bluuebunny/crossref_metadata_2025 huggingface dataset:
Collective redress in labour and social law disputes: An (attractive) option for the EU?
Authors: Rasnača Zane
Published: November 2021

Collective redress has a lot of appeal as an enforcement tool, but historically it has been seen as somewhat unfitting for the European legal landscape. Despite this, many EU national legal systems have introduced collective redress mechanisms. The area of EU labour and social law, however, has been slow to catch up with this trend. This article discusses whether collective redress in labour and social law disputes could be an attractive option for the EU. Relying on an analysis of the legal opportunity structure it proposes some ideas on how to advance. All in all, collective redress is no panacea but could potentially complement and improve the EU enforcement toolbox, particularly in areas where there is evidence of persistent enforcement gaps.
Collective access to national courts for labour law and social policy disputes: Austria
Authors: Brameshuber Elisabeth , Kager Ines
Published: November 2021

With this paper we aimed to give an insight into Austria's labour and social security jurisdiction, notably into different forms of collective redress within this system. As the Austrian Labour and Social Courts Act provides for certain instruments of collective redress, the primary focus will be on those. The main drawback of those existing forms of collective action for labour law matters, however, is the lacking possibility for the single employee to enforce the respective judgement. Hence it can only serve as a legal test case. In that respect, instruments of Austria's general civil procedural law could present a practical alternative to the problem and thus the legal framework and ongoing academic debate about the application of those procedures is also a key part of the paper.
Use of coagulation-fibrinolysis markers for prognostication of Stanford type A acute aortic dissection
Authors: Arima Daisuke , Suematsu Yoshihiro , Kurahashi Kanan , Nishi Satoshi , Yoshimoto Akihiro
Published: November 2021

Purpose

Coagulation-fibrinolysis markers are widely used for the diagnosis of Stanford type A acute aortic dissection (SAAAD). However, the role of these markers in estimating prognosis remains unclear.

Methods

A single-center retrospective study was conducted to identify the relationship between preoperative D-dimer and fibrinogen levels on SAAAD postoperative early prognosis.

Results

Of 238 SAAAD patients who underwent surgery between January 2012 and December 2018, 201 (84.5%) and 37 (15.5%) patients constituted the survival and non-survival groups, respectively, 30 days after surgery. D-dimer and fibrinogen levels in the survival and non-survival groups were 45.2 ± 74.3 vs. 91.5 ± 103.6 μg/mL ( p = 0.014) and 224.3 ± 95.6 vs. 179.9 ± 96.7 μg/mL ( p = 0.012), respectively. According to logistic predictor analysis of 30-day mortality, significant factors showed patent type (OR 10.89, 95% CI 1.66–20.31) and malperfusion (OR 4.63, 95% CI 1.74–12.32). Increasing D-dimer (per +10 μg/mL) and decreasing fibrinogen (per −10 μg/mL) were significantly associated with patent type and malperfusion. Receiver operating characteristic analysis was performed to distinguish between survival and non-survival. The cutoff value of D-dimer was 60 μg/mL (sensitivity 61.1%; specificity 82.5%; area under curve [AUC] 0.713 ± 0.083); fibrinogen was 150 mg/dL (sensitivity 44.4%; specificity 84.0%; AUC 0.647 ± 0.092). Kaplan-Meier survival curve analysis showed that patients with D-dimer levels > 60 μg/mL and fibrinogen levels < 150 mg/dL had significantly low survival rates at 30 days after surgery (60.0%, p < 0.001).

Conclusion

Preoperative coagulation-fibrinolysis markers may be useful for predicting early prognosis in SAAAD.
Management and perinatal outcomes of hypertensive disorders of pregnancy in a low-resource setting in Indonesia
Authors: Tjandraprawira Kevin Dominique , Kusumah Aria Yusti , Kamilah Azka Yumna , Putri Dhini Isti , Ananta Mayang Rizky , Sari Selvi Puspa , Djuwantono Tono , Petrie Aviva
Published: November 2021

Objectives:

To provide up-to-date data concerning hypertensive disorders of pregnancy on maternal and neonatal profiles in Indonesia.

Methods:

Retrospective clinical audit on all pregnancy-associated hypertensive women between 1 January 2020 and 31 March 2020 at Cianjur General District Hospital.

Results:

Preeclampsia accounts for 66.8% (235/352) of hypertensive disorders of pregnancy, gestational hypertension 29% (102/352) and chronic hypertension 4.3% (15/352). Compared to other pregnant women, those with preeclampsia, on average, had higher systolic and diastolic blood pressures and poorer kidney (ureum and creatinine) and liver function (aspartate transaminase enzyme and alanine transaminase enzyme) profiles (p < 0.001, < 0.001, < 0.001, 0.003, 0.033 and 0.002, respectively), and required more intensive care admission. Neonates from women with severe forms of preeclampsia (eclampsia and HELLP syndrome (haemolysis, elevated liver enzymes, low platelets)) had, on average, lower birthweight (p = 0.015 and 0.048, respectively) and birth length (p = 0.021, 0.017). Neonates from eclamptic mothers had poorer APGAR (appearance, pulse, grimace, activity and respiration) scores (p = 0.006 and 0.005, respectively).

