bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Protein Energy Malnutrition on Hospitalized Patients with Chronic Myeloid Leukemia: A United States Population-Based Cohort Study
Authors: Arya Yajur , Syal Arshi , Egert Daniel , Casipit Bruce Adrian , Dourado Claudia , Leighton John Charles
Published: December 2024

Background

Advances in chemotherapeutics and newer TKIs (tyrosine kinase inhibitors) have increased survival in patients with chronic myeloid leukemia (CML). With prolonged survival, these patients are often predisposed to comorbidities affecting their quality of life. Patients with CML suffer from varying degrees of protein-energy malnutrition (PEM) due to multiple factors, including cachexia, sarcopenia, and adverse effects of chemotherapeutics. However, the impact of PEM on outcomes among patients with CML needs further exploration.

Methods

We used the 2020 National Inpatient Sample (NIS) Database to conduct this retrospective cohort study. We identified patients with CML and PEM using appropriate ICD-10 diagnostic codes. We stratified patients with CML based on the presence or absence of PEM. A survey multivariable logistic and linear regression analysis was used to calculate adjusted odds ratios (ORs) for the primary and secondary outcomes. A p-value of <0.05 was considered statistically significant. This study aimed to investigate the impact of PEM on in-hospital mortality, hospital length of stay (LOS), and total hospitalization charges among hospitalized patients with CML.

Results

We identified a total of 3845 hospitalized patients with CML, of which 10.14% (390/3845) had comorbid PEM. The overall in-hospital mortality among patients with CML was 6.38% (245/3845). Among those with concomitant PEM, the mortality rate was significantly higher at 14.10% (55/390, p=0.003). Utilizing a stepwise survey multivariable logistic regression model that adjusted for patient and hospital level confounders, PEM was found to be an independent predictor of increased in-hospital mortality (adjusted OR 2.72; 95% (confidence interval [CI] 1.27-5.83; p=0.010), longer LOS (coefficient 11.58; CI 6.60-16.56; p=0.001), higher total hospitalization charges ($247587; CI $53783-$441391; p=0.012), and increased need for mechanical ventilation (adjusted OR 4.71; CI 1.68-13.15; p=0.003).

Conclusion

Our analysis demonstrated that PEM was widely prevalent in hospitalized patients with CML. It was associated with significantly worsened in-hospital mortality, longer LOS, total cost of healthcare utilization, and increased need for mechanical ventilation. Efforts should be made to promote nutritional assessment and screening mechanisms to include early nutritional support as indicated. Further prospective studies with larger sample sizes are warranted to understand these associations better.
Maternal Death and Postpartum Death in Maputo Mozambique - a Retrospective Autopsy Study
Authors: Emenalom Esther Chioma , Glenzer Michael , Correia Momade , Nhantumbo Virgilio , Songolo Tosha , Luis Elvira , Silva Patricia , von Drygalski Annette
Published: December 2024

Introduction

Maternal mortality (MM) in Sub-Saharan Africa is ≈100-fold higher compared to developed countries. Postpartum hemorrhage (PPH) is estimated to cause 30-50% of deaths.

Aim

To determine the direct contribution of PPH to MM in Mozambique.

Methods

Analysis of autopsy reports of pregnant women who died at Hospital Central Maputo (HCM) between 01/2018 and 01/2022. Extracted data included age, labs and vitals on admission, delivery characteristics, HIV status, and causes of death. Direct causes of MM were split into 5 classifications: PPH, hypertensive diseases, indirect, infection/sepsis, and others.

Results

Based on known mortality rates ≈200 autopsy reports were expected for analysis, but only 64 were available; 8 were excluded for prepartum death. PPH occurred in 22/56 women (39.3%) and was the direct cause of death for 17/56 (30.3%). Figure 1 shows the proportion of direct causes of peri/postpartum death, whereby PPH and hypertensive diseases (28.6%) caused ≈2/3rd of deaths. Labs on admission were available for 39 women. Women who later experienced PPH had lower median hemoglobin (8.6 vs 10 g/dL, p=0.046) and platelets (127,500 vs. 187,000/uL, p=0.039) compared to those who did not.

Conclusion

PPH occurred in ≈40% of dying pregnant women and was documented as the direct cause of death in almost all, with more anemia and thrombocytopenia on admission. Difficulties to locate autopsy reports, and the limited availability of tranexamic acid and blood products reveal the need for infrastructural support, prospective studies, and PPH prevention/intervention protocols to effectively reduce maternal mortality in Sub-Saharan Africa.
Efficacy and Safety of Primary Letermovir Prophylaxis for Cytomegalovirus Infection in Pediatric Patients Undergoing Allogeneic Transplantation: A Single-Centre, Retrospective, Real-World Analysis
Authors: Wang Xin , Jiang Chaoqian , Liu Lipeng , Chen Xia , Ren Yuanyuan , Wan Yang , Zhang Aoli , Zhang Xiaoyan , Shang Yue , Zou Yao , Chen Xiaojuan , Liu Fang , Yang Wenyu , Zhu Xiaofan , Guo Ye
Published: December 2024

Background: Cytomegalovirus (CMV) infection is a common and life-threatening complication following allogeneic haematopoietic stem cell transplantation (allo-HSCT) and patients receiving alternative donor transplantation were at high risk for CMV infection. Letermovir (LET) has been the standard prophylaxis for adult recipients, but published studies in children remain limited, especially for recipients of haploidentical donor (HID) or unrelated cord blood (UCB).

