bluuebunny/crossref_metadata_2025_split huggingface dataset:
Double/Triple Hit Lymphoma Descriptors and Clinicopathologic Determinants of Survival: Analysis of a Pooled Database
Authors: Haddad Philip A , Gupta Supriya , Gupta Ankita , Graham Christopher 
Published: December 2023

Background
B-cell lymphoma with MYC, BCL2, and/or BCL6 rearrangements is classified as double/triple-hit lymphoma (DTHL). They usually, but not always, tend to be high-grade aggressive B-cell lymphoma with a worse prognosis. Despite this classification, DTHL remains a heterogeneous group with varied molecular profiles, biological behaviors, and prognoses. Therefore, we conducted this pooled database analysis to identify the prognostic factors, clinicopathological characteristics, and therapeutic strategies influencing survival in this rare disease.
Methods
To study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 161 cases that fit the diagnostic criteria for DTHL. Kaplan-Meier survival curves were constructed. Cox proportional hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on overall survival (OS) and disease-free survival (DFS).
Results
We compiled a dataset of 161 patients with confirmed DTHL. The median age was 62, with an F:M of 1.08. The median duration of symptoms before diagnosis was 2 months. DTHL involved the lymph nodes (41%), bone marrow (31%), bone (14%), CNS (5%), skin (4%), liver (3%), and spleen (2%). Constitutional symptoms were reported in 20% of cases. The cohort consisted of primary (50%), secondary/transformed (16%), and follicular DTHL (34%). The median OS and DFS of the cohort were 69 and 27 months, respectively. Bone marrow and extra-lymphatic organ involvement were associated with worse DFS and non-significant numerically worse OS. LDH&gt;500 (p=0.006), PAX5-negative (p=0.01), CD79a-negative (p=0.02), and Ki67&gt;80% (p&lt;0.0001) were associated with worse OS. Similarly, CD5+, CD10+, and MUM1+ had worse OS but did not reach statistical significance. Follicular DTHL was associated with the best median OS and DFS, followed by primary, then secondary/transformed in decreasing order. Advanced stage and high IPI were also associated with worse non-significant numerical OS. Age and sex did not impact OS. Compared to no treatment, chemotherapy and stem cell transplant had incrementally superior median OS (3 vs. 55 vs. NR months, p=0.008). Frontline intensive chemotherapy yielded similar DFS and OS to CHOP-like regimens. Patients who attained CR as their best response also had a superior median OS (p&lt;0.0001).
Conclusion
This study presents clinicopathologic data from a cohort of patients with primary, secondary, and follicular DTHL. It identifies the type of DTHL, IHC profile, LDH levels, type of therapy, and quality of response to treatment as critical determinants of OS. Depending on the type (de novo, secondary, or follicular), DTHL seems to behave like 3 different disease entities.
Efficacy of Radiotherapy for Hemostasis in Tumor-Related Bleeding
Authors: Deloughery Emma P , Wilson Byron , Grossberg Aaron 
Published: December 2023

Introduction: Hemorrhage is a common complication of malignancy. When undergoing invasion and angiogenesis, malignancies can produce highly vascular lesions with friable and disorganized vessels that are prone to bleeding (Hughes and Radhakrishna, Br J Hosp Med (Lond), 2019). Among patients with advanced cancer, around 10% have bleeding symptoms, which can impact both the quality and quantity of life (Katano and Yamashita, Cureus, 2021). Palliative radiotherapy (RT) has been associated with achieving hemostasis in a variety of bleeding malignancies, including gastric, bladder, lung, and gynecologic cancers. The goal of this study was to better determine the efficacy of radiotherapy in reducing transfusion requirements.
Methods: A retrospective chart review of patients was performed after IRB approval. Patients who received radiation for controlling malignancy-associated hemorrhage were included in this study. The outcome measure was change in red blood cell (RBC) transfusion requirements from the month prior to the month following palliative RT. Data was obtained from the institution's electronic medical record. Change in transfusion requirements was analyzed using Welch's t-test and bleeding recurrence was analyzed using the exact test of goodness-of-fit.
