bluuebunny/crossref_metadata_2025_split huggingface dataset:
Malignant Histiocytic Neoplasms' Descriptors and Clinicopathologic Determinants of Survival: Analysis of a Pooled Database
Authors: Haddad Philip A , Keerty Dinesh 
Published: December 2023

Background:
Malignant histiocytosis, also known as the M-group per the Histiocyte Society classification, represents a rare, aggressive malignant group of histiocytic neoplasms. It includes histiocytic neoplasms that occur de novo (pMHN) and those that develop in association with other malignant diseases (aMHN). However, little is known about factors that impact MHN clinical outcomes. We conducted this pooled database analysis to delineate key clinicopathological characteristics, prognostic indicators, and treatment modalities that affect survival in this rare histiocytic group.
Methods:
To study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 270 cases of MHN. 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).
Results:
A total of 270 patients with confirmed MHN were identified, with 77% pMHN and 23% aMHN. The median age was 45, with bimodal peaks between 13-26 and 52-65. There was a male preponderance with M:F of 1.6. The most common primary sites of involvement were liver (15%), CNS and spleen (13% each), thoracic, GI, and soft tissues (12% each), bones (11%), skin (10%), and H&N (8%). Lymphadenopathy and bone marrow (BM) were involved in 28% and 18%, respectively. Constitutional symptoms occurred in 12% and hemophagocytic syndrome (HPS) in 6%. The median time of MHN onset in aMHN was 12 months. The median OS of the whole group was 12 months. BM involvement had a worse median OS (p = 0.003). Stage 1 disease had better median OS than higher stages (p = 0.01). Furthermore, unifocal had better median OS than multifocal/multicentric disease (p = 0.0005). The presence of inflammatory background positively impacted OS (p = 0.01). The occurrence of HPS adversely affected OS (p &lt; 0.0001). Compared to no treatment, localized therapies such as surgery (S) and/or radiation therapy (RT) and systemic combination chemotherapy (CT) were statistically superior, with a median OS of 3, 24, and 18 months, respectively (p = 0.02). When MHN was not amenable to complete resection, CT and CT+/-S+/-RT were superior to RT+S (p = 0.03). Having CNS or splenic-lymphatic primary involvement tended to have a numerical but non-significant worse median OS than soft tissue or visceral disease. While female sex, size&lt;10cm, and pMHN seemed to have numerically better OS, they did not reach statistical significance. There was no difference in median OS for age.
Conclusions:
This study presents updated clinicopathologic data from a pooled cohort of patients with MHN. It identifies BM involvement, stage, extent of the disease, the inflammatory background status, occurrence of HPS, and treatment approach as critical determinants of OS.
A Retrospective Analysis of the Trends in Mantle Cell Lymphomas in the United States
Authors: Desai Krishna , Iqbal Sabah , Choi Eugene , Thar Yu Yu , Rather Manzoor , Thirumaran Rajesh 
Published: December 2023

Introduction:
Mantle Cell Lymphoma (MCL) refers to the malignant B lymphocytes arising from the outer (mantle) zone of the lymphoid follicle. This rare and aggressive subtype of Non-Hodgkin Lymphoma, which accounts for ~5 percent of all NHL cases. It is associated with t(11:14) that leads to over-expression of cyclin D1, resulting in tumor cell proliferation via cell cycle dys-regulation, chromosomal instability, and epigenetic regulation. The aim of this study is to understand the epidemiology and survival predictors of MCL.
Methods:
The data was collected from Surveillance, Epidemiology and End Result database Research Plus Data, 17 Registries, Nov 2022 Sub (2000-2020). We extracted Mantle Cell Lymphoma cases diagnosed after 20 years of age, with Lymphoid neoplasm recode 2(a)2.1.3. The analysis was stratified based on age, sex, racial incidence rates, & survival curves based were compared, using the Log-rank test (GraphPad Prism).
Results:
A total of 14166 cases of MCL were found between 2000 to 2020. Out of these, ~70.73% cases were males, and ~29.27% were females. The median age at the time of diagnosis was 69 years. Of the affected population, ~80.60% were Caucasians, ~3.92% were African-Americans, ~4.10% were Asians/Pacific Islanders, only ~0.50% were American Indians/Alaskan Natives, and ~10.32% were Hispanics. The incidence per 1,000,000, as of 2020, was 10.83 for the general population, 13.00 for Caucasians, 5.01 for African-Americans, 13.71 for American Indians/Alaskan Natives, 3.28 for Asians/Pacific Islanders, and 9.43 for Hispanics. Survival curves were not significant when compared based on the race of the patients. However, survival curves showed statistical significance when compared based on gender, with median of survival (mOS) for males was 50 months, and for females mOS was 56 months (p-value 0.0.008, Hazard Ratio 1.084 [Confidence Interval 1.035 to 1.136], using Log-rank test.