Methods: We retrospectively analyzed children with or without LET prophylaxis, who underwent HID or UCB transplantation between January 2021 and December 2023, to evaluate the efficacy and safety of LET for clinically significant CMV infection (csCMVi) up to 180 days after allo-HSCT. Additionally, we analyzed the influence of donor type on the efficacy of LET.

Results: Of the 151 consecutive patients, 67 received LET, including 35 HID recipients and 32 UCB recipients. They were given 120/240 mg of LET daily, with an average start time of day +13 (1-44) after transplantation, and continued until day +100 after transplantation. During the 180 days after transplantation, we found that the LET group had a lower incidence of csCMVi than the non-LET group (13.4% vs. 56.0%, P＜0.001). Among patients with csCMVi, the LET group had a later mean time of infection onset (day +71 vs. day +41, P=0.306), a lower mean CMV DNA peak load (343 IU/ml vs. 1080 IU/ml, P=0.015) and a shorter mean duration (11 days vs. 19 days, P=0.113) than the non-LET group. Furthermore, in the LET group, later administration of LET was identified as a risk factor for the occurrence of csCMVi (hazard ratio: 1.08, 95% CI: 1.01 - 1.16, P=0.020). Regarding donor type, we found that the HID subgroup had a lower incidence of csCMVi during follow-up than the UCB subgroup (1/35 2.9% vs. 8/32 25.0%, P=0.009). In terms of safety, the incidence and severity of adverse events, leukaemia relapse and overall survival were similar between the two groups.

Conclusion: LET is effective and safe in preventing CMV reactivation among Chinese children undergoing alternative donor transplantation, especially in HID recipients.
Validation of a Simplified Diagnostic Algorithm for Deep Vein Thrombosis
Authors: Sharma Sasha , Soon Linnea , de Wit Kerstin , Lazo-Langner Alejandro , Le Gal Gregoire , Bates Shannon , Parpia Sameer
Published: December 2024

Background: Evidence-based deep vein thrombosis (DVT) diagnostic algorithms used in the emergency department have been extensively validated, yet they are rarely followed by emergency physicians. The most well-known, the Wells score, is complex containing up to 13 clinical items, making it difficult to consistently apply in the emergency department. All diagnostic algorithms for DVT combine estimations of clinical pretest probability with D-dimer blood testing, and/or ultrasonography. In an effort to simplify DVT diagnostic algorithms, we developed a simplified rule for DVT testing, named the 2DAY algorithm.

Objectives: The aims of this study were to evaluate the safety and efficiency of the 2DAY algorithm for DVT diagnosis in the emergency department.

Methods: We used patient data from the Canadian multicentre diagnostic management study: the 4D study (NCT02038530), to validate the 2DAY algorithm. Patients were followed to determine if they were diagnosed with venous thromboembolism (proximal DVT or pulmonary embolism) within 90-days following their DVT assessment.

The 2DAY algorithm consists of physician's estimate of whether DVT is the patient's most likely diagnosis and the blood D-dimer result to determine if an ultrasound is required. If DVT is the most likely diagnosis, then DVT is excluded with standard threshold of <500 ng/mL. If DVT is not the most likely diagnosis, then DVT is excluded using the age-adjusted D-dimer threshold. If DVT is not excluded based on the D-dimer result, the patient must undergo proximal ultrasound imaging. Repeat ultrasonography is indicated when the patient has a D-dimer is ≥ 1,500 ng/mL and a negative initial proximal ultrasound.

The primary analysis was the proportion of patients diagnosed with venous thromboembolism within 90-days who had DVT ruled out by the 2DAY algorithm with the corresponding 95% confidence interval (CI) estimated using the Wilson Score method. Similar analysis was used to estimate the efficiency of the 2DAY algorithm defined as the proportion of patients who did not require an ultrasound.

Results: In total, 1497 patients were eligible. Using the 2DAY algorithm, 163 (10.9 %) out of the 1497 patients were diagnosed with DVT. The mean age was 60.3, 41.8% were male, and 5.0% had active cancer. DVT was the most likely diagnosis for 68.1% of patients. From the 1334 patients who had DVT ruled out by the 2DAY algorithm, 10 (0.75%; 95% CI, 0.41-1.37) patients had VTE diagnosed during the 90-day follow-up period. The 2DAY algorithm had an efficiency of 38.6% (578/1497; 95% CI, 36.2-41.1).

Conclusions: The 2DAY algorithm, was found to be safe and efficient in ruling out DVT. Before the 2DAY algorithm can be implemented in daily clinical practice, a prospective validation study is required.
Transformative Outcomes with Short-Term Blinatumomab and Cord Blood Transplantation in Relapsed/Refractory B-Cell ALL
Authors: Nishida Aya , Kuno Mika , Watanabe Otoya , Kaji Daisuke , Taya Yuki , Takagi Shinsuke , Yamamoto Hisashi , Yamamoto Go , Uchida Naoyuki
Published: December 2024

[Background] Blinatumomab is a bispecific T-cell engager (BiTE) antibody with specificity for both CD19, expressed on B cells, and CD3, expressed on T cells. While blinatumomab is known for its efficacy in relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), reports on its use before transplantation are limited, and there are no reports on its use before cord blood transplantation (CBT).

[Objective and Methods] To assess the efficacy, safety, clinical features, and outcomes of blinatumomab before CBT in patients with R/R B-ALL, we retrospectively analyzed patients who received CBT after using blinatumomab for R/R B-ALL at our institution from August 2019 to July 2023.

