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Abstract Hemophagocytic lymphohistiocytosis (HLH) is a rapidly progressing, life-threatening syndrome characterized by excessive immune activation, often presenting as a complex cytokine storm. This hyperactive immune response can lead to multi-organ failure and systemic damage, resulting in an extremely short survival period if left untreated. Over the past decades, although HLH has garnered increasing attention from researchers, there have been few advancements in its treatment. The cytokine storm plays a crucial role in the treatment of HLH. Investigating the detailed mechanisms behind cytokine storms offers insights into targeted therapeutic approaches, potentially aiding in early intervention and improving the clinical outcome of HLH patients. To date, there is only one targeted therapy, emapalumab targeting interferon-γ, that has gained approval for primary HLH. This review aims to summarize the current treatment advances, emerging targeted therapeutics and underlying mechanisms of HLH, highlighting its newly discovered targets potentially involved in cytokine storms, which are expected to drive the development of novel treatments and offer fresh perspectives for future studies. Besides, multi-targeted combination therapy may be essential for disease control, but further trials are required to determine the optimal treatment mode for HLH.

Abstract Background Chromosomal 1q gains and amplifications (+1q21) are frequently observed in patients with newly diagnosed multiple myeloma (NDMM). However, the interpretation of the high‐risk (HR) prognostic implications stemming from 1q21 abnormalities remain challenging to implement effectively. Methods In a comprehensive analysis of 367 consecutive patients with symptomatic MM, we assessed the prognostic significance of +1q21 using FISH with a threshold of 7.4%. The patient cohort was randomly divided into a training set (66.5%, n = 244) and a validation set (33.5%, n = 133). A multivariate Cox regression analysis was conducted to identify significant prognostic factors associated with PFS. Weight scores were assigned to each risk factor based on the β‐value of the corresponding regression coefficient. A predictive risk‐scoring model involving +1q21 was then developed, utilizing the total score derived from these weight scores. The model's discriminative ability was evaluated using the AUC in both the training and validation sets. Finally, we compared the performance of the +1q21‐involved risk with the established R‐ISS and R2‐ISS models. Results Upon initial diagnosis, 159 patients (43.32%) exhibited +1q21, with 94 (59.11%) having three copies, referred to as Gain(1q21), and 65 (40.89%) possessing four or more copies, referred to as Amp (1q21). Both were significantly linked to a reduced PFS in myeloma (p

Background: Immune checkpoint inhibitors (ICIs), especially anti-PD-1/PD-L1 antibodies, have emerged as promising therapeutic options for cervical cancer. However, the efficacy of anti-PD-1 antibody monotherapy is limited. Cryoablation could elicit an anti-tumor immune response, thereby presenting itself as a potential approach to augment the response of ICIs. The aim of our study was to investigate the systemic immunological effects of cryoablation and the potential synergistic anti-tumor effects of cryoablation and anti-PD-1 antibody in cervical cancer. Methods: We established U14 murine bilateral subcutaneous cervical cancer model, wherein the primary tumors were treated with cryoablation. Flow cytometry, immunohistochemistry and RNA-seq were used to analyze the immune cell infiltration and immune-associated pathways in the secondary tumor. Results: Our study revealed that cryoablation reprogrammed the immune landscape, leading to an enhanced infiltration of CD8+ T cell in distant tumors. Cryoablation created a conducive environment for increasing the efficacy of anti-PD-1 immunotherapy. Cryoablation in combination with anti-PD-1 antibody inhibited distant tumors growth and improved mouse survival. Mechanistically, this combination therapy could augment the infiltration of CD8+ T cells, CD4+ T cells, dendritic cells and M1-like tumor-associated macrophages, enhance multiple aspects of antitumor immune response, and reduce immunosuppressive cells such as M2-like tumor-associated macrophages and myeloid-derived suppressor cells in distant tumors. Conclusions: Combination therapy with cryoablation and anti-PD-1 antibody induces an effective abscopal effect in murine model of cervical cancer and may be a novel therapeutic approach for patients with advanced/recurrent cervical cancer.

Abstract Objective TQB3602 is a novel orally bioavailable proteasome inhibitor. This study is the first‐in‐human phase I clinical trial to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of TQB3602 in relapsed/refractory multiple myeloma (RRMM). Methods This is a multicenter phase I clinical trial consisting of the 3+3 dose‐escalation phase and dose expansion phase. Patients with MM who have received ≥2 prior antimyeloma therapies were enrolled. TQB3602 is administered at a dose of 0.5~7mg on days 1, 8, 15 in 28‐day cycle. Results Twenty‐five RRMM patients who relapsed or failed ≥2 lines of therapies were enrolled in the dose escalation phase. Two patients in the 7.0 mg dose group developed dose‐limiting toxicity events (one with grade 2 peripheral neuropathy [PN] complicated by pain and one with diarrhea and abdominal pain), leading to a maximum tolerated dose of 6.0 mg. Any‐grade adverse events (AEs) occurred in 24 (96.0%) patients, while grade ≥3 AEs occurred in 13 (52.0%). The most common grade ≥3 AEs was anemia (6, 24.0%). The incidence rate of PN was 16% with no grade ≥3 PN occurred. TQB3602 was rapidly absorbed, resulting in a time‐to‐plasma peak concentration of 0.8–1.5 h. The mean half‐life was approximately 82 h. The AUClast and Cmax were approximately 1.9 times higher on day 15 than on day 1. Among 22 response‐evaluable patients, 63.7% achieved stable disease or better. Conclusions TQB3602 is well tolerated, with a favorable neurotoxicity profile, and has shown preliminary efficacy in patients with RRMM. The anticipated therapeutic dose was 6 mg and was adopted for an ongoing dose‐expansion phase.

Abstract Background The clinical significance of protein tyrosine phosphatase nonreceptor type 11 mutation (PTPN11mut) in acute myeloid leukemia (AML) is underestimated. Methods We collected the data of AML patients with mutated PTPN11 and wild‐type PTPN11 (PTPN11wt) treated at our hospital and analyzed their clinical characteristics and prognosis. Results Fifty‐nine PTPN11mut and 124 PTPN11wt AML patients were included. PTPN11mut was more common in myelomonocytic and monocytic leukemia, and was more likely to co‐mutate with KRAS, KMT2C, NRAS, U2AF1, NOTCH1, IKZF1, and USH2A mutations than PTPN11wt. The overall survival for AML patients with PTPN11mut was significantly shorter than that for those with PTPN11wt (p = 0.03). The negative impact of PTPN11mut on overall survival was pronounced in the “favorable” and “intermediate” groups of ELN2017 risk stratification, as well as in the wild‐type NPM1 group (p = 0.01, p = 0.01, and p = 0.04). Conclusion PTPN11mut is associated with distinct clinical and molecular characteristics, and adverse prognosis in AML patients.

