bluuebunny/crossref_metadata_2025 huggingface dataset:
Transgender Women on Estrogen Have a Lower Burden of Thrombotic Events Compared to Cisgender Men: A Nationwide Hospital-Based Survey
Authors: Manchkanti Srija , Dayal Sanjana , Ramakrishna Akhila , Streeter Jennifer
Published: December 2023

Due to public recognition and acceptance, more transgender women are being prescribed gender-affirming estrogen therapy. Traditionally, sexual dimorphism has been shown to play a significant role in the pathophysiology of thrombotic phenomena. While genetic factors remain the key players in the divergent male and female phenotypes, limited information is available regarding the thrombo-vascular effects of estrogen therapy in transgender women. Furthermore, available data has been conflicting with respect to vascular outcomes in this specific population. Therefore, more evidence is required to understand the long-term effects of gender-affirming estrogen therapy. In the current study, we investigated the thrombotic outcomes of estrogen therapy in transgender women (male sex assigned at birth), in comparison to cisgender men and cisgender women.

We performed retrospective analyses using the TriNetX database that includes de-identified data for over 250 million patients across 76 certified healthcare organizations. We included all adults over the age of 18 years and excluded those with the presence of documented prothrombotic risk factors such as obesity, diabetes, hyperlipidemia, smoking, and cancer. Within the cohort of cisgender women, we excluded pregnancy and post-menopausal status. The thrombotic outcomes within the transgender cohort were recorded after the start of hormone replacement therapy. To account for thrombotic events, we used search terms such as acute myocardial infarction (MI), cerebral infarcts, pulmonary embolism (PE), and deep vein thrombosis (DVT).

We found 12,369 transgender women, 29,746,302 cisgender men, and 32,591,972 cisgender women that were eligible for our study. The transgender women had lower incidences of MI (0.14% vs. 0.38%, P<0.0001), cerebral infarcts (0.21% vs. 0.49%, P<0.0001), and DVT (0.33% vs. 0.47%, P<0.022) compared to cisgender men. The incidence of PE was comparable in both these groups (P=0.85). Furthermore, we observed that transgender women also experienced significantly lower incidences of cerebral infarcts (0.21% vs. 0.42%, P=0.0003) and a moderately decreased incidence of MI (0.14% vs 0.22%, P=0.062) compared to cisgender women. The incidence of venous thrombosis was similar in these two groups.

Overall, we observed a paradoxical decrease in rates of thrombotic events, suggesting that estrogen may play a protective role against the development of acute MI, cerebral infarction, and DVT in transgender women. Further investigation is required to understand the downstream targets that offer these cardioprotective effects. Importantly, our data may provide clinicians with reassurance that traditional vascular risks associated with estrogen may be less pronounced in males.
Chidamide Combined with a Modified Bu-Cy Conditioning Regimen Improves Survival in Patients with T-Cell Acute Lymphoblastic Leukemia/Lymphoma Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Cao Xuanqi , Li Zheng , Zhang Yanming , Cui Qingya , Ma Yunju , Li Mengyun , Chen Sifan , Yin Jia , Cui Wei , Chen Jia , Sun Aining , Qiu Huiying , Chen Suning , Jin Zhengming , Zhu Xiaming , Wu De-Pei , Tang Xiaowen
Published: December 2023

Backgrounds: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL). Relapse post-HSCT remains the major cause of mortality, highlighting the urgent need for more effective conditioning regimens in reducing relapse rates and improving outcomes for T-cell malignancy. Chidamide, as the first oral subtype-selective histone deacetylase inhibitor (HDACi) approved in China, can lead to a more relaxed chromatin structure through chromatin remodeling, particularly hyperacetylation of lysine residues in the histone tails, which facilitates the expression of tumor suppressor genes as well as the action of alkylating agents busulfan. To date, the role of chidamide in T-ALL/LBL conditioning regimens in allo-HSCT has not been explored.

Methods: We retrospectively compared the clinical efficacy and safety between chidamide combined with a modified Busulfan-Cyclophosphamide (mBuCy) and mBuCy conditioning regimen for T-ALL/LBL patients undergoing allo-HSCT. The chidamide combined with mBuCy regimen was presented in Figure1.

Results: Twenty-two patients received chidamide combined with mBuCy conditioning regimen (Chi group). A matched-pair control (CON) group of 44 patients (matched 1:2) received mBuCy only. The median follow-up time was 683 (range 296-1168) days. Patients in the Chi group showed better 2-year overall survival (OS) and leukemia-free survival (LFS) (85.4 vs. 52.9%, respectively, P = 0.021; 69.1 vs. 42.9%, respectively, P = 0.031). Multivariate analysis showed that chidamide combined with mBuCy was a major positive risk factor for OS (HR 0.18, 95%CI, 0.05-0.63; P = 0.007) and LFS (HR 0.32; 95%CI, 0.13-0.80; P = 0.015). The cumulative incidence rates of grade II-IV and grade III-IV aGVHD were similar (36.4 vs. 38.6%, respectively, P = 0.858; 13.6 vs. 20.5%, respectively, P = 0.735). Patients in the Chi group showed higher incidence of elevated γ-glutamyltransferase and hemorrhagic cystitis than that in the mBuCy group (90.9 vs. 65.9%, respectively, P = 0.029; 36.4 vs. 13.6%, respectively, P = 0.007). No transplantation-related mortality was documented within the first 100 days after transplantation.

