bluuebunny/crossref_metadata_2025 huggingface dataset:
Interstate Rivalries and Expansions in Military Capacity
Authors: Suhas Prashant Hosur , Israelsen Shelli
Published: November 2021

This article addresses the scholarly debate on the relationship between interstate rivalry and military capacity. We draw on Tilly's bellicist theory of state formation in early modern Europe and Thies’ modifications to predatory theory, which prioritizes the role of interstate rivalry on state building, to explain variation in military capacity. We unpack the rivalry mechanism into spatial and positional rivalries and test how these two types of rivalry affect military capacity, and how positional rivalries affect military capacity in the long-term. Using time-series cross-sectional data analysis, we find that positional rivalries increase military capacity in the long term. Also, we find that spatial rivalry influences military capacity in the long-term, but its effects are uneven across indicators of military capacity, and it has a smaller effect on military capacity in comparison to positional rivalries. We conclude that not all types of rivalries have a uniform effect on military capacity and that competition over regional dominance, that is, positional rivalries, are the most impactful on military capacity. This study offers a more nuanced test of Tilly's bellicist theory and Thies’ modified predatory theory on state capacity.
Understanding Anterior Shoulder Instability Through Machine Learning: New Models That Predict Recurrence, Progression to Surgery, and Development of Arthritis
Authors: Lu Yining , Pareek Ayoosh , Wilbur Ryan R. , Leland Devin P. , Krych Aaron J. , Camp Christopher L.
Published: November 2021

Background:

Management of anterior shoulder instability (ASI) aims to reduce risk of future recurrence and prevent complications via nonoperative and surgical management. Machine learning may be able to reliably provide predictions to improve decision making for this condition.

Purpose:

To develop and internally validate a machine-learning model to predict the following outcomes after ASI: (1) recurrent instability, (2) progression to surgery, and (3) the development of symptomatic osteoarthritis (OA) over long-term follow-up.

Study Design:

Cohort study (prognosis); Level of evidence, 2.

Methods:

An established geographic database of >500,000 patients was used to identify 654 patients aged <40 years with an initial diagnosis of ASI between 1994 and 2016; the mean follow-up was 11.1 years. Medical records were reviewed to obtain patient information, and models were generated to predict the outcomes of interest. Five candidate algorithms were trained in the development of each of the models, as well as an additional ensemble of the algorithms. Performance of the algorithms was assessed using discrimination, calibration, and decision curve analysis.

Results:

Of the 654 included patients, 443 (67.7%) experienced multiple instability events, 228 (34.9%) underwent surgery, and 39 (5.9%) developed symptomatic OA. The ensemble gradient-boosted machines achieved the best performances based on discrimination (via area under the receiver operating characteristic curve [AUC]: AUCrecurrence = 0.86), AUCsurgery = 0.76, AUCOA = 0.78), calibration, decision curve analysis, and Brier score (Brierrecurrence = 0.138, Briersurgery = 0.185, BrierOA = 0.05). For demonstration purposes, models were integrated into a single web-based open-access application able to provide predictions and explanations for practitioners and researchers.

Conclusion:

After identification of key features, including time from initial instability, age at initial instability, sports involvement, and radiographic findings, machine-learning models were developed that effectively and reliably predicted recurrent instability, progression to surgery, and the development of OA in patients with ASI. After careful external validation, these models can be incorporated into open-access digital applications to inform patients, clinicians, and researchers regarding quantifiable risks of relevant outcomes in the clinic.
HSV Esophagitis in an Immunocompetent 17-Year-Old
Authors: Rajasekaran Vedika , Rahaman Victoria , Hou Xing , Steele Russell W.
Published: November 2021

Herpes Simplex Virus (HSV) esophagitis is a relatively rare form of infectious esophagitis. Typically, patients with viral esophagitis are immunocompromised. HSV esophagitis in an immunocompetent patient is uncommonly reported. The objective of this case report is to discuss symptoms, investigations, imaging, and treatment of HSV esophagitis in a healthy adolescent male. A previously healthy 17-year-old male presented to the ED of our facility with a 5-day history of fever, odynophagia, lethargy, and 2 episodes of emesis that failed to resolve with antibiotic treatment. Investigations revealed a low platelet count, mild hyponatremia, hypochloremia, and an elevated AST and ALT. A respiratory infection panel as well as CMV IgG, HIV, Rickettsia, and EBV tests were negative. HSV-1 PCR was positive and upper endoscopy revealed a friable mucosa, erythema, and exudates in the lower esophagus and erythematous duodenopathy. The patient received a diagnosis of HSV esophagitis and was treated with a 14-day course of IV to PO acyclovir. There was a rapid improvement of his symptoms with antiviral therapy.
The Role of Gulf Cooperation Council in Conflict Management, 1981–2019: A Comparative Study
Authors: Abdelkhalek Amira Ahmed Elsayed
Published: November 2021