[Result] During the study period, 42 patients received CBT after using blinatumomab for R/R B-ALL in our institute. The median follow-up duration for survivors was 438 days (range: 69-1466). The median age of the patients was 53 years (range: 16-71), with 27 males and 15 females. Among the 42 cases, 12 had Philadelphia chromosome-positive ALL; all 12 cases received blinatumomab in combination with a tyrosine kinase inhibitor. Twenty-four patients received blinatumomab after relapse following chemotherapy, 9 patients had induction failure, 6 patients had minimal residual disease after chemotherapy, and 3 patients received it for other reasons. The median number of blinatumomab courses in this group was 2 (range: 1-4). Treatment discontinuation occurred in 14 cases for the following reasons: liver dysfunction in 4 cases, hypotension in 3 cases, neurological impairment in 3 cases, disease progression in 2 cases, and other reasons in 2 cases. In 8 of the 14 cases where treatment was discontinued, blinatumomab was resumed after steroid therapy. After using blinatumomab, complete remission (CR) was achieved in 35 of the 42 cases (83%). The final disease status at the time of transplantation was CR in 36 cases and non-CR in 6 cases. All 42 cases used CBT as the donor source. Twenty-eight patients received myeloablative pretransplant conditioning, and 14 received reduced-intensity conditioning. The 2-year overall survival (OS) for the 42 cases was 77.9%, progression-free survival (PFS) was 68.6%, relapse rate was 14.6%, and non-relapse mortality cumulative incidence was 25.3%. For patients who received CBT in non-CR, the probability of OS and PFS were lower compared to patients in CR (2-year OS, CR vs. non-CR, 82.6% vs. 50.0%, p = 0.025; 2-year PFS, CR vs. non-CR, 73.1% vs. 41.7%, p = 0.006).

[Discussion] Short-term use of blinatumomab before CBT for R/R B-ALL was safe and effective. Our data indicate that the combination of short-term blinatumomab and CBT could become a formidable treatment option for overcoming R/R B-ALL.
Preclinical Evaluation of an Allogeneic CD22 CAR-NK to Target B-Cell Hematologic Malignancies
Authors: Lee Eunsol , Kim Jeongmin , Kim Seungmin , Jung Miyoung , Kim Yusun , Jeon Youngwoo , Won Sungyong
Published: December 2024

Chimeric antigen receptor (CAR) immunotherapy targeting CD19 has shown remarkable responses and sustained remission in clinical trials for B cell malignancies. However, 30%-60% of patients relapse due to poor CAR-T persistence or CD19 antigen escape, necessitates the exploration of additional targets, with CD22 being an attractive candidate. CD22 is expressed from the pre-B cell stage through mature B cells and is present on most B cell hematologic malignancies. CAR therapy targeting CD22 alone is being investigated as a sequential treatment option to address CD19-negative relapse following CD19-targeted therapy.

We generated CD22 CAR-NK cells to evaluate their anti-tumor efficacy both in vitro and in vivo against CD22-expressing B cell lymphoma cells. Our cord blood-derived CD22 CAR-NK cells were designed to secrete IL-15, supporting NK cell survival and proliferation upon antigen stimulation. Ex-vivo expanded, cryopreserved CD22 CAR-NK cells showed a pure NK cell phenotype (>95%) with high CD22 CAR expression (>90%). These cells demonstrated target-specific cytotoxicity against CD22-positive tumor cells, with no significant cytotoxicity against CD22-negative tumor cells. In long-term cytotoxicity assays, they completely inhibited the growth of CD22-positive tumor cells. In the presence of CD22-positive tumor cells, CD22 CAR-NK cells exhibited substantial cytokine secretion, including IFN-γ and IL-15, indicating their therapeutic potential for CD22-positive B cell malignancies.

In the NALM-6 xenograft model, mice treated with CD22 CAR-NK cells exhibited a significant delay in tumor growth and prolonged survival, with high levels of CD22 CAR-NK cells detected in their peripheral blood. Our study demonstrates that CD22 CAR-NK cells play a crucial role in long-term persistence both in vitro and in vivo, indicating their potential therapeutic efficacy in B cell malignancies. These results highlight the potential of novel CD22 CAR-NK cell therapy as a promising treatment strategy for CD22-positive B cell malignancies and as an option for relapsed/refractory patients who experience antigen loss or failure with anti-CD19-related immunotherapy.
Progression-Free Survival Improvement of Localized Ocular Adnexal MALT Lymphoma Patients with Residual Lesions: Comparative Outcome of Postoperative Treatment Versus Watchful Waiting
Authors: Zhao Chong , Yang Shaoxin , Zhou Yixiong , Shi Jun
Published: December 2024

Background: Ocular adnexal extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (OA-EMZL) is a rare form of indolent non-Hodgkin's lymphoma. The frontline therapeutic modalities for localized patients involve watchful waiting or further treatment after surgery. However, it remains unclear which patient characteristics should prompt postoperative treatment.

Methods: A retrospective cohort study was conducted in a single institution, and 77 patients with newly diagnosed primary localized OA-EMZL were enrolled. We compared progression-free survival (PFS) in patients undergoing watchful waiting versus those receiving treatment after surgery. Based on the surgical method, patients were classified into a complete resection group and an incomplete resection group. PFS of patients receiving treatment and watchful waiting in different groups were compared.

