bluuebunny/crossref_metadata_2025_split huggingface dataset:
Validation Study of Logistic Regression in Classifying Primary Vitreoretinal Lymphoma Vs. Uveitis By IL-6 and IL-10 Levels
Authors: Kuo David , Wei Maggie , Knickelbein Jared , Armbrust Karen , Yeung Ian , Chan Chi-Chao , Sen Nida 
Published: October 2019

Abstract
Background/Aim:
The aim of this study was to assess the utility of intraocular IL-10 and IL-6 analysis by logistic regression in classifying primary vitreoretinal lymphoma (PVRL) vs. uveitis using a logistic regression model trained on a single-center retrospective cohort as well as the previously published ISOLD score compared against the IL-10/IL-6 ratio.
Methods:
Patient diagnoses of PVRL vs. uveitis and associated aqueous and/or vitreous IL-6 and IL-10 levels were retrospectively collected. From this data, cytokine levels were compared between diagnoses with the Mann-Whitney U test and a logistic regression model was developed to classify PVRL vs. uveitis from aqueous and vitreous IL-6 and IL-10 by nested cross-validation. ROC curves were plotted and AUCs were calculated for the IL-10/IL-6 ratio, ISOLD score, and our logistic regression model. Optimal cut-offs for each classifier were determined by the maximal Youden index; and sensitivity, specificity, PPV, and NPV were determined for each cut-off.
Results:
79 lymphoma (10 aqueous, 69 vitreous) and 84 uveitis patients (19 aqueous, 65 vitreous) between 10/5/1999 and 9/16/2015 were included in the study. IL-6 was higher in uveitis vs. lymphoma patients while IL-10 was higher in lymphoma vs. uveitis patients (p <0.01 for all comparisons). For vitreous samples, our logistic regression model achieved an AUC of 98.3%, while ISOLD achieved an AUC of 97.8%, and the IL-10/IL-6 ratio achieved an AUC of 96.3%. The optimal cut-offs for our logistic regression model, ISOLD, and the IL-10/IL-6 ratio achieved sensitivity/specificity of 92.7%/100%, 94.2%/96.9%, 94.2%/95.3% respectively, corresponding to PPV/NPV of 100%/92.9%, 97%/94%, and 95.6%/93.9% respectively. For aqueous samples, all three classifiers achieved 100% AUC with 100% sensitivity/specificity. Odds ratios of PVRL vs. uveitis were 0.981 (aqueous) and 0.992 (vitreous) for IL-6 and 1.030 (aqueous) and 1.060 (vitreous) for IL-10 according to our logistic regression model.
Conclusion:
In this study, logistic regression, as demonstrated by our model and the ISOLD score, showed strong classification performance and generalizability with high sensitivity and specificity. These results, in addition to logistic regression's ability to further improve with more training data suggest a promising step forward in intraocular cytokine analysis for the early diagnosis of primary vitreoretinal lymphoma. Additional validation studies, especially with cohorts that have proven challenging for the IL-10/IL-6 ratio, would further elucidate the strengths and weakness of this approach.

Disclosures
No relevant conflicts of interest to declare.
F5 Sequence Variant Identified in 7 Patients Evaluated for Hypercoagulable State with a Factor V (FV) HR2 Assay
Authors: Leech Margaret M. , Bellissimo Daniel B. , Uhrmacher John A. , Gunawardena Sriya W. , Meyer Michael J. , Bontempo Franklin A. 
Published: October 2019

Abstract
A 15-year-old African-American male with a history of thrombosis was examined for the Factor V HR2 sequence variation (c.3980A>G, p.H1327R) using PCR followed by RsaI digestion. An anomalous restriction pattern was observed: one strand was uncut (wild type) and the other was cleaved once. However, the fragment sizes were 516bp and 312bp instead of the 447bp and 381bp expected from HR2. Sanger sequencing of the PCR product detected a sequence variant (c.3845A>G) in this patient that creates a RsaI site explaining the novel band pattern. The c.3845A>G variant is found within one of four 27bp repeats found in exon 13 of the F5 gene. The HR2 variant is also present in one of the repeats. In this patient's case, the cleavage occurred in an abnormal location (c.3845A>G instead of c.3980A>G), creating the novel banding pattern observed.
Six additional patients being tested for hypercoagulable states were evaluated with the FV HR2 assay and were found to have the same abnormal restriction pattern. The ethnicity of these other patients was not available to our laboratory. Sanger sequencing confirmed the presence of c.3845A>G sequence variant in each of these patients. Unlike the HR2 and FV Leiden variants, the c.3845A>G, p.H1282R variant (rs143333036) is most common in African populations (Minor Allele Frequency 0.012) but the clinical consequences of this variant are unclear. The variant lies within a 27bp repeat similar to the HR2 site and might cause it to be associated with a thrombotic risk similar to the HR2 variant. Further investigation will be required to determine whether the c.3845A>G variant is a population variant with no clinical consequences or whether it represents a genetic prothrombotic risk factor in certain patient populations. Nevertheless, in the laboratory the c.3845A>G, p.H1282R sequence variant may confound results when testing patients for the HR2 (rs1800595) variation.