Results: A total of 6002 patients were screened and 30 cases (63.3% female, average age at radiation treatment 62 years) were included in the study with RT treatment dates 2019-2023. Sixteen malignancy types were represented, with pancreatic adenocarcinoma and endometrial adenocarcinoma being the most common (both 4, 13.3%). Median radiation dose was 13 Gy (range 3-30) delivered over a median of 3.5 fractions (range 1-10). Bleeding was not noted to recur in 73.3% of the cases ( P = 0.02). For those patients with recurrent bleeding, median time from RT to recurrent bleeding was 58 days (range 11-544). Transfusion requirements decreased from an average of 2.7 RBC units over one month prior to completion of RT to 1.1 units for the month following completion of RT ( P = 0.03). Median survival after completion of RT was 132 days (range 3-698).
Conclusion: This study showed that radiation therapy resulted in apparent cessation of hemorrhage in over 70% of cases of hemorrhagic malignancies with a significant decrease in RBC transfusion requirements over one month. This suggests that RT is effective in stopping hemorrhage in a variety of malignancies as well as reducing transfusion requirements. More work is needed to test this hypothesis on larger populations, as well as investigation on the mechanism by which RT results in hemostasis.
Clinical Application of the IPSS-M Prognostic Score in Myelodysplastic Syndrome
Authors: Cheng Jian , Liu Jiangnan , Ge Zheng , Zhang Xinyu , Zhang Qiucheng , Chen Bao-An , Ma Jinlong 
Published: December 2023

Objectives: Patients with myelodysplastic syndrome (MDS) currently get therapy in accordance with their prognosis scores. The newest MDS risk-stratified score, the IPSS-M, isn't still being extensively used in clinical practice and is based on clinical and molecular data. Comparing the IPSS-M score to the current IPSS-R score will enable us to assess the clinical relevance of the IPSS-M score, especially for low-risk MDS patients.
Methods: In order to determine the IPSS-R and IPSS-M scores, we gathered clinical, cytogenetic, and molecular information from 210 MDS patients who were diagnosed between 2016 and 2023 and followed up until April 2023. Harrell's c index and Kaplan-Meier survival analysis were used to examine the impact of the two scores on overall survival (OS).The lower-risk group included patients with IPSS-R≤3.5 and IPSS-M≤0, whereas the higher-risk group included the remaining patients. Analysis was done on the differences in gene mutations between the two risk groups based on the two scoring standards, as well as the impact of IPSS-M reclassification on the choice of therapeutic treatments.
Results: At least one genetic mutation was identified in 77.1% of patients. The genes ASXL1 (21.4%), TET2 (19.0%), TP53 (14.8%), and DNMT3A (13.3%) have the highest frequency of mutations. According to IPSS-R score, the higher-risk group's TP53 gene mutation rate was significantly higher than that of the lower-risk group; According to IPSS-M score, the higher-risk group had more instances of TP53 and ASXL1 gene mutations than the lower-risk group did, while the lower-risk group had a relatively higher incidence of SF3B1 gene mutations than the higher-risk group did. The difference in survival between IPSS-M groups was more prominent than that between IPSS-R groups under Kaplan-Meier survival analysis, which was used to assess the prognostic prediction power of IPSS-R and IPSS-M. When t 50 months, the Harrell's c index of OS predicted by IPSS-M exceeded that of IPSS-R (IPSS-R vs IPSS-M c-index: 0.710vs0.747, 0.692vs0.707, 0.705vs0.726, 0.752vs0.759, 0.743vs0.773, t=10, 20, 30, 40, 50 months), demonstrating that IPSS-M enhanced the outcome prediction.87 patients (41.4%) were re-stratified by IPSS-M, with 65 (30.9%) being upgraded and 22 (10.5%) being degraded. 64 patients (30.5%) who had changes in their IPSS-M scores qualified for reduced therapy, whereas 48 (22.9%) qualified for intensive treatment, including 32 patients who were reclassified as being in the lower risk category based on their IPSS-R scores.
Conclusions: The research shows that IPSS-M offers a more thorough prognostic evaluation than IPSS-R. Certain patients' treatment modalities may need to be changed as a result of modifying IPSS-M in clinical settings, especially those who were previously classified as low-risk.
HIV-Related Diffuse Large B Cell Lymphoma Influences on T Cell Exhaustion
Authors: Jiang Tingting , Peng Yu , Tang Xinyi , Chen Shuang , Yang Zailin , Liu Yao 
Published: December 2023

BACKGROUD
HIV infection leads to T cell dysfunction, which triggers increased incidence of diffuse large B cell lymphoma (DLBCL). It has been shown that PD-1 inhibitors can better restore T cell function and effectively treat HIV-related lymphoma. However, the specific mechanism on the treatment of HIV-related DLBCL patients with PD-1 inhibitors is ambiguous, and related studies on the expression of PD-1 on T cells have not been reported. This study aimed to explore the regulatory role of altered immune function status in the microenvironment of HIV-related DLBCL and to analyze hyper-exhausted T cell subsets.