Conclusions: Our data demonstrate that the conditioning regimen containing chidamide improves the survival of T-ALL/LBL patients without increasing the incidence of transplant-related mortality. A prospective clinical trial is expected to confirm these findings.
Characteristics and Prognosis of Epstein Barr Virus-Positive Diffuse Large B-Cell Lymphoma: A Retrospective, Single-Center Study
Authors: Lin Qiaochu , Liao Lianming , Liu Tingbo , Shen Jianzhen , Luo Xiaofeng , Fu Haiying , Li Xiaofan
Published: December 2023

Objective:

The aim of this study was to analyze the clinical characteristics and prognosis of Epstein Barr virus-positive diffuse large B-cell lymphoma (EBV+DLBCL) in a Chinese cohort.

Methods:

A total of 57 patients diagnosed with EBV+DLBCL from January 1, 2013 to December 31, 2020 were included, and 228 concurrent patients with EBV-DLCBL served as control. The differences between the two groups were compared and the prognosis factors were identified by univariate and multivariate analysis.

Results:

There were 38 man in the EBV+DLBCL group, with a median age of 56 years (rang, 18 to 88). Tumor cells originated from GCB in 15 patients (26.3%), and from non-GCB in 40 patients (70.2%). There were 34 patients (59.6%) with Epstein Barr virus infection. Compared with EBV-DLCBL patients, patients with EBV+DLBCL had B symptoms, hypoalbuminemia, anemia and extranodal involvement>1 more frequently, as well as higher LDH and β2-Microglobulin levels (P < 0.05 foe all). The most common extranodal sites involved were digestive tract, especially, the stomach, nasopharynx, bone marrow and bone. Immunohistochemical staining showed 24 patients (42.1%) in the EBV+DLBCL group were CD30 positive, compared with xxx in patients with EBV﹣DLCBL (P < 0.001). After treatment with rituximab combined with chemotherapy, the EBV+DLBCL patients had a complete response rate and a overall response rate of 55.5% (30/54) and 83.3% (45/54), respectively. With a median follow-up time of 28 months, 22.2% (10/45) patients relapsed. The overall response rate and recurrent rate were similar between the two groups. In multivariate analysis, increased β2-Microglobulin level and bone marrow invasion were independent risk factors for PFS, while increased β2-Microglobulin level and decreased HB were independent risk factors for OS in patients with EBV+DLBCL.

Conclusion: The majority of EBV+DLBCL patients were non-GCB.β2-Microglobulin level and bone marrow invasion were independent risk factors for PFS in patients with EBV+DLBCL, while β2-Microglobulin and HB were independent risk factors for OS in patients with EBV+DLBCL. The therapeutical potentials of targeted medicines, such as CD30 inhibitors and PD-1 inhibitors, deserve to be explored in the future.

Keywords：Epstein Barr virus, diffuse large B-cell lymphoma, prognostic factors
Incidence-Based Mortality (IBM) and Survival for Chronic Myeloid Leukemia (CML) By Age Group: Is There Any Relationship between Age of Diagnosis, IBM and Survival?
Authors: Kenmoe Jerry , Ghimire Calvin , Batool Narjis , Kunadi Arvind
Published: December 2023

Incidence-Based Mortality (IBM) and Survival for Chronic Myeloid Leukemia (CML) by Age group: Is there any relationship between age of diagnosis, IBM and Survival?

Background:

CML is known to affect different age groups differently, with a predominance in adults. CML accounts for about 15% of all new cases of leukemia, with over 50% of the cases being diagnosed in individuals 65 or older.

Our study looked at the variation in 5 and 10 years survival, and probability of death from CML based on different age groups in the US adult populations from 2000-2019 via SEER.gov database.

Methods:

We used Incidence -Based Mortality SEER Research Data, 17 Registries, Nov 2021 Sub (2000-2019), which provides the broadest geographic coverage for incidence-based mortality rates and is roughly 26.5% of the US population (based on the 2020 Census) for the calculation of Incidence-Based Mortality and Survival rates of CML. SEER*Stat 8.4.1 was used to obtain cause-specific survival, with Death due to cancer. We used Join-point software, version 5.0.2. by the National Cancer Institute, annually to create log-linear time trends.

Results:

Fig 1: CML 10-Year Survival rates per 100,000 and age-adjusted to the 2000 US standard population by age groups (50-79)

Our results revealed a significant change in the probability of dying from CML for age groups 60-64 and 70-74.

The Average Annual percent Change (AAPC) for incidence Based Mortality by age groups were 3.71%*(95% CI 1.55 to 6.42 ), 2.87%*(95% CI 0.74 to 5.56), 6.09%*(95% CI 2.97 to 9.03 ), 2.33%*(95% CI 0.38 to 5.84), 4.86%*(95% CI 2.74 to 7.18), 3.38%* (95% CI 2.08 to 4.97) for age groups 50-54, 55-59,60-64,65-69,70-74, and 75-79 respectively.

The trend for 10 year survival shows increasing survival across all age groups.

The AAPC for 10 year survival were 1.74%*(95% CI 0.08 to 4.04), 4.08%*(95% CI 2.25 to 7.33), 2.52% (95% CI -0.22 to 6.21), 5.29%* (95% CI 3.34 to 7.70), 5.42%* (95% CI 2.13 to 9.71), 2.29% (95% CI 1.88 to 6.92).

Conclusion:

Our Study shows a significant difference in the survival rates at 10 years based on age groups, with a pattern of lower survival rates and higher probability of death from CML with increased age at diagnosis.
Does Implementing Calendars Outlining Inpatient Chemotherapy Schedules in Patient Rooms Improve Patient's Experience?
Authors: Wani Kashmira , Dabak Vrushali S.
Published: December 2023

Background: Patients who receive inpatient chemotherapy for malignancy are dealing with both a physically and mentally challenging admission. Their chemotherapy regimen is predetermined and usually only discussed during rounds. Often times, patients feel overwhelmed and may miss the outline of their schedule. Furthermore, patients families may not be able to attend morning rounds and may miss the proposed schedule. This can lead to a feeling of loss of control in both the patient and their family, and thus, frustration. First year medicine residents are also overwhelmed with a large patient load and having to keep track of multiple chemotherapy regimens. We are hoping that by providing a calendar that outlines patient's anticipated chemotherapy schedule, we may be able to give patients a small sense of control back and help residents provide the best care to their patients. Ultimately, we hope that this leads to a better inpatient experience.