Conclusions:
Mantle Cell Lymphoma has a strong predilection for males. It is more commonly diagnosed in the late 60s, median age being 69. Unequal racial distribution was noted, with caucasians (~80%) comprising most of the patient population, and the least commonly encountered were American Indians/Alaskan Natives(~0.50%). However, when incidence rates were calculated per 1,000,000 population in 2020, it was found that the incidence in American Indians/Alaskan Natives (13.71), is drastically higher than the general population(10.83) vs. incidence in Asians/Pacific Islanders(3.28) is significantly lower than the other races. Although race played no role in prognosis, females had better survival rates than males. This retrospective study was done to aid in better understanding of this curable malignancy, despite its rarity, aggressivity and the complexity in treatment.
Clonal Expansion and Differentiation of Stem-like Memory T Cells to Tissue-Resident Memory T Cells Perpetuates Pathogenesis of Chronic Graft-Versus-Host Disease
Authors: Kong Xiaohui , Wang Bixin , Wu Xiwei , Cho Hyejin , Zheng Moqian , Zhang Yuankun , Tang Shanshan , Li Qinjian , Nasri Ubaydah , Wu Alyssa , Qin Hanjun , Pillai Raju , Nakamura Ryotaro , Martin Paul J. , Chen Yuanzhong , Zeng Defu 
Published: December 2023

We and others have shown that tissue-resident memory CD4 + T cells play a critical role in maintaining chronic GVHD pathogenesis. However, the cellular and molecular mechanisms remain largely unknown. Ly108 and (TCF1) expression have been shown to reflect the stemness of memory CD8 + T cells. In the current studies, using the markers Ly108 (TCF1) and CD69, we identified four subsets of memory CD4 + T (Tm) cells in the GVHD target tissues, including Ly108 + CD69 - and Ly108 +CD69 + stem-like Tm cells, as well as Ly108 - CD69 - and Ly108 - CD69 + differentiatedTm cells. Compared to other Tm subsets, the Ly108 - CD69 + subset expressed the highest levels of IFN-γ and GM-CSF without upregulating anergy/exhaustion markers, indicating that they represent a terminally differentiated, tissue resident, pathogenic CD4 + memory T (Trm) subset. The Ly108 + Tm subsets showed self-renewal capacity and differentiation into Ly108 - Tm subsets, as demonstrated by adoptive transfer experiments. Using single-cell RNA sequencing (scRNA-seq) in conjunction with scTCR-seq analysis, we observed that Ly108 +CD69 - Tm subset was clonally related to the expanded Ly108 - CD69 - and Ly108 - CD69 + Tm subsets, suggesting a clonal expansion and differentiation of Ly108 + CD69 - stem-like memory T (Tsm) cells. In addition, we found that IFN-γ primed donor-type antigen-presenting cells (APCs) play an essential role in optimizing the transition from CD4 + Tsm cells to CD4 + Trm cells in STAT3- and BCL6-dependent manner, as indicated by ATAC-Seq analysis. Our results have elucidated a novel pathway of clonal expansion and differentiation of Tsm cells to Trm cells in the GVHD target tissues. These observations provide cellular and molecular mechanisms that explain how chronic GVHD is perpetuated by memory T cells in local tissues.
XK and BW contributed equally.
A Single Center Retrospective Analysis Comparing the Outcomes of Induction Therapy between 7+3 and FLAG-IDA/Venetoclax in Newly Diagnosed Patients with Acute Myeloid Leukemia
Authors: Abdelmessieh Peter , Varshavsky-Yanovsky Asya , Shestovska Yuliya , Khanal Rashmi , Styler Michael , Ballas Brittany , Ridgway Forrest , Sorrentino Michele , Ojala Anne , Fung Henry C. 