Results: The median age was 59, with a male predominance (male : female = 1.45:1). The orbit (58, 75.32%) and the conjunctiva (10, 12.99%) were the most frequently involved anatomical structures. Of the 77 patients, 39 underwent watchful waiting, whereas 38 received further treatment, including localized radiotherapy, immunotherapy, or immunochemotherapy. The 5-year PFS for patients who received treatment or watchful waiting were 91.68% and 69.46%, respectively (P = 0.036). Regarding surgical methods, 21 patients underwent complete resection of the neoplasm, whereas 56 had residual lesions after surgery. In the complete resection group, 15 out of 21 and 6 out of 21 patients received watchful waiting and treatment, respectively. The 5-year PFS were 85.71% and 100%, respectively (P = 0.342). In the incomplete resection group, 24 out of 56 patients received further treatment. They had longer PFS (5-year PFS, 90.28%) compared with patients who underwent watchful waiting (5-year PFS, 62.22%) (P = 0.041). Treatment choice of radiotherapy or immunochemotherapy was not associated with PFS (P = 0.601). Of the 77 patients, ten relapsed, of which 8 had undergone watchful waiting. Seven out of eight patients had recurrence at the primary site, and one patient had distant recurrence, subsequently converting to DLBCL.

Conclusions: Overall, postoperative treatment is needed for primary localized OA-EMZL patients with residual lesions. Both radiotherapy and chemotherapy can be alternatives.
Protein and Gene Levels of DNAJC21 and RNF5 Proven to be Novel Drug Targets for Immune Thrombocytopenia: Insights from Mendelian Randomization-Based Post-GWAS Research
Authors: Li Jun , Li Xiaoli , Zhu Xiaofan
Published: December 2024

Background The clinical manifestation of Immune thrombocytopenia (ITP) is heterogeneous, and its unclear pathogenesis makes treatment challenging. Traditionally, ITP has been considered an autoantibody-mediated platelet destruction disorder. Thus, identifying suitable plasma proteins for novel therapeutic regimens is crucial.

Methods This study employed Proteome-Wide colocalization, which included data from deCODE Genetics and the UK Biobank Pharma Proteomics Project (UKB-PPP) to screen potential proteins. To determine causality, Mendelian Randomization (MR) was conducted, treating candidate proteins as exposures and using ITP's Genome-wide association studies (GWAS) summary statistics from FinnGen R11 as outcome. The inverse variance weighted (IVW) method was primarily relied upon when all methods indicated a consistent direction of effect, while the Wald ratio method was employed if only one instrumental variable (IV) remained. Multiple sensitivity analyses and false-discovery rate adjustments (FDR-adjusted) were conducted to enhance robustness and reliability. Transcriptome-wide colocalization from the eQTLGen consortium was also performed to verify if gene levels corresponded with previously confirmed proteins. If consistent, further MR analysis was continued as described.

Results Through Proteome-Wide colocalization, proteins with a Posterior Probability of Hypotheses 4 (PP.H4.abf) ≥ 0.3 were included for further MR analysis. After screening, 17 proteins from deCODE and 16 from UKB-PPP were identified, with 4 proteins overlapping between datasets. Eventually, 19 proteins from both datasets were confirmed to have significant effects on ITP. Here, we report proteins with PP.H4.abf exceeding 0.7, indicating a strong association with ITP. After FDR correction, DNAJC21 and RNF5, which only appeared in the UKB-PPP dataset and not in deCODE, showed to be risk (OR=4.07, 95% CI=2.26-7.31, P=8.91e-06) and protective (OR=0.02, 95% CI=0.01-0.05, P=6.51e-13) factors, respectively. Further Transcriptome-wide colocalization and MR results confirm that the gene levels of DNAJC21 and RNF5 have similar effects to their protein levels, with DNAJC21's gene positively associated with ITP (OR=1.99, 95% CI=1.40-2.85, P=4.04e-04) and RNF5's gene negatively associated with ITP (OR=0.70, 95% CI=0.57-0.85, P=1.32e-03).

Conclusions In this study, protein and gene levels of DNAJC21 were shown to increase the risk of ITP, while RNF5's protein and gene levels demonstrated a protective effect. Mutations in DNAJC21 had been linked to Bone Marrow Failure Syndrome (BMF), while RNF5 was primarily associated with immune reactions. Therefore, the discovery of the roles of DNAJC21 and RNF5 helps to elucidate the underlying mechanisms and develop novel drug targets for ITP.
Direct Visualisation of BCMA Bispecific Antibody and the Myeloma Immune Microenvironment
Authors: Er Jeremy , Joel Rimes , Amanda Light , Dowling Mark R , Harrison Simon J , Hawkins Edwin
Published: December 2024

Introduction: Multiple myeloma is haematological malignancy that remains difficult to cure despite recent therapeutic advances. Novel T cell redirecting therapies such as CAR-T cells and bispecific antibodies have shown promising efficacy in the relapse setting However, durable responses have yet to be achieved. Mechanisms of resistance and the dynamics of immune cell interactions within the bone marrow remain poorly defined. Here, we used in situ imaging of the bone marrow in living mice (intravital imaging) to characterise immune cell interactions with myeloma in the context of murine BCMA bispecific antibody therapy.

Methods: We used a traceable myeloma cell line derived from the spontaneous Vk*MYC mouse model (Vk14451-GFP) that recapitulates human disease. To visualise the cytotoxic immune response, Vk14451 cells were transplanted into recipient mice where CD8 T cells were labelled with fluorescent tomato protein (E8I-Cre tomato). >Five weeks post-transplant, multi-day intravital imaging of the calvarium bone marrow was performed using 2-photon microscopy. This imaging approach was performed in the absence or presence of murine BCMA bispecific antibody. Mice were treated with 1 to 4 doses of the bispecifc antibody to visualise immune and myeloma responses.