The Gulf Cooperation Council (GCC) is considered one of the most important regional organizations in the Middle East and North African (MENA) region, which effectively solves some of the crises in the sub-region and the wider Middle East. GCC has employed many diplomatic procedures to address regional crises, including mediation, negotiation, and arbitration. Undoubtedly, GCC has successfully resolved some intrastate conflicts, particularly border conflicts among its member states. However, despite these achievements, the GCC has failed to resolve several regional disputes, and the continuation of such crises threatens the region’s security and stability. This article seeks to explore why the GCC institutions are ineffective in resolving some regional crises. In doing so, it addresses the comparative study by focusing on two case studies (the Iraq–Iran War and the ongoing Yemen Crisis) and provides three main results: first, the GCC has not directly intervened as an institution to resolve certain disputes; however, some GCC members have acted on its behalf and represented it. Second, despite the GCC member states’ efforts, they are still unable to resolve and settle some disputes because they prioritize self-interest over collaboration. Third, the conflict of interest of various regional actors contributes to the lack of significant progress in resolving crises.
Translation and Validation of the Mongolian Version of the Childbirth Experience Questionnaire
Authors: Parchaa Tsetsegmaa , Togoobaatar Ganchimeg , Fukuzawa Rieko Kishi , Chunagsuren Badamkhand , Tseleejav Batbold , Nyam Naranbaatar , Katsumata Asako Takekuma
Published: November 2021

Women’s experiences of childbirth have a significant impact on mother and child health and well-being as well as quality of care. A valid and reliable tool is needed to assess women's experience. This study aim was to adapt the Childbirth Experience Questionnaire to the Mongolian context and assess its psychometric properties. The study conducted between October and January 2019 at the public maternity hospital in Ulaanbaatar by recruiting a total of 828 low-risk postpartum women. The response rate was 92% (n = 761). Confirmatory factor analysis indicated a good fit for the 4-factor model. Reliability was good for the overall instrument (Cronbach's alpha = 0.83) and for individual domains (Cronbach's alphas ranging from 0.45 to 0.80). The overall and domain scores were significantly higher among women who had previous birth experience, who did not receive oxytocin augmentation, and who experienced a shorter labor duration (<12 h).The Mongolian version of the Childbirth Experience Questionnaire is a valid and reliable tool for exploring the childbirth experience. It can be used to promote women-centered, respectful care in maternity hospitals.
Chimeric Antigen Receptor T Cell Targeting to CD19 and CD22 Combined with Anti-PD-1 Antibody Induce High Response in Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma
Authors: Zhang Ying , Li Jiaqi , Zong Xiangping , Zhou Jin , Jia Sixun , Geng Hongzhi , Lou Xiaoyan , Kang Liqing , Yu Lei , Wu Depei , Li Caixia
Published: November 2021

Objective: Despite the remarkable success of chimeric antigen receptor modified T (CAR-T) cell therapy for refractory or relapsed B cell non-Hodgkin lymphoma (R/R B-NHL), high rates of treatment failure and relapse after CAR-T cell therapy are considerable obstacles to overcome. Preclinical models have demonstrated that anti-PD-1 antibody is an attractive option following CAR-T therapy to reverse T cell exhaustion. Thus, we investigated their combination in R/R B-NHL.

Methods: We performed a prospective, single-arm study of CAR-T cell combined with anti-PD-1 antibody treatment in R/R B-NHL (NCT04539444). Anti-PD-1 antibody was administrated on day 1 after patients received sequential infusion of anti-CD19 and anti-CD22 second-generation CAR-T cells, and the efficacy and safety of the combination treatment were evaluated.

Results: From August 1, 2020 to June 30, 2021, a total of 11 patients were enrolled and completed at least 3 months follow-up. The median follow-up time is 5.8 months. Overall response was achieved in 9 of 11 patients (81.8%), and the complete response (CR) was achieved in 8 of 11 patients (72.7%). All 8 patients achieving CR still sustained remission at the last follow-up. The progression-free survival (PFS) and overall survival (OS) rates at 6 months were 80.8% and 100.0%, respectively. Cytokine release syndrome (CRS) occurred in only 4 patients (all were grade 1), and no neurotoxicity were observed.

Conclusion: This study suggests that CAR-T cells combined with anti-PD-1 antibody elicit a safe and durable response in R/R B-NHL.

Keywords: chimeric antigen receptor modified T cell, anti-PD-1 antibody, CD19/CD22, refractory or relapsed B cell non-Hodgkin lymphoma

Disclosures

No relevant conflicts of interest to declare.

OffLabel Disclosure:

We use the T cells were transduced with a lentivirus encoding the CD19-4-1BB-CD3 z and CD22-4-1BB-CD3 ztransgene to produce CAR-T cells. The main purpose of our study is to improve the response rate in patients with R/R B-NHL.
Mesenchymal Stromal Cells Plus Anti-CD25 Antibody and Calcineurin Inhibitors for Steroid-Resistant Acute Graft-Versus-Host Disease: A Multicenter, Randomized, Phase 3 Trial
Authors: Zhao Ke , Lin Ren , Fan Zhiping , Chen Xiaoyong , Wang Yu , Huang Fen , Xu Na , Zhang Xi , Zhang Xin , Xuan Li , Wang Shunqing , Lin Dongjun , Deng Lan , Nie Danian , Weng Jianyu , Li Yonghua , Zhang Xiaohui , Li Yuhua , Xiang Andy Peng , Liu Qifa
Published: November 2021

INTRODUCTION Steroid-resistant (SR) acute graft-versus-host disease (aGVHD) lacks standard second-line treatment. Mesenchymal stromal cells (MSCs) have potential efficacy in SR aGVHD. To assess efficacy and safety of MSCs combined with anti-CD25 antibody and calcineurin inhibitors as second-line therapy for SR aGVHD.