Methods: Patients admitted to the hematology/oncology floor at Henry Ford Health Hospital in Detroit, Michigan over three months were screened, and those receiving inpatient chemotherapy were selected. Within this group, any patient that was getting inpatient chemotherapy for longer than three days was asked if they would like to participate in the study. If the patient agreed, they were provided a calendar that outlined their chemotherapy schedule. Calendars were updated if any adjustments were made to the schedule. At the end of their inpatient stay, patients filled out a questionnaire asking if the calendar helped them understand their schedule better. The primary resident caring for the patient was also asked if the calendar helped them keep track of their patient's schedule.

Results: Overall, patients responded positively to the calendars. We have preliminary data on ten patients and four providers from three months. On average, on a scale of 1-10 (with 1 indicating not helpful at all, and 10 indicating extremely helpful) patients rated the calendars helping them at a level of 7.5. Patients found that the calendars particularly helped their families who were not able to come visit in the hospital. Providers found the calendars extremely helpful, rating the calendars at a level of 10. We will continue to collect data and update our results.

Conclusions: Implementing patient calendars in inpatient rooms helps patients keep track of their chemotherapy schedules and leads to a positive inpatient experience. We are hoping to implement this as a standard of care in all inpatient rooms on the hematology/oncology floor.
Ruxolitinib Versus Best Available Therapy for Polycythemia Vera: A Systematic Review and Meta-Analysis
Authors: Roca Mora Maria Meritxell , Ribeiro Guimaraes Catharina , Afzal Farhan , Godoi Amanda , Valenzuela Andres
Published: December 2023

Background: Polycythemia vera (PV) is characterized by dysregulated Janus kinase (JAK) activation, leading to excessive production of blood cells, increased risk of thrombotic and hemorrhagic events, and an impairment on the quality of life of patients. Ruxolitinib, a JAK1/JAK2 inhibitor, has shown promising results in recent trials, but its comparative efficacy to best available therapy (BAT) remains unclear. We aimed to perform a systematic review and meta-analysis comparing the efficacy and safety of Ruxolitinib versus BAT for patients with PV.

Methods: We systematically searched PubMed, Embase, and Cochrane Central for clinical studies published up to July 1st comparing Ruxolitinib to BAT. BAT was defined as hydroxyurea, interferon or pegylated interferon, pipobroman and anagrelide. Efficacy outcomes assessed were complete response to therapy and reduction in the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) score; safety outcomes were thromboembolism, anemia, and herpes. We pooled outcomes as risk ratios (RR) with 95% confidence intervals (CI). Statistical analysis was performed with Review Manager version 5.4.1. Heterogeneity was assessed with I² statistics. The protocol was registered in PROSPERO (ID: CRD42023427977).

Results: A total of five studies met our inclusion criteria, of which four were randomized trials. Our analysis encompassed a population of 684 patients, including 336(49%) allocated to the Ruxolitinib group, and 348(51%) allocated to the BAT group. Ruxolitinib had a significantly greater response to treatment compared to BAT (RR 1.97; 95% CI 1.03 -3.77; p=0.04; I²=60%; Fig 1A) and significantly reduced MPN-SAF score by at least 50% (RR 2.50; 95% CI 1.29-4.86; p=0.007; I²=76%; Fig 1B). Additionally, use of Ruxolitinib showed a significantly higher incidence of herpes infection (RR 3.57; 95% CI 1.27 -10.04; p=0.02; I²=0%; Fig 1C) and anemia (RR 1.97; 95% CI 1.15-3.37; p=0.01; I²=50%; Fig 1D). There were no significant differences between the two treatment groups regarding thromboembolic events (p=0.07; Fig 1E).

Conclusion: Our meta-analysis reveals that Ruxolitinib exhibits superior efficacy in achieving a complete response for PV patients compared to BAT and in reducing MPN-SAF score by ≥50%. While no significant difference was observed in thromboembolic events, Ruxolitinib demonstrated significant risk of anemia and herpes infection.
A Prospective Phase II Study of Radiotherapy Followed By Tiselizumab Combined with R-CHOP in the Untreated Follicular Lymphoma Patients with Bulky Disease in China
Authors: Li Wei , Zhang Ximei , Gao Fenghua , Yao Yixin , Wang Xianhuo , Zhang Huilai
Published: December 2023

Background

Follicular lymphoma (FL) is the second most common B cell lymphoma subtype and chemoimmunotherapy treatment is the standard therapy for patients with high tumor burden. Bulky disease was associated with shorter median PFS compared to non-bulky disease in FL patients. Radiation and anti-programmed death-1 (PD-1) monoclonal antibody are both effective in FL and also have a synergistic effect. We assessed the potential benefit of Tiselizumab (a humanized monoclonal antibody targeting PD-1), radiotherapy combined with RCHOP as first-line treatment in FL patients with bulky disease.