Results: Direct visualisation of T cells in situ in the absence of therapeutic intervention revealed CD8 T cells were excluded from areas of myeloma infiltration. Furthermore, CD8 T cells that gained entry to tumour had significantly altered cell interactions compared to T cells in healthy bone marrow. Following administration of a dose of bispecific antibody, we observed drastic changes in the biology and spatial distribution of CD8 T cells within the bone marrow. Surprisingly, following activation the immunosuppressive myeloma microenvironment had no effect on the ability of CD8 T cells to engage with myeloma cells within tumour foci and undergo rapid expansion. However, we observed significant changes in the persistence of T cells within the myeloma foci. In addition, in cohorts of mice that received repeated dosing of bispecific antibody, we observed loss of tumour control. In these mice, we still observed access of T cells to the tumour foci and active proliferation. However, we did not observe sustained interactions and active killing of MM cells suggesting development of a tumour agnostic state of T cells.

Conclusion: This dynamic analysis of immune cell interactions with myeloma within the bone marrow microenvironment suggests that targeting persistence of activated T cells may play a key role in the therapeutic efficacy of T cell redirecting therapies.

Declaration: This research was supported by Bristol Myers Squibb. The company had no role in analysing the data or preparing the abstract
Does Cytokine Release Syndrome Predict Cancer Remission within 30 Days Following Chimeric Antigen Receptor T-Cell Therapy?
Authors: Al Masalmeh Nada , Salehi Mahta , Barbar Arslan , Doherty Jason , Rajeh Nabeel , Kunwor Ranju
Published: December 2024

Purpose:

This study aims to investigate whether Cytokine Release Syndrome (CRS) following Chimeric Antigen Receptor T-cell (CAR-T) therapy in patients with relapsed or refractory large B-cell lymphoma (LBCL) and mantle cell lymphoma, predicts cancer remission/response within 30 days. Remission was defined as a Deauville score of 3 or below, 30 days post-therapy.

Method:

This retrospective, single-center study included patients aged ≥18 years with (LBCL) and mantle cell lymphoma who underwent apheresis between 2019 and 2023 for (CAR-T) therapy at one academic medical center in the United States. Patients were categorized based on the presence of (CRS) following CAR-T therapy, regardless of grade. Statistical analyses, including chi-squared and Wilcoxon Mann-Whitney U tests, were conducted to compare remission rates between CRS and non-CRS groups. Additionally, Firth's penalized logistic regression was used due to the small sample size.

Results:

The study included 32 patients, with 81.25% (26/32) experiencing (CRS). There was no statistically significant relationship indicating an association between the onset of CRS and achieving a response on the day 30 PET scan. This lack of significance might be due to the small sample size and imbalance between CRS and non-CRS groups. However, there was a notable trend indicating that patients with CRS had higher remission rates (73.08%) compared to those without CRS (50%), although the effect was not statistically significant (p=0.272).

Conclusions:

The preliminary findings suggest that while CRS may correlate with higher remission rates post-CAR-T therapy, the small sample size limits definitive conclusions. Future research should focus on larger cohorts and consider the severity of CRS to better understand its predictive value for remission.
The Gut Microbiota Lachnospiraceae and Its Bacterial Metabolite Vanillylamine Significantly Alleviate Myelosuppression Caused By Abdominal and Pelvic Tumor Chemotherapy
Authors: Chen Zhenhui , Yu Lu , Guo Xiaotong , Fan Hongying
Published: December 2024

Acute and chronic myelosuppression occurs in up to 80% of abdomen pelvic tumor patients undergoing chemoradiotherapy, severely impacting survival outcomes and quality of life. Currently, treatments for chemotherapy-induced acute myelosuppression are limited and inadequate for prevention, highlighting the urgent need for novel preventative and therapeutic strategies.

We investigated the role of gut microbiota in a 5-fluorouracil (5-FU)-induced acute myelosuppression mouse model using a four-antibiotic cocktail to disrupt the gut microbiota. Metagenomics of intestinal contents and single-strain gavage mouse models identified key gut bacteria that mitigate myelosuppression. Untargeted metabolomics of intestinal contents and a metabolite gavage mouse model revealed key bacterial metabolites that alleviate myelosuppression. Bioinformatics analysis, in vitro whole gut microbial culturing, and LC-MS confirmed that Lachnospiraceae produce the critical metabolite vanillylamine. Molecular mechanisms were explored using HE staining, flow cytometry, colony assays, RNA sequencing, Western blot, qPCR, and siRNA gene knockdown to understand how Lachnospiraceae and vanillylamine alleviate myelosuppression and accelerate ST-HSC proliferation.

Our findings show that antibiotic-induced dysbiosis exacerbates 5-FU-induced myelosuppression and increases mortality in mice. Conversely, Lachnospiraceae and Akkermansiaceae significantly alleviate myelosuppression and accelerate ST-HSC proliferation. Metabolites such as vanillylamine and several indole-derived metabolites from gut bacteria also alleviate myelosuppression and promote ST-HSC proliferation. Lachnospiraceae positively correlates with vanillylamine production, and Lachnospiraceae-derived vanillylamine significantly activates the JNK pathway, accelerating ST-HSC proliferation.

