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Abstract Proteasome inhibitors (PIs) are crucial in treating multiple myeloma but carry a risk of thrombotic microangiopathy (TMA), especially with carfilzomib use. This systematic review includes 44 studies with 115 cases of PI-induced TMA, where carfilzomib was implicated in 101 cases. Treatment approaches varied: 28 patients received supportive care, 43 underwent therapeutic plasma exchange (TPE), 9 were treated exclusively with eculizumab (ECU), and 13 received both TPE and ECU. Notably, eculizumab significantly improved outcomes for patients unresponsive to initial TPE, achieving complete remission in seven cases. The need for dialysis emerged as a significant predictor of outcomes, often indicating a poor prognosis. For patients suspected of having PI-TMA, it is advisable to discontinue the offending medication promptly, even without definitive laboratory confirmation. In cases where diagnosis is challenging, kidney biopsy may assist if conditions permit. Comprehensive evaluation of the complement system, including genetic mutations, function, and associated complement inhibitory factor antibodies, should be included in the assessment of PI-TMA. Early administration of eculizumab may be beneficial in cases of suspected complement abnormalities or suboptimal response to initial treatments.

Abstract The tumor microenvironment (TME) plays an important role in the occurrence and progression of Acute Myeloid Leukemia (AML). Single-cell sequencing has enabled researchers to explore the correlation between TME subgroups and tumor prognosis, distinguish the existence of drug-resistant subgroups of tumor cells, and unravel the complexity of the AML cellular heterogeneity. We used bone marrow immune cell enrichment analysis from public databases to screen prognostic genes, construct prognostic models, and validate their prognostic significance on independent external datasets and patient samples. A total of 18,251 single cells were obtained to establish prognostic scoring models for 10 key genes including CCL5, ETLS2, and IL2RA.The AML cases were divided into two groups: high-risk and low-risk. The low-risk group exhibited a higher survival rate than the high-risk group. The areas under curves (AUC) of 1-, 3- and 5-year survival curves in the TCGA and GEO training sets were greater than 0.8 and 0.6, respectively, indicating effective prediction. The model’s prognostic efficacy was confirmed across multiple validation sets. It demonstrated increased expression of ETS2, CCL5, and IL2RA in AML samples compared to controls, which was associated with decreased overall survival (OS). This prognostic scoring model based on tumor immune infiltration provides a reference for developing novel treatment strategies for recurrent/refractory AML.

Tumor cells voraciously consume nutrients from their environment to facilitate rapid proliferation, necessitating effective strategies to manage nutrient scarcity during tumor growth and progression. A pivotal regulatory mechanism in this context is the Integrated Stress Response (ISR), which ensures cellular homeostasis under conditions such as endoplasmic reticulum stress, the unfolded protein response, and nutrient deprivation. Within the ISR framework, the kinase GCN2 is critical, orchestrating a myriad of cellular processes including the inhibition of protein synthesis, the enhancement of amino acid transport, autophagy initiation, and angiogenesis. These processes collectively enable tumor survival and adaptation under nutrient-limited conditions. Furthermore, GCN2-mediated pathways may induce apoptosis, a property exploited by specific therapeutic agents. Leveraging extensive datasets from TCGA, GEO, and GTEx projects, we conducted a pan-cancer analysis to investigate the prognostic significance of GCN2 expression across diverse cancer types. Our analysis indicates that GCN2 expression significantly varies and correlates with both adverse and favorable prognoses depending on the type of cancer, illustrating its complex role in tumorigenesis. Importantly, GCN2 also modulates the tumor immune microenvironment, influencing immune checkpoint expression and the functionality of immune cells, thereby affecting immunotherapy outcomes. This study highlights the potential of targeting GCN2 with specific inhibitors, as evidenced by their efficacy in preclinical models to augment treatment responses and combat resistance in oncology. These findings advocate for a deeper exploration of GCN2′s multifaceted roles, which could pave the way for novel targeted therapies in cancer treatment, aiming to improve clinical outcomes.