Disclosures
No relevant conflicts of interest to declare.
Intensity and Duration of Anticoagulation in Non-Cirrhotic, Non-Malignant Portal Vein Thrombosis
Authors: Sukumar Senthil , Shen Yu-Min 
Published: October 2019

Abstract
Introduction:
Portal vein thrombosis (PVT) can result in significant morbidity and mortality. There are currently no clinical studies reviewing either the intensity or duration of anticoagulant therapy. There is a paucity of data to guide the overall management of this entity and current practice is extrapolated from studies on management of deep vein thrombosis of the lower extremities and pulmonary embolism.
Methods:
All available electronic medical records with a diagnosis of PVT were reviewed from 2005-2016 at hospitals affiliated with the University of Texas Southwestern Medical Center. Patients with cirrhosis, active malignancy, or procedure within the preceding 3 months were excluded. Eighty-four patients met inclusion criteria. The charts were screened for patient demographics, etiology of PVT, type of anticoagulation therapy, and duration and response to therapy.
Results:
Demographic, treatment and outcome data is summarized in table 1. Patient ages ranged 18-84 years; 49 male. Etiology identified include Infectious (18%), Locally Inflammatory (34%), Systemic Hypercoagulable State (24%), or Idiopathic (24%). The majority of patients were treated with Vitamin K Antagonist (61%) followed by no treatment (17%). Average duration of therapy was categorized by months: <3 (20%), 3-6 (15%), 6-12 (16%), or >12 (49%). Outcome of treatment included resolved (28%), chronic (34%), or not reported (39%). When outcomes were stratified by etiology, intensity (in those patients treated with VKA for whom INR data was available), or duration there was no apparent difference in rate of clot resolution compared with progression to chronic cavernous transformation (tables 2-4).
Conclusions:
This first retrospective review studying the efficacy of treatment in PVT reveals that a similar number of patients develop cavernous transformation (indicating chronic PVT) regardless of the etiology, intensity, or duration of treatment. This data suggests that treatment with anticoagulation may not be impactful in this select group of patients. However, it is still recommended to pursue treatment in those patients presenting with a symptomatic acute thrombus given risk of mortality associated with clot progression. Furthermore, no single modality of anticoagulation has shown to be superior in the presented outcome data. Larger prospective studies are needed to further clarify if anticoagulation is effective in this clinical entity.

Disclosures
No relevant conflicts of interest to declare.
Cumulative Incidence of Blood Stream Infections during Acute Myeloid Leukemia Treatment in the Netherlands: A 15-Year Overview
Authors: Schwartz Emily Risa , Klein Kim , de Haas Valerie , Lissenberg-Witte Birgit , Ball Lynn , Dors Natasja , Van den Heuvel-Eibrink Marry M , Knops Rutger , Tissing Wim , Versluys Birgitta A. , Zwaan Christian M. , van Litsenburg Raphaele R.L. , Kaspers Gertjan J.L. 
Published: October 2019