In conclusion, gut bacteria such as Lachnospiraceae and their metabolites like vanillylamine accelerate ST-HSC proliferation through activating the JNK pathway and alleviate chemotherapy-induced acute myelosuppression, enriching our understanding of the gut-bone marrow axis.
A Better Efficacy of an Escalating Strategy over Thrombopoietin Receptor Agonist-Based Second-Line Therapy in Children Severe Persistent/Chronic Thrombocytopenia: A Multicenter Prospective Study from China
Authors: Wu Runhui , Fu Lingling , Lin Xi
Published: December 2024

Background: The first international recommendations for second-line therapy in children with severe persistent/chronic thrombocytopenia (SP/CITP) are thrombopoietin receptor agonists (TRAs) or TRAs-based strategies, however, only 30% of them could achieve sustain response off treatment (SRoT), leading to a heavy medical burden, especially for the SP/CITP children in developing countries. The result of our previous escalating treatment pilot study showed the possibility to solve this problem.

Objective: Comparing the efficacy of the escalating treatment to TRAs-based second-line treatment, to provide a better treatment option for children SP/CITP.

Methods: A prospective, multicenter clinical cohort study enrolled SP/CITP children, with one-year follow-up, we compared the escalating group to the group using TRAs-based second-line treatment directly, for the treatment outcomes (response/remission of platelet count, bleeding control, side effects related to treatment) and costs outcomes (escalation status, SRoT and treatment costs).

Results: A total of 143 analyzable cases were enrolled (72 males, 71 females), with 110 cases in the escalating group (EG) and 33 patients in the TRAs-based second-line treatment group (TG) (12 cases using TRAs monotherapy and 21cases using TRAs-based combination therapies). There were without differences in baseline characteristics (Ps>0.05).

Comparison between EG and TG showed that without differences in duration response(DR), remission(R) rates and also the grades of bleeding at 6 and 12 months (Ps>0.05), but with fewer side effects related to treatment (9.0% in EG and 39.4% in TG, P＜0.001).

In EG, with 57% responding to HDD and 26% to RTX, only 16% of them needed to escalate to add TRAs, leading to 74.5% achieving SRoT within 150（75-180）treatment days whereas 0% in TG. The cost of treatment was significantly lower in EG ($68.26/kg/year) than either the monotherapy group ($395.11/kg/year) or the combination therapies group ($373.85/kg/year) from TG during 12 months of follow-up period (P<0.001).

Conclusion: The escalating strategy achieved comparable clinical efficacy with fewer treatment-related side effects to TRA-based second-line treatment. By utilizing individualized and stratified treatment, the escalating strategy could shorten the treatment duration, attain treatment discontinuation, and save treatment costs significantly. It is a better option second-line treatment strategy for children SP/CITP.
Clinical Implications of Residual Immunophenotypically Normal Plasma Cells within Bone Marrow at Various Disease Stages in Multiple Myeloma
Authors: Yan Wenqiang , Shi Lihui , Xu Jingyu , Li Lingna , Cui Jian , DU Chenxing , Yu Tengteng , Zhang Shuaishuai , Lv Rui , Sui Weiwei , Deng Shuhui , Xu Yan , Zou Dehui , Qiu Lu-Gui , Hao Mu , An Gang
Published: December 2024

Introduction

Residual normal plasma cells (NPCs) within bone marrow (BM) act as competitors of abnormal plasma cells, playing an important clinical role during the malignant transformation and disease aggressiveness in plasma cell disorders. Previous studies have described the relationship between the persistence of NPCs and survival outcomes at several timepoints, but its clinical significance remain to be fully elucidated across various disease courses. Following the clearance of tumor plasma cells post-treatment, the numerical or proportional alterations in NPCs during the minimal residual disease (MRD) phase could also indicate the evolution of response depth and changes in the immune microenvironment. To date, however, there has been a scarce of research specifically addressing residual NPCs at the MRD stage.

Methods

In light of this, we conducted a comprehensive retrospective study utilizing a substantial flow cytometry dataset comprising 1363 MM patients and nearly 5000 MRD samples across all disease courses from the National Longitudinal Cohort of Hematological Diseases in China (NICHE, NCT04645199).

Results

Our results revealed that 47 (4.5%) newly diagnosed myeloma patients with high NPC ratio (≥5%) within bone marrow (BM) exhibited distinct indolent features, characterized by lower tumor burden, reduced frequencies of cytopenia, immunoparesis, and high-risk cytogenetics. Importantly, high residual NPC ratio at diagnosis or relapse was independently associated with favorable survival outcomes. Furthermore, high absolute level of NPCs at undetectable MRD timepoint was also related with superior clinical benefit and immune reconstitution. Among MRD-positive patients, NPCs ratio within BMPCs was significantly negatively correlated with residual tumor cell levels post-treatment. In addition to MRD status, grouping based on NPC ratio (< 50%, 50-90%, ≥90%) at MRD phase demonstrated better risk stratification for detectable MRD patients compared to residual tumor log levels. The dynamic NPC ratio time-dependent model could classify patients into three groups with diverse longitudinal change trends, which lead to distinct survival outcomes.

Conclusions

Collectively, the persistence of residual NPCS serves not only as a valuable complementary biomarker for risk stratification but also provides valuable insights on reclassifications and kinetics of MRD.
Effect of Sarcopenia and Nutritional Risk Factors in Patients with Multiple Myeloma
Authors: Shen Xuxing , Yu Jiapei , Cheng Xin , Yao Ye , Jin Yuan , Shi Qinglin , Li Jianyong , Chen Lijuan
Published: December 2024

Background:

Multiple myeloma (MM) is a hematological malignancy with poor prognosis. Fitness-based prognosis predict may help facilitate therapeutic strategies. This study was objective to explore the prognostic significance of sarcopenia, prognostic nutritional index (PNI), and controlling nutritional status (CONUT) in patients with MM.