METHORDS A randomized phase 3 trial involved 203 SR aGVHD patients at 10 centers in China (September 2014-March 2019). Final follow-up was on June 30, 2020. Participants were randomized in a 1:1 ratio to receive second-line therapy (anti-CD25 antibody combined with calcineurin inhibitors) with MSCs (n=101) or without MSCs (n=102). The primary endpoint was overall response (OR) at day 28 with a predefined threshold of -20%. Secondary and safety endpoints included durable OR at day 56, failure-free survival, overall survival (OS), chronic GVHD (cGVHD), infection, haematological toxicity and relapse.

RESULTS Of 203 patients, 198 (97.5%; mean age, 30.1years; 40.4% women) completed the study. OR at day 28 was higher in the MSCs group than in the control group (82.8% [82 patients] vs 70.7% [70]; odds ratio, 2.00; 95% confidence interval [CI], 1.01-3.94; P=.043). Durable OR at day 56 was also higher in the MSCs group (78.8% [78 patients] vs. 64.6% [64]; odds ratio, 2.02; 95% CI, 1.08-3.83; P=.027). The median failure-free survival was longer in the MSCs group compared with control group (11.3 months vs. 6.0 month; hazard ratio (HR) 0.68; 95% CI, 0.48-0.95, P=.024). The 2-year cumulative incidence of cGVHD was 39.5% (95% CI, 29.3%-49.4%) and 62.7% (51.4%-72.1%) in the MSCs and control groups (HR 0·55, 95% CI, 0·36-0·84; P=0·005). Within 180 days after study treatments, the most common grade 3 and 4 adverse events were infections (65 [65.7%] in the MSCs group vs 78 [78.8%] in the control group), haematological toxicity (37 [37.4%] vs 53 [53.5%]).

CONCLLUSIONS MSCs plus second-line treatments may increase the efficacy of SR aGVHD, decrease drug toxicity of second-line therapy and cGVHD development, and are well tolerated.

Disclosures

No relevant conflicts of interest to declare.
Decision Analysis of Allogeneic Stem Cell Transplantation for Primary Myelofibrosis
Authors: Cipkar Christopher , Kumar Srishti , Thavorn Kednapa , Kekre Natasha
Published: November 2021

Introduction: Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by cytopenias, splenomegaly and a risk of leukemic transformation. In light of newer therapies such as ruxolitinib that are not curative but can improve quality of life, the timing of transplant needs more in-depth analysis to determine which patients would benefit from an early versus delayed transplant strategy.

Methods: We developed a Markov cohort model to simulate the long-term disease trajectory in patients with PMF and predict the optimal timing of transplant stratified by a Dynamic International Prognostic Scoring System (DIPSS) risk. Our model consisted of five health states including alive with PMF, alive after leukemic transformation, alive after transplant, alive after relapse and death. Transition probabilities between health states were acquired from published literature on the natural history of the disease and outcomes following transplantation. The model was run over a patient's lifetime until all patients transitioned to the death state. We used a cycle length of one-month to represent the natural progression of PMF. The structure of the Markov model is delineated in Figure 1. In this decision model, a hypothetical cohort of patients begins in the Alive-PMF state and can transition after each monthly cycle to other health states. Patients could remain in an alive state for any number of cycles without transitioning to another health state, indicated by the arrow wheels. We performed probabilistic analyses by jointly varying all model parameters over 1000 simulations and calculated 95% confidence intervals (CI) for the model outcome.

Results: Regardless of DIPSS risk, all patients with PMF benefited from a transplant with respect to life expectancy gained (Figure 2). Life expectancy gains from a transplant among patients with high-risk disease peak at 9.7 months (95% CI: 9.5-9.9) from diagnosis, while patients with intermediate-2 disease have a peak gain in life expectancy at 16.6 months (95% CI: 16.4-16.8). Intermediate-1 DIPSS risk patients have a more delayed time frame where the net gain in life expectancy from transplant begins to slow at 20.5 months (95% CI: 20.2-20.7). Patients with low risk DIPSS had greater net gain in life expectancy the longer transplant was delayed; this trend plateaued at 29 to 45 months, when thereafter net gain in life expectancy begins to be lost (Figure 1).

Conclusion: Our modeling suggests that transplant processes including donor selection and pre-transplant work-up are indicated upfront for patients diagnosed with intermediate-2 and high risk PMF, while this can be delayed for patients with low or intermediate-1 risk disease. This model should provide clinicians with guidance on when to refer eligible patients with PMF for transplantation.

Figure 1 Figure 1.

Disclosures

Kekre: Novartis: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.
Efficacy and Safety of Fecal Microbiota Transplantation in the Treatment of Acute and Chronic Steroid-Refractory Graft-Versus-Host Disease after Hematopoietic Stem Cell Transplantation
Authors: Huang Fen , Lv Pinjing , Liu Qifa
Published: November 2021

Despite major improvements in allogeneic hematopoietic stem cell transplantation over the last decades, steroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) cause high mortality. SR-GVHD is a therapeutic challenge. Increasing evidence reveals that gut microbiota play a significant role in GVHD. Several small sample clinical trials indicates fecal microbiota transplantation (FMT) is the viable solution for SR-GVHD.In this retrospective survey, we reported outcome data from 29 patients aged 16-61 years who had underwent a total of 44 FMTs (range, 1-3) as salvage-therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=18, all grade II or III, all gastrointestinal tract involvement) or SR-cGVHD (n=11, all moderate or severe, progressive involvement of the gastrointestinal tract, lungs, liver, skin and mouth). The median number of prior systemic GVHD-therapies was 3 for both SR-aGVHD (range, 1-4) and SR-cGVHD (range, 1-5). The overall response rate (ORR) was 55.6% (10/18) in SR-aGVHD including 7 CRs (38.9%), while for SR-cGVHD the ORR was 54.5% (6/11, all partial responses). Among the complications of FMT with a possible cause-effect relationship there were: 11 fever, 3 fecal bacterial culture positive, 2 constipation. No serious adverse events clearly related to FMT occurred.FMT may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial.