Abstract
Background/Objectives
Despite the use of antibiotic prophylaxis, bacterial infections remain the leading cause of treatment-related morbidity in children with acute myeloid leukemia (AML). The objectives of this study were to: 1) evaluate the cumulative incidence of blood stream infection (BSI) during treatment according to the last three consecutive protocols of the Dutch Childhood Oncology Group (DCOG); 2) determine the most common bacterial pathogens; and 3) determine risk factors.
Design/Methods
A retrospective chart review was performed on 246 patients (DCOG treatment protocols ANLL-97/AML-12 n=119, AML-15 n=60, DB-AML01 n=67) diagnosed with de novo AML (APL and Down syndrome excluded) between 1998-2013. All patients received prophylaxis with co-trimoxazole. From AML-15 onwards, patients also received prophylactic fluoroquinolones. BSIs were defined as a positive blood culture confirmed by the hospital's microbiologist. The cumulative incidence of BSIs was determined using competing risk analysis with death, switch to another protocol, or stem cell transplantation as competing events. Age, sex, BMI, white blood cell count (WBC) at diagnosis, cytogenetics, and treatment protocol were evaluated as risk factors.
Results
Median age was 6.4 years [range 17.4], 58% were male. The cumulative incidence of BSIs was 78.2%. The most common pathogens were Staphylococcus epidermidis (15.6%), Streptococcus mitis (14.9%) and other Staphylococci (11.6%). ANLL-97/AML-12 (78%) and AML-15 (72%) showed a lower BSI incidence than DB-AML01 (84%; hazard ratio(HR)s 0.69 [0.50-0.97], p=0.033 and 0.59 [0.40-0.89], p=0.012, respectively). WBC >20x109/l was associated with a lower risk of infections (HR 0.72 [0.54-0.96], p=0.026). The other risk factors were not statistically significant.
Conclusion
The most recent DCOG protocol was associated with the highest incidence of BSIs, probably as a result of the high intensity of this protocol. Furthermore, the use of prophylactic antibiotics with gram-negative coverage may have resulted in a relatively higher incidence in gram-positive BSI. The high incidence stresses the urge to improve anti-infective supportive care measures.

Disclosures
No relevant conflicts of interest to declare.
Donor-Derived Second Generation of CD19 CAR-T Cell Therapy for Relapsed B-Cell Acute Lymphoblastic Leukemia after Allogenic Stem Cell Transplantation
Authors: Zhang Rongli , He Yi , Yang Donglin , Wang Ying , Feng Sizhou , Wang Jianxiang , Han Ming-Zhe 
Published: October 2019

Abstract
Background: Patients with B cell acute lymphoblastic leukemia (B-ALL) relapsed after allogenic hematopoietic stem cell transplantation have poor prognosis. Donor lymphocyte infusion (DLI) have shown limited success in the setting of relapse by a mere increase in median survival by 6 months and a significant risk of acute and chronic graft-versus-host disease (GVHD) and additional risk of marrow aplasia. The second generation chimeric antigen receptor-T cell (CAR-T) for CD19 is a promising treatment for relapsed and refractory B-ALL, but the effectiveness and safety of donor-derived second generation of CD19 CAR-T cell infusion for relapsed B-ALL after allogenic stem cell transplantation have not been determined.
Methods: Between July 2017 and June 2018, 6 adult patients with B-ALL relapsed (2 patients were hematologic relapsed; 4 patients were minimal residual disease(MRD)-positive) after allogenic stem cell transplantation were enrolled, including 5 sibling-matched stem cell transplantation and 1 haploidentical transplantation . Donor's T cells were infected with lentivirus carrying CD19 CAR plasmid which containing CD19 scfv (HI-19 clone) and 4-1BB-CD3ζ signaling domains to generate CAR-T cells. Patients received FAC (fludarabine:25-30mg/m2/d*3, cyclophosphamide:350mg/m2/d*2, cytosine arabinoside:100mg/m2/d*4) pretreatment and then total (1.25-3.5)*106/kg donor-derived 4-1BB CAR-T cell were infused in consecutive 2 or 3 days .
Results: All the patients achieved MRD negative remission and complete donor chimerism. Three patients experienced grade 2 cytokine release syndrome (CRS) and received 6-8mg/kg interleukin-6 receptor blocker (tocilizumab) treatment ; the other 3 just experienced grade 1 CRS. None of these patients needed glucocorticoid treatment. No patients developed acute or chronic graft-versus-host disease (GVHD). Now all the 6 patients are alive and show complete donor chimerism with MRD negative remission. The median follow-up time are 243.5days.
Conclusion: Donor-derived second generation of CD19 CAR-T cell treatment for relapsed B-ALL after allogenic stem cell transplantation were effective and safe, which may be confirmed with more clinical studies.
Key words: donor-derived CD19 CAR-T cell therapy, allogenic stem cell transplantation, B cell acute lymphoblastic leukemia, relapse

Disclosures
No relevant conflicts of interest to declare.
Donor-Specific Isoagglutinin Clearance in ABO Mismatched Stem Cell Transplant Recipients: How Long Should It Normally Take?
Authors: Aneke John Chinawaeze , Sondi Nayana , Thyagu Santhosh , Cserti-Gazdewich Christine M. , Pendergrast Jacob 
Published: October 2019