Published: December 2023

Introduction
Induction chemotherapy (IC) in acute myeloid leukemia (AML) in younger and fit patients has historically combined an anthracycline (ie, daunorubicin or idarubicin) with the antimetabolite cytarabine, which has been termed the 7 + 3 regimen. Response rates with this current standard approach show complete response rates of 70-80%, however 30-40% still eventually relapse. Recently, the MD-Anderson group published a phase II study in which the drug venetoclax was added to the standard anthracycline/cytarabine induction regimen of FLAG-IDA. Results from this study showed an impressive 96% response rate for newly diagnosed (ND) AML patients. Based on these results we began to adopt this approach for our patients. We have induced 21 patients with this approach at our institution and have had comparable results.
No study has compared outcomes between this approach and that of standard 7 +3 in regards to response rates. Based on our improved outcomes we compared outcomes between these two approaches in our patient population by doing a retrospective chart based review on all patients that received cytotoxic induction treatment for ND-AML between 2000-2023.
Methods
Patients between 2020-2023 that were treated with induction cytotoxic chemotherapy for AML, based on WHO 2016 criteria, were retrospectively reviewed. Patients either received 7+3 or 7+3 plus midostaurin if they were FLT3+ in one arm or FLAG-IDA/Venetoclax. Patients received FLAG-IDA/Venetoclax regardless of FLT3+ status or risk of disease. Patients with extra medullary disease were excluded from this review as well as patients that received an IDH1 or 2 inhibitors in combination with 7 +3.
Results
Overall 39 patients were included in this study, 20 patients in the FLAG-IDA/Venetoclax arm and 19 patients in the 7/3 arm. In patients which response was able to be evaluated patients in the FLAG-IDA/Venetoclax cohort had a 100% overall response rate with a 95% (N = 19/20) complete response rate. Patients in the 7/3 cohort the complete remission rates were 66% (N = 12/16) with 3 of the patients achieving a complete remission with re-induction. Sixty-day morality rate was 5% (N = 1/20) in patients receiving FLAG-IDA/Venetoclax compared to 16% (N = 3/19). In terms of neutrophil recovery and toxicity results were comparable in both arms, with the average day to cell recovery being the similar in both groups.
Conclusions
FLAG-IDA/Venetoclax compared to standard 7/3 +/- FLT3 directed therapy in our patient population resulted in improved response rates and decreased 60-day mortality. Our results are similar to previously published reports in patents with ND-AML. Toxicity profiles were similar with the clear benefit of decreased early morality are increased response rates.
A Phase 1b Trial of DISC-0974, an Anti-Hemojuvelin Antibody, in Patients with Myelofibrosis and Anemia
Authors: Gangat Naseema , Foran James M. , Halpern Anna B. , Rampal Raajit K. , Novikov Natasha , Buch Akshay , Pelletier Olivia , Savage William , Tefferi Ayalew 
Published: December 2023

Hepcidin, a central regulator of iron homeostasis, is pathologically elevated in patients with myelofibrosis (MF) and anemia. Chronic elevations in hepcidin contribute to the onset and severity of anemia. DISC-0974 is an investigational, first-in-class, monoclonal antibody that blocks hemojuvelin, a co-receptor in the bone morphogenetic protein-signaling pathway driving hepcidin expression. Preclinical studies have shown that DISC-0974 suppresses hepcidin and increases serum iron. A healthy volunteer study has demonstrated dose-dependent reductions in serum hepcidin, increases in serum iron with doses up to 56 mg administered subcutaneously, and increasing trends in reticulocyte count, reticulocyte hemoglobin, mean corpuscular hemoglobin, total hemoglobin (Hgb), and red blood cell count.
In this Phase 1b/2a, open-label, multiple-ascending dose study (NCT05320198), we are assessing the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of DISC-0974 in patients with MF and anemia.
Eligible participants include patients over 18 years of age with intermediate-2 or higher-risk MF and anemia. MF is required to be confirmed using the World Health Organization 2016 criteria. Anemia is defined per protocol as Hgb &lt; 10 g/dL or transfusion dependence, as defined by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT). A stable dose of hydroxyurea and/or Janus kinase (JAK) inhibitor is allowed on trial. Major exclusion criteria include: liver iron concentration ≥ 7 mg/g dry weight; splenectomy; nutritional, genetic, infectious, or autoimmune causes of anemia. Dose escalation is based on a Bayesian optimal interval design with accelerated titration. Safety Review Committee assessments gate escalation decisions. Dosing occurs monthly for a total of 6 doses.