Methods

This was a single center, single arm, phase II study. Patients with previously untreated follicular lymphoma were enrolled from the department of lymphoma, Tianjin Medical University Cancer Institute and Hospital. The bulky disease was received radiation (dose:18～24Gy) before RCHOP. Patients began chemoimmunotherapy 1～2 weeks later than radiation. Treatment included Tiselizumab (200 mg iv d1) plus R-CHOP (rituximab 375 mg/m 2 intravenous [IV] day 2, cyclophosphamide 750 mg/m 2 IV day 3, doxorubicin 50 mg/m 2 IV day 3, vincristine 1.4 mg/m 2 [maximum 2.0 mg total] IV day 3, and prednisone 100 mg oral days 3-7, 21～28 days for one cycle ) for six cycles. Rituximab was given every 2 months to patients who were complete metabolic response /partial metabolic response（CMR/PMR）after first-line chemo until 2 years. Response was assessed by PET/CT scan after cycle 4 and cycle 6. The primary endpoint was complete response rate (CRR).

R esults

FromFebruary 2021 to June 2023, 6 patients were enrolled. 4 patients finished all 6 cycles treatment. 1 patient was dead because of COVID-19 who was PMR after 5 cycles treatment. The last one with CMR stopped chemotherapy because of COVID-19 and only received 4 cycles treatment. The median follow-up is 15 months. 5 patients achieved CMR in the mid-term evaluation and were still on remission in June 2023. The CRR was 83.3% and the overall response rate was 100%. The common adverse events were nausea, vomiting, bloating, loss of appetite, constipation, and diarrhea. The most common grade 3/4 adverse events were neutropenia (66.7% ), thrombocytopenia (16.7% ), and leukopenia (66.7% ).

Conclusion

Tiselizumab, radiotherapy combined with RCHOP is effective and tolerable in the untreated FL patients with bulky disease. More patients will be enrolled to estimate the efficacy and safety.
Summary of the Best Evidence for Nutritional Support in Patients with Acute Gastrointestinal Graft-Versus-Host Disease
Authors: Wen Yanling , Yang Jingwen , Cai Zhen , Cheng Tao
Published: December 2023

[Abstract]

Objective: To retrieve, evaluate and integrate the best evidence summary of nutritional support for patients with acute gastrointestinal graft-versus-host disease after hematopoietic stem cell transplantation at home and abroad. Methods: According to the “6S” model, domestic and foreign computer decision support systems, guideline networks, websites of relevant professional societies or institutions, professional books, and comprehensive databases were systematically searched to screen literatures related to nutritional support for patients with acute gastrointestinal graft-versus-host disease, including guidelines, clinical decision-making, evidence summary, expert consensus, expert opinion, systematic review, and original research. The search time limit was from the establishment of the database to March 2023. Five researchers evaluated the quality of the literature, extracted evidence and integrated it. Results: A total of 12 articles were included, including 1 clinical decision, 4 guidelines, 1 evidence summary, 1 expert consensus, 3 systematic reviews, 1 cohort study, 1 expert opinion,. A total of 14 best evidences were summarized from 4 aspects, including scientific diet and tolerance assessment, nutrient selection, nutritional support method selection, and multidisciplinary cooperation. Conclusions: This study systematically integrates the relevant evidence of nutritional support in patients with acute gastrointestinal graft-versus-host disease, and can provide evidence-based evidence for nutritional support in patients with acute gastrointestinal graft-versus-host disease. When applying evidence, it is recommended that clinical nurses comprehensively consider the actual clinical situation and the wishes of patients, and carefully select evidence.

Keywords acute gastrointestinal graft-versus-host disease，nutritional support，malnutrition，evidence-based nursing
Risk Factors and Prognostic Scoring Model for 28-Day Mortality in Hematologic Patients with Stenotrophomonas M altophilia Bacteremia
Authors: Guo Wenjing , Jiang Erlie , Feng Sizhou
Published: December 2023

Objective: Patients with hematologic diseases are at a higher risk for Stenotrophomonas maltophilia(SM) bacteremia, which poses significant burden on morbidity and mortality. The aim of this study was to evaluate the early predictors of 28-day mortality in hematologic patients with SM bacteremia and to construct a reliable prediction model which can be used to identify patients at higher risk for mortality.

Methods: This retrospective analysis of 131 hospitalized patients diagnosed with SM bacteremia was conducted in a tertiary blood disease center in Tianjin, China, from January 2012 to June 2023. Univariate analysis and multivariate logistic regression analysis were used to identify prognostic risk factors and develop a prognostic mortality scoring system and internally validated by bootstrap method (resampling = 1000).

Results: The overall 28-day mortality rate in our study was 29.77% (39/131). The mean age was 45 (IQR 30.5-56.0) years and 70 individuals (53.44%) were diagnosed with myeloid malignancies. The existing condition severity-related scores did not perform well in predicting 28-day mortality for the patients in our population (AUROC values: SOFA: 0.842; ECOG: 0.831; APACHE Ⅱ: 0.709; SAPS Ⅱ: 0.675; aCCI: 0.654; Pitt score: 0.629).

Through univariate and multivariate analysis, we identified four independent risk factors associated with 28-day mortality: SOFA score (OR = 3.67, 95% CI 1.99-6.78, P < 0.001; score = corresponding SOFA score), age ≥ 60 years (OR = 6.95, 95% CI 1.44-33.55, P = 0.0158; score = 2), bloody sputum or hemoptysis (OR = 5.32, 95% CI 1.08-26.29, P = 0.0402; score = 2) and neutropenia duration ≥ 25 days (OR = 3.92, 95% CI 1.01-15.26, P = 0.0487; score = 1). These factors were used to develop a prognostic scoring model, which yielded good discrimination (AUC = 0.889, 95% CI: 0.829-0.949) and calibration (Hosmer-Lemeshow goodness-of-fit test P = 0.998), with similar performance in the internal bootstrap validation (AUC = 0.888). Furthermore, all patients were divided into the high-risk group (≥ 7 points) and the low-risk group (< 7 points) based on the model and compared using Kaplan-Meier curves and log-rank tests. Additionally, we founded that the use of trimethoprim-sulfamethoxazole (TMP/SMX) after infection was associated with a better prognosis ( P = 0.012).