Disclosures

No relevant conflicts of interest to declare.
A Systematic Literature Review and Meta-Analysis of the Incidence of Serious or Severe Hypersensitivity Reactions after Administration of Ferric Derisomaltose and Ferric Carboxymaltose
Authors: Biggar Patrick , Kennedy Nicholas , Pöhlmann Johannes , Pollock-Wilkins Richard F
Published: November 2021

Background and Aims

Intravenous (IV) iron is the preferred treatment for patients with iron deficiency (ID) and iron deficiency anemia (IDA) in a variety of clinical situations. Although uncommon, administration of modern IV iron formulations can result in hypersensitivity reactions and, very rarely, anaphylactic reactions. The objective of the present study was to systematically review the literature to identify and analyze data on the incidence of serious or severe hypersensitivity reactions (HSRs) after administration of different IV iron formulations.

Methods

A prospectively-registered systematic literature review (SLR) was conducted to identify prospective, active comparator randomized controlled trials (RCTs) comparing ferric derisomaltose (FDI) (also known as iron isomaltoside 1000) or ferric carboxymaltose (FCM) with other IV iron formulations or oral iron. The primary endpoint was the incidence of serious or severe hypersensitivity reactions occurring on the day or day after dosing of IV iron, based on pre-specified terms (MedDRA classification).

Results

Data were obtained from ten prospective, active comparator RCTs of FDI (N=3,474) and seven prospective, active comparator RCTs of FCM (N=2,683), two of which were head-to-head comparisons of FDI and FCM. The trials enrolled a total of 10,467 patients, of whom 6,157 were treated with either FDI or FCM. The number of patients experiencing any serious or severe hypersensitivity reactions was 5/3474 with FDI (0.14%) versus 29/2683 (1.08%) with FCM; Bayesian inference of proportions showed the reaction rates to be significantly lower with FDI relative to FCM (Figure).

Conclusions

To our knowledge, the present analysis represents the first SLR and meta-analysis of the incidence of serious or severe HSRs after administration of FDI vs FCM based on pre-specified MedDRA terms. The SLR conducted for the present meta-analysis, identified 15 prospective, head-to-head RCTs including 10,467 patients, of whom 3,474 and 2,683 were treated with FDI and FCM, respectively. The analysis demonstrated that serious or severe hypersensitivity reactions were uncommon with the newer high-dose IV iron formulations; and showed a significantly lower incidence of serious or severe hypersensitivity reactions with FDI compared to FCM.

Figure 1 Figure 1.

Disclosures

Biggar: Vifor-Fresenius: Consultancy; Pharmacosmos: Consultancy; Medice: Consultancy. Pöhlmann: Pharmacosmos A/S: Consultancy. Pollock-Wilkins: Pharmacosmos A/S: Consultancy.
A Retrospective Analysis of the Efficacy of Low-Dose Metronomic Cyclophosphamide for Treatment in Patients with Low Grade Non-Hodgkin Lymphoma
Authors: Han Boram , Kim Bum Jun , Kim Ho Young , Zang Dae Young , Lim Hyun , Kang Ho Suk , Soh Jae Seung , Kim Hyo Jung
Published: November 2021

Background

Low-dose metronomic cyclophosphamide chemotherapy is an emerging strategy offering a potentially less toxic yet effective treatment modality. We evaluated the efficacy and safety of low-dose metronomic cyclophosphamide in patients with low grade non-Hodgkin lymphoma (NHL) by retrospectively reviewing the data.

Method

The patients received oral cyclophosphamide (50 mg per day) and/or oral methotrexate (2.5 mg twice weekly) until disease progression or unacceptable toxicity was noted.

Results

Of the 36 patients, 17 (47.2%) were male, median age was 66.4 years (range, 37-91 years), and subtypes of NHL were mucosa associated lymphoid tissue lymphoma (55.6%), small lymphocytic lymphoma (13.9%), follicular lymphoma (11.1%), mantle cell lymphoma (8.3%), nodal marginal zone lymphoma (4.5%), splenic marginal zone lymphoma (2.8%), and lymphoplasmacytic lymphoma (2.8%). The stage I, II, III, IV were 38.9%, 13.9%, 11.1%, 36.1%, respectively and 55.6% of patients received this regimen as the first-line treatment, mainly due to frailty, refusal to standard chemotherapy.

The overall best response rate (ORR) was 73.5% (12 complete responses, CRs and 13 partial responses, PRs), with 29.1 months of the median duration of response and the disease control rate was 88.2%. The median treatment duration was 8.8 months (range, 0.1-38.4 months); the median progression-free survival (PFS) was 43.5 months, and the median overall survival (OS) was not yet reached. Especially, the ORR in patients who were treated with metronomic cyclophosphamide as the first line treatment and as more than the second line treatment were 78.9% (10 CRs, 5 PRs) and 66.6% (2 CRs, 9 PRs), respectively. The median PFS were not reached in the first line cyclophosphamide treatment group and 26.5 months (range, 5.7-47.2 months) in the other group (p=0.110), and similarly, the median OS were not reached and 64.4 months (0-135.7 months) (p=0.058), respectively.

