bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Potential Roles of Mucosa-Associated Invariant T Cells in the Pathogenesis of Gut Graft-Versus-Host Disease after Hematopoietic Stem Cell Transplantation
Authors: Mengge Gao , Hong Yan , Xiangyu Zhao , Sun Yuqian , Kong Jun , Wang Zhidong , Wang Fengrong , Wang Jingzhi , Yan Chenhua , Wang Yu , Huang Xiaojun , Zhao Xiaosu 
Published: November 2021

Abstract
Background & Purpose: Gut acute graft-versus-host disease (aGVHD) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is associated with high mortality. Mucosal-associated invariant T cells (MAITs) are a group of innate-like T cells enriched in the intestine that can be activated by riboflavin metabolites from various microorganisms. However, little is known about the function or mechanism of action of MAIT in the occurrence of gut aGVHD in the human body.
Methods & Cases: In our study, multiparameter flow cytometry (FCM) was used to evaluate the number of MAIT cells (MAITs) and functional cytokines. 16S V34 region amplicon sequencing analysis was used to analyse the intestinal flora of transplant patients. In vitro stimulation and coculture assays were used to study the activation and function of MAITs. The number and distribution of MAITs in intestinal tissues were analysed by immunofluorescence technology. We prospectively studied the enrolled 150 consecutive patients who underwent allo-HSCT in our institute.
Results: The number and frequency of MAITs in infused grafts in gut aGVHD patients were lower than those in non-gut aGVHD patients (Figure). Recipients with a high number of MAITs in infused grafts had a higher abundance of intestinal flora in the early post-transplantation period (+14 days). At the onset of gut aGVHD, the number of MAITs decreased in peripheral blood, and the activation marker CD69, chemokines CXCR3 and CXCR4 and transcription factors Rorγt and T-bet tended to increase. Furthermore, when gut aGVHD occurred, the proportion of MAIT17 was higher than that of MAIT1. The abundance of intestinal flora with non-riboflavin metabolic pathways tended to increase in gut aGVHD patients. MAITs secreted more granzyme B, TNF-α and IFN-γ under the stimulation of IL-12/IL-18 (non-TCR signal) and secreted most of the IL-17 under the stimulation of CD3/CD28 (TCR signal). MAITs inhibited the proliferation of CD4+ T cells in vitro.
Conclusions: In conclusion, the lower number of MAITs in infused grafts was related to the higher incidence of gut aGVHD, and the number of MAITs in grafts may affect the composition of the intestinal flora of recipients early after transplantation. The flora of the riboflavin metabolism pathway activated MAITs and promoted the secretion of intestinal protective factors to affect the occurrence of gut aGVHD in humans.
Figure 1 Figure 1.

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

Abstract
Background: Significant difference existed in survival outcomes of primary central nervous system lymphoma (PCNSL) patients. The aim of this study was to establish a prognostic nomogram to access personalized survival rate of PCNSL patients.
Methods: 2947 patients were extracted from the Surveillance, Epidemiology, and End Results database as the training cohort. 177 patients diagnosed from 2006-2020 in Sun Yat-Sen University cancer center were identified as the external validation cohort. Cox proportional hazards model was performed to identify independent factors for establishing the nomogram. Concordance index (C-index) and calibration curves were used to test the accuracy of the model.
Results: Age, tumor site, lymphoma subtype, surgery and chemotherapy were significant predictors included in the nomogram. C-index in the training and validation cohort were 0.701 and 0.653, respectively. Calibration curves showed favorable consistency of nomogram-predicted and actual probability of overall survival (OS). The decision curve analysis (DCA) curves exhibited great clinical application. We published a web calculator for convenient clinical practice and established a risk classification system that significantly distinguished patients into four groups. Results of the primary cohort were well confirmed in the validation cohort.
Conclusion: We developed a nomogram and a web calculator of OS prediction for PCNSL, which may assist in medical consultation, treatment decision making and clinical study design.
Figure 1 Figure 1.

