor for venous thromboembolism. Factors like site of the primary cancer, associated comorbidities, obesity, and baseline cytopenias play an important role in predicting the risk in cancer patients. Several risk assessments models have been proposed in the literature, however, the Khorana risk predictive model is the most favored tool used in the literature. Patient characteristics like site of primary, baseline hemoglobin/platelets/WBC and BMI are the main components of this scoring system. Patients are classified into low (0), intermediate (1-2) and high (> 3) risk groups. Low dose prophylactic anticoagulation (Apixaban 2.5 mg BID or Rivaroxaban 10 mg daily) for up to 6 months is indicated in patients with score 2 or higher.

Methods:

83 patients with a new cancer diagnosis in the years 2018 and 2019 who received chemotherapy and developed a venous thromboembolism (VTE) after the cancer diagnosis were identified from the cancer registry at Edwards Comprehensive Cancer Center. All the components of Khorana score including patient's baseline body mass index (BMI), white blood cell count (WBC), hemoglobin, platelet count and site of the primary were collected. Compliance with prophylactic anticoagulation (Khorana score =/>2) was evaluated.

Results:

Among 83 patients identified, 61 % and 39 % were female and males, respectively with a mean age of 59 years. The mean duration of onset of VTE was 18 months from the time of cancer diagnosis. The mean Khorana score was 1.1. 34 % of patients(n=28) were found to have a Khorana score of =/> 2 and prophylactic anticoagulation was indicated. Only 7 % of patients (n=2) received prophylactic anticoagulation. The reason for no prophylactic anticoagulation was not documented in all the cases.

Conclusion:

In patients with a higher risk of VTE, a very low compliance rates for prophylactic anticoagulation were found at our cancer center. Poor documentation and failure to address the risk of VTE are possible reasons for the low compliance rates. Necessary steps needed to improve the compliance rates are warranted including education of the healthcare providers about current available guidelines to decrease risk of VTE in cancer patients. Dedicated lectures and sessions will be organized and educational materials highlighting the importance of VTE risks and prophylactic anticoagulation will be provided to the healthcare providers at the cancer center.

Disclosures

No relevant conflicts of interest to declare.
Increased mTORC2 Pathway Activation in Lymph Nodes of Imcd-Tafro
Authors: Phillips Alexis D , Kakkis Joseph K , Tsao Patricia Y , Pierson Sheila K , Fajgenbaum David C
Published: November 2021

Idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening disorder involving polyclonal lymphoproliferation and organ dysfunction due to excessive cytokine production, including interleukin-6 (IL-6). Anti-IL-6 therapy is recommended first-line and effective in 34-45% of patients. mTOR, which functions through mTORC1 and mTORC2, is a recently-discovered therapeutic target. The mTOR inhibitor sirolimus, which preferentially inhibits mTORC1, has led to sustained remission in a small cohort of anti-IL-6 refractory iMCD patients with thrombocytopenia, anasarca, fever, renal dysfunction, and organomegaly (TAFRO). However, sirolimus has not shown uniform effect, potentially due to its limited mTORC2 inhibition. To investigate mTORC2 activation in iMCD, we quantified the mTORC2 effector protein pNDRG1 by immunohistochemistry of lymph node tissue from iMCD-TAFRO (N=6) patients and iMCD patients not meeting TAFRO criteria (iMCD-NOS; N=8) (Table 1) as well as autoimmune lymphoproliferative syndrome (ALPS) (N=6), Hodgkin lymphoma (positive controls, N=8), and metastasis-free sentinel lymph nodes (normal controls, N=8).

In iMCD-TAFRO, pNDRG1 expression was elevated in the interfollicular space (IF) (P=0.005), germinal centers (GC) (P=0.002), and mantle zones (MZ) (P=0.007) relative to normal controls (Figure 1A). pNDRG1 staining was increased in the IF (P=0.005) of iMCD-NOS relative to normal controls and there was no difference in the GC (P=0.59) and the MZ (P=0.30) (Figure 1B). Next, we compared pNDRG1 expression in iMCD-TAFRO and iMCD-NOS to ALPS, an mTOR-driven, sirolimus-responsive lymphoproliferative disorder.Our results revealed increased pNDRG1 staining in iMCD-TAFRO GC relative to ALPS (P=0.02) (Figure 1C). There were no differences in pNDRG1 expression between iMCD-NOS and ALPS in any region (Figure 1C). Notably, the strongly positive pNDRG1 cells had spindle-shaped morphology resembling stromal cells (Figure 1H).