Conclusions: The prediction model, utilizing SOFA score, age, bloody sputum or hemoptysis and neutropenia duration, proves to be an effective tool for early identification of hematologic patients with SM bacteremia at high risk of mortality.
The Efficacy and Prognosis of Advanced Myelodysplastic Syndrome in Children
Authors: Liu Chenmeng , Li Xiaolan , Chen Yunlong , Wan Yang , Lan Yang , Zhang Jingliao , Zhu Xiaofan , Yang Wenyu
Published: December 2023

Pediatric myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell neoplasm with an annual incidence of 1-4 cases/million. The low incidence of advanced MDS in children and poor prognosis attract our attention. However, there are limited reports on the scheme and efficacy of pediatric advanced MDS. In this study, we retrospectively analyzed the efficacy of chemotherapy in pediatric advanced MDS and assessed the prognosis of patients. According to 2016 World Health Organization (WHO) classification of haematolymphoid tumours, 30 newly diagnosed pediatric advanced MDS patients during Dec 2007 to Apr 2022 from our single center were selected as the research object. The clinical data and prognosis were analyzed. The median age of patients is 8 years (range: 1-15years). The median bone marrow blast is 15.75% (range: 5-29.5%), while the median peripheral blood blast is 4% (range: 0-29%). Cytogenetic analysis was available for 29 patients, 69% (20/29) cases had abnormal karyotype. Monosomy 7 (37.9%) was the most common cytogenetic abnormality. Out of the total, 7 patients were treated with CAG/HAG regimen (C: aclarubicin 6mg d1-14, H: homoharringtonine 1mg/m 2d1-14, A: cytarabine 10mg/m 2 q12h d1-14, and G: Granulocyte Colony-stimulating Factor 200mg/m 2 d1-14 ), 8 patients with decitabine (20mg/m 2 d1-5), 11 patients with decitabine and CAG/HAG, 4 patients with AML-like chemotherapy (Daunorubicin+cytarabine+etoposide ) or other. The evaluation of response of therapy was available in 25 patients, 5 cases (20%) in partial remission (PR), 11 cases (44%) in complete remission (CR), 9 cases in(36%)non-remission (NR). The total response rate of chemotherapy is 60%, with CAG/HAG therapy 33%, decitabine therapy 43%, combined CAG/HAG and decitabine therapy 78%, AML-like chemotherapy 100%. The total complete remission rate of chemotherapy is 44%, with CAG/HAG therapy 17%, decitabine therapy 43%, combined CAG/HAG and decitabine therapy 56%, AML-like chemotherapy 67%. Patients receiving CAG/HAG in combination with decitabine had higher response rates compared to CAG/HAG or decitabine alone (OR=17.5, 95% CI 1.2-250.3, P=0.035). With a median follow-up of 20 months (range: 1-158months), 23 patients received HSCT after chemotherapy, and they had a higher 2-year overall survival rate compared to those who did not undergo transplantation (86% vs 0%, p<0.001). Decitabine combined with CAG/HAG improve the response rate of advanced pediatric MDS. Chemotherapy bridged hematopoietic stem cell transplantation significantly improves the prognosis of advanced pediatric MDS.
The Prognostic Value of Common Cardiovascular Biomarkers in the Survival of Patients with DLBCL
Authors: Xu Yi , Shi Yuanfei , Sun Jianai , Zheng Xiaolong , Li Xueying , Wang Jinghan , Yu Wenjuan , Tong Hongyan , Jin Jie , Xie Wanzhuo
Published: December 2023

Background

Diffused large B-cell lymphoma (DLBCL) is a subgroup of highly heterogenous and aggressive hematological malignancy. IPI scoring tools have been used to predict survival in DLBCL patients retrospectively. Moreover, it is indicated that cardiovascular biomarkers can predict long-term survival in myelodysplastic syndrome. To structure a more accurate prognostic model directing survival, we constructed retrospective research in our clinical institution with common cardiovascular biomarkers, for instance, IL-6, Troponin I, BNP, hydroxybutyrate dehydrogenase and creatine phosphokinase. Besides, other risk factors of cardiovascular diseases such as lipids are also taken into consideration.

Method

We retrospectively researched a total of 284 patients who were first diagnosed with DLBCL from January 2011 to November 2022, among whom 205 patients were sequenced by next-generation sequencing (NGS) before receiving therapy. Characteristics of democracy and clinical data were collected and analyzed. The primary objective is to investigate the prognostic value of common cardiovascular biomarkers in the long-term survival of DLBCL patients.

Results

A total of 284 patients were enrolled with a median follow-up time of 21.8 months. The inclusive criteria are: patients who are newly diagnosed with DLBCL and clinical data of cardiovascular mark can be retrospect, moreover, to eliminate the influence of cardiac failure we excluded those whose ejection fraction was lower than 30%.

There are 78 patients with high levels of BNP (HIGH-BNP group) and 119 patients with high levels of IL-6 (HIGH-IL6 group). In the HIGH-BNP group, overall survival is poorer than the control group (p<0.001, HR=3.07, 95%CI 1.97-4.78). Besides, in the HIGH-IL6 group, the tendency shows similitude, with a lower survival ratio (p=0.025, HR=2.65, 95%CI 1.30-5.40). Among 205 patients who received NGS sequencing, 2270 genes mutation have been detected. the most frequently detected genes are PIM1 (324, 14.3%), KMT2D (73, 3.2%), BCL6 (80, 3.5%), TP53 (63, 2.8%) and MYD88 (57, 2.5%).