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

Abstract
Background: Stage III follicular lymphoma (FL) is currently still considered incurable after RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy and rituximab maintenance. Radiotherapy plays a vital role in early-stage FL, but the value remains unclear in stage III FL. Here, we reported the results of invasive field radiotherapy (IFRT) combined with rituximab maintenance versus rituximab maintenance alone in patients with stage III FL who achieved complete remission (CR) or partial response (PR) after induction chemotherapy.
Methods: From January 2015 and January 2020, patients aged 18-70 years with CR or PR after induction chemotherapy in stage III FL, grade 1, 2 or 3a and CD20 positive in immunohistochemical feature were randomly assigned (1:1) to receive IFRT combined rituximab maintenance or rituximab maintenance alone after induction chemotherapy in multicenter. The primary endpoint was progression-free survival at 5 years. This study is registered with Chinese ClinicalTrials.gov, number ChiCTR2000032550.
Results: 63 patients were randomly assigned to IFRT combined rituximab maintenance (IFRT+R arm) and 66 patients to rituximab maintenance alone (R arm) after induction chemotherapy. The dose of IFRT was 30Gy. After a medium follow-up of 48 months (range 7-72 months), the 5-year progression free survival (PFS) were significantly improved in patients with IFRT +R, with 87.8% versus 67.1% (HR, 0.32; 95% CI, 0.14-0.72, P=0.006). Patients with IFRT +R also have a better overall survival (OS), OS was 96.6% versus 80% (HR, 0.28; 95% CI, 0.09-0.92, P=0.036). Thirty-six (57%) patients in IFRT+R arm and twenty-four (36%) patients in R arm suffered toxic effects (P=0.02). Grade 3 and 4 adverse events were recorded in 17 patients (27%) in IFRT+R arm and 11 (16%) in R arm (P=0.200).
Conclusion: On the basis of rituximab maintenance, IFRT demonstrated promising efficacy and manageable toxicity in stage III FL, with longer PFS and OS compared with rituximab alone.
Figure 1 Figure 1.

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

Abstract
Background:
Malignancy is an independent risk factor for venous thromboembolism. Factors like site of the primary cancer, associated comorbidities, obesity, and baseline cytopenias play an important role in predicting the risk in cancer patients. Several risk assessments models have been proposed in the literature, however, the Khorana risk predictive model is the most favored tool used in the literature. Patient characteristics like site of primary, baseline hemoglobin/platelets/WBC and BMI are the main components of this scoring system. Patients are classified into low (0), intermediate (1-2) and high (&gt; 3) risk groups. Low dose prophylactic anticoagulation (Apixaban 2.5 mg BID or Rivaroxaban 10 mg daily) for up to 6 months is indicated in patients with score 2 or higher.
Methods:
83 patients with a new cancer diagnosis in the years 2018 and 2019 who received chemotherapy and developed a venous thromboembolism (VTE) after the cancer diagnosis were identified from the cancer registry at Edwards Comprehensive Cancer Center. All the components of Khorana score including patient's baseline body mass index (BMI), white blood cell count (WBC), hemoglobin, platelet count and site of the primary were collected. Compliance with prophylactic anticoagulation (Khorana score =/&gt;2) was evaluated.
Results:
Among 83 patients identified, 61 % and 39 % were female and males, respectively with a mean age of 59 years. The mean duration of onset of VTE was 18 months from the time of cancer diagnosis. The mean Khorana score was 1.1. 34 % of patients(n=28) were found to have a Khorana score of =/&gt; 2 and prophylactic anticoagulation was indicated. Only 7 % of patients (n=2) received prophylactic anticoagulation. The reason for no prophylactic anticoagulation was not documented in all the cases.
Conclusion:
In patients with a higher risk of VTE, a very low compliance rates for prophylactic anticoagulation were found at our cancer center. Poor documentation and failure to address the risk of VTE are possible reasons for the low compliance rates. Necessary steps needed to improve the compliance rates are warranted including education of the healthcare providers about current available guidelines to decrease risk of VTE in cancer patients. Dedicated lectures and sessions will be organized and educational materials highlighting the importance of VTE risks and prophylactic anticoagulation will be provided to the healthcare providers at the cancer center.