Background Relapsed/refractory (R/R) central nervous system lymphomas (CNSLs) are associated with a poor prognosis. Relmacabtagene autoleucel (relma-cel), expressing the same chimeric antigen receptor (CAR) as lisocabtagene maraleucel, with an optimized commercial-ready process developed in China, demonstrated remarkable efficacy and manageable safety in the pivotal RELIANCE study. However, no published data are available on the “real-world” use of relma-cel, especially for patients with CNS involvement.Patients and methods Retrospective analyses were conducted for commercial relma-cel used in patients with R/R CNSL at 12 clinics. The primary endpoint was to evaluate the proportion of patients who achieved complete response (CR) at 3 months. Secondary endpoints included best complete response (BCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS), and the incidence of adverse events.Results Among the 22 CNSL patients (12 primary CNSLs; 10 secondary CNSLs), the best overall response rate was 90.9% and the BCR rate was 68.2%. With median follow-up of 316 days (range, 55–618 days), the estimated 1-year PFS rate, DOR, and OS rate were 64.4%, 71.5%, and 79.2%, respectively. Significant clinical benefits were observed in patients who were in durable CR or partial response to the most recent prior therapy preleukapheresis and received relma-cel as consolidation therapy (n=8), with 1-year PFS rate of 100.0% versus 41.7% (p=0.02). In addition, in terms of primary endpoint, non-CR at 3 months postinfusion seemed to be predictive of a worse prognosis, with an estimated 1-year PFS of 83.3% versus 37.0% (p=0.03), respectively. CRS occurred in 72.9% of patients (grade 3: 4.5%) and immune effector cell-associated neurotoxicity syndrome in 36.4% of patients (grade 3: 4.5%). With the add-on agent PD-1 inhibitor (tislelizumab) to the ongoing BTKi, significant re-expansions of CAR T-cell were detected by quantitative PCR or flow cytometry after a median of 2 weeks (range, 12–32 days).Conclusions This study was the first and largest real-world study of commercial relma-cel for R/R CNSL, demonstrating promising efficacy and acceptable safety. We reaffirmed the benefit of immuno-agents such as BTKi or PD-1 inhibitor on CAR T-cell re-expansion and hypothesized a dual-agent CAR-T related combinatorial therapies, which warrants further validation. Most importantly, we highlighted the earlier use of CAR T-cell therapy as a consolidative therapy for patients sensitive to salvage therapy, which provided an impetus and inspired-future strategy.

BackgroundAngioimmunoblastic T-cell lymphoma (AITL) is characterized by high recurrence rates and poor prognosis, and effective first-line treatment is lacking. Recently, histone deacetylase inhibitors (HDACi), such as chidamide, have been found to induce durable remissions in AITL patients.MethodsPatients with untreated AITL from March 2015 to March 2023 were retrospectively collected and divided into chemotherapy (ChT) group and chidamide combined with chemotherapy (C-ChT) group based on the first-line treatment received. The comparison of efficacy and safety between the two groups was conducted.Results86 patients with newly diagnosed AITL were enrolled, in which 35 patients were in the ChT group and 51 in the C-ChT group. The objective response rate (ORR) of C-ChT group was significantly higher than that of ChT group (84.3% vs. 60%, P= 0.011), and had superior progression-free survival (PFS) (27 months vs. 12 months, P= 0.025). However, no significant difference in overall survival (OS) was observed between the two groups (P= 0.225). In addition, the responding patients who received autologous stem cell transplantation (ASCT) had superior PFS compared to those who did not (P= 0.015).ConclusionsCompared with ChT regimen, C-ChT regimen was well tolerated and had superior ORR and PFS in patients with untreated AITL. ASCT may contribute to longer PFS in remission patients.

Abstract Background Plasma cell neoplasms are a group of hematologic neoplasms that often develop in the elderly population. The relationship between cholesterol levels and hematologic malignancy has been identified in population studies. However, it is still unclear if there is a relationship between cholesterol levels and plasma cell neoplasm in European ancestry. Methods Prospective cohorts included 502,507 individuals from the UK Biobank who were followed up to 2019 and assessed total cholesterol(TC) levels, low‐density lipoprotein (LDL) levels, high‐density lipoprotein (HDL) levels, apolipoprotein A (ApoA) and apolipoprotein B (ApoB) as risk factors for plasma cell neoplasms with Cox proportional hazard regression and restricted cubic spline model. We also used two‐sample Mendelian randomization to determine if the cholesterol level has a causal effect on developing plasma cell neoplasms. Results We observed 1819 plasma cell neoplasm cases during 14.2 years of follow‐up in the UK Biobank. We found higher blood serum cholesterol levels at baseline were associated with a lower risk of plasma cell neoplasm in our study. All lipid profiles we analyzed in this study were inversely associated with plasma cell neoplasm risk (all ptrend

Abstract Background Immune checkpoint inhibitors (ICIs) shed new light on triple‐negative breast cancer (TNBC), but only a minority of patients demonstrate response. Therefore, adaptive immune resistance (AIR) needs to be further defined to guide the development of ICI regimens. Methods Databases, including The Cancer Genome Atlas, Gene Ontology Resource, University of California Santa Cruz Genome Browser, and Pubmed, were used to screen epigenetic modulators, regulators for CD8+ T cells, and transcriptional regulators of programmed cell death‐ligand 1 (PD‐L1). Human peripheral blood mononuclear cell (Hu‐PBMC) reconstruction mice were adopted for xenograft transplantation. Tumor specimens from a TNBC cohort and the clinical trial CTR20191353 were retrospectively analyzed. RNA‐sequencing, Western blotting, qPCR and immunohistochemistry were used to assess gene expression. Coculture assays were performed to evaluate the regulation of TNBC cells on T cells. Chromatin immunoprecipitation and transposase‐accessible chromatin sequencing were used to determine chromatin‐binding and accessibility. Results The epigenetic modulator AT‐rich interaction domain 1A (ARID1A) gene demonstrated the highest expression association with AIR relative to other epigenetic modulators in TNBC patients. Low ARID1A expression in TNBC, causing an immunosuppressive microenvironment, promoted AIR and inhibited CD8+ T cell infiltration and activity through upregulating PD‐L1. However, ARID1A did not directly regulate PD‐L1 expression. We found that ARID1A directly bound the promoter of nucleophosmin 1 (NPM1) and that low ARID1A expression increased NPM1 chromatin accessibility as well as gene expression, further activating PD‐L1 transcription. In Hu‐PBMC mice, atezolizumab demonstrated the potential to reverse ARID1A deficiency‐induced AIR in TNBC by reducing tumor malignancy and activating anti‐tumor immunity. In CTR20191353, ARID1A‐low patients derived more benefit from pucotenlimab compared to ARID1A‐high patients. Conclusions In AIR epigenetics, low ARID1A expression in TNBC contributed to AIR via the ARID1A/NPM1/PD‐L1 axis, leading to poor outcome but sensitivity to ICI treatment.