Conclusion

Cardiovascular biomarkers can properly predict DLBCL patient survival.
Association of Hypometilating Agents (HMA) + Venetoclax (VEN) in the Therapy of Acute Myeloid Leukemias Evolved from Myelodysplastic Syndromes (AML-MDS) Already Treated with Azacytidine
Authors: Latagliata Roberto , Cambò Benedetta , Piccioni Anna Lina , Federico Vincenzo , Cristiano Gianluca , Lugli Elisabetta , Rizzo Lorenzo , Santopietro Michelina , Mazzone Carla , Bonifacio Massimiliano , Palmieri Raffaele , Poloni Antonella , Biagi Annalisa , Binotto Gianni , Delfina Marzia , Annunziata Mario , Molteni Alfredo , Piedimonte Monica , Carmosino Ida , Di Veroli Ambra , Niscola Pasquale , Riva Marta , Capodanno Isabella , Curti Antonio , Di Rienzo Nicola , Fenu Susanna , Crugnola Monica
Published: December 2023

Background Survival of high-risk Myelodysplastic Syndromes (MDS) treated with azacytidine during the dysplastic phase and then evolved in Acute Myeloid Leukemia (AML-MDS) is very poor. While the association of hypometilating agents (HMA) and venetoclax (VEN) is widely used in de novo AML not eligible for intensive chemotherapy, very few data are available in patients (pts) with AML-MDS.

Methods Data of 42 pts with AML-MDS treated frontline with HMA+VEN in 19 hematologic Centres in Italy outside clinical trials from 5/2018 to 3/2023 were retrospectively collected and analysed. Composite overall response rate [ORR; complete remission (CR) + CR with incomplete hematologic recovery (iCR) + partial remission (PR) + hematologic improvement (HI)], duration of response and overall survival (OS) were assessed.

Results: Baseline characteristics at evolution in AML are reported in the Table. Median interval from initial MDS diagnosis to evolution was 16.7 months [interquartile range (IQR) 8.2-30.1]. Pts were treated for a median of 3 courses (IQR 2-6): HMA were administered at standard dosage, VEN daily doses in the 1 st cycle are reported in the Table. On the whole, 34 pts (81.0%) had at least one hematologic toxicity of grade 3-4: in particular, severe neutropenia (PMN < 0.5 x 10 9/l) was reported in 32 pts (76.1%). Eighteen pts (42.8%) had at least one infective episode during the treatment: pulmonary infections were reported in 9 pts (21.4%). Response to treatment is shown in the Table: ORR was 52.4%, with a median response duration of 17.8 months (95%CI 3.3-32.2). After a median follow-up from AML evolution of 6.1 months (IQR 2.2-11.6), 31 pts (73.8%) died and 11 (26.2%) were alive. Median OS from AML evolution of the whole cohort was 6.9 months (95%CI 4.7-9.1), Pts with any response to HMA+VEN had a significantly longer OS compared to pts with progressive/stable disease [15.6 (95%CI 11.3-19.8) versus 3.3 (95%CI 0.7-5.8) months, respectively (p<0.001)] (Figure).

Conclusions: Our real-life data suggested that HMA+ VEN combination could be useful also in AML-MDS already treated with azacytidine in the dysplastic phase, with an ORR of about 50% in pts unfit for intensive approaches: however, hematologic and infective toxicities were severe and the response duration was short, with a persistently poor median OS. As a consequence, addition of other targeted therapies driven by NGS should be explored in the next future.
KLF2 Regulates NLRP3 Inflammasome Priming and Activation in Murine Myeloid Cells
Authors: Mukherjee Devashis , Satyavolu Sriram , Thomas Asha , Li Yuexin , Nayak Lalitha
Published: December 2023

Introduction: Krüppel-like factor-2 (KLF2) is a critical nodal transcription factor and a tonic repressor of myeloid cell activation. Loss of KLF2 is associated with a pro-inflammatory and pro-thrombotic state. Mice deficient in myeloid-KLF2 (MK2KO) experience significantly higher mortality from lipopolysaccharide (LPS), and have increased serum and tissue levels of pro-inflammatory cytokines such as IL-1β. IL-1β is a product of NLRP3 inflammasome priming and activation, which has been implicated in numerous inflammatory and immune-mediated diseases. Neutrophils are the first responders of the innate immune system and are responsible for bacterial antigen detection. We thus aimed to elucidate the role of KLF2 in the regulation of NLRP3 inflammasome activation and subsequent IL-1β release in the neutrophil compartment.

Methods: 8-week old adult MK2KO ( Lyz2Cre/ Klf2fl/fl) and control ( Lyz2Cre) mice were used for obtaining neutrophils from the bone marrow. Neutrophils were plated in RPMI-1640 media and stimulated with 10 ng/mL of LPS for 1 hour (h) and 2 h, followed by nigericin for 30 minutes. LPS acts as a priming agent for NLRP3 inflammasome assembly, and nigericin is a potassium ionophore which enables the activation step and subsequent IL-1β release. Supernatant was used for IL-1β ELISA and cell lysate was used for protein extraction and Western blotting to quantify NLRP3 protein expression. GraphPad Prism was used for statistical analyses.

Results: Neutrophils from both MK2KO and Cre mice have significantly increased production of IL-1β when stimulated with LPS followed by nigericin (Figure 1), and loss of KLF2 leads to significantly increased IL-1B release from neutrophils. MK2KO neutrophils also have significantly more NLRP3 protein expression as compared to Cre neutrophils at baseline, and in response to LPS and nigericin (Figure 2). This increase in NLRP3 protein expression was time dependent and dose-dependent (Figure 2).