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

Abstract
Idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening disorder involving polyclonal lymphoproliferation and organ dysfunction due to excessive cytokine production, including interleukin-6 (IL-6). Anti-IL-6 therapy is recommended first-line and effective in 34-45% of patients. mTOR, which functions through mTORC1 and mTORC2, is a recently-discovered therapeutic target. The mTOR inhibitor sirolimus, which preferentially inhibits mTORC1, has led to sustained remission in a small cohort of anti-IL-6 refractory iMCD patients with thrombocytopenia, anasarca, fever, renal dysfunction, and organomegaly (TAFRO). However, sirolimus has not shown uniform effect, potentially due to its limited mTORC2 inhibition. To investigate mTORC2 activation in iMCD, we quantified the mTORC2 effector protein pNDRG1 by immunohistochemistry of lymph node tissue from iMCD-TAFRO (N=6) patients and iMCD patients not meeting TAFRO criteria (iMCD-NOS; N=8) (Table 1) as well as autoimmune lymphoproliferative syndrome (ALPS) (N=6), Hodgkin lymphoma (positive controls, N=8), and metastasis-free sentinel lymph nodes (normal controls, N=8).
In iMCD-TAFRO, pNDRG1 expression was elevated in the interfollicular space (IF) (P=0.005), germinal centers (GC) (P=0.002), and mantle zones (MZ) (P=0.007) relative to normal controls (Figure 1A). pNDRG1 staining was increased in the IF (P=0.005) of iMCD-NOS relative to normal controls and there was no difference in the GC (P=0.59) and the MZ (P=0.30) (Figure 1B). Next, we compared pNDRG1 expression in iMCD-TAFRO and iMCD-NOS to ALPS, an mTOR-driven, sirolimus-responsive lymphoproliferative disorder.Our results revealed increased pNDRG1 staining in iMCD-TAFRO GC relative to ALPS (P=0.02) (Figure 1C). There were no differences in pNDRG1 expression between iMCD-NOS and ALPS in any region (Figure 1C). Notably, the strongly positive pNDRG1 cells had spindle-shaped morphology resembling stromal cells (Figure 1H).
These results suggest increased mTORC2 activity in iMCD and that dual mTORC1/mTORC2 inhibitors may be a rational therapeutic approach for anti-IL-6 treatment refractory patients. Further studies are needed to confirm this finding, uncover cell types showing increased mTORC2 expression, and investigate therapeutic approaches.
Figure 1 Figure 1.

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

Abstract
Nucleophosmin1 (NPM1) is one of the most frequently mutated genes in AML, is often associated with a favorable prognosis and seems to be a suitable target structure for immunotherapeutic approaches. Other groups and ours described specific immune responses of CD8-positive T cells against immunogenic epitopes derived from the mutational region of NPM1 in AML patients (pts).
In this extended immunological study, we investigated immune responses against the mutational epitope of NPM1 but also against other LAA in NPM1 mut compared to NPM1 wt pts. 30 AML pts were analyzed using FACS analysis, tetramer staining and colony forming immunoassays (CFI). 15 NPM1 mut and 15 NPM1 wt pts were investigated in CFI to detect CTL mediated immune responses against leukemic progenitor/stem cells (LPC/LSC). We also added immune checkpoint inhibitors to investigate whether these immune responses could be enhanced.
Against the LAA PRAME-P3, WT1 and RHAMM-R3 we detected similar frequencies of T cell responses in CFI in NPM1 mut compared to NPM1 wt pts. Antigen specific immune responses were detected in CFI by comparing growth of patient cells alone with growth by addition of antigen specific CTL and calculating colony reduction.
Comparing NPM1 mut/NPM1 wt pts many had an immune response to LAA, more than 50% of the pts in both cohorts exhibited an immune response against all epitopes.
In NPM1 wt pts no responses were found against the NPM1 epitope as expected, whereas NPM1 mut patients showed a high frequency of immune responses in 10/15 NPM1 mut AML pts (67%) in CFI a reduction of colonies was detected.
With the addition of anti-PD1 antibody to CFI we detected an increase of immune responses. For the LAA responses were similar comparing NPM1 mut/NPM1 wt.
Compared to LAA, the epitope NPM1 showed a particularly strong immune response when the antibody anti-PD1 was added. All 15 NPM1 mut pts showed an immune response with anti-PD1, with a median reduction of colonies of 47%. 7 of 15 NPM1 mut pts showed a strong immune response against LPC/LSC in CFI with more than 50% reduction of colonies.
The data suggest that especially NPM1 mut patients are suitable candidates for antibody therapy with the PD1 antibody. Combination with another immunotherapy such as an NPM1 specific vaccine would be a possibility. Even though no advantage in therapy with the anti-PD1 antibody has yet been shown in the overall AML collective, this therapy could be an option for patients with NPM1 mutated AML.