Abstract Background About 10% of hematologic malignancies are multiple myeloma (MM), an untreatable cancer. Although lactate and branched-chain amino acids (BCAA) are involved in supporting various tumor growth, it is unknown whether they have any bearing on MM prognosis. Methods MM-related datasets (GSE4581, GSE136337, and TCGA-MM) were acquired from the Gene Expression Omnibus (GEO) database and the Cancer Genome Atlas (TCGA) database. Lactate and BCAA metabolism-related subtypes were acquired separately via the R package “ConsensusClusterPlus” in the GSE4281 dataset. The R package “limma” and Venn diagram were both employed to identify lactate-BCAA metabolism-related genes. Subsequently, a lactate-BCAA metabolism-related prognostic risk model for MM patients was constructed by univariate Cox, Least Absolute Shrinkage and Selection Operator (LASSO), and multivariate Cox regression analyses. The gene set enrichment analysis (GSEA) and R package “clusterProfiler"were applied to explore the biological variations between two groups. Moreover, single-sample gene set enrichment analysis (ssGSEA), Microenvironment Cell Populations-counter (MCPcounte), and xCell techniques were applied to assess tumor microenvironment (TME) scores in MM. Finally, the drug’s IC50 for treating MM was calculated using the “oncoPredict” package, and further drug identification was performed by molecular docking. Results Cluster 1 demonstrated a worse prognosis than cluster 2 in both lactate metabolism-related subtypes and BCAA metabolism-related subtypes. 244 genes were determined to be involved in lactate-BCAA metabolism in MM. The prognostic risk model was constructed by CKS2 and LYZ selected from this group of genes for MM, then the prognostic risk model was also stable in external datasets. For the high-risk group, a total of 13 entries were enriched. 16 entries were enriched to the low-risk group. Immune scores, stromal scores, immune infiltrating cells (except Type 17 T helper cells in ssGSEA algorithm), and 168 drugs’IC50 were statistically different between two groups. Alkylating potentially serves as a new agent for MM treatment. Conclusions CKS2 and LYZ were identified as lactate-BCAA metabolism-related genes in MM, then a novel prognostic risk model was built by using them. In summary, this research may uncover novel characteristic genes signature for the treatment and prognostic of MM.

Abstract Background There is no standard first‐line immunochemotherapy regimen for transplant‐ineligible patients with mantle cell lymphoma (MCL) currently, and the efficacy of various treatment remains unclear. Methods We conducted a Bayesian network meta‐analysis (NMA) of all eligible randomized controlled trials. Pairwise comparisons and ranking of different first‐line treatment options were performed. Results Nine studies were included in the NMA, involving a total of 2897 MCL patients. The BR‐Ibrutinib+R regimen showed the best progression‐free survival (PFS), with a surface under the cumulative ranking curve (SUCRA) of 0.89 and probability of being the best treatment (PbBT) of 69%. The VR‐CAP regimen was the most potential intervention to improve overall survival (OS), with a SUCRA of 0.89 and PbBT of 63%. Compared with the R‐CHOP regimen, the BR regimen achieved a better PFS (hazard ratio [HR] 0.45 [95% credible interval 0.2–0.96]). The BR‐Ibrutinib+R regimen (HR 0.14 [0.02–0.99]), BR+R regimen (HR 0.19 [0.034–0.99]), and BR regimen (HR 0.3 [0.08–1.03]) were superior to CHOP regimen with better PFS. The R‐FC regimen (HR 2.27 [1.01–5.21]) or FC regimen (HR 3.17 [1.15–8.71]) was inferior to the VR‐CAP regimen with a worse OS. Conclusions Our study presents the most promising first‐line treatment strategy for transplant‐ineligible MCL patients in terms of PFS and OS, which provides innovative treatment strategy for MCL treatment.

Abstract The outbreak of coronavirus disease 2019 (COVID-19) posed an unprecedented challenge on public health systems. Despite the measures put in place to contain it, COVID-19 is likely to continue experiencing sporadic outbreaks for some time, and individuals will remain susceptible to recurrent infections. Chimeric antigen receptor (CAR)-T recipients are characterized by durable B-cell aplasia, hypogammaglobulinemia and loss of T-cell diversity, which lead to an increased proportion of severe/critical cases and a high mortality rate after COVID-19 infection. Thus, treatment decisions have become much more complex and require greater caution when considering CAR T-cell immunotherapy. Hence, we reviewed the current understanding of COVID-19 and reported clinical experience in the management of COVID-19 and CAR-T therapy. After a panel discussion, we proposed a rational procedure pertaining to CAR-T recipients with the aim of maximizing the benefit of CAR-T therapy in the post COVID-19 pandemic era.

BackgroundSince no randomized controlled trials have directly compared the efficacy and safety of immunotherapy with daratumumab versus lenalidomide/bortezomib/dexamethasone (RVD) in the frontline treatment of transplant-ineligible newly diagnosed multiple myeloma (TIE-NDMM), this study systematically reviewed the clinical studies regarding immunotherapy with daratumumab and RVD regimen in the treatment of TIE-NDMM to explore the optimization direction of the best first-line therapy.MethodsThe Cochrane Library, PubMed, Embase, and Web of Science databases were searched to collect studies on regimens containing daratumumab or RVD/RVD-lite for TIE-NDMM. Pooled and meta-analysis was then performed to compare the overall response rate (ORR), stringent complete remission (sCR) and CR rate, progression-free survival (PFS), overall survival (OS) and treatment-related discontinuation rate between daratumumab-containing immunotherapy regimen and RVD/RVD-lite regimen by using R 4.3.1 software.ResultsNine prospective clinical trials were included, including 1795 TIE-NDMM or NDMM without intent for immediate ASCT. Among them, 938 patients were treated with daratumumab-based immunotherapy and 857 with RVD/RVD-lite regimens. Meta-analysis results showed that The daratumumab-based regimen showed a significantly higher CR/sCR rate than RVD/RVD-lite for TIE-NDMM (47% vs. 24%, P