Conclusion: KLF2 negatively regulates the transcriptional expression of NLRP3 and loss of KLF2 leads to increased NLRP3 inflammasome priming, at baseline and in response to LPS. Loss of KLF2 also affects the second step of the NLRP3 inflammasome pathway - the activation step, leading to increased IL-1β release in neutrophils in adult mice. Ongoing studies are examining the mechanisms underlying KLF2 control of NLRP3 transcription and other aspects of inflammasome activation. Inflammasome activation has been implicated in sepsis-related mortality due to the pro-inflammatory cytokine storm, and thus modulating KLF2 might help in developing novel targets to reduce this burden of mortality.
CREB1 Promotes Immune Escape of Multiple Myeloma Cells By Inducing HLA-E
Authors: Ismael Aya , Robinette Allen , Dona Kameron , Kudalkar Ruchi , Manning Vincent , Galloway Joshua , Cocucci Emanuele , Cottini Francesca
Published: December 2023

Introduction: Multiple Myeloma (MM) is a disease of clonal plasma cells, which accumulate in the bone marrow (BM) and rely on the support of the microenvironment to survive. Immune escape is a common resistance mechanism employed by tumor cells to avoid cytotoxicity by effector immune cells. HLA-E, a non-classical major histocompatibility complex (MHC) class I molecule, inhibits the function of specific subtypes of Natural Killer (NK) and T cells, leading to tumor immune escape. HLA-E expression correlates with worse progression-free survival in newly diagnosed patients with MM. Therefore, we decided to better elucidate the function and regulation of HLA-E expression in MM.

Results: We observed that HLA-E mRNA expression increases in the transformation from normal plasma cells to MM. Since INF-gamma induces HLA-E in MM cells and CREB1 itself promotes the production of IFN-gamma, we hypothesize that CREB1 could regulate HLA-E expression in MM. We first analyzed RNA-sequencing data from patients with MM in the CoMMpass database: gene set enrichment analysis (GSEA) showed increased expression of several pathways related to interferon signaling in patients with high CREB1 expression. We then specifically looked at differences in HLA-E and we confirmed that patients with high CREB1 expression had statistically significant higher HLA-E levels compared with patients with low CREB1 expression. CHIP-sequencing assays in MM cell lines demonstrated that CREB1 can directly influence HLA-E expression by binding to HLA-E promoter. To further prove these data, we evaluated HLA-E levels in gain-of and loss-of function models of CREB1. We observed an increase of HLA-E levels by overexpression of wild type CREB1 and reduction of HLA-E levels by CREB1 silencing or pharmacological inhibition of CREB1 with 666-15 (CREBi).

We then investigated the relationship between CREB1 and STAT1. Indeed, IFN-gamma signals through the STAT1-JAK pathway. Interestingly, while treatment with IFN-gamma strongly induces HLA-E without affecting CREB1 levels or its function, CREBi + INF-gamma reduces HLA-E, STAT1, and phospho-STAT1 levels. Conversely, immunomodulatory drugs (lenalidomide-LEN and pomalidomide-POM) and HDAC inhibitor, Panobinostat, promote the phosphorylation of STAT1, resulting in the transcription of IFN-target genes, including HLA-E. The increase in HLA-E was then reverted by CREB1 inhibition. Since HLA-E impairs NK cell function, we treated MM cells in the presence of NK cells with CREBi alone or in combination with immunomodulatory drugs (IMiDs). Treatment with CREBi or CREBi + IMiDs potentiated the killing effects of NK cells. Animal studies are ongoing to confirm these data in vivo.

Conclusion: In conclusion, our study defines the role of CREB1 in modulating HLA-E expression; CREB1 inhibition improves NK cell-mediated cytotoxicity in MM, representing a novel strategy to tackle immune escape.
Real Event Analysis of the Efficacy and Safety of Polatuzumab Vedotin Combination Regimen in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma
Authors: Shi Yuanfei , Xu Yi , Wang Jinghan , Zheng Xiaolong , Li Xueying , Jin Jie , Tong Hongyan , Xie Wanzhuo
Published: December 2023

Abstract：

Objective Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodges lymphoma (NHL) subtype, although R⁃CHOP treatment cured about 60% of patients. However, 40%-45% of patients do not respond to first-line therapy or relapse after an initial response, and this segment of patients has a poor prognosis. Therefore, the use of targeted drugs and the exploration of drug combination schemes are particularly important, among them, anti-CD79B antibody-drug conjugate (ADC) polatuzumab vedotin (Pola) combined with Bendamustine-Rituximab (BR) and Pola combined with R-CHOP are promising therapeutic options. To analyze the efficacy and safety of Pola combined with BR and Pola combined with R-CHOP in the treatment of relapsed/refractory DLBCL (R/R DLBCL).

Methods The single-arm, Phase II clinical study commenced at our center in May 2023. Eligible patients were R/R DLBCL patients with Ann Arbor stages 3-4, ages 36 to 88 years, who had received at least one previous standard chemotherapy regimen. The clinical data of 17 patients enrolled in our center from May 2023 to August 2023 were retrospectively analyzed, including 10 males and 7 females. The median age was 69 (ranged 36-88) years. 12 patients were treated with Pola-BR and 5 with Pola-R-CHOP, the clinical characteristics, medication regimen, efficacy and occurrence of adverse reactions were analyzed. To explore the causes of adverse reactions between the Polar-BR group and the Polar-R-CHOP group.

Results Data as of August 1, 2023, in the efficacy evaluation of 17 patients, the overall response rate (OR) was 71% (12/17) and the complete response (CR) rate was 53% (9/17). Progressive free survival (PFS), median follow-up of 45 days, with 3 cases (12%) experiencing disease progression. Compared with the Pola-BR group, the Pola-RCHOP group had a lower incidence of adverse reactions. The main adverse event was a pulmonary infection, of which 33% (4/12) were in the Polar-BR group and 25% (1/5) were in the Polar-R-CHOP group, and no severe pneumonia occurred in either group.