The regimen was generally well tolerated, with small numbers of grade 3-4 toxicities; neutropenia (2%), anemia (3%), thrombocytopenia (3%), fatigue (4%), and anorexia (1%).

Conclusion

We concluded that low-dose metronomic cyclophosphamide represents efficacious and well-tolerated treatment for low-grade NHL patients.

Disclosures

No relevant conflicts of interest to declare.
How Important Are in-Person Clinic Visits during Maintenance Therapy for Pediatric Acute Lymphoblastic Leukemia?
Authors: Rabinowicz Ron , Hitzler Johann K , Punnett Angela
Published: November 2021

B ackground

Acute Lymphoblastic Leukemia (ALL) is the most common cancer seen in the pediatric age group. The treatment consists of an initial intensive phase of chemotherapy followed by a prolonged period of maintenance chemotherapy intended to reduce the risk of relapse. Children are commonly seen in clinic every 4-6 weeks for bloodwork and physical examination during the maintenance phase. The COVID-19 pandemic has prompted consideration of alternative means of providing medical care. The objective of this study was to determine the proportion of in-person clinic visits during ALL maintenance therapy for which the outcome of the physical examination resulted in a change of patient management.

Methods

A retrospective chart review of children diagnosed with precursor-B ALL between January 2017 and December 2018, and who were in maintenance therapy between September 2019 and February 2020, was conducted. All routine maintenance visits were reviewed to identify new physical examination findings and patient outcomes and classified as either "could be managed virtually" or "essential in-person visit". For the latter, a second classification was conducted to distinguish between visits necessitating a change of management versus not.

Results

Eighty-five children were diagnosed with precursor B ALL and continued to maintenance treatment during the study period. 10 children were excluded as not meeting the inclusion criteria or not evaluable. Of the remaining 75 children, 54 were male (72%) and 21 female (28%). The median age at diagnosis was 4.83 years (0.73 - 14.8 years). 39 patients (52%) had standard risk ALL, 35 patients (46.7%) had high risk ALL and one patient had Infant ALL (1.3%) A total of 240 routine maintenance visits were included in the final analysis. An abnormal physical exam finding was noted in 20 visits (8.3%) and of these, new findings were noted in 14 (5.8%). 6 visits were classified as essential in-person visits (2 for new bruising, 1 for new limp, 1 for new lymphadenopathy, 1 for acute otitis media, and 1 for new wheezing). Among the 14 visits with new exam findings, only 5 had an impact on patient management and of these, only 2 (0.8%) were classified as obligate in-person visit for requiring immediate management (acute otitis media and wheezing).

Conclusion

Our results demonstrate that most in-person visits can be provided as virtual visits without affecting patient outcomes. The results of this study provide the foundation for a prospective study that will evaluate the benefits, risks and families' preferences associated with virtual visits and delineate the optimal frequency and timing of in-person clinic visits during ALL maintenance therapy.

Figure 1 Figure 1.

Disclosures

No relevant conflicts of interest to declare.
Efficacy and Safety of Generic Dasatinib As First-Line Treatment in Patients with Chronic Myeloid Leukemia in Chronic Phase: Final Analysis with 2-Year Follow-up
Authors: Jin Jie , Meng Li , Yu Wenjuan , Liu Peng , Du Xin , Lou Jin , Wang Weiguang
Published: November 2021

Purpose: Generic dasatinib, a second-generation tyrosine kinase inhibitor (TKI), was approved as a second-line treatment for chronic myeloid leukemia (CML) patients in chronic phase (CP) in china. We initiated a prospective, multi-center and single-arm clinical trial (NCT04925141) from May 2016 to October 2018 to evaluate efficacy and safety of generic dasatinib as first-line treatment in China. The primary endpoint was achieved, here we reported the 2 years follow-up results to see its long-term clinical benefit in Chinese patients.

Methods:The study included the newly diagnosed CML-CP patients who was diagnosed by the presence of Philadelphia (Ph) chromosome and/or presence of BCR-ABL fusion gene. Key inclusion criteria were as follows: 1) Age ≥ 18 years; 2) The CML subjects in chronic phase with the Ph+ definitive diagnosis were within 6 months before the onset of administration of the study drug; 3) The ECOG performance grades of 0-2; 4) Sufficient main organ functions. All newly diagnosed patients were given 100mg/d (initial dose) of the generic dasatinib. The primary endpoint was molecular major response (MMR) calculated based on the BCR-ABL1 ≤ 0.1% at the 12th month. Secondary endpoints were proportion of subjects who achieved and maintained MMR at 3, 6, and 18 months; Cumulative MMR rates at 6, 12, and 24 months were determined. All patients were followed up through the hospital outpatient departments at second, fourth and eighth weeks, and third, sixth, ninth, twelfth, eighteenth, and twenty-fourth months. The follow-up ended on December 6, 2019. The SAS 9.2 software was utilized for all statistical analyses in this study, and the two-sided test was performed to see variances.