Conclusion:

Hypertensive disorders of pregnancy exerts adverse maternal and neonatal outcomes, particularly among eclampsia and HELLP-syndrome neonates. Various challenges remain for optimal management.
Towards nationally curated data archives for clinical radiology image analysis at scale: Learnings from national data collection in response to a pandemic
Authors: Cushnan Dominic , Berka Rosalind , Bertolli Ottavia , Williams Peter , Schofield Daniel , Joshi Indra , Favaro Alberto , Halling-Brown Mark , Imreh Gergely , Jefferson Emily , Sebire Neil J , Reilly Gerry , Rodrigues Jonathan C L , Robinson Graham , Copley Susan , Malik Rizwan , Bloomfield Claire , Gleeson Fergus , Crotty Moira , Denton Erika , Dickson Jeanette , Leeming Gary , Hardwick Hayley E , Baillie Kenneth , Openshaw Peter JM , Semple Malcolm G , Rubin Caroline , Howlett Andy , Rockall Andrea G , Bhayat Ayub , Fascia Daniel , Sudlow Cathie ,   NCCID Collaborative, Jacob Joseph
Published: November 2021

The prevalence of the coronavirus SARS-CoV-2 disease has resulted in the unprecedented collection of health data to support research. Historically, coordinating the collation of such datasets on a national scale has been challenging to execute for several reasons, including issues with data privacy, the lack of data reporting standards, interoperable technologies, and distribution methods. The coronavirus SARS-CoV-2 disease pandemic has highlighted the importance of collaboration between government bodies, healthcare institutions, academic researchers and commercial companies in overcoming these issues during times of urgency. The National COVID-19 Chest Imaging Database, led by NHSX, British Society of Thoracic Imaging, Royal Surrey NHS Foundation Trust and Faculty, is an example of such a national initiative. Here, we summarise the experiences and challenges of setting up the National COVID-19 Chest Imaging Database, and the implications for future ambitions of national data curation in medical imaging to advance the safe adoption of artificial intelligence in healthcare.
Incidence of malignancy in multiple sclerosis: A cohort study in the Danish Multiple Sclerosis Registry
Authors: Nørgaard Mette , Veres Katalin , Sellebjerg Finn T , Svingel Lise S , Foch Caroline , Boutmy Emmanuelle , Sabidó Meritxell , Magyari Melinda
Published: November 2021

Background

The association between multiple sclerosis and malignancy is controversial and a current appraisal is needed.

Objective

To determine the incidence of malignancy in patients with multiple sclerosis compared with the general population and in relation to disease-modifying therapy.

Methods

Patients with multiple sclerosis (1995 – 2015) were matched by birth year and sex to individuals without multiple sclerosis in the general population. Patients with multiple sclerosis initiating disease-modifying therapy were evaluated using landmark period analysis. Malignancy risk was assessed by incidence rates, incidence rate ratios, and standardised incidence ratios.

Results

The standardised incidence ratio of any malignancy (excluding non-melanoma skin cancer) in patients with multiple sclerosis ( n = 10,557) was 0.96 (95% CI 0.88 – 1.06), and there was no increased incidence of specific malignancy types compared with the general population cohort ( n = 103,761). At the 48-month landmark period, the age-adjusted incidence per 100,000 person-years of any malignancy (excluding non-melanoma skin cancer) was 436.7 (95% CI 361.0 – 512.4) in patients newly treated with immunomodulator-only and 675.1 (95% CI 130.4 – 1219.9) in patients newly treated with immunosuppressant-only.

Conclusions

There was no increased incidence of malignancy overall or by type in patients with multiple sclerosis compared neither with the general population nor in relation to disease-modifying therapy.
Optimal timing for laparoscopic cholecystectomy in the treatment of gallbladder calculi incarceration
Authors: Bao Jian-Heng , Wang Yu-Jie , Shang Hai-Tao , Hao Cheng-Fei , Liu Jun-Jian , Zhang De-Lin , Han Shu-Wang , Li Zhong-Lian
Published: November 2021

Objective

Laparoscopic cholecystectomy (LC) has become a popular method in the treatment of gallbladder calculi incarceration (GCI). This study aimed to investigate the effect of early and delayed LC on patients with GCI to determine the optimal timing for LC.

Methods

The clinical data of 639 patients with GCI who had received LC were analyzed retrospectively. According to the duration of symptoms before admission and that from admission to LC, the patients were divided into different groups. The relationship between conversion and postoperative complications was compared among the different groups.

Results

Seventy-two patients (11.27%) underwent conversion to laparotomy, and 65 patients (10.17%) had postoperative complications. Patients in the LC > 15 d group were older ( p < 0.001), had a longer operation time ( p < 0.001), had a longer duration of hospitalization ( p < 0.001), had a higher proportion of conversion ( p < 0.001), and had a higher incidence of postoperative complications ( p < 0.001). Type 2 diabetes mellitus (T2DM) (RR = 1.701; 95% CI: 1.410–2.047; p < 0.001) and duration from admission to LC (RR = 7.072; 95% CI: 3.044–16.431; p < 0.001) were independent risk factors for conversion. Older age, T2DM, CRP, duration of symptoms before admission >3  m, and duration from admission to LC > 15 d were independent predictors of postoperative complications.

Conclusion

For patients younger than 65 years without contraindications, early operation should be performed within 3 d after admission to reduce the operation time, hospitalization time, conversion, and postoperative complications.
The Perceived Demands of Ice Hockey Goaltending Movements on the Hip and Groin Region: An Elite Coach and Player Perspective
Authors: Wörner Tobias , Frayne Ryan J. , Magnusson Thomas , Eek Frida
Published: November 2021

Background:

Many ice hockey goaltending techniques force hip joints and groin muscles into extreme ranges of motion, which may increase the risk of hip and groin problems.

Purpose:

To explore how elite goaltenders and goaltending coaches perceive the demands of common goaltending techniques on the hip and groin region. We further explored differences in perception between goaltenders and their coaches as well as between junior (age <20 years) and senior (age ≥20 years) goaltenders.

Study Design:

Cross-sectional survey.