Methods:

We conducted a retrospective analysis of the data derived from 214 patients with newly diagnosed multiple myeloma (NDMM) at Jiangsu Province Hospital from January, 2016 to December, 2022. Skeletal muscle mass was measured by whole-body low-dose CT/PETCT images at diagnosis and further normalized for stature to calculate the skeletal muscle index (SMI). Patients with a low SMI were defined as sarcopenic. Prognostic nutritional index (PNI) was calculated by the following equation: PNI=serum albumin (g/L)+5×peripheral blood lymphocyte count(×109/L). Elements including serum albumin, total cholesterol, and peripheral blood lymphocyte count were collected for estimating the Controlling Nutritional Status (CONUT) score. The thresholds of sarcopenia, PNI, and CONUT were determined by ROC curve analysis, and participants were divided into three groups according to these three metrics. The Kaplan-Meier survival analysis was utilized to investigate the relationship between these indicators as well as collectively prognosis. Independent prognostic predictors of overall survival (OS) were identified using the Cox regression model.

Results:

A total of 72(33.6%) patients were confirmed as sarcopenic, with a higher prevalence in female(P＜0.001), over 65 years of age (P=0.022), and those with a BMI below 24 kg/m2(P＜0.001). Survival curves showed that sarcopenia, low PNI, and high CONUT were all correlated with adverse survival outcomes. The combined model was apparently associated with PFS (P=0.0284) and OS (P=0.0004), and patients with concurrent sarcopenia, low PNI, and high CONUT had the worst survival rates. Multivariate analysis indicated that sarcopenia emerged as a significant and independent predictor of inferior OS (HR=1.820, P=0.048) in NDMM patients.

Conclusion:

In conclusion, sarcopenia served as an autonomous prognostic indicator OS in individuals with NDMM. The integration of PNI and CONUT with sarcopenia was effective in predicting prognosis in MM patients.
Clinicopathological Features of Kikuchi-Fujimoto Disease: Retrospective Observational Study
Authors: Nishimura Yoshito , Nishimura Midori Filiz , Sakao Chikako , Nishikori Asami , Habermann Thomas M. , Dispenzieri Angela , Sato Yasuharu
Published: December 2024

Introduction:

Kikuchi-Fujimoto disease (KFD), is a rare inflammatory disease of unknown etiology, typically presenting with transient fever and cervical lymphadenopathy. It is recently classified as a tumor-like lesion in the World Health Organization Classification 5th Edition. There are few large-scale studies on patient demographics and clinical course. This study aims to report detailed clinicopathological features of KFD.

Methods:

We reviewed 112 cases of KFD diagnosed at Okayama University Department of Pathology and Oncology, Okayama, Japan between 2012 and 2022. Patients who were diagnosed with autoimmune diseases or bacterial/tuberculous lymphadenitis after the initial presentation as KFD were excluded.

Results:

The average age of the included cases was 29.4 years (range:6 to 77 years) with slight female predominance (n = 51/115, 44.3% for male; n = 61/115, 53.0% for female). For the included cases of 30 years or older, there were more females than males. The cervical lymph nodes were the most commonly affected sites (85%). For the 70 patients who had complete follow-up data available in the electric medical records, the recurrence rate was 23%, without a difference between males and females. Laboratory tests demonstrated significantly lower complement 4 (C4) levels (p = 0.038) and a higher rate of positive antinuclear antibodies (p = 0.007) in the relapsed cases than in the cases without documented recurrence. The mean number of days prior to confirm the diagnosis was 71.5 days. Among the representative lymph node histology classification, proliferative type was the most common (n = 75; 77%), followed by necrotizing (n = 22; 22%), and xanthomatous (n = 1; 1%). The patients with necrotizing type had significantly enlarged lymph nodes (p = 0.047) and longer duration of symptoms (p = 0.009) compared to the proliferating type.

Discussion:

The present study provides data from a large KFD cohort to provide comprehensive clinicopathological information to date. While KFD is known to predominantly affect female, there were considerably more males up to age 30 than females, Being young and adolescent male KFD patients was associated with atypical features. Future studies are warranted to confirm the findings noted in the results, to clarify clinicopathological differences in the male young adolescent KFD, and further characterize the classical female KFD cases, including histological features, treatment responses, and association with autoimmune or malignant hematology conditions.

Conclusion:

In this study, we analyzed a large number of KFD cases and clarified characteristics. The comprehensive clinicopathological features provided by the present results may be useful in elucidating the pathogenesis and predicting the clinical course of such clinically challenging cases, including association with autoimmune diseases and its long-term outcomes.
Estimated Prevalence of β-Thalassemia in the United States in 2023
Authors: Fu Kasey , Lawson-Michod Katherine , Goodman Michael , Lally Cathy , Ojodu Jelili
Published: December 2024

Introduction: The number of β-thalassemia (BT) prevalent cases in the US was previously estimated at 2,600 and state-specific prevalence data are limited. Here, we use newborn screening data to estimate the current number of BT and transfusion dependent β-thalassemia (TDT) cases in the US.