Primary endpoints include safety and tolerability assessments of adverse events (AEs), clinical laboratory assessments, vital signs, physical examinations, and electrocardiograms. Secondary endpoints include anemia response as defined by the IWG-MRT, transfusion response as defined by a decrease of 50% in transfusion requirement over any 8-week period, standard PK parameters and PD metrics including serum hepcidin-25, iron, transferrin saturation, ferritin, and hematology biomarkers. All data are summarized using descriptive statistics.
Initial data show a dose-related increase in pharmacokinetic parameters. DISC-0974 treatment led to dose-dependent reductions in serum hepcidin-25 and increases in serum iron levels. There have been no serious AEs or AEs leading to study withdrawal. Most AEs were mild, transient, and unrelated to DISC-0974.
As of August 1, 2023, enrollment and dose escalation are ongoing. Safety, PK, and PD data from at least the first two cohorts will be presented.
Characterization of JNJ-79635322, a Novel BCMAxGPRC5DxCD3 T-Cell Redirecting Trispecific Antibody, for the Treatment of Multiple Myeloma
Authors: Pillarisetti Ram , Yang Danlin , Yao Jianhong , Smith Melissa , Luistro Leopoldo , Vulfson Peter , Testa James , Packman Kathryn , Brodeur Scott , Attar Ricardo M. , Elsayed Yusri , Philippar Ulrike 
Published: December 2023

Background: Multiple myeloma (MM) is a genetically complex and heterogenous malignancy with a poor survival rate and accounts for approximately 10% to 15% of all hematologic cancers. Despite advances in myeloma therapy, MM remains incurable. Deep and durable clinical responses have been observed when targeting the tumor associated antigens BCMA and GPRC5D with immunotherapies. Additionally, data presented at ASCO this year demonstrated a further improvement in ORR when BCMA and GPRC5D bispecifics were given in combination to relapsed or refractory MM patients. These data suggest that broader antigen coverage by redirecting T cells to two tumor surface antigens is an effective means to harness the immune system to deplete cancer cells. Targeting two tumor antigens may also reduce the likelihood of antigen escape as a primary reason for relapse. Here, we describe JNJ-79635322, a trispecific antibody targeting B-cell maturation antigen (BCMA) and G-Protein-coupled receptor class 5 member D (GPRC5D), which are both highly expressed on plasmablasts and plasma cells in myeloma patient samples. Dual antigen recognition on plasma cells with a trispecific T-cell engaging antibody engineered with a CD3 arm has the potential to enhance tumor binding through avidity that could result in efficient depletion of malignant clonal populations and prevent tumor antigen loss mediated resistance.
Methods: JNJ-79635322 is a trispecific antibody composed of an anti-CD3 binding domain an anti-BCMA binding domain, and an anti-GPRC5D binding domain. It was selected based on biophysical assessment and showed activity in multiple myeloma models.
Results: JNJ-79635322 induced potent cytotoxicity in various myeloma cell lines in vitro with concomitant T-cell activation. Importantly, JNJ-79635322 was able to deplete both dual (BCMA and GPRC5D) and single (BCMA or GPRC5D) target expressing cells efficiently. In addition, dose dependent depletion of H929 myeloma cells was observed in a more physiological healthy fresh whole blood co-culture assay. In vivo, JNJ-79635322 exhibited potent antitumor activity compared to vehicle and antibody controls in a murine MM xenograft prevention model (single target expressing clonal H929 cells) and two tumor regression models (RPMI 8226 and MM.1S cells).
Conclusion: JNJ-79635322 is a potential first-in-class trispecific antibody targeting BCMA and GPRC5D with the ability to deplete dual and single target expressing MM clones in preclinical studies vitro and in vivo. A Phase 1 dose-escalating study of JNJ-79635322 in myeloma patients is ongoing (NCT05652335).
Secondary Hemophagocytic Lymphohistiocytosis in Adults: A Single Institution Case Series
Authors: Singh Rishabh , Nain Priyanshu , Chatterjee Tulika , Kandula Manasa 
Published: December 2023

Introduction:
Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome caused by the abnormal activation of macrophages and T cells. The primary form, resulting from lymphocyte-related mutations, is more common in children, while the secondary (acquired) form known as sHLH prevails in adults. sHLH is often triggered by infections or malignancies (Mal-HLH) but can also be induced by autoinflammatory disorders called macrophage activation syndrome (MAS; or MAS-HLH). We present a retrospective case series of adults treated for sHLH at a single institution from 2012 to 2023.