Conclusion Compared with the traditional R-CHOP regimen, Polar+BR/RCHOP has better therapeutic effect and a better application prospects for R/R DLBCL patients.
Loss of Platelet 12-Lipoxygenase Aggravates the Severity of Sars-Cov-2 Infection
Authors: Andrade Ana Claudia , Lacasse Emile , Dubuc Isabelle , Gudimard Leslie , Puhm Florian , Queiroz Celso , Allaeys Isabelle , Prunier Julien , Dumais Élizabeth , Flamand Nicolas , Droit Arnaud , Boilard Eric , Flamand Louis
Published: December 2023

Uncontrolled inflammation and dysregulation of platelet activity, leading to venous thromboembolic events are hallmark pathological findings of severe COVID-19. Considering that 12-lipoxygenase (12-LOX) is a key enzyme regulating platelet activity, we investigated its contribution during SARS-CoV-2 infection.

To examine the role of platelet-type 12-LOX, we performed intranasal infections of angiotensin-converting enzyme 2 transgenic mice (K18-hACE2) and K18-hACE2 knockout mice for the Alox12 gene, which encodes the platelet 12-LOX enzyme, using 500 TCID50 of the SARS-CoV-2 Delta strain. Notably, Alox12 knockout mice exhibited more severe disease and higher lethality. To decipher the drivers of this increased severity, we evaluated pulmonary tissue inflammation in mice. The Alox12 knockout mice showed elevated levels of central inflammatory cytokines/chemokines such as IFN-α, IFN-γ, IL-6, CCL-3, CCL-2, CCL-4, CXCL-1, CXCL-9 measured by Luminex multiplex assays. These results were corroborated by histopathological analysis, indicating a higher inflammatory score on the third and fifth day post-infection. Despite 12-LOX's role in platelet activation, we found no signs of higher coagulation processes in the pulmonary tissues of knockout animals, as evidenced by histopathology and preliminary transcriptome analysis of lung tissue.

Furthermore, we investigated the effect of 12-LOX loss on whole blood leukocyte populations by flow cytometry throughout the infection. No significant differences in these populations were observed in the knockout animals relative to WT mice. To explore the impact of 12-LOX metabolites on pulmonary inflammation, we performed mass spectrometry analysis of the main biolipids. Our study unveiled a significant decrease in the levels of inflammatory mediators, namely 12-HETrE, PGE1, 12-HEPE, Maresin-2, 12-HETE, 15-HETE, 11-HETE, LTB4, and 12-KETE, in the lungs of Alox12 knockout mice.

Taken together, our results underscore the critical role of platelet 12-LOX in regulating pulmonary inflammation during SARS-CoV-2 infection. Loss of this enzyme disrupts even more the production of inflammatory mediators following infection, exacerbating disease severity. Our findings highlight the relevance of platelet 12-LOX activity in the regulation of pulmonary inflammation after SARS-CoV-2 infection, shedding light on potential therapeutic targets.
Autologous Hematopoietic Stem Cell Transplantation May Overcome the Adverse Impact of IKZF1 on the Prognosis of B-ALL in CR1 with No Detectable Minimal Residual Disease
Authors: Wang Jiali , Zhang Rongli , Jiang Erlie
Published: December 2023

Purpose: Ikaros family zinc finger 1 (IKZF1) mutation may serve as a poor prognostic factor in B-cell acute lymphoblastic leukemia (B-ALL). This study explored the impact of autologous hematopoietic stem cell transplantation (auto-HSCT) on the outcome of B-ALL patients with IKZF1 alterations.

Methods: we detected the IKZF1 mutation at diagnosis in the bone marrow of adult patients with B-ALL, and analyzed the clinical data of these patients retrospectively.

Results: A total of 38 B-ALL patients in CR1 were enrolled in the study, including 8 recipients of auto-HSCT and 30 of allo-HSCT. The treatment efficacy was evaluated from a model stratified on the risk classification and minimal residue disease (MRD) status after three chemotherapy cycles. Auto-HSCT demonstrated comparable 3-year overall survival (OS) (75% vs. 89.4%, p = 0.893) and leukemia-free survival rates (80% vs. 75.3%, p = 0.471) compared to allo-HSCT for patients with negative MRD (Figure 1). There was also no significant difference on 3-year relapse rate between auto-HSCT and allo-HSCT groups (20% vs. 26%, p=0.394).

Conclusion: Auto-HSCT may be an attractive treatment for B-ALL patients of IKZF1 mutation with negative MRD after three chemotherapy cycles. The adverse impact of IKZF1 on prognosis may be overcome by auto-HSCT.
Altered Cellular Dynamics and Surface Expression Promote Long-Lived Plasma Cell Survival
Authors: Jing Zhixin , Fooksman David
Published: December 2023

Serological memory following vaccination decline with aging, indicating reduced survival of new plasma cells (PCs). We report that with age, bone marrow (BM) PC pool is enriched in long-lived plasma cells (LLPCs), leading to reduced PC turnover, suggesting increased competition. Using in vivo imaging, we find that LLPCs are highly organized into April-dependent clusters. Based on bulk RNA sequencing, and flow-based surface phenotyping, LLPCs exhibit unique transcriptome and proteome, fine tuning expression of key cell surface molecules, including CD93, CD81, CXCR4, CD326, CD44 and CD48, important for adhesion and homing. To test their functional role, Cxcr4 was conditionally deleted in PCs following immunization, which led to rapid mobilization from the BM, reduced survival of antigen-specific PCs, and accelerated decay of antibody titer. Analysis of endogenous LLPCs BCR repertoire exhibits reduced diversity, reduced somatic mutations, and increased public clones and IgM isotypes, particularly in young mice, suggesting non-random selection into the LLPC pool that is age-dependent.