Summary: Background: Primary immune thrombocytopenia (ITP) is an autoimmune disease, and rituximab (RTX) induces long-term effect as second-line treatments. Zuberitamab is an innovative anti-CD20 monoclonal antibody, which was first developed in China and launched in diffuse large B lymphoma. This study aimed to investigate the safety, efficacy, and anticipated therapeutic dose of zuberitamab in Chinese ITP patients. Methods: This randomised, double-blind, placebo-controlled, phase 2 study was conducted at 26 hospitals in China. Eligible patients were aged 18–70 years, had primary immune thrombocytopenia for more than 6 months, and did not respond or relapsed after previous treatment and had a pre-treatment platelet count of

At present, GPX4's role in the occurrence and development of diffuse large B lymphoma (DLBCL) is rarely reported. This study's purpose is to explore GPX4's significance in the diagnosis, treatment, and pathological mechanisms of DLBCL. The TIMER 2.0, GEPIA, and GEO databases were used to analyze GPX4's expression levels in DLBCL tissue, peripheral blood, and single cells, and evaluate its potential performance as a therapeutic and diagnostic marker. Cell experiments validate GPX4's role in DLBCL cells. And revealed the potential mechanism of GPX4's action from three aspects: immunity, pathogenic gene expression, and protein interaction. The results indicate that GPX4 can be used as a biomarker for treatment and diagnosis (FC > 1.5, P 0.8, KM-P value

Hepatosplenic T cell lymphoma (HSTCL) is a particularly difficult-to-treat form of lymphoma, with many patients exhibiting primary resistance to chemotherapy. At present, no effective strategy for treating relapsed and refractory HSTCL has been established, with treatment being hampered by questions of how best to overcome chemoresistance to allow patients to attain more durable therapeutic benefits. While there have been marked advances in immunotherapy, allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains one of the primary approaches to curing HSTCL. Of patients who undergo immunochemotherapeutic treatment, many are resistant to conventional chemotherapeutic drugs yet remain sensitive to radiotherapy. We selected to employ a transplant pretreatment regimen consisting of total -body irradiation (TBI) and administered this regimen to two patients with HSTCL. Both patients achieved complete remission (CR) after transplantation, demonstrating extended periods without disease recurrence. We systematic reviewed previously published instances involving allo-HSCT in patients with HSTCL. We have found a total of 67 patients who have received allo-HSCT. In general, age

Recombinant human TPO (rhTPO) is effective for refractory/relapsed primary immune thrombocytopenia (ITP), but optimal dosing regimen remains elusive. In this multicenter, randomized, controlled trial, a total of 282 adult ITP patients (mean age 47.3 years; 82 men) with a platelet count ≤30 × 109/L or >30 × 109/L with active bleeding randomly received a once daily (QD) subcutaneous injection of 7500 U (n = 64) or 15000 U rhTPO for 14 injections, or 15000 U or 30000 U rhTPO once every other day (QOD) for 7 injections. The primary outcomes included change from baseline in platelet count and total response rate (TRR) on day 14. On day 14, the median increase of platelet count from baseline was the highest in the 15000-U QD group (167.5 × 109/L, interquartile range [IQR] 23.0–295.0 × 109/L), followed by the 30000-U QOD group (57.5 × 109/L, IQR 9.0–190.0 × 109/L) (ANCOVA P

Abstract The tumor microenvironment plays an important role in various processes, including tumorigenesis, cancer progression, and metastasis. Immune signatures have been identified and verified for use in diagnosis and prognosis prediction. We used single-sample Gene Set Enrichment Analysis to evaluate tumor immune cell infiltration score (TIICs) and verify their prognostic significance in both training and validation cohorts and using this information to build a prognostic model. A total of 1281 samples were obtained for further evaluation of the immune enrichment scores of 28 immune cells, showing that Th17 cell contributed most significantly to survival. Using the median TIICs as a cutoff to divide the samples into two groups, we found that the high-TIICs group was associated with favorable outcomes in both the training and validation sets. We then constructed a prognostic model to predict the 6, 8, and 10-year survival outcomes. Further analysis showed that immune score and tumor purity were higher in the high-TIICs group, while the matrix score was lower in this group. Forty-two differentially expressed genes were identified between the two groups. This new prognostic model based on immune cell infiltration indicates the potential for TIICs in predicting prognosis and as targets for treatment.