Abstract Aims The purpose of this prospective, randomized study was to investigate the effectiveness and safety of the ixazomib+cyclophosphamide+dexamethasone (ICd) and ixazomib+dexamethasone (Id) regimens in newly diagnosed multiple myeloma (NDMM) who were elderly and frail and to compare the two regimens. Methods Patients were randomly grouped into ICd and Id group. The primary end point was ORR, and patients who received at least two cycles were analyzed. The median follow‐up was 13.5 months. After nine induction cycles, patients were instructed to take single ixazomib for maintenance. Results The overall response rate in the ICd and Id groups was 78.9% and 70.6%, respectively, whereas the very good partial remission or better rate was 47.4% and 23.5%, respectively. For the ICd and Id groups, the response rate after 4 cycles was 76.5% and 57.1%, and the median duration to response was 2 and 4 months, respectively. Adverse events (AEs) included gastrointestinal intolerance, rash, fatigue, and thrombocytopenia, with severe AEs occurring in 21.1% and 23.5% patients in the ICd and Id groups, respectively, and the AEs were manageable. Both the QLQ‐C30 and QLQ‐MY20 scales indicated that ICd and Id regimens could help maintain and improve the quality of life(QoL). Conclusions The ICd and Id regimens might be effective and well‐tolerated in elderly and frail patients with NDMM. In addition, a favorable outcome was observed that ICd might tend to cause faster and higher remission than Id regimen without increasing the risk of AEs. The long‐term effectiveness and safety of the two regimens need further investigation.

BackgroundThe use of 5-hydroxytryptamine-3 receptor antagonists (5HT3RA) has long been considered the standard regimen for preventing chemotherapy-induced nausea and vomiting (CINV) prior to hematopoietic stem cell transplantation (HSCT). However, their therapeutic outcomes have been unsatisfactory. NEPA, an oral formulation combining the neurokinin-1 receptor antagonist netupitant and the 5HT3RA palonosetron, has received regulatory approval for the management of highly and moderately emetogenic chemotherapy. This study aims to compare the efficacy of NEPA with that of 5HT3RA alone in preventing CINV among patients undergoing multiday conditioning chemotherapy prior to HSCT.Patients and methodsWe conducted a retrospective analysis of patients who underwent HSCT between September 2019 and September 2022. Efficacy outcomes were assessed based on the rates of patients achieving complete response (CR: no emesis and no use of rescue medication), complete control (CC: CR without significant nausea), no vomiting, and no significant nausea.ResultsThe NEPA group consisted of 106 patients, while the 5HT3RA group included 107 patients. The NEPA group exhibited significantly higher rates of CR compared to the 5HT3RA group during the overall phase (71.7% vs. 32.7%, P

Adoptive cellular immunotherapy with chimeric antigen receptor (CAR) T cells has emerged as a novel modality for treating relapsed and/or refractory B-cell non-Hodgkin lymphoma (B-NHL). With increasing approval of CAR T-cell products and advances in CAR T cell therapy, CAR T cells are expected to be used in a growing number of cases. However, CAR T-cell-associated toxicities can be severe or even fatal, thus compromising the survival benefit from this therapy. Standardizing and studying the clinical management of these toxicities are imperative. In contrast to other hematological malignancies, such as acute lymphoblastic leukemia and multiple myeloma, anti-CD19 CAR T-cell-associated toxicities in B-NHL have several distinctive features, most notably local cytokine-release syndrome (CRS). However, previously published guidelines have provided few specific recommendations for the grading and management of toxicities associated with CAR T-cell treatment for B-NHL. Consequently, we developed this consensus for the prevention, recognition, and management of these toxicities, on the basis of published literature regarding the management of anti-CD19 CAR T-cell-associated toxicities and the clinical experience of multiple Chinese institutions. This consensus refines a grading system and classification of CRS in B-NHL and corresponding measures for CRS management, and delineates comprehensive principles and exploratory recommendations for managing anti-CD19 CAR T-cell-associated toxicities in addition to CRS.

Abstract Objective Despite the availability of new agents, elderly patients with multiple myeloma (MM) usually present with poor outcomes due to the heterogeneity of disease conditions, especially immune deficiency. Regulatory B cells (Bregs) can be involved in immune defects by exerting immune regulatory functions in MM. In order to provide more evidence‐based practice for the elderly MM, the study established and assessed a stratified therapeutic model with studies on Bregs for Chinese Elderly Multiple Myeloma in 2021 (CEMM2021). Methods In this open‐label, non‐interventional, prospective study in the real world, 159 newly diagnosed MM (NDMM) patients over 65 years old were sequentially recruited and bone marrow aspirates prior to treatment were obtained to detect the ratios of Bregs by flow cytometry. Results Based on the CEMM2021 model, 147 patients had received at least one cycle of induction therapy, including bortezomib/dexamethasone (Bd) (n = 80), lenalidomide/dexamethasone (Rd) (n = 27), Bd with a third agent X (Bd + X) (n = 27), and other regimens (n = 13). The proportions of patients achieving very good partial response or better were comparable among Bd, Bd + X, and Rd groups (41.9% vs. 54.5% vs. 44.0%, p = 0.472). Besides, the progression‐free survival (PFS) and overall survival (OS) were not significantly different among Rd, Bd, and Bd + X groups. Multivariable analysis showed that induction efficacy less than partial response (PR) were poor prognostic factors for PFS, while Revised‐International Staging System (R‐ISS) III and efficacy less than PR were poor prognostic factors for OS. This study also found that the ratios of bone marrow Bregs 4.2 (p = 0.000) were closely correlated with OS in the elderly MM. Conclusions For the elderly NDMM, the CEMM2021 algorithm in our center might provide a valuable reference for the guidance of therapeutic strategies, with the combination of Bregs resulting in an effective and clinically meaningful prediction in contemporary treatment.