Abstract
Introduction: In patients undergoing ABO-incompatible stem cell transplants, recipient isoagglutinins with specificity for donor antigens are expected to slowly become undetectable during the post-transplant period, presumably secondary to the loss of recipient plasma cells via either conditioning chemotherapy or graft-versus-host-disease. Conversely, the persistence or return of these anti-donor isoagglutinins may induce hemolytic anemia or pure red cell aplasia, and may even signify disease relapse. In order to define the expected time to clearance of these donor isoagglutinins at our institution, a retrospective study was performed
Methods: The transfusion records of all major-side or bidirectionally ABO-incompatible stem cell transplants performed at an academic cancer hospital between May 2009 and July 2018 were reviewed. Patients without detectable anti-donor isoagglutinins at time of transplant were excluded. Isoagglutinin clearance was defined as non-reactivity of patient plasma against donor-type reverse grouping cells occurring during the post-transplant period; relapse was defined as a 2+ or stronger reaction after one or more non-reactive results
Results: A total of 280 patients were included in analysis, of which 44 were native group A, 42 group B and 194 group O. Average age was 52 (±13) years and 130 (46%) were female. Compatibility samples were sent to the UHN blood bank during the post-transplant period for a median of 156 days (IQR 74-370 days). During this time period, donor-targeting/host-derived isoagglutinin clearance was documented in 192 (69%) patients at a median of 48 days (IQR 23-116.5) post-transplant. Of these, 52 (30%) experienced a subsequent return of reactivity at a median 98 days post-transplant (IQR 54-216). Amongst the 128 patients with at least 28 days of post-transplant monitoring and no return of previously cleared isoagglutinins, the median time to clearance was 60 days (IQR 26.5 - 127.5 days). There was no statistically significant difference in time to isoagglutinin clearance between those with and without a subsequent return of reactivity, and time to durable clearance did not correlate with patient age, sex or native ABO group.
Conclusions: Amongst patients undergoing major-side or bidirectionally ABO incompatible stem cell transplants, the majority will have cleared their donor-specific isoagglutinins within 120 days of stem cell infusion, although this does not guarantee against later return of reactivity. Thus, the persistence of donor-specific isoagglutinins beyond 120 days post-transplant, or the subsequent return of previously cleared isoagglutinins, may be considered abnormal results which warrant notification of the clinical team by the hospital transfusion service.

Disclosures
No relevant conflicts of interest to declare.
The Nek2 Genetic Knockout Mouse Model Provides Novel Treatment Strategies in Myeloma and Lymphoma
Authors: Can Li , Nadiminti Kalyan , Zhu Yuqi , Jethava Yogesh , Frech Ivana , Tricot Guido J. , Zhan Fenghuang 
Published: October 2019

Abstract
Background; Major progress in the treatment of B cell tumors has been made in the past decades. Nevertheless, relapses and refractoriness to currently available chemotherapy and even to high dose therapy with stem cell transplantation still cause significant mortality. NEK2, NEver in Mitosis Gene A (NIMA)-Related Kinase 2, is a serine/threonine kinase. High expression of NEK2 increases cell survival and drug resistance, resulting in poor clinical outcome in multiple cancers including multiple myeloma and lymphoma. In this study, we used genetic mouse models to evaluate whether NEK2 is a druggable target in the treatment of B cell tumors including myeloma and diffuse large B-cell lymphoma (DLBCL).
Materials and Methods: We have generated Nek2 knockout mice and crossed these with Eµ-Myc mice. RNA-sequencing was performed to determine signaling pathways related to Nek2 inhibition. Both NEK2 and USP7 (a protein interacting with NEK2) inhibitors were applied to treat myeloma and DLBCL in vitro and in vivo.
Results: Mouse studies showed that Nek2 played a critical role in B cell tumor development and progression. Specifically, in genetic Eμ-MYC transgenic mice, which spontaneously develop DLBCL and Burkitt lymphoma, knockout of Nek2 prevented B cell tumor development and significantly extended mouse survival. Further, immunohistochemistry analyses showed that Nek2 was highly detected in biopsies from aggressive Burkitt lymphoma patients. Our data also indicate that both NEK2 and USP7 inhibitors significantly inhibited myeloma cell and lymphoma cell growth in vitro and in vivo models and without apparent toxicity to normal tissues. Intriguingly, the combination of USP7 inhibitor P5091 with doxorubicin blocked B cell lymphoma development and extended lymphoma mouse survival.
Conclusions: Our studies demonstrate the importance of Nek2 function in tumorigenesis and progression in B cell lineage malignancies. Both NEK2 and USP7 inhibitors showed excellent efficacy in the treatment of myeloma and B-cell lymphoma.