The management of pregnant women with immune thrombocytopenia who fail to respond to corticosteroids and intravenous immunoglobulin is an intractable clinical challenge because of the limited availability of evidence-based information. Recombinant human thrombopoietin (rhTPO) is recommended for refractory immune thrombocytopenia (ITP). To date, however, few studies have investigated rhTPO treatment during pregnancy. We retrospectively reviewed four cases who were diagnosed with ITP and treated with rhTPO during pregnancy in our center from January 2015 to June 2020. Of the four cases, two (50%) responded to rhTPO treatment. No adverse events were noted in the newborns. Our findings indicate that rhTPO treatment is safe for patients with refractory gestational ITP, and that subcutaneous injection is a convenient delivery method that does not lead to adverse events. Thus, rhTPO may be a viable alternative treatment option for patients with refractory gestational ITP who do not respond to first-line therapies.

Paraneoplastic pemphigus (PNP) is a rare life-threatening disease which always associated with an underlying neoplasm. Tumor-related PNP most commonly precedes the detection of a hematological malignancy, with some cases seen during disease remission following cytotoxic drug therapy or radiotherapy. The lung is the most frequently-involved site in PNP, second only to the eyes, and involvement is seen in 59.2% to 92.8% of PNP cases. Bronchiolitis obliterans (BO) is the end stage of respiratory involvement and is regarded as life-threatening. The key point in treatment of PNP is to control the associated underlying hematologic neoplasia. High-dose systemic corticosteroids combined with other immunosuppressants are considered the first line of treatment. Other therapies that have shown beneficial effects include plasmapheresis, intravenous immunogloblin (IVIG), and more recently, daclizumab, alemtuzumab, and rituximab. There is no effective treatment for BO with PNP, and suppression of the cellular immune response may be necessary. Patients with PNP-BO associated with lymphoma mostly die within approximately 1 year. Herein, we reported a patient who diagnosed with PNP-BO concurrent with chronic lymphocytic leukemia. He was successful treated with ibrutinib and had achieved the longest survival which suggested that ibrutinib may be the best treatment choice for such patient.

Multiple myeloma (MM) is an incurable hematological malignancy that lacks effective therapeutic interventions. Ferroptosis is a newly discovered form of cell death that has shown great potential for MM therapy. As a proteasome inhibitor and necroptosis inducer, shikonin (SHK) performs dual functions in MM cells. However, whether SHK inhibits the development of MM via ferroptosis or any other mechanism remains elusive. Here, we provide evidence that SHK treatment was capable of inducing ferroptosis and immunogenic cell death (ICD) in MM. The results showed that SHK treatment induced lactate dehydrogenase release, triggered cell death, evoked oxidative stress, and enhanced ferrous iron and lipid peroxidation levels. Furthermore, treatment with ferroptosis inhibitors reversed SHK-induced cell death, which indicated that ferroptosis contributed to this phenomenon. Meanwhile, ferroptosis was accompanied by the extracellular release of Adenosine 5’-triphosphate (ATP) and High mobility group protein B1 (HMGB1), which are characteristics of ICD. Further investigation showed that glutamic-oxaloacetic transaminase 1 (GOT1) acted as a critical mediator of SHK-induced ferroptosis by promoting ferritinophagy. In conclusion, our findings suggest that SHK exerts ferroptotic effects on MM by regulating GOT1-mediated ferritinophagy. Thus, SHK is a potential therapeutic agent for MM.

The outcomes of myelodysplastic syndrome (MDS) patients with SF3B1 mutation, despite identified as a favorable prognostic biomarker, are variable. To comprehend the heterogeneity in clinical characteristics and outcomes, we reviewed 140 MDS patients with SF3B1 mutation in Zhejiang province of China. Seventy-three (52.1%) patients diagnosed as MDS with ring sideroblasts (MDS-RS) following the 2016 World Health Organization (WHO) classification and 118 (84.3%) patients belonged to lower risk following the revised International Prognostic Scoring System (IPSS-R). Although clonal hematopoiesis-associated mutations containing TET2, ASXL1 and DNMT3A were the most frequent co-mutant genes in these patients, RUNX1, EZH2, NF1 and KRAS/NRAS mutations had significant effects on overall survival (OS). Based on that we developed a risk scoring model as IPSS-R×0.4+RUNX1×1.1+EZH2×0.6+RAS×0.9+NF1×1.6. Patients were categorized into two subgroups: low-risk (L-R, score 1.4) group. The 3-year OS for the L-R and H-R groups was 91.88% (95% CI, 83.27%-100%) and 38.14% (95% CI, 24.08%-60.40%), respectively (P