BackgroundThe topic of minimal residual disease (MRD) has emerged as a crucial subject matter in the domain of oncology in recent years. The detection and monitoring of MRD have become essential for the diagnosis, treatment, and prognosis of various types of malignancy.AimsThe purpose of this study is to explore the research trends, hotspots, and frontiers of MRD in the last two decades through bibliometric analysis.MethodsWe employed Web of Science databases to carry out a bibliometric visualization analysis of research on 8,913 academic papers about MRD research from 2002 to 2022. VOSviewer, CiteSpace, RStudio, and a bibliometric online analysis platform were mainly used to conduct co-occurrence analysis and cooperative relationship analysis of countries/regions, institutions, journals, and authors in the literature. Furthermore, co-occurrence, co-citation, and burst analyses of keyword and reference were also conducted to generate relevant knowledge maps.ResultsIn the past 20 years, the number of MRD research papers has presented an overall rising trend, going through three stages: a plateau, development, and an explosion. The output of articles in the United States was notably superior and plays a dominant role in this field, and the Netherlands had the highest average citation per article. The most productive and influential institution was the University of Texas MD Anderson Cancer Center. Blood published the most papers and was the most cited journal. A collection of leading academics has come to the fore in the research field, the most prolific of which is Kantarjian HM. It was found that the application of MRD in “acute myeloid leukemia”, “acute lymphoblastic leukemia”, “multiple myeloma”, as well as the detection technology of MRD, are the research hotspots and frontiers in this domain. Furthermore, we analyzed the co-citation network of references and found that the top 10 co-cited references were all associated with MRD in hematological malignancies.ConclusionThis bibliometric visualization analysis conducted a thorough exploration into the research hotspots and trends in MRD from 2002 to 2022. Our findings can aid researchers in recognizing possible collaborations, guiding future research directions, and fostering the growth of MRD detection and monitoring technologies.

BackgroundThe overall survival of peripheral T-cell lymphoma (PTCL) is dismal. Histone deacetylase (HDAC) inhibitors have exhibited promising treatment outcomes for PTCL patients. Therefore, this work aims to systematically evaluate the treatment outcome and safety profile of HDAC inhibitor-based treatment for untreated and relapsed/refractory (R/R) PTCL patients.MethodsThe prospective clinical trials of HDAC inhibitors for the treatment of PTCL were searched on the Web of Science, PubMed, Embase, ClinicalTrials.gov, and Cochrane Library database. The pooled overall response rate, complete response (CR) rate, and partial response rate were measured. The risk of adverse events was evaluated. Moreover, the subgroup analysis was utilized to assess the efficacy among different HDAC inhibitors and efficacy in different PTCL subtypes.ResultsFor untreated PTCL, 502 patients in seven studies were involved, and the pooled CR rate was 44% (95% CI, 39-48%). For R/R PTCL patients, there were 16 studies included, and the CR rate was 14% (95% CI, 11-16%). The HDAC inhibitor-based combination therapy exhibited better efficacy when compared with HDAC inhibitor monotherapy for R/R PTCL patients (P = 0.02). In addition, the pooled CR rate was 17% (95% CI, 13-22%), 10% (95% CI, 5-15%), and 10% (95% CI, 5-15%) in the romidepsin, belinostat, and chidamide monotherapy subgroups, respectively. In the R/R angioimmunoblastic T-cell lymphoma subgroup, the pooled ORR was 44% (95% CI, 35-53%), higher than other subtypes. A total of 18 studies were involved in the safety assessment of treatment-related adverse events. Thrombocytopenia and nausea were the most common hematological and non-hematological adverse events, respectively.ConclusionThis meta-analysis demonstrated that HDAC inhibitors were effective treatment options for untreated and R/R PTCL patients. The combination of HDAC inhibitor and chemotherapy exhibited superior efficacy to HDAC inhibitor monotherapy in the R/R PTCL setting. Additionally, HDAC inhibitor-based therapy had higher efficacy in angioimmunoblastic T-cell lymphoma patients than that in other subtypes.

Abstract Background Pomalidomide in combination with dexamethasone has demonstrated positive results in patients with relapsed or refractory multiple myeloma (RRMM), but no data are available in China. We conducted a multicenter, single-arm trial to examine the efficacy and safety of bioequivalent generic pomalidomide plus low-dose dexamethasone in Chinese RRMM patients. Methods Adult (≥ 18 years of age) RRMM patients who progressed after at least two previous treatments, including bortezomib and lenalidomide, were eligible. Pomalidomide was given orally at 4 mg/day on days 1 to 21 of a 28-day cycle. Dexamethasone was given at 40 mg/day (either orally or intravenously; 20 mg/day at 75 years or older) on days 1, 8, 15, and 22 of each cycle. Treatment continued until disease progression or intolerable adverse events (AEs). The primary end point was objective response rate (ORR). Results Seventy-four patients were enrolled between February 2017 and February 2019. All patients had progressed within 60 days of their last therapy. 74.3% of the patients were resistant to lenalidomide, 31.1% had renal insufficiency and 33.8% had high-risk cytogenetic RRMM. The median follow-up duration was 33.0 months (range 31.1–34.8 months). The ORR was 37.8% in the overall analysis, 32.7% in lenalidomide-refractory patients, 36.0% in patients with high-risk cytogenetics and 34.8% in RRMM patients with renal impairment. The median progression-free survival was 5.7 months (95% CI 3.7–8.8 months). The median overall survival was 24.3 months (95% CI 14.4–41.1 months). The most common grade 3 and 4 treatment-emergent adverse events (TEAEs) were neutropenia (63.5%), leukopenia (37.8%), thrombocytopenia (28.4%), and anemia (31.1%). Pulmonary infection (27.0%) was the most frequent grade 3 and 4 nonhematologic TEAE. No previously unreported AEs were observed. No venous thromboembolism was reported. Conclusions Pomalidomide in combination with low-dose dexamethasone is effective and safe in Chinese RRMM patients. Trial registration The study is registered at Chinese Clinical Trial Registry (ChiCTR) ( ChiCTR-OIC-17013234 , first registered on 03/11/2017).