Results: A total of 59 patients were included in this trail, with median age of 44 (19 - 70), and 7% of the subjects were at high risk based on the Sokal index for the disease prognosis. The primary endpoint MMR rate at the 12th month was 80.8% which had been published. At 12 months, the cumulative response rate (CCyR) was 85.5% (47/55) and the cumulative MMR was 76.4% (42/55). Here we are reporting the 2 years follow ups. At 24 months, the complete hematological response (CHR) was 88.4%, the cumulative MMR rate was 73.7%, the cumulative MR4.0 rate was 63.6%, the cumulative MR4.5 rate was 58.2%, and the cumulative complete molecular response (CMR) rate was 58.2%. The most common adverse events (AEs) was thrombocytopenia (42.4%) in hematology and pleural effusion (20.3%) in non-hematology, only 11.9% and 1.7% of whom were grade III~IV respectively.

Conclusion: This was the first report on domestic dasatinib as the first-line treatment for CML-CP patients received a clinical benefit with 24 months in China. Safety was similar with that of the original study data.

Figure 1 Figure 1.

Disclosures

No relevant conflicts of interest to declare.
Treatment with the Recombinant SLIT2 Protein Delays AML Leukemogenesis In Vivo
Authors: Simoes Luise A de Albuquerque , Weinhäuser Isabel , Pereira-Martins Diego A , Ortiz Rojas César Alexander , Bianco Thiago Mantello , Cavaglieri Rita de Cassia , Rego Eduardo M
Published: November 2021

Accumulating evidence suggest that the axon guidance molecules SLIT and ROBO are not only implicated in physiological process but also in cancer progression. Depending on the type of cancer the SLIT-ROBO axis can either act as a tumor suppressor gene, in which case the SLIT2 promoter site is frequently hypermethylated or as an oncogene, whereby high expression is often associated with poor prognosis. In the context of acute myeloid leukemia (AML), low expression of SLIT2 has been associated with low overall survival (OS) (Golos et al., 2019), while the functional role of SLIT2 remains largely unknown. Recently, we showed that the knockdown of SLIT2 increased cell proliferation of acute promyelocytic leukemia (APL) cells resulting in a more aggressive course of disease progression in vivo using the murine transgenic APL model (Weinhäuser et al., 2020). Here, we aimed to study the functional role of SLIT2 in a more heterogeneous disease, such as AML.

Using different publicly available datasets. (GSE58477, normal karyotype blasts: 62, healthy CD34 +: 10; GSE63409, LSC: 14, HSC: 5) we detected increased methylation at the SLIT2 promoter site of AML leukemic cells compared to healthy CD34 + cells suggesting SLIT2 tumor suppressive functions. In addition, we measured decreased levels of SLIT2 in the bone marrow (BM) plasma of AML patients compared to healthy donors. To assess the biological role of SLIT2, we treated AML cell lines (KASUMI1, MV411, and MOLM13) with recombinant SLIT2 (50 ng/mL) in vitro. Administration of SLIT2 reduced AML cell growth, colony formation and induced cell cycle arrest in the G1 phase for all AML cell lines. Conversely, the knockdown of SLIT2 promoted increased THP-1 and OCI-AML3 cell proliferation. Next, we determined whether the treatment with SLIT2 could delay leukemogenesis in vivo using the AML cell line MV4-11. Engraftment was monitored by luciferase bioluminescent signal and NSGS mice were either treated with recombinant SLIT2 using a dose of 25 ng/g of body weight or vehicle (control group). SLIT2 therapy resulted in a lower disease burden, decreased leukemic infiltration in the BM and spleen, reduced spleen size, and increased OS compared to the control group (p<0.05). In conclusion, we showed that SLIT2 methylation is recurrent in AML patients and that the level of SLIT2 in the plasma of AML patients is reduced. Moreover, SLIT2 treatment appears to have a cytostatic effect on different AML cell lines delaying leukemogenesis in vivo. Overall, our study reveals the therapeutic potential of SLIT2 in hematological malignancies, which could be used as an adjuvant in the clinic.

Disclosures

No relevant conflicts of interest to declare.
Anticoagulation Practices Using Activated Clotting Time in Veno-Venous Extracorporeal Membrane Oxygenation for Patients with Respiratory Failure: A Systematic Review and Met-Analysis
Authors: Parmar Kanak , Vutthikraivit Wasawat , Singh Amritpal , Morataya Christina , Del Rio Pertuz Gaspar , Cavazos Annia , Tijani Lukman , Nugent Kenneth , Argueta Erwin
Published: November 2021

Background

Veno-Venous Extracorporeal Membrane Oxygenation (ECMO) technology provides as a alternative approach in the intensive care of patients with respiratory failure due to varied causes who are not responsive to conventional treatment. As per the 2014 Extracorporeal Life Support Organization (ELSO) guidelines, in order to to maintain circuit patency and minimize thromboembolic complications, anticoagulation is used, but the optimal strategy remains to be defined. Activated clotting time (ACT) is the most utilized bedside test to adjust anticoagulation. Therefore, we performed an extended analysis of all published studies on the incidence of thromboembolic and bleeding events in patients with acute respiratory distress syndrome who were put on ECMO.

Methods

A comprehensive search of several databases from inception to November 25, 2020, limited to English language and excluding animal studies, was conducted. The databases included Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus. The studies were classified into low anticoagulation target (ACT<180) or high anticoagulation target (ACT>180). A meta-analysis was performed of all eligible studies with the data on the incidences of thromboembolic and bleeding complications in patients with ARDS on VV-ECMO during different intensities of anticoagulation.