Disclosures
No relevant conflicts of interest to declare.
Suppression of FVIII Antibody Production By FVIII BAR T-Cell in Vitro in the Presence of Inhibitors
Authors: Parvathaneni Kalpana , Zhang Ai-Hong , Scott David W. 
Published: October 2019

Abstract
To modulate B-cell responsiveness to FVIII, we previously generated cytotoxic cells expressing FVIII C2 or A2 immunodominant domains as chimeric receptors. We termed these antigen-expressing engineered T cells, "BARs", for B-cell Antibody Receptor. These CD8 T cells directly interact and kill FVIII-specific B cells and anti-FVIII hybridomas in prophylactic experiments in vitro and in vivo. It was not known whether these BAR CD8s could function or would be blocked in the presence of circulating antibodies to the expressed BAR domains. To test this, we cultured FVIII C2 or A2 BAR CD8 T cell with a mixture of monoclonal antibodies specific for these domains (up to 10 BU), and then added them to spleen cells from FVIII-immunized mice. These spleen cells were then re-stimulated with FVIII and the antibody response was determined after 5 days. Our results showed that these BAR CD8 T cells were not blocked in their ability to suppress the antibody response to FVIII under these conditions. Coupled with the observation that BAR-T cells can be stimulated to proliferate by anti-FVIII monoclonals, these results suggest that BAR cytotoxic activity may still be effective in the presences of inhibitors. (Supported by NIH grant R01 HL126727)

Disclosures
No relevant conflicts of interest to declare.
Clinical Outcomes Using Mycophenolate and Tacrolimus for Graft Versus Host Disease Prophylaxis in Patients Undergoing Allogenic Stem Cell Transplant: A Single Institution Experience
Authors: Hashmi Hamza , Bhandari Shruti , Wu Xiaoyong , Rai Shesh Nath , Tse William , Emmons Robert V.B. 
Published: October 2019

Abstract
Introduction: Graft versus host disease [GVHD] remains the major factor underlying transplant related morbidity and mortality among recipients of allogeneic stem cell transplant [allo-SCT]. The choice of GVHD prophylaxis is largely determined by HLA disparity between the donor and the recipient and the intensity of the conditioning regimen. Mycophenolate mofetil [MMF] plus calcineurin inhibitor [CNI] combination is mostly used in reduced intensity [RI] and non-myeloablative conditioning [NMAC] whereas methotrexate and CNI combination is preferred in myeloablative conditioning [MAC]. We present single institution outcomes in patients undergoing allo-SCT with MMF and CNI as the only combination for GVHD prophylaxis.
Methods: Data from all adult patients who underwent allo-SCT at our institution from 2007 to 2016 was collected from our Center for Blood and Marrow Transplant Research [CIBMTR] portal. Only patients who received both MMF and CNI as GVHD prophylaxis were included in the analysis.
Results: Total 141 patients [table 1] were included with the median age of 50 years. Most patients were female [52%] and white [85%]. Disease characteristics included AML 56.7%, ALL 14.2%, CML 7.7%, MDS/MPD 7.7%, HL/NHL 6.4% and others 7%. MAC was used in 75.2% whereas NMAC/RI conditioning was used in 24.8% of the patients. Peripheral blood was the predominant source of stem cell graft [81%]. Donor status included 30.5% HLA matched related, 63.8% HLA mismatched/matched unrelated and 4.9% HLA mismatch related. Incidence of acute GVHD at day 100 was 49.6% [grade I 16.5%; grade II-IV 33.1%], acute GVHD at day 365 was 59.6%, and chronic GVHD at day 365 was 48.1% [limited 13.5%; extensive 34.6%]. One year overall survival [OS] was 51% [95% CI 42-59%]. OS was significantly associated with race (p = 0.033) and conditioning regimen (p = 0.036), favoring better survival with white race and NMAC/RIC regimen.
Discussion: Based on historical cohort, combination of methotrexate and tacrolimus is associated with acute graft versus host disease in 89% [grade I 11%; grade II-IV 78%], chronic graft versus host disease in 94% [limited 32%; extensive 65%] and one year overall survival of 47%. Hence our single institutional analysis shows that the combination of mycophenolate and tacrolimus is superior to methotrexate and tacrolimus combination for prevention of acute and chronic graft versus host disease as well as 1-year overall survival. We suggest that well-designed randomized controlled clinical trials be conducted to verify these findings.

Disclosures
No relevant conflicts of interest to declare.