Methods:

We developed a model to categorize common ice hockey goaltending techniques into quantifiable units and invited elite goaltenders and coaches in Sweden to complete an online survey. Participants were asked to rate the perceived demands of each technique on the hip and groin using a Likert scale (not at all, slightly, somewhat, very, or extremely demanding). Using the chi-square test, the proportion of participants perceiving each technique as very or extremely demanding were compared between goaltenders and coaches as well as between senior and junior goaltenders.

Results:

We received responses from 132 goaltenders and 43 coaches. The stances most frequently perceived as very or extremely demanding were the reverse vertical horizontal post-play (40%) and the butterfly save (25%). Among transitions, movements into the post were most frequently rated as very or extremely demanding (11%–40%). Several techniques were perceived as demanding by a larger share of coaches than goaltenders (difference, 13%–46%; P < .001–.028) and a larger share of senior versus junior goaltenders (difference, 12%–20%; P = .13–.18).

Conclusion:

The post-play and the butterfly were the goaltending techniques most frequently perceived as demanding, and more coaches than goaltenders percieved these techniques demanding. The results of this study may inform injury prevention efforts for ice hockey goaltending.
A Cross-sectional Study of Patients and Physicians on the Impact of Myeloproliferative Neoplasms on Patient Health: The Landmark Survey From Taiwan
Authors: Chang Cheng-Shyong , Chen Chieh-Wen , Chiang I-Ju , Ku Fan-Chen , Lee Yee-Ming , Siddiqui Asif
Published: November 2021

Patients with myeloproliferative neoplasm (MPN), including myelofibrosis, polycythemia vera, and essential thrombocythemia, experience a pronounced symptom burden. This study aimed to collect information from physicians and patients in Taiwan to explore their perceptions regarding MPN, treatment goals, and satisfaction with disease management. A cross-sectional, online survey was conducted among patients and physicians from September 2018 to November 2018 in Taiwan as a subset of the expansion of the Landmark survey. Overall, 50 patients with MPN and 30 physicians participated in this study. The symptom burden was low, with the mean number of symptoms experienced being 1.8. The most frequent symptom per physicians’ perception was fatigue, whereas it is not the most common symptom from MPN patients’ perspective. Blood count was the key indicator to determine treatment success from patients’ view, whereas presence of a new symptom was the key indicator from physicians’ perspective. Concordant with previous studies, our study revealed a lack of alignment between physician and patient perceptions relating to treatment goals and disease management. Nevertheless, the physical, emotional, work/activities and financial impacts on patients were minimal in Taiwan.
A Novel Risk Scoring System to Predict Survival in Soft Tissue-Related Extramedullary Multiple Myeloma
Authors: Huang Beihui , Wang Qing , Li Wuping , Zhao Ying , Li Juan
Published: November 2021

Objective:

Extramedullary multiple myeloma (EMM) is an aggressive subtype of multiple myeloma, especially those soft tissue-related extramedullary multiple myeloma (EM-S). Plasma cells often infiltrate in extramedullary tissues, but the proportion of plamas cells in bone marrow is not high, so FISH test often produces false negative results. Therefore, the R-ISS staging system cannot predict the really prognosis of this type of patients. A novel risk score is needed for these patients.

Methos: A cohort of 73 patients with EM-S in four centers in China were included, excluding those only with bone related extramedullary multiple myeloma, primary or secondary plasma leukemia. We performed univariate and multivariate Cox regression analysis, generated risk scores to predict outcomes in EM-S MM and compared with R-ISS staging.

Results: In the Cox multivariate model, high LDH, low count of platelet、central nervous system involved, abdominal viscera involved (including liver, spleen, pancreas, kidney) and Ki67≥70% were found to significantly and independently predict outcomes for EM-S. According to these parameters, the patients were divided into three groups: the low-risk group with a median TTP of 14.13 months, and the medium-risk group with a median TTP of 8.53 months. In the high-risk group, the median TTP was 2.73 months (p<0.05 between any two groups). This novel risk is better to predict prognosis of this group of patients than R-ISS stage, in which the TTP in R-ISS stage I was 20.33 months, R-ISS stage II 9.83 months, and R-ISS stage III 4.83 months (p=0.065). Conclusion: The novel risk stratification for EM-S may be may be superior to R-ISS for EM-S MM patients.

Figure 1 Figure 1.

Disclosures

No relevant conflicts of interest to declare.
Efficacy and Safety of CD19-Targeted CAR-T Cell Therapy for Refractory/Relapsed B-Cell Lymphoma: A Single Center of Real World Data
Authors: Huang Jing , Fei Jia , Ou Ruiming , Liu Zhi , Zheng Liling , Zhu Yangmin , Shen Huijuan , Du Yuanyuan , Zhou Qinjun , Chen Jiali , Zhou Changhua , Yan Rongrong , Wang Jiale , Liu Shuang , Zhang Qing
Published: November 2021