Results

A total of 6 eligible studies (4 retrospective and 2 case series) were identified, including in total 190 patients for 100 patient years. Our study showed that there is two times higher chances of bleeding when ACT goal is >180 versus a lower ACT range of <180 (Risk ratio 2.07, 95% CI 1.23-3.46, P 0.0056). The incidence of thrombosis did not change in the two group (Risk ratio 1.17, 95% CI 0.45-3, P 0.7516).

Conclusions

Currently there is a lack of data for anticoagulation strategies during VV-ECMO for patients in respiratory failure. Our study aimed to find an appropriate anticoagulation target for this patient group. The results show that although anticoagulation is required for circuit patency, there is an increased risk of bleeding when higher anticoagulation targets are set.

Disclosures

No relevant conflicts of interest to declare.
Relative Interfering Effects of In Vivo Direct Oral Anticoagulants on Routine Coagulation Tests
Authors: Kim Jinju , Song Yejin , Kim Hyun-Jeong , Yang Mi-Sook , Song Jaewoo
Published: November 2021

Background:

The interfering effects of DOACs on the screening coagulation tests, such as prothrombin time (PT), activated partial thromboplastin time (APTT), and fibrinogen assay, have been shown mainly by in vitro spiking experiments. However, the effects of DOACs on coagulation tests in real-world samples from anticoagulated patients are unknown because of the difficulty in selectively eliminating DOAC from blood samples already containing DOACs.

Method:

Citrated blood samples were drawn from patients on anticoagulation therapy (rivaroxaban and edoxaban). In addition, blood samples from patients not on anticoagulation were collected. PT INR and APTT were measured from those samples by coagulometers from two manufacturers (Roche t711, Swiss and ACL-TOP, USA). We also measured DOAC levels from the same samples by anti-FXa activity (Hyphen Biomed, France). Then, we compared the test results in relation to the DOAC levels.

Results:

The PT INR, APTT, and fibrinogen assay results from non-anticoagulated patients measured by the two coagulometers were comparable (PT INR: y = -3.353 + 1.029 x; APTT: y = -6.276 + 1.101x; fibrinogen: y = -3.353 + 1.029 x; Passing Bablok). We included blood samples from 61 patients on rivaroxaban and 75 patients on edoxaban. From the rivaroxaban samples we observed the regression line change for PT INR (y = 0.6303 + 0.3712x) and for APTT (y = -10.71+1.358x). The comparability of fibrinogen assay was not affected significantly (y = -17.39+1.01x). From the edoxaban samples we also observed the similar change of the regression line (PT INR: y = 0.4728 + 0.5661x; APTT: y = -133.07+2.014x). Fibrinogen levels were comparable (y = -28.95+1.082x).

Conclusion:

The susceptibility of screening coagulation tests to the interfering effects of in vivo DOAC is dependent on the reagents and coagulometers.

Figure 1 Figure 1.

Disclosures

No relevant conflicts of interest to declare.
Clinical Analysis of Air-Leak Syndrome Following Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Patients
Authors: Zhao Wei , Chen Man , Zhao Yanli , Wang Hui , Lu Peihua , Xiong Min
Published: November 2021

Background: Air-leak syndrome (ALS) occurs when there is leakage of gas from the alveoli, which results in clinical symptoms including cough and sputum, dyspnea, and hypoxemia. ALS is rare but potentially life-threatening in patients who have received an allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is an independent prognosis factor of patients undergoing HSCT. However, the clinical features and risk factors for post-transplant ALS among pediatric patients have rarely been explored.

Aims: This study analyzed the clinical characteristics, risk factors, clinical treatment options and prognosis to provide a scientific basis for ALS prevention and treatment for pediatric patients.

Methods: We retrospectively reviewed patients who were diagnosed with ALS following allo-HSCT between January 2013 and December 2019 at the Hebei Yanda Lu Daopei Hospital, and analyzed the role of ALS in the prognosis of the HSCT.

Results: A total of 2026 pediatric patients received an HSCT between January 2013 and December 2019. The ALS incidence rate was 1.4% (28 of 2,206 patients) with a survival rate of 64.3% (10 of 28 patients). The median overall survival (OS) time was 429 days (range: 55-1614 days). Sixteen patients were males and 12 were female. The median patients age was 12 years old (range: 1-16 years), and the median follow-up time was 871 days (range: 55-2973 days).We divided ALS into two categories: 15 cases of bronchiolitis obliterans syndrome (BOS) and 13 cases of idiopathic pneumonia syndrome (IPS). There was a significant difference in OS between the twogroups (80% among BOS patients versus 46% among IPS patients; P=0.037). Logical regression analysis showed that gender, an unmatched transplant donor and recipients (P=0.049), time to first occurrence of graft-versus-host disease after transplantation (P=0.021), and dosage of methylprednisolone >0.5mg/kg at the onset of ALS (P=0.049), were independent risk factors for poor prognosis in ALS. In addition, we found fluticasone, azithromycin, and montelukast (FAM) could significantly improve the prognosis following ALS (P=0.005). Compared with IPS, our results showed that some patients with BOS may benefit from imatinib (P=0.055), ruxolitinib (P=0.009), or pirfenidone (P=0.044).

Conclusion: ALS is a rare manifestation of pulmonary complications following HSCT among pediatric patients. Our analysis demonstrates that early diagnosis and FAM treatment may improve the survival rate of ALS following HSCT among pediatric patients.