Methods:
Retrospective data was collected using the EDW database, and 36 patients were identified using ICD 9/10 codes 288.4 and D76.1 for HLH. Subsequently, a manual review of electronic medical records was conducted; criteria for inclusion were age &gt;18 years at the time of diagnosis and meeting HLH-2004 criteria ( Panel-1).
Results:
Out of the 36 patients reviewed, 11 met the criteria and were included in the analysis. These cases occurred between 2015 and 2023. The median age at diagnosis was 52 (range 18 to 81). The female-to-male ratio in our study was 4:7. Most patients (73%) were white. Additionally, 45% of the patients were immunocompromised.
91% of the patients presented with fever, while only 45% had splenomegaly. Trilineage cytopenias were observed in all patients. In our study, 5/11 had hypofibrinogenemia, and 6/11 had hypertriglyceridemia. Hemophagocytosis was evident in 91% of the patients. Natural Killer (NK) cell activity was measured in 4 patients, and all exhibited low or no NK cell activity. In 10 out of 10 patients, soluble IL-2 receptors were elevated.
None of the patients in the study had hepatomegaly, but all had transaminitis and hyperbilirubinemia, and 82% had elevated alkaline phosphatase levels. Elevated lactate levels were observed in 78% of patients, and 27% had a rash. Neurological features were observed in 6 out of 10 patients. Lactate dehydrogenase was elevated in all patients with a median value of 1551 U/L (range 354 - 3689)
Presumed etiologies for sHLH included malignancy (4), infection (3), autoimmune disease (3), and unknown cause (1). Treatment was highly individualized based on the underlying trigger and was guided by the HLH-94 protocol ( Panel-2). All patients received high-dose steroids, 6/11 received etoposide, and 2 received intrathecal therapy for neurological involvement.
Conclusion:
At a median follow-up period of 16 days, five patients had died. The survival rates at 30 days and 1 year were 45% and 27%, respectively. The overall mortality rate was 55%. While mortality rates were 75% in the Mal-HLH arm and 67% in the infectious arm, all patients with MAS-HLH survived while performing the study indicating a better prognosis for patients with this type of HLH.
Provisional Prognostic Score for Blastic Plasmacytoid Dendritic Cell Neoplasm
Authors: Haddad Philip A , Gaddam Shiva Jashwanth 
Published: December 2023

Background
BPDCN is an aggressive hematologic malignancy which often involves the skin. This disorder has gone through many iterations over the years, being classified initially as a blastic NK-cell lymphoma, then a subset of AML, and finally recognized as a unique myeloid neoplasm. While BPDCN often follows an aggressive course, its outcomes vary considerably. We conducted this study to develop a provisional BPDCN prognostic score (BPS) for this rare disease.
Methods
We used our constructed BPDCN database, which contains retrospective data on 273 cases. Such data included demographics such as sex, age, and race. It also included disease presentation symptoms, duration of symptoms before diagnosis, site(s) of the disease, blood counts, coexisting comorbidities, disease immunohistochemical and molecular phenotype, types of treatment, and survival outcomes. Of the 273 cases, only 218 had complete survival and outcomes data, the sample chosen for this study. Cox proportional-hazards model and Log-rank tests were used to assess the influence of clinicopathologic factors on overall survival (OS). We included factors that statistically impacted OS and scored them by the impact of their hazard ratios.
Results
The median OS of the cohort was 16 months. The following dichotomous variables were identified as impactful prognostic factors in this cohort: Age&gt;60 (10 vs. 30 months), lymphadenopathy (14 vs. 42 months), bone marrow involvement (14 vs. NR months), splenomegaly (10 vs. 16 months), and disseminated skin disease (13 vs. NR months). A prognostic model was devised using these variables to identify different levels of risk. Each variable was assigned a score of 1 when present, except for age&gt;60, splenomegaly, and disseminated skin disease, that were assigned 2 points each as they had the highest hazard ratios of all the other variables. In this exploratory cohort, low risk was assigned a score of 0-2, intermediate risk a score of 3-4, and high risk a score of 5-8. This prognostic score system led to our cohort's most optimal risk discriminatory model, where low, intermediate, and high risk had a median OS of NR, 24, and 10 months, respectively (p&lt;0.0001).
Conclusion
This BPS is a promising new tool for risk-stratifying patients with BPDCN. However, it still requires prospective validation.