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

Abstract

MLL-rearranged (MLLr) leukemias count for more than 80% of infant leukemia, ~5-10% of B-cell acute lymphoblastic leukemia (B-ALL), and ~10% of acute myeloid leukemia (AML) cases, where they confer a particularly poor outcome. Despite treatment with intensive multi-agent chemotherapy, most MLLr patients achieved an initial remission but ultimately relapsed. Bromo- and Extra-Terminal domain inhibitors (BETi) prevent the progression of many cancer types in preclinical studies, including MLLr leukemia. However, the mechanisms controlling drug response and resistance of BET inhibitors are not well understood.
We have addressed this timely, crucial scientific question by completing genetic screens to explore potential BETi resistance mechanisms. By conducting genome-wide and targeted loss-of-function CRISPR screens using MLLr AML cell lines upon BETi treatment including ABBV-744, JQ1, and dBET1, we discovered that Speckle Type POZ (SPOP) gene deficiency leads to significant BETi resistance in in vitro cell culture systems (SEM, OCI-AMl2 and MV4,11), and by in vivo transplantation of human MLLr leukemia SEM cells into immune-deficient mice. However, no BETi resistance phenotype was seen in non-MLLr SPOP-deficient cells. SPOP was previously reported as an adaptor protein to bridge the E3 ubiquitination complex component CUL3 to the substrate proteins BRD4 and MYC in prostate and many other solid cancers. However, in SPOP knockout MLLr leukemia cells, TRIM24, not BRD4 and MYC, was identified as a substrate likely responsible for SPOP's role in drug resistance. Genetically blocking TRIM24 via CRISPR knockout in SPOP-knockout cells reversed the BETi resistance phenotype. Transcriptomic analysis of TRIM24-deficient cells identified the GSK3A signature as the top influenced pathway. Additionally, proteomics expression analysis and a kinase vulnerability CRISPR screen also indicated that resistant cells are sensitive to GSK3B inhibition. Further validation by CRISPR knockout and pharmaceutical blockage of GSK3A/3B (by ChIR-98014) sensitized the SPOP-deficient resistant cells to BETi treatment in vitro. In SEM xenograft models in NSG mice, ABBV-744 or CHIR-98014 minimally impacted human CD45 + leukemia cell proliferation while synergistic treatment significantly reduced the tumor progression.
In summary, our data suggest the novel SPOP/TRIM24/GSK3A/3B axis plays an essential role in BETi therapy-resistant leukemia cells. Targeting GSK3A/3B pathways by ChIR-98014 can overcome SPOP-associated BETi resistance in in vivo preclinical models of MLLr leukemia. Successful outcomes following combination therapy using ChIR-98014 and BETi in PDX models would translate to a clinical application that holds the promise to cure MLLr leukemia.

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

Abstract

Background: After allogeneic hematopoietic stem cell transplantation (allo-SCT), 35%-45% of patients suffer disease relapse, resulting in dismal outcomes. Several strategies have been adopted to prolong disease-free intervals. Hypomethylating agents (HMA) seem to have a range of properties favorable to post-allo-SCT maintenance. They mediate a direct anti-leukemic effect in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), regardless of their molecular mutation profile. Moreover, their abilities to induce a CD8+ tumor-specific T cell response, together with the expansion of regulatory T cells, leads to an epigenetically enhanced graft-versus-leukemia effect that is not counterbalanced by an increased risk of graft-versus-host disease (GVHD).
Materials and Methods: Two investigators independently searched the Embase and MEDLINE databases for relevant studies published from inception to 31 January 2021. The inclusion criteria were as follows: (1) the studies had to be either randomized controlled trials or cohort studies; (2) the patients underwent allo-SCT for AML or MDS; (3) the studies compared 2 patient groups: one receiving HMA maintenance post-allo-SCT, and the other being an observational group; and (4) the studies needed to report at least one of our primary outcomes of interest; overall survival (OS), relapse-free survival (RFS), grade II-IV acute GVHD, and chronic GVHD.
Results: Eleven eligible studies compared HMA maintenance to observation following allo-SCT for AML or MDS. The OS of the HMA maintenance group was superior to the observation group, with a pooled odds ratio (OR) of 2.52 (95% CI, 1.60-3.94; I 2, 51%; Figure 1A). Similarly, a pooled meta-analysis found that the RFS was significantly better for patients receiving HMA maintenance, with a pooled OR of 2.64 (95% CI, 1.79-3.90; I 2, 0%; Figure 1B). Moreover, the cumulative incidence of relapse (CIR) was significantly lower in patients who received HMAs. The HMA group also had lower non-relapse mortality (NRM) compared with the observation group. Overall, the incidences of grade II-IV acute GVHD and chronic GVHD did not differ in both groups. However, when looking specifically at those receiving decitabine maintenance, the rate of chronic GVHD seemed to be lower compared with observation alone.
Conclusions: The current systematic review and meta-analysis illustrated that AML and MDS patients receiving HMA maintenance after allo-SCT had better outcomes in regards to OS, RFS, NRM, CIR as well as a reduced incidence of chronic GVHD.
Figure 1. Forest plots of the meta-analysis of HMA maintenance compared with observation. (A) OS rate. (B) RFS rate.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.