METHODS
Three patients with DLBCL, two patients with HIV and 11 patients with HIV-related DLBCL who were treated from September 2021 to December 2022 at the Chongqing University Cancer Hospital of were included. Single cell sequencing was used to analyze immune cell and tumor cell related genes in patients'lymph node tissues. InferCNV was used to distinguish normal and malignant B lymphocytes. Gene set enrichment analysis (GSEA) was used to find the expression of exhaustion genes and related signaling pathways in immune cells. And relevant exhausted immune cells were analyzed and validated by flow cytometry.
RESULTS
Compared to the HIV and DLBCL groups, the HIV-related DLBCL group had a higher level of expression of the gene PDCD1, a higher level of expression of CD23(FCER2) in normal B lymphocytes, and a greater difference in malignant B lymphocytes, with a lower percentage of TCF1-positive exhausted T cells and a higher level of CXCL13-positive exhausted T cells (Fig.1-3). Compared with the HIV group, the percentage of follicular helper T cells (T fh) was lower in the HIV-related DLBCL group. The results of the Pseudotime analysis showed two main developing directions of TCF1-positive exhausted T cells (Fig.4). The state2 was primarily the direction of TCF1-positive exhausted T cell development in the HIV group and the HIV-related DLBCL group, and the state3 was primarily the direction of TCF1-positive exhausted T cell development in the DLBCL group and the HIV-related DLBCL group.
CONCLUSION
Patients with HIV-related DLBCL are more at risk of T cell exhaustion. In this study, we found that HIV-related DLBCL induced T cell exhaustion has different states and shows two differentiation directions, and state2 may correlate with HIV-induced T cell exhaustion. T cell exhaustion states may be used for disease status and clinical efficacy assessment of HIV-related DLBCL.
Novel Targeted Agents in Combination with R-ICE (R-ICE-X) Based on Genotyping in Relapsed/Refractory DLBCL
Authors: Shen Yige , Cao Yiwen , Cheng Shu , Xu Pengpeng , Wang Li , Zhao Weili 
Published: December 2023

Background: Relapsed/refractory (R/R) DLBCL constitutes 40% of all DLBCL cases. Coventional salvage regimens, such as R-ICE, R-GDP, and R-DHAP, have an overall response rate (ORR) of 60% and a complete response rate (CR) of 30-40%. For patients who have achieved complete metabolic remission as determined by PET-CT evaluation after salvage therapy, undergoing autologous transplantation is crucial in order to achieve durable long-term survival. The outcomes of these R/R DLBCL remain to be improved.
Aims: This prospective study aims to investigate whether adding novel agents to R-ICE (R-ICE-X) based on genetic subtypes could improve clinical efficacy in R/R DLBCL. This trial is registered at clinicaltrials.gov (NCT05348213).
Method:In this study, patients with R/R DLBCL aged 18 -75 years were enrolled. All patients were assigned and stratified by genetic subtype and received different targeted agents combined with R-ICE. The efficacy was evaluated after 3 courses of R-ICE-X (every 21 days). Patients with CR/PR were subsequently treated with autologous hematopoietic stem cell transplantation or 3 courses of R-ICE-X consolidation and lenalidomide maintenance for up to 12 months. See the detail in the figure. The primary endpoint was the overall response rate (ORR), and the secondary endpoints were the 2-year progression-free survival (PFS) rate, 2-year overall survival (OS) rate, and safety evaluation.
Results: At the time of data cut-off, a total of 66 patients were enrolled, with a median age of 61(20-75) years. In the patients with R-ICE-zanubrutinib group (n=28), the ORR was 84.0%, with 15 patients (15/25, 60.0%) achieved CR and 6 patients (6/25, 24.0%) achieved PR. The 1-year PFS rate and OS rate were 68.2% and 90.5%, respectively. In the patients with lenalidomide combined with R-ICE (n=28), 16 patients (16/26, 61.5%) achieved CR, 4 patients (4/26, 15.4%) achieved PR, and the ORR was 76.9%. The 1-year PFS and OS rates were 78.5% and 100.0%, respectively. In the patients with the R-ICE-decitabine group (n=7), the ORR was 66.7%, with 4 patients (4/6, 66.7%) achieving CR. The 1-year PFS rate and OS rate were 50.0% and 60.0%, respectively. The number of other groups needs to be further updated. Among 66 patients, 17 patients had autologous transplantation (ASCT) and 1-year PFS and OS of patients with ASCT were both 87.1%. The number of other groups will be further updated.