【Abstract】 Objective To investigate the efficacy and safety of CD19-targeted chimeric antigen receptor T cell (CAR-T cell) for refractory/relapsed B-cell lymphoma. Methods The efficacy and safety of CD19-CAR-T cells(4-1BB costimulatory domain) in treatment of 12 patients with relapsed/refractory B-cell lymphoma from March 2018 to December 2019 in the Department of Hematology of Guangdong Second Province Hospital were collected analyzed retrospectively. There were 9 patients (75%) with diffuse large B cell lymphoma, 1 patient with blastic variant of mantle cell lymphoma, 1 patient(8.3%) with Burkitt lymphoma, 1 patient with B cell non-Hodgkin lymphoma that cannot be classified. 3 patients (25%) with large mass (≥7.5cm) and 9 patients (75%) with ECOG score ≥2. The number of chemotherapy courses received before transfusion was 4-9, the median number of chemotherapy courses was 7. All 12 patients were autogenous mouse CAR-T cells. Fludarabine + Cyclophosphamide (FC) regimen was used for pretreatment before transfusion, and the number of CAR-T cells was 1 ~ 3.69×10 6/kg. Results All 12 patients received CD19-targeted CAR-T cell therapy. There were 9 patients had treatment response, and the total effective rate was 75%. Among them, there were 3 patients with complete response (CR), with CR rate of 25%, and 6 patients with partial response (PR), with PR rate of 50%. Among the 3 patients with CR remained CR at the follow-up date. Among the 6 patients with PR, 4 showed disease progression in the second month after transfusion, and 2 showed disease progression in the third month after transfusion. All the 9 patients with effective treatment had different degrees of cytokine release syndrome (CRS), including 3 level-1 CRS, 4 level-2 CRS, and 2 level-3 CRS. Two of them had grade 2 CRES, and all CRS and CRES were controlled after treatment with IL-6 receptor antagonists and glucocorticoids. None of the 3 patients failed to respond to treatment had CRS. Conclusion CD19-targeted CAR-T cell immunotherapy has been shown to be effective in CD19-antigen positive B-cell lymphoma, and adverse CRS reactions during treatment can be controlled after treatment. Patients who obtained CR seemed to be able to maintain long-term CR status, while patients who failed to obtain CR showed disease progression within a short period of 3 months, suggesting that patients who obtained CR at an early stage could achieve better efficacy. Therefore, how to identify patients who receive CR at an early stage may be a research direction for the clinical application of CAR-T cell immunotherapy in B-cell lymphoma.

【Key words】Chimeric antigen receptor T-cell; Relapsed/refractory B cell lymphoma; Efficacy; Safety; Cytokine release syndrome

Disclosures

No relevant conflicts of interest to declare.
Early Platelets Elevation after Complete Remission in Favorable- and Intermediate-Risk Acute Myeloid Leukemia Is an Independent Predictor of Favorable Outcomes:a Retrospective Study
Authors: Wen Xiaoling , Zhang Ruijuan , Li Ruoqi , Zhai Jiahong , Yang Suxia , Wang Yaozi , Zhang Xialin , Tan Yanhong , Yang Linhua
Published: November 2021

Platelet (PLT) recovery after chemotherapy is associated with the prognosis in patients with acute myeloid leukemia (AML); however, its predictive value is yet controversial. A total of 206 de novo non-M3 AMLs treated at the Second Affiliated Hospital of Shanxi Medical University from January 2014 to December 2020 and achieved complete remission (CR) were analyzed in this retrospective study. The overall survival (OS) and relapse-free survival (RFS) were assessed using Kaplan-Meier and Cox regression analyses.According to receiver operating characteristic (ROC) curve analysis, 312×10 9/L was confined as the cutoff of the PLT count, and hence, we divided patients into high PLT group (≥312×10 9/L) and low PLT group (100≤PLT<312×10 9/L). Multivariate analysis revealed that early (we defined the highest PLT count from 28-42 days after induction chemotherapy as early platelet count and called it D28 PLT) high PLT count (≥312×10 9/L) recovery showed favorable RFS (hazard ratio (HR)=0.409, p=0.001) and OS (HR=0.394, p=0.001). The subgroup analysis demonstrated that patients in the favorable- and intermediate-risk (non-adverse-risk ) group with D28 PLT≥312×10 9/L showed better survival outcomes (RFS: HR=0.289, p=0.001; OS: HR=0.266, p<0.001) compared to those with 100≤PLT<312×10 9/L. The current study showed that early high PLT count recovery at CR in non-adverse-riskAMLs is an independent positive predictive factor for survival outcomes.

Disclosures

No relevant conflicts of interest to declare.
Protective Role of Plasminogen Deficiency in Non-Alcoholic Fatty Liver Disease and Glucose Dysmetabolism
Authors: Hur Woosuk Steve Steve , Nyugen Y-Van , Flick Matthew J.
Published: November 2021

Obesity is global health problem with 40% of the world population being classified as overweight (BMI > 25) and 13% as obese (BMI > 30). Obesity drives chronic metabolic inflammation leading to metabolic syndrome, cardiovascular disease, fatty liver disease, Type II diabetes, and certain cancers. A documented clinical manifestation of obesity is perturbed and dysregulated hemostatic system leading to a procoagulant and anti-fibrinolytic state that ultimately results in an increased risk of thrombosis.

Previous work suggested that clotting system components thrombin and fibrin engage in reciprocal mechanisms and contribute to the development of obesity. Specifically, we have shown that fibrin accumulates within obese adipose tissue and liver of obesity patients and mice challenged with a high fat diet (HFD) and colocalizes with macrophages, a key driver of inflammation in obesity. Despite the fact that obesity is known to be linked to an impaired fibrinolytic system, a potential functional contribution of fibrinolytic proteases to the development of obesity and associated downstream diseases has been understudied.

Here, we tested the hypothesis that elimination of the fibrinolytic protease plasminogen would increase HFD-driven fibrin deposition and exacerbate macrophage accumulation and subsequent weight gain and obesity-associated pathologies. Contrary to our hypothesis, plasminogen-deficient (Plg-) mice gained as much weight as the Plg+ mice after 20 weeks on HFD. However, whereas the liver mass of HFD-challenged Plg+ mice was significantly higher than that of low fat diet (LFD)-fed mice, the livers of HFD-fed Plg- mice had a mass comparable to LFD-fed mice. HFD-fed Plg- mice had reduced hepatocellular damage, measured by plasma ALT activity, as well as reduced hepatosteatosis, measured by hepatic triglyceride content and liver histology, compared to HFD-fed Plg+ mice. Circulating cholesterol levels in HFD-fed Plg -/- mice were comparable to LFD-fed Plg- mice, while it was significantly elevated in HFD-fed Plg+ mice. While the epididymal white adipose tissue mass was higher in HFD-fed Plg- mice compared to HFD-fed Plg+ mice, the brown adipose tissue mass was comparable. However, there was an upregulation of uncoupling protein-1 (UCP-1) expression BAT of HFD-fed Plg- mice. Glucose clearance was more efficient in HFD-fed Plg- mice compared to HFD-fed Plg+ mice in a glucose tolerance test. Collectively, our data suggest that plasmin(ogen) contributes to HFD-induced fatty liver disease and glucose dysmetabolism.