These results suggest increased mTORC2 activity in iMCD and that dual mTORC1/mTORC2 inhibitors may be a rational therapeutic approach for anti-IL-6 treatment refractory patients. Further studies are needed to confirm this finding, uncover cell types showing increased mTORC2 expression, and investigate therapeutic approaches.

Figure 1 Figure 1.

Disclosures

Fajgenbaum: EUSA Pharma: Research Funding; N/A: Other: Holds pending provisional patents for 'Methods of treating idiopathic multicentric Castleman disease with JAK1/2 inhibition' and 'Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease'; Pfizer: Other: Study drug for clinical trial of sirolimus.
Enhanced Stimulation of Antigen-Specific Immune Responses Against NPM1-Mutated AML
Authors: Greiner Jochen Marlies , Schneider Vanessa , Schrezenmeier Hubert , Hofmann Susanne , Götz Marlies
Published: November 2021

Nucleophosmin1 (NPM1) is one of the most frequently mutated genes in AML, is often associated with a favorable prognosis and seems to be a suitable target structure for immunotherapeutic approaches. Other groups and ours described specific immune responses of CD8-positive T cells against immunogenic epitopes derived from the mutational region of NPM1 in AML patients (pts).

In this extended immunological study, we investigated immune responses against the mutational epitope of NPM1 but also against other LAA in NPM1 mut compared to NPM1 wt pts. 30 AML pts were analyzed using FACS analysis, tetramer staining and colony forming immunoassays (CFI). 15 NPM1 mut and 15 NPM1 wt pts were investigated in CFI to detect CTL mediated immune responses against leukemic progenitor/stem cells (LPC/LSC). We also added immune checkpoint inhibitors to investigate whether these immune responses could be enhanced.

Against the LAA PRAME-P3, WT1 and RHAMM-R3 we detected similar frequencies of T cell responses in CFI in NPM1 mut compared to NPM1 wt pts. Antigen specific immune responses were detected in CFI by comparing growth of patient cells alone with growth by addition of antigen specific CTL and calculating colony reduction.

Comparing NPM1 mut/NPM1 wt pts many had an immune response to LAA, more than 50% of the pts in both cohorts exhibited an immune response against all epitopes.

In NPM1 wt pts no responses were found against the NPM1 epitope as expected, whereas NPM1 mut patients showed a high frequency of immune responses in 10/15 NPM1 mut AML pts (67%) in CFI a reduction of colonies was detected.

With the addition of anti-PD1 antibody to CFI we detected an increase of immune responses. For the LAA responses were similar comparing NPM1 mut/NPM1 wt.

Compared to LAA, the epitope NPM1 showed a particularly strong immune response when the antibody anti-PD1 was added. All 15 NPM1 mut pts showed an immune response with anti-PD1, with a median reduction of colonies of 47%. 7 of 15 NPM1 mut pts showed a strong immune response against LPC/LSC in CFI with more than 50% reduction of colonies.

The data suggest that especially NPM1 mut patients are suitable candidates for antibody therapy with the PD1 antibody. Combination with another immunotherapy such as an NPM1 specific vaccine would be a possibility. Even though no advantage in therapy with the anti-PD1 antibody has yet been shown in the overall AML collective, this therapy could be an option for patients with NPM1 mutated AML.