Conclusion: Novel targeted agents in combination with R-ICE (R-ICE-X) regimen was well tolerated and efficacy in R/R DLBCL patients, meanwhile, it could be a promising bridging regimen for ASCT. The study is ongoing and further results will be continuously released.
Efficacy of Daratumumab in 34 Patients with Newly Diagnosed Multiple Myeloma in Real World Study
Authors: Li Xiangxin , Wang Lingling , Li Fanglin , Zhou Hai , Liu Na , Yu Shuang , Feng Qi , Li Hao , Wang Luqun 
Published: December 2023

Obj ective: To observe the efficacy and safety of daratumumab (Dara) for newly diagnosed multiple myeloma (NDMM) in the real world.
Methods: The clinical data of 34 patients with NDMM treated with Dara in 3 medical centers in Shandong Province was collected.Treatment options included 15 Dara-Vd, 5 Dara-d, 4 Dara-Rd, 4 Dara-RVd, 3 Dara-ICd, 2 Dara-VCd and 1 Dara-Id. The efficacy was evaluated and the classification of M protein expression, cytogenetics, creatinine clearance and minimal residual disease (MRD) were gathered. NGF MRD-negative was used as the intermediate endpoint of survival prediction to evaluate the related influencing factors.
Results: There were 19 male among the 34 NDMM patients and 21 cases were &lt;65 years. 9 cases completed 2 treatment cycles, 11 completed 4 treatment cycles and 14 completed 6 treatment cycles. The univariate association between efficacy (sCR, CR,VGPR, PR, SD and PD) and the clinical feature showed a statistically significant association between ECOG score and efficacy ( P=0.002).The best response for CR is 38.2% (13/34)) with 0 score, 8.8% (3/34) with 1 score, 5.9% (2/34) with 2 score ,while none with 3 score. As the efficacy was divided into 2 groups (CR and other effects), the CR rate after 2,4, and 6 cycles showed a linear trend (Fisher test P=0.025, linear trend test=7.062, P=0.008). COX multivariate analysis showed the achievement of NGF MRD-negative was associated with increased cycle number, in which 8.8% (3/34) after 2 cycles, 24% (6/25) after 4 cycles and 35.7% (5/14) after 6 cycles, while no association with other factors as gender, ISS stage and cytogenetics. We observed that the incidence of hematological adverse reactions above grade 3 was 20.5%(7/34), mainly neutropenia and thrombocytopenia. Other non-haematological adverse reactions were infection (44.1%) and peripheral edema (41.2%).
Conclusion: Although efficacy was limited in high ECOG scores, Dara based regimen regardless of gender, age, disease stage was a good choice for NDMM in our observation. With the increase of treatment cycles, deep remission was more outstanding with tolerable side effects.
Linking DNA Damage Response to Ferroptosis for Leukemia Stem Cell Eradication
Authors: Malik Bilal , Hassan Nunki , Wang Jenny Y. 
Published: December 2023

Relapse in acute myeloid leukemia (AML) is associated with an unfavorable prognosis, primarily due to the poor response to conventional chemotherapy, which has shown disappointing overall outcomes over the past 30 years. The main culprits behind leukemogenesis and therapy resistance are leukemia stem cells (LSCs), characterized by their unique features of self-renewal and evasion from cell death. In our recent work, we have identified a critical self-renewal pathway, RSPO3-LGR4/p-PKAc, which exhibits aberrant activation in relapsed or refractory AML (Salik et al. Cancer Cell, 2020). Blocking this pathway holds the potential to eradicate resistant LSCs and treat relapsed AML effectively.