Disclosures

No relevant conflicts of interest to declare.
High-Throughput Chemical Screen on Acute Myeloid Leukemia Stem Cells Identifies Novel Anti-LSC Compounds
Authors: Iasenza Isabella Angela , Safa Safia , Barabe Frederic , Cellot Sonia , Wilhelm Brian T. , Eppert Kolja
Published: November 2021

Acute myeloid leukemia (AML) is an aggressive form of blood cancer defined by the uncontrolled proliferation and clonal expansion of immature myeloblast cells in the blood and bone marrow, leading to hematopoietic failure. Despite the use of aggressive and cytotoxic standard-of-care drugs, patients often relapse and succumb to the disease partially due to the inability of medically unfit patients to withstand the cytotoxic treatments, regrowth from minimal residual disease and the chemo-resistant nature of leukemic stem cells (LSCs) which can remain in a quiescent state and reside in a protective bone marrow niche. Hence, novel therapies targeting unique leukemic stem cell biology are highly needed to eliminate and avoid reoccurrence.

High-throughput screens of human AML LSCs are not performed due to technical issues such as low LSC frequency within primary samples, an inability to purify LSCs, and the difficulty maintaining and expanding primary patient samples and LSCs in vitro. We were able to optimize conditions for a 4-week in vitro large-scale expansion (>600 million bulk) of the primary human AML sample 8227 (OCI-AML-8227), functionally validated to be enriched for LSCs in long-term xenotransplant assays (Eppert et al., 2011). These optimized conditions enabled the isolation and maintenance of the LSC-containing fraction for a chemical screen. We isolated the CD34+ LSC-containing fraction (>90% purity) and performed a high-throughput screen of 11,166 chemical molecules using a CellTiter Glo assay followed by a counter screen against normal CD34+ cord blood (CB) hematopoietic stem and progenitor cells.

From this HT screen, a total of 61 hits had >70% inhibition on CD34+ 8227 cells and <30% inhibition on CD34+ CB cells. We also identified glucocorticoids, which were also identified in our prior small-scale anti-LSC screen where they were found to specifically drive human LSCs to terminally differentiate (Laverdière & Boileau, et al., 2018).

We then performed dose response assays for each candidate compounds and confirmed 35 potent anti-LSC compounds with IC 50 < 1 μM. This refined the types of compounds to including anti-apoptotic inhibitors, GSK inhibitors, protease inhibitors, metabolism inhibitors, HDAC inhibitors, BET inhibitors, nucleic acid synthesis inhibitors, cell cycle inhibitors and Wnt/β-catenin inhibitors. This is interesting as some of the classes of these compounds (inhibitors of GSK, BET, nucleic acid synthesis, Wnt/β-catenin and metabolism) have been shown to target bulk and leukemic stem cells in AML in vitro and in vivo.

We now aim to examine LSC eradication in a panel of genetically defined primary AMLs confirmed through in vitro and in vivo assays. Our goal is to be able to understand and establish the molecular mechanisms and biomarkers on primary functional LSCs.

Disclosures

No relevant conflicts of interest to declare.
Diagnosis and Treatment of Acquired Hemophilia: One Single-Center Experience from PR. China
Authors: Zhou Rong-Fu , Xu Yueyi , Gao Wenjin
Published: November 2021

Objective: To deepen the understanding of the clinical manifestations of acquired hemophilia A for timely and correctly treatment.

Methods: The clinical data of the acquired hemophilia A patients diagnosed in the hospital from Jan 2006 to Mar 2021 were retrospectively analyzed, and the relevant literature was reviewed.

Results: 17 patients with acquired hemophilia A, male: female =10: 7, median age 61 years (19 to 78 years), were diagnosed and treated in the hospital with the median time from the onset to diagnosis 21 days (2 days to 6 months). Six patients had comorbidity, including hepatitis B carrying, chronic myelomonocytic leukemia, diabetes, hypertension and positive autoantibodies, pemphigoid and gastric cancer, respectively. Other 11 patients were healthy before the onset. All patients had large large ecchymosis of skin, and one case was combined with hematuria, and one case with retroperitoneal hematoma. All patients had APTT extension (45s-144.7s) and the prolonged APTT could not be corrected with normal mixed plasma with and without incubation at 37℃ for 2 hours. FVIII activity was 1% - 8.9% and inhibitor titer 2 - 128 Bu/ml. All patients with bleeding were with prothrombin complex/recombinant activated coagulation factor VII, some of them with pd-coagulation factor FVIII preparations. Inhibitors were removed with prednisone acetate (1 case) + chemotherapy (1 case), prednisone acetate / + CTX (11 cases) + chemotherapy (1 case), prednisone acetate/prednisolone + mabthera (2 cases) + CTX (1 case), respectively. The removal time of inhibitor was from 8 days to 4 years. During the treatment process, two patients developed lower extremity venous thrombosis, and one patient was complicated with lung infection.