Disclosures

Greiner: Bristol Myers Squibb: Other: Unspecified Relationship. Schneider: AbbVie: Current Employment. Schrezenmeier: Novartis: Honoraria; Apellis: Honoraria; Sanofi: Honoraria; Alexion, AstraZeneca Rare Disease: Honoraria, Other: Travel support, Research Funding; Roche: Honoraria.
Interrogating Novel Bromodomain Inhibition Resistance Mechanism in Mllr Leukemia
Authors: Li Chunliang , Wright Shaela , Hu Jianzhong , Zhang Yang , Hyle Judith , Lu Rui
Published: November 2021

MLL-rearranged (MLLr) leukemias count for more than 80% of infant leukemia, ~5-10% of B-cell acute lymphoblastic leukemia (B-ALL), and ~10% of acute myeloid leukemia (AML) cases, where they confer a particularly poor outcome. Despite treatment with intensive multi-agent chemotherapy, most MLLr patients achieved an initial remission but ultimately relapsed. Bromo- and Extra-Terminal domain inhibitors (BETi) prevent the progression of many cancer types in preclinical studies, including MLLr leukemia. However, the mechanisms controlling drug response and resistance of BET inhibitors are not well understood.

We have addressed this timely, crucial scientific question by completing genetic screens to explore potential BETi resistance mechanisms. By conducting genome-wide and targeted loss-of-function CRISPR screens using MLLr AML cell lines upon BETi treatment including ABBV-744, JQ1, and dBET1, we discovered that Speckle Type POZ (SPOP) gene deficiency leads to significant BETi resistance in in vitro cell culture systems (SEM, OCI-AMl2 and MV4,11), and by in vivo transplantation of human MLLr leukemia SEM cells into immune-deficient mice. However, no BETi resistance phenotype was seen in non-MLLr SPOP-deficient cells. SPOP was previously reported as an adaptor protein to bridge the E3 ubiquitination complex component CUL3 to the substrate proteins BRD4 and MYC in prostate and many other solid cancers. However, in SPOP knockout MLLr leukemia cells, TRIM24, not BRD4 and MYC, was identified as a substrate likely responsible for SPOP's role in drug resistance. Genetically blocking TRIM24 via CRISPR knockout in SPOP-knockout cells reversed the BETi resistance phenotype. Transcriptomic analysis of TRIM24-deficient cells identified the GSK3A signature as the top influenced pathway. Additionally, proteomics expression analysis and a kinase vulnerability CRISPR screen also indicated that resistant cells are sensitive to GSK3B inhibition. Further validation by CRISPR knockout and pharmaceutical blockage of GSK3A/3B (by ChIR-98014) sensitized the SPOP-deficient resistant cells to BETi treatment in vitro. In SEM xenograft models in NSG mice, ABBV-744 or CHIR-98014 minimally impacted human CD45 + leukemia cell proliferation while synergistic treatment significantly reduced the tumor progression.

In summary, our data suggest the novel SPOP/TRIM24/GSK3A/3B axis plays an essential role in BETi therapy-resistant leukemia cells. Targeting GSK3A/3B pathways by ChIR-98014 can overcome SPOP-associated BETi resistance in in vivo preclinical models of MLLr leukemia. Successful outcomes following combination therapy using ChIR-98014 and BETi in PDX models would translate to a clinical application that holds the promise to cure MLLr leukemia.

Disclosures

No relevant conflicts of interest to declare.
Maintenance with Hypomethylating Agents after Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia and Myelodysplastic Syndrome: A Systematic Meta-Analysis
Authors: Kungwankiattichai Smith , Ponvilawan BEN , Roy Claudie , Tunsing Pattaraporn , Kuchenbauer Florian , Owattanapanich Weerapat
Published: November 2021

Background: After allogeneic hematopoietic stem cell transplantation (allo-SCT), 35%-45% of patients suffer disease relapse, resulting in dismal outcomes. Several strategies have been adopted to prolong disease-free intervals. Hypomethylating agents (HMA) seem to have a range of properties favorable to post-allo-SCT maintenance. They mediate a direct anti-leukemic effect in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), regardless of their molecular mutation profile. Moreover, their abilities to induce a CD8+ tumor-specific T cell response, together with the expansion of regulatory T cells, leads to an epigenetically enhanced graft-versus-leukemia effect that is not counterbalanced by an increased risk of graft-versus-host disease (GVHD).