BackgroundMeningioma is a common type of intracranial tumor in adults. It rarely arises in the chest, with only a few case reports in the English literature. Here, we report the case of a patient with a primary ectopic meningioma (PEM) located in the thoracic cavity.Case presentationA 55-year-old woman presented with exercise-induced asthma, chest tightness, intermittent dry cough and fatigue for several months. Computed tomography revealed the presence of a huge mass in the thoracic cavity, with no connection to the spinal canal. Lung cancer and mesothelioma were suspected, and surgery was performed. Grossly, the mass was a grayish-white solid 9.5 cm × 8.4 cm × 5.3 cm in size. The microscopic morphology of the lesion was consistent with that of typical central nervous system meningioma. The pathological subtype was transitional meningioma. The tumor cells were arranged in a fascicular, whorled, storiform and meningithelial pattern, with occasional intranuclear pseudo-inclusions and psammoma bodies. In focal areas tumor cells were considerably dense, and the cells were round or irregular in shape, with less cytoplasm, uniform nuclear chromatin, and visible nucleoli and mitoses (2/10 HPF). By immunohistochemistry, the neoplastic cells showed strong and diffuse staining with vimentin, epithelial membrane antigen and SSTR2 with variable expression of PR, ALK and S100 protein. However, the cells were negative for GFAP, SOX-10, inhibin, CD34, STAT6, smooth muscle actin, desmin, CKpan, D2-40, WT-1, CK5/6 and CD45. The highest proliferation index by Ki-67 was 15%. The abnormal expression of ALK led to the initial misdiagnosis of an inflammatory myofibroblastic tumor. After 12 months of follow-up, no disease progression was observed.ConclusionThe presence of primary ectopic meningiomas in the thoracic cavity is extremely rare, and this tumor is easily misdiagnosed clinically. Imaging is suggested to determine the location and possible differential diagnosis, while the final diagnosis should be via pathological examination. Immunohistochemistry is crucial for disease diagnosis. Owing to our limited knowledge of PEM, its pathogenesis and tissue of origin remain unclear. Clinicians should pay close attention to such potential patients. The present case report may provide insights into the diagnosis and therapy of patients with this tumor.

BackgroundThe prognosis of patients with peripheral T-cell (PTCL) or lymphoblastic T-cell lymphoma (T-LBL) remains poor under current conditioning regimens before receiving autologous stem cell transplantation (ASCT).MethodsPatients with PTCL or T-LBL were enrolled to receive ASCT using the conditioning regimen of chidamide, cladribine, gemcitabine, and busulfan (ChiCGB). Positron emission tomography-computed tomography (PET/CT) was used to evaluate the response to ASCT. Overall survival (OS) and progression-free survival (PFS) were employed to assess the patient outcome, and adverse events were used to assess the regimen’s safety. The survival curve was estimated via the Kaplan-Meier method.ResultsTwenty-five PTCL and 11 T-LBL patients were recruited. The median time to neutrophile and platelet engraftments was 10 days (8–13 days) and 13 days (9–31 days), respectively. The 3-year PFS and OS were 81.3 ± 7.2% and 88.5 ± 5.4% for all patients; 92.0 ± 5.4% and 81.2 ± 8.8% for PTCL patients; and both 81.8 ± 11.6% for T-LBL patients, respectively. The 3-year PFS and OS were both 92.9 ± 4.9% for patients with complete response (CR) but 50.0 ± 17.7% and 75.0 ± 15.3% for patients with non-CR, respectively. Infection was the most common non-hematological toxicity, and all toxicities were mild and controllable.ConclusionsChiCGB was a potentially effective and well-tolerated conditioning regimen to improve the prognosis of patients with aggressive T-cell lymphoma. Future randomized controlled trials are needed to assess ChiCGB as a conditioning regimen for ASCT.

Abstract Janus kinase 2 (JAK2) hyperactivation by JAK2 V617F mutation leads to myeloproliferative neoplasms (MPNs) and targeting JAK2 could serve as a promising therapeutic strategy for MPNs. Here, we report that Flonoltinib Maleate (FM), a selective JAK2/FLT3 inhibitor, shows high selectivity for JAK2 over the JAK family. Surface plasmon resonance assays verified that FM had a stronger affinity for the pseudokinase domain JH2 than JH1 of JAK2 and had an inhibitory effect on JAK2 JH2V617F. The cocrystal structure confirmed that FM could stably bind to JAK2 JH2, and FM suppressed endogenous colony formation of primary erythroid progenitor cells from patients with MPNs. In several JAK2 V617F-induced MPN murine models, FM could dose-dependently reduce hepatosplenomegaly and prolong survival. Similar results were observed in JAK2 V617F bone marrow transplantation mice. FM exhibited strong inhibitory effects on fibrosis of the spleen and bone marrow. Long-term FM treatment showed good pharmacokinetic/pharmacodynamic characteristics with high drug exposure in tumor-bearing tissues and low toxicity. Currently, FM has been approved by the National Medical Products Administration of China (CXHL2000628), and this study will guide clinical trials for patients with MPNs.

Inducing senescence in cancer cells is an emerging strategy for cancer therapy. The dysregulation and mutation of genes encoding cyclin‐dependent kinases (CDKs) have been implicated in various human cancers. However, whether CDK can induce cancer cell senescence remains poorly understood. We observed that CDK16 expression was high in multiple cancer types, including lung cancer, whereas various replicative senescence models displayed low CDK16 expression. CDK16 knockdown caused senescence‐associated phenotypes in lung cancer cell lines. Interestingly, the CDK16 3′ UTR was shortened in cancer and lengthened in senescence models, which was regulated by alternative polyadenylation (APA). The longer 3′UTR [using the distal polyA (pA) site] generated less protein than the shorter one (using the proximal pA site). Since microRNAs (miRNAs) usually bind to the 3′UTR of target genes to suppress their expression, we investigated whether miRNAs targeting the region between the shortened and longer 3′UTR are responsible for the reduced expression. We found that miR‐485‐5p targeted the 3′UTR between the distal and proximal pA site and caused senescence‐associated phenotypes by reducing protein production from the longer CDK16 transcript. Of note, CDK16 knockdown led to a reduced expression of MYC proto‐oncogene, bHLH transcription factor (MYC) and CD274 molecule (PD‐L1), which in turn enhanced the tumor‐suppressive effects of senescent cancer cells. The present study discovered that CDK16, whose expression is under the regulation of APA and miR‐485‐5p, is a potential target for prosenescence therapy for lung cancer.