Conclusion: Patients with unexplained bleeding and prolonged APTT should be conducted normal mixed plasma correction test, coagulation factor activity and inhibitor titer examination. After correctly diagnosis, bypass agents /coagulation factor VIII preparations should be given timely for hemostasis, protocol based on glucocorticoid + CTX/mabthera to remove the inhibitor and symptomatic treatment for patients with primary comorbidity disease at the same time.

Disclosures

No relevant conflicts of interest to declare.
Ethnic Disparities in AL Amyloidosis Outcomes Among Hospitalized Patients in the United States
Authors: Al Hadidi Samer , Dongarwar Deepa , Salihu Hamisu , Schinke Carolina , Thanendrarajan Sharmilan , Zangari Maurizio , van Rhee Frits
Published: November 2021

INTRODUCTION

Health disparities in immunoglobulin light chain (AL) amyloidosis have not been well described. We aimed to assess if health disparities between non-Hispanic (NH)-Whites, NH-Blacks and Hispanics exist and to describe differences between different ethnic/racial groups.

METHODS

We conducted a retrospective cross-sectional analysis of in-patient AL amyloidosis hospitalizations from 2016 to 2018 using the Nationwide Inpatient Sample (NIS), a database which provides nationally representative information on hospitalizations in the U.S. The studied period was chosen to capture data from the ICD-10-CM codes to avoid misclassification of AL amyloidosis which was grouped with other cases of ATTR amyloidosis in the ICD-9-CM coding system. All hospitalizations in adults (age ≥18 years) were included. The exposure for the study was the occurrence of AL amyloidosis in the discharge records. Outcomes were [1] in-hospital death [2] chemotherapy use; [3] intensive care unit (ICU) utilization; [4] palliative care consultation. The analysis for this study was performed using R program version 3.5.1; a 5% type I error rate for all hypothesis tests (two-sided) was assumed.

RESULTS

Admissions related to AL amyloidosis constituted 0.03% of all hospitalizations in the study period (25,470 of 90,869,381). The prevalence of AL amyloidosis related hospitalizations was higher in NH-Blacks when compared with NH-Whites (42.8 vs.28.1 per 100,000 hospitalizations). AL amyloidosis related in-hospital mortality rate was higher in NH-Whites and Hispanics when compared to NH-Blacks (6.6%% and 6.2% vs. 4.9%). In-hospital mortality with AL amyloidosis was higher in older patients, males and those who self-paid for their treatment. Utilization of ICU care was more common in NH-Blacks when compared to NH-Whites (6% vs. 4.8%). Hispanics had the lowest inpatient chemotherapy use (1.7% vs. 2.9%). Multivariable adjusted association between race/ethnicity and various outcomes showed a trend towards lower in-hospital mortality in NH-Blacks when compared to NH-Whites (OR: 0.76, 95% CI: 0.55-1.05, p=0.09) and lower utilization of palliative care services in NH-Blacks when compared with NH-Whites (OR: 0.61, 95% CI: 0.42-0.88, p=0.01). Despite very low numbers of transplant related admissions, such admissions occurred only in NH-Whites.

CONCLUSIONS

Our findings highlight disparities in AL amyloidosis care for NH-Blacks and Hispanics. NH-Blacks tend to have lower in-hospital mortality with higher utilization of ICU care, nevertheless, they receive the lowest palliative care services. Despite the higher utilization of ICU care, data suggest possible superior outcomes of AL amyloidosis in NH-Blacks when compared to NH-Whites.

Disclosures

No relevant conflicts of interest to declare.
Quantification and Characterisation of Nano-Sized Particles in Cryoprecipitate Units
Authors: Hwang Ji Hui , Tung John-Paul , Flower Robert L , Pecheniuk Natalie M
Published: November 2021

Background

Cryoprecipitate is an important blood product derived from fresh frozen plasma. It is primarily used to replenish fibrinogen levels in patients. Currently, there is a lack of studies characterising nano-sized particles, including extracellular vesicles (EVs) in cryoprecipitate. EVs play a key role in cell-to-cell communication in physiological and pathological conditions, through the transference of their bioactive cargo such as proteins, lipids, or nucleic acids. This study utilised modern techniques such as nanoparticle tracking analysis (NTA) to characterise these EVs.

Methods

We obtained ten individual cryoprecipitate units and determined their particle concentration and size distribution using optimised NTA parameters on the Nanosight NS300 instrument.

To prevent blockage of the Nanosight's micro-fluidics, samples are routinely filtered before sample injection. Therefore, we wanted to investigate if different filter materials could impact NTA measurements for cryoprecipitate. Samples were filtered with either regenerated cellulose (RC) or polytetrafluoroethylene (PTFE), with non-filtered samples as control. A one-way ANOVA with Tukey post hoc test was used to compare the particle parameters (particle concentration, mean, mode). Significance was set at p<0.05.

Results

The results showed that different cryoprecipitate units varied in their particle concentration and size, with an average concentration of 2.501 x 10 11 ± 1.098 x 10 11 particles per mL and a particle mean of 133.8 ± 7.5 nm and mode of 107.9 ±11.06 nm. In addition, only samples filtered using RC were there no significant changes in the measured particle parameters (particle concentration, p=0.936; mean, p=0.999; mode, p=0.996) compared to the non-filtered samples. A significant difference was observed in the mean of particle size between PTFE and RC filters (112.7 ± 6.033 nm, 42 133.8 ± 7.503 nm, p =<0.0001) and between PTFE and non-filtered (112.7 ± 6.033 nm, 133.7 ± 13.63 nm, p =0.0015). PTFE significantly reduced the particle mean compared to both RC and non-filtered.

Conclusions

Our findings revealed that NTA could be used as a novel method to measure particles in cryoprecipitate. Furthermore, RC filters are compatible with quantitative NTA analysis compared to PTFE filters.