Materials and Methods: Two investigators independently searched the Embase and MEDLINE databases for relevant studies published from inception to 31 January 2021. The inclusion criteria were as follows: (1) the studies had to be either randomized controlled trials or cohort studies; (2) the patients underwent allo-SCT for AML or MDS; (3) the studies compared 2 patient groups: one receiving HMA maintenance post-allo-SCT, and the other being an observational group; and (4) the studies needed to report at least one of our primary outcomes of interest; overall survival (OS), relapse-free survival (RFS), grade II-IV acute GVHD, and chronic GVHD.

Results: Eleven eligible studies compared HMA maintenance to observation following allo-SCT for AML or MDS. The OS of the HMA maintenance group was superior to the observation group, with a pooled odds ratio (OR) of 2.52 (95% CI, 1.60-3.94; I 2, 51%; Figure 1A). Similarly, a pooled meta-analysis found that the RFS was significantly better for patients receiving HMA maintenance, with a pooled OR of 2.64 (95% CI, 1.79-3.90; I 2, 0%; Figure 1B). Moreover, the cumulative incidence of relapse (CIR) was significantly lower in patients who received HMAs. The HMA group also had lower non-relapse mortality (NRM) compared with the observation group. Overall, the incidences of grade II-IV acute GVHD and chronic GVHD did not differ in both groups. However, when looking specifically at those receiving decitabine maintenance, the rate of chronic GVHD seemed to be lower compared with observation alone.

Conclusions: The current systematic review and meta-analysis illustrated that AML and MDS patients receiving HMA maintenance after allo-SCT had better outcomes in regards to OS, RFS, NRM, CIR as well as a reduced incidence of chronic GVHD.

Figure 1. Forest plots of the meta-analysis of HMA maintenance compared with observation. (A) OS rate. (B) RFS rate.

Figure 1 Figure 1.

Disclosures

No relevant conflicts of interest to declare.
Optimization of Thrombin Generation in Hemophilia a
Authors: Van De Berg Tom , Beckers Erik AM , Hackeng Tilman M.
Published: November 2021

Background: Hemophilia A (HA) is a bleeding disorder characterized by decreased or absent FVIII. Clinical analysis of coagulation potential in this patient population is classically based on APTT based FVIII assays. Although both the one-stage FVIII assay and the chromogenic FVIII assay can measure FVIII concentrations reliably these types of assays only give insight on the initiation of coagulation. Global coagulation assays, like thrombin generation (TG), can be used to measure the full coagulation spectrum of initiation, amplification and propagation. However the frequently used commercially available TG kits lack sensitivity for measurements of hemophilia plasma within the lower FVIII ranges which are essential in explaining differences in bleeding phenotype.

Aim: We aim to optimize the sensitivity of the TG-assay for measurements in hemophilia A patients, especially in the lower FVIII ranges.

Methods: In order to minimize patient specific sensitivity a hemophilia A pool plasma (HAPP) was created. Analysis of the influence of pre-analytical variables, like contact activation inhibitors, on the assay was performed. Initiation of coagulation by different reagents was compared for sensitivity towards factor FVIII titrations in patient plasma. Other assay variables like phospholipids and temperature were adjusted to increase sensitivity even further.

Results: Commonly used tissue factor (TF) initiated TG at varying concentrations was unable to significantly differentiate in FVIII levels below 20%. In contrast, TG activation with low concentrations of TF in presence of FXIa appeared to be highly sensitive for FVIII changes both in high and low ranges. Additionally, a representative baseline TG-curve in severe HA plasma could only be produced using this dual TF/FXIa-activation. There was a value in the addition of contact activation inhibitors in the assay. Higher phospholipid concentrations seem to benefit this assay setup compared to a TF only setup.

Conclusion: TF/FXIa dual activation thrombin generation increased assay sensitivity in severe hemophilia plasma, allows for dose-dependent measurements in low FVIII ranges and provides a solid baseline curve that can be used for further clinical evaluation of coagulation potential and possibly therapeutic monitoring in hemophilia A.

Figure 1 Figure 1.

Disclosures

Hackeng: ACS Biomarker BV: Current Employment, Current equity holder in publicly-traded company; Coagulation Profile BV: Current Employment, Current equity holder in publicly-traded company.