Figure 1 Figure 1.

Disclosures

No relevant conflicts of interest to declare.
Combination of Haploidentical Hematopoietic with Low-Dose TBI and Cord Blood Transplantation for Hematologic Malignancies
Authors: Qian Shenxian , Yang Fan , Shi Pengfei
Published: November 2021

Objective: To evaluate the efficacy and safety of the combination of haploidentical hematopoietic with low-doseTotal body irradiation（TBI）and cord blood transplantation for hematologic malignancies.

Methods: This study was conducted as a retrospective review of medical records of 5 patients with hematologic malignancies who received a combination of haploidentical hematopoietic with low-dose TBI and cord blood transplantation at Affiliated HangZhou first people's hospital of Zhejiang University school of medicine, from March to June 2021.

Results: 5 patients were included for the analysis. There were 1 acute myeloid leukemia (AML),2 acute lymphoblastic leukemia (ALL) and 2 Non-Hodgkin's Lymphoma(NHL). The minimal residual disease (MRD) of the two patients with ALL was positive before allo-HCT.Median age of patients at the time of allo-HCT was 30 years (range 21-63 years). All patients received low-dose TBI(4-6GY) +antithymocyte globulin（ATG）based conditioning.Cord blood units were selected based on the results of HLA typing and cell doses evaluated before freezing. Units with at least 4/6 matched HLA loci became the candidates. The median values of absolute total nucleated cell counts were 139.0 (80.8-240.0) × 10 7 / kg in The haploidentical grafts and 2.25 (1.32-3.10)× 10 7 / kg in the cord blood units,respectively. The median doses of CD34+ cells infused were 28.6 (22.0-51.1) × 10 5 / kg in the haploidentical grafts and 1.5 (1.0-3.5)×10 5/kg in the cord blood units, respectively.All patients attained complete engraftment,of which 3 were haploidentical engraftment and 2 were mixed hematopoietic chimerism that included haploidentical and cord blood engraftment.The median time to neutrophil engraftment was 12 (10-22) days and 13 (11-22) days for platelets. All patients were in complete remission with MRD-negetive during a median follow-up of 83 (34-136) days.No patients developed grade II-IV acute graft versus host desease.

Conclusion:The results suggested that the combination of haploidentical hematopoietic with low-dose TBI and cord blood transplantation may potentially improve the outcome of HSCT. It offers a transplant alternative for patients with hematologic malignancies who lack matching donors.

Disclosures

No relevant conflicts of interest to declare.
Bone Marrow Adipocyte Promotes Epithelial-Mesenchymal-Transition-like Activation in Multiple Myeloma Via CXCL-12/CXCR4 Axis
Authors: Shu Ling-Ling , Chen Shuzhao , Li Jinyuan , Wang Weida , Liu Yang , Li Yang , Huang Han-Ying , Wu Xiaoping , Liang Yang
Published: November 2021

Extra-medullary disease (EMD) in multiple myeloma (MM) is associated with poor prognosis and resistance to chemotherapy. The bone marrow microenvironment is a key regulator of myeloma metastatic progression through the secretion of growth factors that activate epithelial-mesenchymal transition (EMT)-like characters. Bone marrow adipocyte (BMA) accumulates in obese patients and displays distinct immune regulatory properties rather than provides energy substrates, forming a bulk portion of the bone marrow microenvironment. Emerging evidence indicates the potential for adipocytes to influence cancer cell progression through the secretion of adipokines that can induce EMT activation. The molecular mechanisms underlying how adipocytes enhance multiple myeloma progression is largely unknown. The present study aims to investigate the precise mechanism of BMA promoting myeloma EMT-like activation and new potential therapeutic strategies targeting bone marrow adipocytes.

Newly diagnosed MM patients in our cancer center were recruited and divided into lean or obese group according to their body mass index (BMI). The bioinformatics-based analysis of transcriptome sequencing data for bone marrow stromal cells (BMSCs) derived from lean and obese MM patients identified that obese patients showed more obvious EMT-like transcriptional regulation characteristics and altered the expression of genes regulating EMT (Fig A), which was further confirmed by the immunohistochemistry staining of bone marrow biopsy (Fig B). Co-culture bone marrow adipocytes with myeloma cells significantly enhanced the proliferation and migration (Fig C-D). The transcriptome sequencing data of BMA further demonstrated that CXCL12 was enriched in BMA derived from obese MM patients (Fig E). We further confirmed that CXCL12 secreted by adipocytes induce EMT-like activation in myeloma cells, and the effect of CXCL12 expression on EMT is mediated through activation of CXCR4 (Fig F-G). Blocking of CXCR4 signaling in myeloma cells, decreased proliferation and invasion capabilities of myeloma cells cultured with CXCL12 (Fig H-I). Together, our results suggest that bone marrow adipocytes can enhance the aggressive behavior of myeloma cells and induce an EMT-like activation through paracrine CXCL12/CXCR4 signaling (Fig J).

In conclusion, paracrine signaling by BMAs can induce EMT-like activation and results in increased proliferation and invasion characteristics of myeloma cells. These results suggested that targeting CXCL12/CXCR4 may act as a regulator of EMD through EMT-like transcriptional modulation, thus representing a potential therapeutic strategy to prevent MM disease progression.

Figure 1 Figure 1.

Disclosures

No relevant conflicts of interest to declare.