In this study, our data directly link the self-renewal pathway to ferroptosis resistance through activation of antioxidant defense, which confers protection on AML LSCs against detrimental effects of oxidative stress. We also found that aberrant activation of RSPO3-LGR4/p-PKAc suppressed the DNA damage response (DDR) pathway consequently leading to genomic instability, DNA repair defects, increased stemness and AML aggressiveness. Our whole-genome sequencing and knockout mouse studies showed that deletion of the key DDR gene caused substantial mutations on multiple pathways including DNA damage repair (e.g., Slf1) and self-renewal (e.g., Hox cluster genes), contributing to a more aggressive and therapy-resistant phenotype in AML initiation and progression. Single cell multi-omics sequencing and CRISPR/Cas9 knockout mouse models uncovered essential antioxidant enzymes as downstream targets of DDR pathway inhibition in AML patient-derived LSCs. These antioxidant enzymes induced by DDR pathway inhibition had protective effects against oxidative attack due to the ability to decompose reactive oxygen species (ROS) and detoxify excess iron. ShRNA-mediated stable knockdown of antioxidant enzymes impaired LSCs by increasing accumulation of iron and ROS and sensitized LSCs to ferroptosis (an iron-dependent and ROS-reliant cell death). Our analysis of AML dataset from TCGA (The Cancer Genome Atlas, N Engl J Med 2013) displayed a positive correlation of high expression of antioxidant genes with poor prognosis in a cohort of 172 AML patients (p&lt;0.019), indicating the clinical importance of antioxidant dysregulation in cancer.
Collectively, we report here a functional relationship of DDR pathway inhibition and antioxidant defense mechanism that is regulated by RSPO3-LGR4/p-PKAc self-renewal pathway and contributes to ferroptosis resistance in AML LSCs. Targeting essential pathway components enables LSCs to become sensitive to oxidative damage and ferroptosis and perturbs leukemia progression, presenting a promising new therapeutic approach for relapsed or refractory AML.
Fatal Pulmonary Embolism, Fatal Bleeding and Intracranial Hemorrhage with Systemic and Catheter-Directed Thrombolysis in Intermediate-High and High-Risk Pulmonary Embolism: A Systematic Review with Meta-Analysis
Authors: Patel Anuj Bharatkumar , Mai Vicky , Caiano Lucia , Mercier Mathieu , Carrier Marc , Le Gal Gregoire , Castellucci Lana 
Published: December 2023

Background: Thrombolysis, either systemic (ST) or catheter-directed (CDT), may reduce mortality in patients with intermediate-high and high-risk pulmonary embolism (PE), but with an increased risk of major bleeding (MB). Moreover, uncertainties remain for other efficacy and safety outcomes, such as fatal PE, fatal bleeding, and intracranial hemorrhage (ICH).
Aims: To evaluate fatal PE, fatal bleeding and ICH with ST and CDT in patients with intermediate-high and high-risk PE.
Methods: We performed a systematic search in MEDLINE, EMBASE and Cochrane from inception to December 2022. Randomized trials and cohort/observational studies of patients with intermediate-high and high-risk PE were included. We report fatal PE, fatal bleeding and ICH; mortality and MB have been previously reported. Pooled proportions with their 95% confidence interval (CI) were calculated for each treatment group.
Results: One hundred and fifty-eight studies (87,874 patients) were included. In patients treated with ST, 30-day mortality and MB occurred in 10.4% (95%CI 6.6%-14.8%; I 2=99%) and in 8.0% (95%CI 5.8%-10.5%; I 2=96%), respectively. Fatal PE occurred in 3.9% (95%CI 2.1%-6.3%; I 2=88%), fatal bleeding in 1.7% (95%CI 1.3%-2.3%; I 2=8%) and ICH in 1.6% (95%CI 1.3%-1.9%; I 2=17%). In patients treated with CDT, 30-day mortality and MB occurred in 5.3% (95%CI 3.6%-7.3%; I 2=93%) and in 5.4% (95%CI 3.8%-7.2%; I 2=87%), respectively. Fatal PE occurred in 1.5% (95%CI 1.0%-2.0%; I 2=2%), fatal bleeding in 1.2% (95%CI 0.8%-1.6%; I 2=0%) and ICH in 0.6% (95%CI 0.4%-0.9%; I 2=7%). In patients treated with anticoagulation alone, 30-day mortality and MB occurred in 9.9% (95%CI 7.1%-13.1%; I 2=97%) and in 3.8% (95%CI 2.6%-5.4%; I 2=66%), respectively. Fatal PE occurred in 3.3% (95%CI 1.9%-5.2%; I 2=65%), fatal bleeding in 0.5% (95%CI 0.2%-0.9%; I 2=0%) and ICH in 0.7% (95%CI 0.3%-1.3%; I 2=64%).
Conclusion: In patients with intermediate-high and high-risk PE, fatal PE was non-negligeable in all treatment modalities and must be balanced with equally important fatal bleeding event rates. Additional studies are needed to further assess these efficacy and safety parameters of thrombolytics in patients with intermediate-high and high risk PE.