Methodology: We requested results for newborn screening data for BT from 26 state public health programs. The goal was to estimate the total number of clinically significant BT cases that included BT subgroups: β-thalassemia major (BTM), β-thalassemia intermedia (BTI), and hemoglobin E β-thalassemia (HbEBT). As BT primarily affects individuals of Mediterranean and Southeast Asian ancestry, and very few cases are expected to occur in smaller states with relatively homogeneous US-born populations, we included states with at least 500,000 foreign-born residents, or states with a population of at least 5 million. Due to how the states' data collection and reporting varied, cases were standardized into BTM, BTI, and HbEBT consistent with reporting in the literature. The total prevalence of BT in the US in 2023 was estimated using a modified life table model based on the median US birth incidence for all BT groups and survival probabilities. State-specific BT birth incidence and the median for the census region were used in a sensitivity analysis. Additional sensitivity analyses using varying definitions of TDT were conducted.

Results: Based on 17 states reporting data sufficient for analysis, the national median BT birth incidence was 1.46 cases per 100,000 live births. When applying the US median birth incidence to all states in the life table model, the total number of BT cases in the US in 2023 was 3,665, equivalent to 1.07 per 100,000 persons. However, based on sensitivity analyses the estimated prevalence was as high as 4,214 cases (1.23 per 100,000). The number of prevalent TDT cases was 2,611 and as high as 3,036 in sensitivity analyses.

Conclusion: Our results suggest that the previously reported number of 2,600 individuals receiving care for thalassemia in the US is likely an underestimate. Variations observed in the reported BT birth incidence by state could be due to true population differences as well as variation in newborn screening reporting. More research is needed to understand the epidemiological trends of BT in the US as the implications of undercounting BT cases are significant when considering healthcare resource planning.
Effective Treatment of Refractory Aplastic Anemia with Romiplostim after Failure of Multiple Thrombopoietin Receptor Agonists: A Single-Center Retrospective Study
Authors: Lin Xijuan , Yang Chen , Liu Ziwei , Zhuang Junling , Chen Miao , Han Bing
Published: December 2024

Background: Romiplostim (ROMI), a second-generation thrombopoietin receptor agonist (TPO-RA), has shown promising results in patients with refractory aplastic anemia (AA); however, its optimal dosage, efficacy, and safety in patients with refractory AA who experienced treatment failure with immunosuppressive therapy (IST) and other types of TPO-RAs remain unclear. In the present study, we aimed to retrospectively assess the efficacy and safety of high-dose ROMI (with an initial dosage of 20 μg/kg per week) in these patients.

Patients and m ethods: Patients who received ROMI consecutively for at least 3 months between April 8, 2023 and October 23, 2023, and were followed up for at least 6 months after therapy were analyzed. All enrolled patients had failed to respond and stopped the previous treatments for at least 3 months before receiving ROMI.

Results: Eleven patients were followed up for at least 6 months; all experienced treatment failure with IST and at least two types of other TPO-RAs. They had a median age of 54 years (range: 27-77 years), and eight (72.7%) were women. The patients' initial and maximal ROMI dose was 20 μg/kg per week. At a median follow-up of 8 months (range, 6-8 months), 72.7% (8/11) of the patients reached the response criteria at a median of 1 month (range: 1-3 months). Of these patients, 54.5% (6/11) met the criteria for a complete response at a median of 2.5 months (range: 1-3 months), and 27.3% (3/11) achieved a trilineage response. No severe ROMI-related adverse events that led to treatment discontinuation or dosage reduction were observed. Notably, 12.5% (1/8) of the responders relapsed at 5 months after stopping ROMI for 2 months.

Conclusion: High-dose ROMI with an initial dosage of 20 μg/kg per week is effective and safe for patients with refractory AA who experienced treatment failure with IST and multiple oral TPO-RAs, exerting a rapid response.
Rbm38 Regulates Heme Biosynthesis Via Fine-Tuning the RNA Alternative Splicing, Stability and Translation of Porphyrin Metabolic Enzyme Gene Ferrochelatase (Fech)
Authors: Xie Xinshu , Zou Ailin , Liu Kang , Liu Lu , Mei Yang
Published: December 2024

Studies in vitro implicated Rbm38 as a key regulator of erythroid enucleation in terminal erythropoiesis, while it has not yet been verified and fully elucidated by in vivo animal models. To directly assess the role of Rbm38 in erythropoiesis in vivo, we generated both Rbm38 whole-body knockout and conditional knock-out mousemodels. Here, we find ex vivo cultured Rbm38 knockout (KO) fetal erythroblasts and bone marrow lineage-negative cells exhibit normal nuclear extrusion to form reticulocytes. Moreover, reticulocyte generation has not been compromised in the bone marrow of Rbm38-deficientmice. Rbm38-/- RBCs own declined hemoglobin content and are susceptible to oxidative stress-induced hemolysis. The Rbm38-deficient mice also develop microcytic hypochromic anemia with dysregulated iron homeostasis, decreased mitochondrial heme biosynthesis, and accumulated free protoporphyrin (PPIX) in erythrocytes and feces that resemble human erythropoietic protoporphyria (EPP) disease. Mechanistically, Rbm38 controls the incorporation of ferrous iron (Fe2+) into PPIX to form heme by modulating the alternative splicing (AS), mRNA decay and translation of the porphyrin metabolic enzyme gene Ferrochelatase (Fech). Importantly, enforced expression of Fech largely restores the erythroid maturation defect and ameliorates anemia in the Rbm38-/- transplants. We further show that the genetic variants in the human RBM38 gene locus influence the PPIX levels in erythrocytes from healthy cohorts. Our findings demonstrate a dispensable role of Rbm38 for erythroid enucleation in vivo and highlight its key function in terminal erythroid maturation by orchestrating the RNA splicing, stability and translation involved in heme biosynthesis.