BackgroundPost-transplant cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG) are both common graft-versus-host disease (GVHD) prophylaxis strategies in allo-HSCT from unrelated donors. However, no consensus has reached on which regimen is optimal. Although several studies concerning this topic exist, the outcomes of different studies still conflict with each other. Therefore, an overall comparison of the two regimens is urgently needed to help make informed clinical decisions.MethodsStudies comparing PTCy and ATG regimens in unrelated donor (UD) allo-HSCT were searched in four critical medical databases from inception to April 17, 2022. The primary outcome was grade II-IV aGVHD, grade III-IV aGVHD and chronic GVHD (cGVHD), and the secondary outcomes included overall survival (OS), relapse incidence (RI), non-relapse mortality (NRM), and several severe infectious complications. The quality of articles was assessed by the Newcastle-Ottawa scale (NOS), and data were extracted by two independent investigators and then analyzed by RevMan 5.4.ResultsSix out of 1091 articles were eligible for this meta-analysis. Compared with the ATG regimen, prophylaxis based on PTCy achieved a lower incidence of grade II-IV aGVHD incidence (RR=0.68, 95% CI 0.50-0.93, P=0.010, I2 = 67%), grade III-IV aGVHD (RR=0.32, 95% CI 0.14-0.76, P=0.001, I2 = 75%), NRM (RR=0.67, 95% CI 0.53-0.84, P=0.17, I2 = 36%), EBV-related PTLD (RR=0.23, 95% CI 0.09-0.58, P=0.85, I2 = 0%) and better OS (RR=1.29, 95% CI 1.03-1.62, P=0.0001, I2 = 80%). The cGVHD, RI, CMV reactivation and BKV-related HC showed no significant difference between the two groups (RR=0.66, 95% CI 0.35-1.26, P

Abstract Background Colorectal cancer is a malignant gastrointestinal cancer, in which some advanced patients would develop cancer cachexia (CAC). CAC is defined as a multi-factorial syndrome characterized by weight loss and muscle loss (with or without fat mass), leading to progressive dysfunction, thereby increasing morbidity and mortality. ApcMin/+ mice develop spontaneous intestinal adenoma, which provides an established model of colorectal cancer for CAC study. Upon studying the ApcMin/+ mouse model, we observed a marked decrease in weight gain beginning around week 15. Such a reduction in weight gain was rescued when ApcMin/+ mice were crossed with MMP12−/− mice, indicating that MMP12 has a role in age-related ApcMin/+-associated weight loss. As a control, the weight of MMP12−/− mice on a weekly basis, their weight were not significantly different from those of WT mice. Methods ApcMin/+; MMP12−/− mice were obtained by crossing ApcMin/+ mice with MMP12 knockout (MMP12 −/−) mice. Histological scores were assessed using hematoxylin-eosin (H&E) staining. MMP12 expression was confirmed by immunohistochemistry and immunofluorescence staining. ELISA, protein microarrays and quantitative Polymerase Chain Reaction (qPCR) were used to investigate whether tumor could up-regulate IL-6. Cell-based assays and western blot were used to verify the regulatory relationship between IL-6 and MMP12. Fluorescence intensity was measured to determine whether MMP12 is associated with insulin and insulin-like growth factor 1 (IGF-1) in vitro. MMP12 inhibitors were used to explore whether MMP12 could affect the body weight of ApcMin/+ mice. Results MMP12 knockout led to weight gain and expansion of muscle fiber cross-sectional area (all mice had C57BL/6 background) in ApcMin/+ mice, while inhibiting MMP12 could suppress weight loss in ApcMin/+ mice. MMP12 was up-regulated in muscle tissues and peritoneal macrophages of ApcMin/+ mice. IL-6 in tumor cells and colorectal cancer patients is up-regulation. IL-6 stimulated MMP12 secretion of macrophage. Conclusions MMP12 is essential for controlling body weight of Apc Min/+ mice. Our study shows that it exists the crosstalk between cancer cells and macrophages in muscle tissues that tumor cells secrete IL-6 inducing macrophages to up-regulate MMP12. This study may provide a new perspective of MMP12 in the treatment for weight loss induced by CAC.

Multiple myeloma (MM), a hematologic malignancy, is characterized by malignant plasma cells clonal proliferation. Many evidences indicated the indirect interaction between hypoxic environment and immune state in MM tumorigenesis, but the underlying mechanism remains unclear. MM-related datasets were downloaded from the Gene Expression Omnibus (GEO) database. The R packages were applied for screening protective differentially expressed genes (DEGs) and risk DEGs. The signature was constructed based the most prognostic gene signature in the training and assessed in the validation cohorts. The immune cell infiltration, the expression of the HLA family and immune checkpoint genes inside the low- and high-risk groups were compared to determine the differences in immune infiltration and immunotherapy responses. Moreover, the expression of HLA families and immune checkpoints inside the low- and high-risk groups was markedly disordered. The results indicated hypoxia- and immune-related genes, including CHRDL1, DDIT4, DNTT, FAM133A, MYB, PRR15, QTRT1, and ZNF275, were identified and used to construct a prognostic signature. Role of DDIT4 in multiple myeloma was confirmed in vivo and in vitro. DDIT4 knockdown inhibited MM cell viability, migration and invasion potential as well as promoted myeloma cells apoptosis under hypoxia. Taken together, our study may contribute to the treatment and prognosis prediction of MM.

Abstract Background Hetrombopag, a novel thrombopoietin receptor agonist, has been found in phase I studies to increase platelet counts and reduce bleeding risks in adults with immune thrombocytopenia (ITP). This phase III study aimed to evaluate the efficacy and safety of hetrombopag in ITP patients. Methods Patients who had not responded to or had relapsed after previous treatment were treated with an initial dosage of once-daily 2.5 or 5 mg hetrombopag (defined as the HETROM-2.5 or HETROM-5 group) or with matching placebo in a randomized, double-blind, 10-week treatment period. Patients who received placebo and completed 10 weeks of treatment switched to receive eltrombopag, and patients treated with hetrombopag in the double-blind period continued hetrombopag during the following open-label 14-week treatment. The primary endpoint was the proportion of responders (defined as those achieving a platelet count of ≥ 50 × 109/L) after 8 weeks of treatment. Results The primary endpoint was achieved by significantly more patients in the HETROM-2.5 (58.9%; odds ratio [OR] 25.97, 95% confidence interval [CI] 9.83–68.63; p

Abstract Despite considerable progress has been achieved in the treatment of acute myeloid leukemia over the past decades, relapse remains a major problem. Novel therapeutic options aimed at attaining minimal residual disease-negative complete remission are expected to reduce the incidence of relapse and prolong survival. Natural killer cell-based immunotherapy is put forward as an option to tackle the unmet clinical needs. There have been an increasing number of therapeutic dimensions ranging from adoptive NK cell transfer, chimeric antigen receptor-modified NK cells, antibodies, cytokines to immunomodulatory drugs. In this review, we will summarize different forms of NK cell-based immunotherapy for AML based on preclinical investigations and clinical trials.