Disclosures

No relevant conflicts of interest to declare.
Patterns of Family History of Cancer in Adults with Hematologic Malignancies
Authors: Seiter Karen , Swa Kyaw , Htun Kyaw , Baskind Paul , Liu Delong
Published: November 2021

Hematologic malignancies have generally been considered to be sporadic diseases. More recently several germ line mutations that lead to hereditary hematologic malignancies have been discovered, even in adults. We sought to evaluate the frequency of a family history of hematologic or other malignancy in pts admitted to the hospital for treatment of a hematologic malignancy. We also studied exposure history including use of cigarettes. All pts signed informed consent. Pts were entered prospectively and interviewed with a standard questionnaire. 702 pts (median age 61.9: range 16.3-91.3 years) were enrolled. Diagnoses were AML: 396 pts, aplastic anemia: 5 pts, ALL: 96 pts, CLL: 24 pts, CML 42 pts, CMML 10 pts, MDS 30 pts, MM 19 pts, MPD 10 pts, and NHL 70 pts. 473 pts (67.4%) had a family member with cancer. There was a total of 1037 cancers in these family members. The median number of family members with cancer was 1 (range 0-10). The frequency of each type of family member cancer is displayed in the table. 19.7% of pts had a family member with leukemia or other hematologic malignancy (leukemia: 12.0%, other hematologic: 7.7%). Compared to pts with a hematologic malignancy other than AML, pts with AML were more likely to have a family member with any type of cancer (72.4% vs 60.7%, p=0.001). Pts with AML were also more likely to have a family member with a history of any type of hematologic malignancy (22.4% vs 16.0%, p=0.03), but not specifically a history of leukemia (13.4% vs 10.1%, p=0.11). Compared to pts with hematologic malignancies other than AML, pts with AML were also more likely to have a family member with prostate cancer (16.2% vs 9.5%, p=0.01), or breast cancer (29.5% vs 21.9%, p=0.02). 51.4% of pts had a history of smoking (either current or prior). Pts with AML were more likely to be current or former smokers compared to pts with other hematologic malignancies (55.8% vs 45.8%, p=0.008). These data support the role of genetics and exposure in adults with AML.

Figure 1 Figure 1.

Disclosures

Seiter: Delta FLY: Research Funding; Novartis: Honoraria; Rafael: Research Funding; Sun Pharma: Research Funding; Jazz: Honoraria, Research Funding; Glycomimetics: Research Funding; Incyte: Honoraria; Forma: Research Funding; Celgene (BMS): Honoraria, Research Funding. Liu: Beigene: Honoraria, Speakers Bureau; Pfizer: Research Funding; Astellas: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Speakers Bureau; Incyte: Honoraria; Celgene: Research Funding.
Follicular Lymphoma Grade 3A Is Different from Grade 1/2 in the Real World
Authors: Li Chunyuan , Yang Ping , Wan Wei , Liu Shuozi , Jing Hongmei
Published: November 2021

Background: follicular lymphoma (FL) is histologically subdivided into grades 1/2(FL1/2), 3A(FL3A), and 3B(FL3B). FL3B is more like diffuse large B-cell lymphoma (DLBCL), while the clinical approach to FL1/2 and FL3A has been debated. We aim to explore the clinical, biological characteristics and outcomes between them.

Methods: A retrospective analysis of 195 de novo FL patients within the same time frame (1999 to 2020) was identified. 141 patients were FL1/2, and 54 patients were FL3A.

Results: Comparing with FL1/2, FL3A patients tend to present ECOG≥1, B symptoms, bone marrow involvement, digestive tract involvement, elevated LDH, Ki-67≥30%, CD10 negative, and multiple myeloma oncogene-1(MUM1) positive, while Ann Arbor stage I or II was usually seen in FL1/2. After received CHOP±R (cyclophosphamide, doxorubicin, vincristine and prednisone ±rituximab), the 5-year overall survival (OS) was 89.5% for FL1/2 and 61.1% for FL3A [ HR =3.742(95%CI:1.838-7.620),P <0.0001], the 5-year progression-free survival (PFS) was 62.5 for FL1/2 and 47.6% for FL3A [ HR =2.113(95%CI:1.297-3.443),P =0.003].

Conclusion: FL3A is more aggressive both clinically and biologically compared with FL1/2, and more attention should be paid to the difference of treatment between them.

Figure 1 Figure 1.

Disclosures

No relevant conflicts of interest to declare.
The Comparison of Dasatinib 70 Mg/Day to 100 Mg/Day in Newly Diagnosed Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP): A Multicenter, Prospective, Randomized Controlled Study
Authors: Yu Dan , Yang Zhuangzhi , Cheng Hui , Jiang Rui , Guo Jingming , Wan Chucheng , Qin Jun , Zhang Youshan , Yuan Guolin , Jiang Daozi , Zhang Chun , Liu Fang , Zhang Min , Chen Shiming , Liang Caixia , Zou Jing , Wu Zhiwei , Zou Xiuping , Han Danlei , Chen Xu , Wang Li , Lv Tingting , Tian Xiaolong , Xie Yanping , An Hongyu , Yan Li , Zhang Yicheng , Li Weiming
Published: November 2021

Background:

The purpose of this study is to compare efficacy and safety of patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with frontline dasatinib 70 mg/day with those who received standard-dose dasatinib 100 mg/day.

Method:

From July 2019 to July 2021, 81 patients with newly diagnosed CML-CP were enrolled across 11 centers. All of the patients were randomly treated with dasatinib 70 mg/day (N=43) or standard-dose dasatinib 100 mg/day (N=38).