Inactivation of the adenomatous polyposis coli (APC) gene is the initiating event in familial adenomatous polyposis (FAP) patients. Up to 90% of FAP patients show intestinal tumors and other extracolonic malignancies including hepatoblastomas, desmoid tumors, and brain cancer. APC mutation mice (ApcMin/+ mice) develop benign polyps in the intestinal tract. It has been reported that small numbers of ApcMin/+ mice develop breast carcinomas. Here, we found that approximately 1.6% of ApcMin/+ mice suffered skin neoplasm. The results demonstrated that these skin tumors are not derived from intestinal adenomas. Sequencing of skin tumors of ApcMin/+ mice and ApcMin/+ mice skin. The data showed that somatic mutations and gene expression levels changed greatly in skin tumors compared to control. Similarly, APC mutation accounts for 27% in the patients of nonmelanoma skin carcinomas in cancer database, and two above genes mutation coexist was observed in all patients. Furthermore, using gene mutation reagent (DMBA)–treated ApcMin/+ mice skin, the skin epithelium and glandular begin hyperplasia in ApcMin/+ mice. These findings revealed that the somatic mutation hit on the germline mutation increase the tumor incidence, suggesting that the somatic mutation should be avoided if the germline mutation exists in one body.

Chidamide has demonstrated significant clinical benefits for patients with relapsed/refractory (R/R) PTCL in previous studies. This multi-center observational study was aimed to evaluate the objective response rate (ORR), overall survival (OS), and safety of chidamide. From February 2015 to December 2017, 548 patients with R/R PTCL from 186 research centers in China were included in the study. Among the 261 patients treated with chidamide monotherapy, ORR was 58.6% and 55 patients (21.1%) achieved complete response (CR). Among the 287 patients receiving chidamide-containing combination therapies, ORR was 73.2% and 73 patients (25.4%) achieved CR. The median OS of all patients was 15.1 months. The median OS of patients receiving chidamide monotherapy and combination therapies was 433 and 463 days, respectively. These results demonstrate a significant survival advantage of chidamide treatments as compared with international historical records. Common adverse effects (AEs) were hematological toxicities. Most AEs in both monotherapy and combined treatments were grade 1–2. No unanticipated AEs occurred. In conclusion, chidamide-based therapy led to a favorable efficacy and survival benefit for R/R PTCL. Future studies should explore the potential advantage of chidamide treatment combined with chemotherapy.

Macrophage migration inhibitory factor (MIF) has been shown to promote disease progression in many malignancies, including multiple myeloma (MM). We previously reported that MIF regulates MM bone marrow homing and knockdown of MIF favors the extramedullary myeloma formation in mice. Here, based on MIF immunostaining of myeloma cells in paired intramedullary and extramedullary biopsies from 17 patients, we found lower MIF intensity in extramedullary MM (EMM) versus intramedullary MM (IMM). Flow cytometry and histology analysis in xenograft models showed a portion of inoculated human MM cells lost their MIF expression (MIFLow) in vivo. Of note, IMM had dominantly MIFHigh cells, while EMM showed a significantly increased ratio of MIFLow cells. Furthermore, we harvested the extramedullary human MM cells from a mouse and generated single-cell transcriptomic data. The developmental trajectories of MM cells from the MIFHigh to MIFLow state were indicated. The MIFHigh cells featured higher proliferation. The MIFLow ones were more quiescent and harbored abundant ribosomal protein genes. Our findings identified in vivo differential regulation of MIF expression in MM and suggested a potential pathogenic role of MIF in the extramedullary spread of disease.

The original article [1] contains several errors.

Abstract Background Previous research suggested that single gene expression might be correlated with acute myeloid leukemia (AML) survival. Therefore, we conducted a systematical analysis for AML prognostic gene expressions. Methods We performed a microarray-based analysis for correlations between gene expression and adult AML overall survival (OS) using datasets GSE12417 and GSE8970. Positive findings were validated in an independent cohort of 50 newly diagnosed, non-acute promyelocytic leukemia (APL) AML patients by quantitative RT-PCR and survival analysis. Results Microarray-based analysis suggested that expression of eight genes was each associated with 1-year and 3-year AML OS in both GSE12417 and GSE8970 datasets (p

The immunocytokine scFvMEL/TNF, a fusion protein composed of human tumor necrosis factor (TNF) and a single-chain Fv antibody (scFv) scFvMEL targeting the melanoma gp240 antigen, demonstrates impressive cytotoxic effects against human melanoma cell lines in vitro. Pharmacokinetic studies of 125I-scFvMEL/TNF in BALB/c mice showed that the construct clears from the circulation with a terminal-phase half-life of 17.6 hours after intravenous administration. The maximum tolerated dose of scFvMEL/TNF in nude mice was 4 mg/kg, i.v., on a daily ×5 schedule. There were no changes in gross pathology, clinical chemistry, or hematologic parameters in mice treated at doses of up to 3 mg/kg. Therapeutic studies at a dose of 2.5 mg/kg on athymic mice bearing established (~ 50 mm3) human melanoma A375GFP xenograft tumors transfected with green fluorescent protein demonstrated potent tumor suppression and complete tumor regression of all lesions. There was no subsequent outgrowth of tumors from mice rendered tumor-free. These data show that scFvMEL/TNF can target melanoma cells in vivo and can result in pronounced antimelanoma effects after systemic administration. Toxicology studies indicate the relative safety of this agent at doses that are therapeutically effective and provide guidance to projected phase I starting doses on patients at this schedule.

GrB/scFvMEL, a fusion protein composed of human granzyme B (GrB) and the single-chain antibody scFvMEL, targets melanoma gp240 antigen and exerts impressive cytotoxic effects by inducing apoptosis. We evaluated the effects of GrB/scFvMEL on chemotherapy, radiation therapy, metastasis in vitro, and the growth of human melanoma A375 xenograft tumors in nude mice. GrB/scFvMEL showed synergistic cytotoxicity when coadministered with doxorubicin, vincristine or cisplatin, and additive effects, in combination with etoposide or cytarabine. Optimal cytotoxic effects were obtained when cells were treated first with GrB/scFvMEL followed by exposure to the agent (rather than the reverse). Pretreatment of A375 cells with GrB/scFvMEL significantly sensitized melanoma cells to ionizing radiation assessed using a clonogenic survival assay. Subtoxic doses of GrB/scFvMEL inhibited the invasion of A375 cells into Matrigel. GrB/scFvMEL (37.5 mg/kg) was administered intravenously to nude mice bearing A375 tumors. Saline-treated tumors increased 24-fold, whereas tumors treated with GrB/scFvMEL showed a significant tumor growth delay increasing four-fold. Tumor tissue displayed an increase in apoptotic nuclei compared to control. Thus, the targeted delivery of GrB to tumors may have a significant potential for cancer treatment. Targeted therapeutic agents specifically designed to impact cellular apoptotic pathways may represent a novel class of therapeutic agents.