Results:

Among 81 enrolled patients, 16 patients were off study at different times for different reasons.All patients achieved hematological remission after 3 months of treatment, and the best response rates were 84.00% (21/25) and 88.89% (24/27) for 70mg/d and 100mg/d groups (P>0.05).At 6 months, the best response, complete cytogenetic response (CCyR) and major molecular response (MMR) rate were 94.44% vs 92.86% (P > 0.05), 94.44% vs 92.86% (P > 0.05) and 55.56% vs 71.43% (P > 0.05), respectively.At 9 months, the rates of CCyR and MMR were 90.91% vs 88.89% (P > 0.05) and 66.67% vs 72.73% (P > 0.05);CCyR and MMR by 12 months, respectively, were 90.91% vs 100.00% (P > 0.05), 81.82% vs 80.00% (P > 0.05).The adverse events (AEs) of the two groups were mild, and there was no significant difference (P > 0.05).The most common grade ≥3 hematological AEs in 70 mg/d group were leukopenia (1/43), neutropenia (1/43) and anemia (2/43), and In 100mg/d group were leukopenia (4/38), neutropenia (6/38), anemia (3/38) and thrombocytopenia (3/38).

Conclusions:

Our study suggests that patients with newly diagnosed CML-CP treated with dasatinib 70 mg/day or 100 mg/day, there is no significant difference in efficacy and safety. Decreasing the dose of dasatinib can ensure the efficacy of patients, while reducing the economic burden of patients and increasing patient compliance.

Disclosures

No relevant conflicts of interest to declare.
Functional Verification of Novel ELMO1 Variants By Live Imaging in Zebrafish
Authors: Xue Rongtao , Wang Ying , Wang Tienan , Lyu Mei , Mo Guiling , Fan Xijie , Li Jianchao , Yen Kuangyu , Yu Shihui , Xu Jin , Liu Qifa
Published: November 2021

ELMO1 (Engulfment and Cell Motility1) is a gene involved in regulating cell motility through the ELMO1-DOCK2-RAC complex. Contrary to DOCK2 (Dedicator of Cytokinesis 2) deficiency, which has been reported to be associated with immunodeficiency diseases, variants of ELMO1 have been associated with autoimmune diseases, such as diabetes and rheumatoid arthritis (RA). To explore the function of ELMO1 in immune cells and to verify the functions of novel ELMO1 variants in vivo, we established a zebrafish elmo1 mutant model. Live imaging revealed that similar to mammals, the motility of neutrophils and T-cells was largely attenuated in zebrafish mutants. Consequently, the response of neutrophils to injury or bacterial infection was significantly reduced in the mutants. Furthermore, the reduced mobility of neutrophils could be rescued by the expression of constitutively activated Rac proteins, suggesting that zebrafish elmo1 mutant functions via a conserved mechanism. With this mutant, three novel human ELMO1 variants were transiently and specifically expressed in zebrafish neutrophils. Two variants, p.E90K (c.268G>A) and p.D194G (c.581A>G) could efficiently recover the motility defect of neutrophils in the elmo1 mutant; however, the p.R354X (c.1060C>T) variant failed to rescue the mutant. Acts as a dominant-negative form, p.R354X (c.1060C>T) which failed to rescue the elmo1 mutant and inhibited neutrophil movement in siblings. Based on those results, we identified that zebrafish elmo1 played conserved roles in cell motility, similar to higher vertebrates. Using the transient-expression assay, zebrafish elmo1 mutants could serve as an effective model for human variant verification in vivo.

Disclosures

No relevant conflicts of interest to declare.
NL-201, a De Novo Agonist of IL-2 and IL-15 Receptors, Demonstrates Synergistic Antitumor Activity with Anti-PD-1 Checkpoint Inhibitor Therapy in a Preclinical Non-Hodgkin Lymphoma Model
Authors: Huard Justin , Tatalick Laurie , Walkey Carl , Swanson Ryan
Published: November 2021

NL-201 is a potent, selective, and long-acting computationally designed alpha-independent agonist of the IL-2 and IL-15 receptors that is being developed as an immunotherapy for cancer. NL-201 binds to the beta and gamma subunits, selectively stimulating dose-dependent expansion and tumor infiltration of cytotoxic CD8+ T cells and natural killer (NK) cells, thereby enhancing the immune response to the tumor. Absence of binding to the IL-2 alpha subunit reduces the undesirable effects of traditional IL-2 therapies, such as vascular leak syndrome and expansion of immunosuppressive regulatory T cells. In this abstract, we demonstrate that NL-201, alone or in combination, demonstrates robust antitumor activity in preclinical models of non-Hodgkin lymphoma (NHL).

We have previously demonstrated that NL-201 has marked antitumor activity in multiple syngeneic tumor models, including the A20 lymphoma model. These observations in lymphoma have been extended to explore the effects of NL-201 in combination with anti-mPD-1 checkpoint inhibitor therapy in vivo. In this model, NL-201 and anti-mPD-1 demonstrated tumor growth inhibition and increased median survival (21 days each vs 17 days as observed in control) when given alone. In combination, NL-201 and anti-mPD-1 resulted in increased antitumor activity and significant prolongation of survival (>51 days). We have also demonstrated that NL-201 does not directly induce signaling or cell death in B cell−derived NHL, suggesting that the observed antitumor activity is due to activation of non-malignant host immune cells.

Additional in vitro and in vivo NHL models are being tested to enhance understanding of the interaction between NL-201 and other approved therapies within the hematopoietic tumor microenvironment. These data will be used to design future clinical trials of NL-201 in novel regimens to treat hematological malignancies.

Disclosures

Huard: Neoleukin Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Patents & Royalties. Tatalick: Neoleukin Therapeutics, Inc.: Consultancy, Current equity holder in publicly-traded company, Other: Independent paid nonclinical consultant for Neoleukin. Walkey: Neoleukin Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Swanson: Neoleukin Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties.