Iron overload adversely effects bone marrow haematogenesis via SIRT-SOD2-mROS in a process ameliorated by curcumin.

BACKGROUND: Iron overload, which is common in patients with haematological disorders, is known to have a suppressive effect on haematogenesis. However, the mechanism for this effect is still unclear. The antioxidant curcumin has been reported to protect against iron overload-induced bone marrow damage through an as-yet-unknown mechanism. METHODS: We established iron overload cell and mouse models. Mitochondrial reactive oxygen species (mROS) levels, autophagy levels and the SIRT3/SOD2 pathway were examined in the models and in the bone marrow of patients with iron overload. RESULTS: Iron overload was shown to depress haematogenesis and induce mitochondrion-derived superoxide anion-dependent autophagic cell death. Iron loading decreased SIRT3 protein expression, promoted an increase in SOD2, and led to the elevation of mROS. Overexpression of SIRT3 reversed these effects. Curcumin treatment ameliorated peripheral blood cells generation, enhanced SIRT3 activity, decreased SOD2 acetylation, inhibited mROS production, and suppressed iron loading-induced autophagy. CONCLUSIONS: Our results suggest that curcumin exerts a protective effect on bone marrow by reducing mROS-stimulated autophagic cell death in a manner dependent on the SIRT3/SOD2 pathway.

Unrelated Donor Peripheral Blood Stem Cell Transplantation for Patients with ß-Thalassemia Major Based on a Novel Conditioning Regimen.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only available curative treatment for patients with ß-thalassemia major (ß-TM). However, the problem of finding a suitable sibling donor with well-matched human leukocyte antigens is still a major obstacle to curing these patients. With the progress in high-resolution HLA typing technology and supportive care, outcomes after allogeneic HSCT from an HLA well-matched unrelated donor (UD) now approach those of well-matched sibling donors. However, UD HSCT is hampered by an increased risk of graft-versus-host disease and transplant-related mortality. Here we report the outcome of transplantation in patients with ß-TM using a novel WZ-14-TM transplant protocol, based on cyclophosphamide, intravenous busulfan, fludarabine, and antithymocyte globulin, in our center. Forty-eight patients between 2 and 11 years of age with ß-TM received HLA well-matched UD peripheral blood stem cell transplantation following the WZ-14-TM protocol. All of the transplanted patients achieved donor engraftment. The incidences of grade II to IV acute and chronic graft-versus-host disease were 8.3% and 8.3%, respectively. The overall survival and thalassemia-free survival rates were both 100%. This encouraging result suggests that the WZ-14-TM protocol is a feasible and safe conditioning regime for patients with ß-TM undergoing UD HSCT.

Mean platelet volume predicts prognosis in patients with diffuse large B-cell lymphoma.

To determine the prognostic value of baseline mean platelet volume (MPV) in diffuse large B-cell lymphoma (DLBCL) patients. We retrospectively analyzed 161 DLBCL patients who received R-CHOP chemotherapy. The associations between MPV and clinicopathological factors were assessed. A low MPV (MPV ≤ 9.1 fl, cut-off was calculated by receiver operating characteristics) was not associated with any other clinicopathological factors. Patients with MPV ≤ 9.1 fl experienced a shorter progression-free survival (PFS) (2-year PFS rate, 60.6% vs 84.0%, P = 0.003) and overall survival (OS) (2-year OS rate, 70.4% vs 87.9%, P = 0.030), compared with those with MPV > 9.1 fl. The multivariate analysis demonstrated that MPV ≤ 9.1 fl was an independent prognostic factor of OS (Hazard Ratio [HR] = 0.588, P = 0.045) and PFS (HR = 0.456, P = 0.010). Therefore, we demonstrated that low baseline MPV is an independent prognostic marker of poor outcome in patients with DLBCL.

Peripheral blood lymphocyte/monocyte ratio following completion of first-line therapy predicts early relapse in patients with diffuse large B cell lymphoma.

To investigate whether the post-therapy lymphocyte/monocyte ratio (ALC/AMC ratio or LMR) predicts early relapse in patients with diffuse large B cell lymphoma (DLBCL), we enrolled 125 consecutive patients with DLBCL and followed up from 2005 to 2015 in our hospital. The LMR was measured following completion of first-line therapy. We found that the LMR following completion therapy was a strong predictor of early relapse, which is less than 12 months after diagnosis. A low LMR was significantly associated with early relapse in both univariate [odds ratio (OR) = 8.8; P = 0.006] and multivariate analysis (OR = 8.951; P = 0.011). The low-LMR group (<2.9) had poorer outcomes than the high-LMR group (≥2.9), with a lower 2-year progression-free survival rate (78.9 versus 97.1 %, P = 0.002) and 2-year OS rate (82.5 versus 98.5 %, P = 0.002). This study suggests that a lower LMR following completion of first-line therapy can be used as a marker to predict early relapse in patients with DLBCL.

Characterization of γδ regulatory T cells from peripheral blood in patients with multiple myeloma.

γδ regulatory T cells are able to inhibit the activation and function of T cells involved in antigen-specific immune responses. This study aimed to investigate the potential role of γδ regulatory T cells in inhibiting anti-tumor immune responses in patients diagnosed as multiple myeloma (MM). We measured the levels of γδ T cells, the distribution and clonally amplified TCR Vγ and VδT cells in peripheral blood of healthy donors, patients recently diagnosed with MM, and MM patients in remission cohorts. In addition, we evaluated the ability of γδ regulatory T cells to inhibit the proliferation of CD4+CD25- T cells and detected the expression of immunoregulatory-associated molecules. We found that the levels of γδ regulatory T cells from the peripheral blood in patients of MM were significantly higher than those in healthy donors. Comparison of γδT regulatory cells function in MM and healthy donors showed similarly inhibitory effects on the proliferation of T cells. Additionally, TLR8 expression level increased significantly in MM patients compared to healthy donors, while the expression levels of Foxp3, CD25, CTLA4, GITR, GATA3 and Tbet in MM patients and healthy donors showed no significant difference. Taken together, our study reveals the potential role of γδ regulatory T cells in inhibiting anti-tumor immune responses in MM patients.

Recent warming evidence inferred from a tree-ring-based winter-half year minimum temperature reconstruction in northwestern Yichang, South Central China, and its relation to the large-scale circulation anomalies.

High-resolution winter temperature reconstructions in China are rare, yet vital for the comprehensive understanding of past climate change. In the present work, the first winter-half year minimum mean temperature from previous November to current April in northwestern Yichang, South Central China, was reconstructed back to 1875 based on tree-ring material. The reconstruction can explain 55 % of the variance over the calibration period during 1955-2011. The temperature maintained at comparatively low level before 1958, and an abnormal warming was seen since 1959. However, the warming trend stagnated after 2000 AD. 2001-2010 was the warmest decade not only during the instrumental period but also during the whole reconstructed period. The reconstruction indicates good spatial resemblance to other temperatures series in adjacent areas and Northern Hemisphere, yet the recent warming in this study is earlier and more prominent than that of Southeast China. This work also manifests that the winter-half year minimum temperature in study area has good agreement with summer (June-September) maximum temperature variation in Southeast China at decadal scale, except that the winter-half year warming in recent decades is more evident than summer. This reconstruction is not only useful in improving our knowledge of long-term temperature variation but also useful in predicting the tree growth dynamics in the future in the study area.

Treatment selection for gastric cancer with portal hypertension: clinical management.

BACKGROUND: Treatment for gastric cancer with portal hypertension must consider the eradication of the tumor and the change of hemodynamics in portal hypertension (PHT). Few reports have described the surgical procedures and postoperative complications of surgery for gastric cancer associated with PHT. METHODS: The clinical data of 22 patients with PHT undergoing curative surgery for gastric cancer during 5 years were retrospectively analyzed. For 12 patients classified in Child's class A, D2 lymph node (LN) dissection was performed, and 10 patients classified into Child's class B were treated with D1 LN dissection. Surgical treatment included total gastrectomy combined with pericardial devascularization, distal subtotal gastrectomy, distal subtotal gastrectomy combined with splenectomy, and distal subtotal gastrectomy combined with pericardial devascularization with posterior gastric artery and left inferior phrenic artery preserved. A liver biopsy was analyzed in all patients. RESULTS: Postoperative complications developed in 50 % (11/22 patients) and the mortality rate was 9 % (2/22). The rate of postoperative ascites in patients with Child's class A was much lower than in those with Child's class B (P < 0.05). "Operation time," "volume of hemorrhage," "platelet count," and "treatment of PHT" are all risk factors of liver function deterioration. However, there was no significant difference in liver function deterioration rate between patients with Child's class A and Child's class B (P > 0.05). The occurrence rate of complications in patients with PHT was much higher compared to those without with PHT (P < 0.05). CONCLUSIONS: Individualized selection of surgical approaches is crucial for treatment of gastric carcinoma accompanied by PHT. Surgical treatment should be based on preoperative TNM stage, liver function, and degree of PHT.

Identification and validation of a platelet-related signature for predicting survival and drug sensitivity in multiple myeloma.

Background: Significant progress has been achieved in the management of multiple myeloma (MM) by implementing high-dose therapy and stem cell transplantation. Moreover, the prognosis of patients has been enhanced due to the introduction of novel immunomodulatory drugs and the emergence of new targeted therapies. However, predicting the survival rates of patients with multiple myeloma is still tricky. According to recent researches, platelets have a significant impact in affecting the biological activity of tumors and are essential parts of the tumor microenvironment. Nonetheless, it is still unclear how platelet-related genes (PRGs) connect to the prognosis of multiple myeloma. Methods: We analyzed the expression of platelet-related genes and their prognostic value in multiple myeloma patients in this study. We also created a nomogram combining clinical metrics. Furthermore, we investigated disparities in the biological characteristics, immunological microenvironment, and reaction to immunotherapy, along with analyzing the drug susceptibility within diverse risk groups. Results: By using the platelet-related risk model, we were able to predict patients' prognosis more accurately. Subjects in the high-risk cohort exhibited inferior survival outcomes, both in the training and validation datasets, as compared to those in the low-risk cohort (p < 0.05). Moreover, there were differences in the immunological microenvironments, biological processes, clinical features, and chemotherapeutic drug sensitivity between the groups at high and low risk. Using multivariable Cox regression analyses, platelet-related risk score was shown to be an independent prognostic influence in MM (p < 0.001, hazard ratio (HR) = 2.001%, 95% confidence interval (CI): 1.467-2.730). Furthermore, the capacity to predict survival was further improved when a combined nomogram was utilized. In training cohort, this outperformed the predictive value of International staging system (ISS) alone from a 5-years area under curve (AUC) = 0.668 (95% CI: 0.611-0.725) to an AUC = 0.721 (95% CI: 0.665-0.778). Conclusion: Our study revealed the potential benefits of PRGs in terms of survival prognosis of MM patients. Furthermore, we verified its potential as a drug target for MM patients. These findings open up novel possibilities for prognostic evaluation and treatment choices for MM.

Prognostic significance of ß2-microglobulin decline index in multiple myeloma.

Purpose: To assess the prognostic significance of ß2-microglobulin decline index (ß2M DI) in multiple myeloma (MM). Methods: 150 MM patients diagnosed with MM were enrolled in this study. Cox proportional hazards model was used to analyze the uni- and multivariate prognosis in training cohort (n=105). A new combined prognostic model containing ß2M DI was built up based on the data in training cohort. The validation group was used to verify the model. Results: ß2M DI showed significant correlation with prognosis in both uni- and multivariate analyses and had a good correlation with complete response (CR) rate and deep remission rate. The ROC and calibration curves in validation cohort (n=45) indicated a good predictive performance of the new model. Based on the median risk score of the training group, we classified patients into high- and low- risk groups. In both training and validation groups, patients in the low-risk group had longer overall survival (OS) time than that in the high-risk group (p<0.05). Conclusion: ß2M DI is a good predictive index for predicting treatment response and survival time in MM patients. The prognostic model added with ß2M DI showed a better correlation with OS.

Online short videos promoting public breast cancer literacy: a pretest-posttest control group trial on efficiency, attitude, and influencing factors.

Background: Short videos on social media are playing an increasingly important role in cancer health education today. It is important to explore how the actual communication effect of health videos and the knowledge absorption of users are influenced by different factors of the video creation process. Objective: The objective of our study is to access the factors influencing breast cancer health education through short videos on efficiency and quality. Methods: Three pairs of videos about breast health were created and participants completed questionnaires before and after watching the videos. A paired t-test was used to analyze within-group change scores. RM-ANOVA was used to assess the relationship between the pretest, posttest, and three variables. Results: Watching short videos can significantly increase viewers' knowledge of related health topics (p < 0.05). The viewers' concentration level while watching was significantly higher for the video with background music (BGM) than for the video without BGM (p = 0.006). The viewers' willingness to share was significantly higher for the video with a progress bar than for the video without a progress bar (p = 0.02). Using an interpreter wearing a doctor's uniform instead of casual wear and setting a progress bar can significantly improve the efficiency of knowledge absorption (p < 0.05). Conclusion: A uniformed interpreter, BGM and a progress bar are factors influencing the efficiency of short health videos. They can be applied in video making to explore better ways of promoting cancer health education in the new mobile Internet environment.

Comprehensive analysis of ferroptosis-related genes in immune infiltration and prognosis in multiple myeloma.

Background: One particular type of cellular death that is known as ferroptosis is caused by the excessive lipid peroxidation. It is a regulated form of cell death that can affect the response of the tumor cells. Currently, it is not known if the presence of this condition can affect the prognosis of patients with multiple myeloma (MM). Methods: In this study, we studied the expression differences and prognostic value of ferroptosis-related genes (FRGs) in MM, and established a ferroptosis risk scoring model. In order to improve the prediction accuracy and clinical applicability, a nomogram was also established. Through gene enrichment analysis, pathways closely related to high-risk groups were identified. We then explored the differences in risk stratification in drug sensitivity and immune patterns, and evaluated their value in prognostic prediction and treatment response. Lastly, we gathered MM cell lines and samples from patients to confirm the expression of marker FRGs using quantitative real-time PCR (qRT-PCR). Results: The ability to predict the survival of MM patients is a challenging issue. Through the use of a risk model derived from ferroptosis, we were able to develop a more accurate prediction of the disease's prognosis. They were then validated by a statistical analysis, which showed that the model is an independent factor in the prognosis of MM. Patients of high ferroptosis risk scores had a much worse chance of survival than those in the low-risk groups. The calibration and power of the nomogram were also strong. We noted that the link between the ferroptosis risk score and the clinical treatment was suggested by the FRG's significant correlation with the immune checkpoint genes and the medication sensitivity. We validated the predictive model using qRT-PCR. Conclusion: We demonstrated the association between FRGs and MM, and developed a new risk model for prognosis in MM patients. Our study sheds light on the potential clinical relevance of ferroptosis in MM and highlights its potential as a therapeutic target for patients with this disease.

Identification and validation of a novel cuproptosis-related gene signature in multiple myeloma.

Background: Cuproptosis is a newly identified unique copper-triggered modality of mitochondrial cell death, distinct from known death mechanisms such as necroptosis, pyroptosis, and ferroptosis. Multiple myeloma (MM) is a hematologic neoplasm characterized by the malignant proliferation of plasma cells. In the development of MM, almost all patients undergo a relatively benign course from monoclonal gammopathy of undetermined significance (MGUS) to smoldering myeloma (SMM), which further progresses to active myeloma. However, the prognostic value of cuproptosis in MM remains unknown. Method: In this study, we systematically investigated the genetic variants, expression patterns, and prognostic value of cuproptosis-related genes (CRGs) in MM. CRG scores derived from the prognostic model were used to perform the risk stratification of MM patients. We then explored their differences in clinical characteristics and immune patterns and assessed their value in prognosis prediction and treatment response. Nomograms were also developed to improve predictive accuracy and clinical applicability. Finally, we collected MM cell lines and patient samples to validate marker gene expression by quantitative real-time PCR (qRT-PCR). Results: The evolution from MGUS and SMM to MM was also accompanied by differences in the CRG expression profile. Then, a well-performing cuproptosis-related risk model was developed to predict prognosis in MM and was validated in two external cohorts. The high-risk group exhibited higher clinical risk indicators. Cox regression analyses showed that the model was an independent prognostic predictor in MM. Patients in the high-risk group had significantly lower survival rates than those in the low-risk group (p < 0.001). Meanwhile, CRG scores were significantly correlated with immune infiltration, stemness index and immunotherapy sensitivity. We further revealed the close association between CRG scores and mitochondrial metabolism. Subsequently, the prediction nomogram showed good predictive power and calibration. Finally, the prognostic CRGs were further validated by qRT-PCR in vitro. Conclusion: CRGs were closely related to the immune pattern and self-renewal biology of cancer cells in MM. This prognostic model provided a new perspective for the risk stratification and treatment response prediction of MM patients.

A novel glycolysis-related gene signature for predicting the prognosis of multiple myeloma.

Background: Metabolic reprogramming is an important hallmark of cancer. Glycolysis provides the conditions on which multiple myeloma (MM) thrives. Due to MM's great heterogeneity and incurability, risk assessment and treatment choices are still difficult. Method: We constructed a glycolysis-related prognostic model by Least absolute shrinkage and selection operator (LASSO) Cox regression analysis. It was validated in two independent external cohorts, cell lines, and our clinical specimens. The model was also explored for its biological properties, immune microenvironment, and therapeutic response including immunotherapy. Finally, multiple metrics were combined to construct a nomogram to assist in personalized prediction of survival outcomes. Results: A wide range of variants and heterogeneous expression profiles of glycolysis-related genes were observed in MM. The prognostic model behaved well in differentiating between populations with various prognoses and proved to be an independent prognostic factor. This prognostic signature closely coordinated with multiple malignant features such as high-risk clinical features, immune dysfunction, stem cell-like features, cancer-related pathways, which was associated with the survival outcomes of MM. In terms of treatment, the high-risk group showed resistance to conventional drugs such as bortezomib, doxorubicin and immunotherapy. The joint scores generated by the nomogram showed higher clinical benefit than other clinical indicators. The in vitro experiments with cell lines and clinical subjects further provided convincing evidence for our study. Conclusion: We developed and validated the utility of the MM glycolysis-related prognostic model, which provides a new direction for prognosis assessment, treatment options for MM patients.

Development and validation of a cuproptosis-associated prognostic model for diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous disease. Therefore, more reliable biomarkers are required to better predict the prognosis of DLBCL. Cuproptosis is a novel identified form of programmed cell death (PCD) that is different from oxidative stress-related cell death (e.g., apoptosis, ferroptosis, and necroptosis) by Tsvetkov and colleagues in a recent study released in Science. Cuproptosis is copper-dependent PCD that is closely tied to mitochondrial metabolism. However, the prognostic value of cuproptosis-related genes (CRGs) in DLBCL remains to be further elucidated. In the present study, we systematically evaluated the molecular changes of CRGs in DLBCL and found them to be associated with prognosis. Subsequently, based on the expression profiles of CRGs, we characterized the heterogeneity of DLBCL by identifying two distinct subtypes using consensus clustering. Two isoforms exhibited different survival, biological functions, chemotherapeutic drug sensitivity, and immune microenvironment. After identifying differentially expressed genes (DEGs) between CRG clusters, we built a prognostic model with the Least absolute shrinkage and selection operator (LASSO) Cox regression analysis and validated its prognostic value by Cox regression analysis, Kaplan-Meier curves, and receiver operating characteristic (ROC) curves. In addition, the risk score can predict clinical characteristics, levels of immune cell infiltration, and prognosis. Furthermore, a nomogram incorporating clinical features and risk score was generated to optimize risk stratification and quantify risk assessment. Compared to the International Prognostic Index (IPI), the nomogram has demonstrated more accuracy in survival prediction. Furthermore, we validated the prognostic gene expression levels through external experiments. In conclusion, cuproptosis-related gene signature can serve as a potential prognostic predictor in DLBCL patients and may provide new insights into cancer therapeutic targets.

[Toxicity Management and Efficacy Evaluation of BCMA-CART in the Treatment of Relapsed and Refractory Multiple Myeloma].

OBJECTIVE: To investigate the toxicity management and efficacy evaluation of BCMA-chimeric antigen receptor T cells(CART) in the treatment of relapsed and refractory multiple myeloma (MM). METHODS: The efficacy and adverse reactions of 21 patients with MM who received BCMA-CART treatment at the First Affiliated Hospital of Wenzhou Medical University from December 2017 to September 2020 were evaluated, and the efficacy assessment and survival analysis for high-risk patients and non-high-risk patients were evaluated. RESULTS: After infusion of BCMA-CART cells in 21 MM patients, the number of effective cases was 17, of which the complete remission (sCR/CR) was 10, and the partial remission (VGPR/PR) was 7. The median OS time for all patients was 19.4 months, and the median PFS time was 7.9 months. The number of patients with extramedullary disease(EMD), high-risk genetics, and ISS stage Ⅲ were 5, 15 and 8, and the effective number was 3, 11 and 6, respectively. The treatment of 3 patients without high-risk factors was effective. The median OS and median PFS of patients with EMD were 14.2 and 2.5 months, respectively, which were shorter than those of patients without EMD (19.4 months and 8.9 months, respectively). The median OS and median PFS of patients with high-risk cytogenetic factors and ISS Ⅲ were not significantly different from those of non-high-risk patients. Cytokine release syndrane (CRS) occurred in 20 patients, of which 14 cases were Grade 1 CRS, while 6 were Grade 2, no CRS of Grade 3 or above occurred. IL-6 receptor inhibitors were used in 9 patients. All CRS were controlled effectively, and no patients had neurological toxicity. CONCLUSION: BCMA-CART is a certain curative effect in the treatment of relapsed and refractory multiple myeloma, and the adverse reactions can be well controlled through close monitoring and timely treatment.

Helicobacter pylori Regulates the Apoptosis of Human Megakaryocyte Cells via NF-κB/IL-17 Signaling.

OBJECTIVE: To investigate the role of Helicobacter pylori (HP) on the regulation of NF-κB/IL-17 signaling, mechanisms underlying apoptosis in human megakaryocyte cell lines Dami. METHODS: Firstly, the mouse model of immune thrombocytopenia (ITP) was established. Then, the mice were subjected to gastric perfusion with HP. Next, the changes in platelet and bone marrow megakaryocyte classification were assessed in each group. Human megakaryocyte Dami cells were treated with HP in vitro for 3, 6, or 9 h; and the rates of apoptosis in each group were then evaluated with flow cytometry. Fluorescent quantitative PCR and Western blotting were implemented for assessing the expression of Bcl-2 and Bax, which are related to apoptosis, and p65, which is associated with the NF-κB pathway. The expression of these proteins was also evaluated after treatment with PDTC, an inhibitor of the NF-κB pathway inhibitor. RESULTS: In vivo, exogenous administration of HP was found to increase the optical density value for the anti-HP antibody in HP-infected BALB/c mice. Meanwhile, the platelet counts in the HP-infected ITP mice model were significantly reduced compared with non-infected ITP mice. In vitro, the apoptotic rate of Dami cells increased gradually with the prolongation of the exposure to HP; the most noticeable change was at 6 h, and there was a significant difference between 0 h and 6 h. The expression of Bax, p-p65, and IL-17 also increased progressively with the prolongation HP exposure, while the expression of anti-apoptotic Bcl-2 protein decreased gradually, especially at 6 h, and the expression of total p65 did not change significantly compared with baseline. Anecdotally, these effects were reversed by the application of pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB signaling. CONCLUSION: HP can promote platelet destruction in ITP mice, and the underlying mechanisms may be related to accelerating apoptosis of megakaryocytes by the activation of the NF-κB/IL-17 pathway.

PET Imaging of CD8 via SMART for Monitoring the Immunotherapy Response.

Imaging of CD8 receptors on T-cells by positron emission tomography (PET) has been considered a promising strategy for monitoring the treatment response to immunotherapy. In this study, a trial of imaging CD8 with our newly developed sequential multiple-agent receptor targeting (SMART) technology was conducted. Mice bearing a subcutaneous colorectal CT26 tumor received three times different immunotherapy treatments (PD1 or CTLA4 or combined). On either day 7 or day 14 after the first time treatment, the PET imaging study was performed with sequentially administered TCO-modified anti-CD8 antibody and 64Cu-labeled MeTz-NOTA-RGD. However, no positive response was detected, probably due to (1) inappropriate selection of biomarkers for the SMART strategy, (2) limited TCO modification on the anti-CD8 antibody, and (3) inadequate response of the CT26 tumor to the selected immunotherapies. Therefore, the potential of applying SMART in imaging CD8 was not demonstrated in this study, and further optimization will be necessary before it can be applied in imaging CD8.

Prognostic Significance of Cytokine Release Syndrome in B Cell Hematological Malignancies Patients After Chimeric Antigen Receptor T Cell Therapy.

Cytokine release syndrome (CRS) is the most common on-target toxicity of chimeric antigen receptor (CAR) T cell therapy. However, the prognostic significance of CRS has not been well elucidated. The aim of our study was to evaluate the association between CRS and efficacy after anti-CD19 CAR-T therapy in a retrospective cohort of 22 patients with relapsed/refractory B cell hematological malignancies. The complete remission (CR) rates after CAR-T therapy were 68%, and median value for progression-free survival (PFS) was 6.8 months. Eight of 22 (36.4%) patients showed ≥ grade 2 CRS. Statistical analysis found that patients with ≥ grade 2 CRS had higher CR rates and longer PFS than those with < grade 2 CRS. Moreover, bridging hematopoietic stem cell transplantation was another independent predictor for PFS. These data suggested that appropriate CRS may be beneficial to the efficacy of CAR-T therapy. The Clinical Trial Registration number is NCT03110640, NCT03302403.

Development of Dual Receptor Enhanced Pre-Targeting Strategy-A Novel Promising Technology for Immuno-Positron Emission Tomography Imaging.

PET imaging has become an important diagnostic tool in the era of precise medicine. Various pre-targeting systems have been reported to address limitations associated with traditional immuno-PET. However, the application of these mono-receptor based pre-targeting (MRPT) strategies is limited to non-internalizable antibodies, and the tumor uptake is usually much lower than that in the corresponding immuno-PET. To circumvent these limitations, we develop the first Dual-Receptor Pre-Targeting (DRPT) system through entrapping the tumor-receptor-specific radioligand by the pre-administered antibody. Besides the similar ligation pathway happens in MRPT, incorporation of a tumor-receptor-specific peptide into the radioligand in DRPT enhances both concentration and retention of the radioligand on tumor, promoting its ligation with pre-administered mAb on cell-surface and/or internalized into tumor-cells. In this study, 64Cu based DRPT shows superior performance over corresponding MRPT and immuno-PET using internalizable antibodies. Besides, the compatibility of DRPT with short-lived and generator-produced 68Ga is demonstrated, leveraging its advantage in reducing radio-dose exposure. Furthermore, the feasibility of reducing the amount of the pre-administered antibody is confirmed, indicating the cost saving potential of DRPT. In summary, synergizing advantages of dual-receptor targeting and pre-targeting, we expect that this DRPT strategy can become a breakthrough technology in the field of antibody-based molecular imaging.

A phase I study of CAR-T bridging HSCT in patients with acute CD19+ relapse/refractory B-cell leukemia.

Chimeric antigen receptor (CAR)-T cell therapy is a novel cellular immunotherapy for relapsed/refractory(R/R) B acute lymphoblastic leukemia (B-ALL). However, the survival duration of CAR-T cells in vivo is noteworthy, and in some cases recurrence occurs following CAR-T cell therapy. There is controversy over the benefits of bridging to allo-HSCT after CAR-T cell therapy. The present study explored the efficacy and safety of CD19 chimeric antigen receptor (CAR) T-bridged allogeneic hematopoietic stem cell transplantation (allo-HSCT) treatment in relapsed/refractory B-cell acute lymphocytic leukemia (R/R B-ALL). A total of 9 patients with B-ALL treated at The First Affiliated Hospital of Wenzhou Medical University between December 2016 and November 2017 were included. The results demonstrated that the total response rate on day 28 after receiving CD19-CAR T-cell therapy was 100% (9/9) and all patients exhibited complete remission. The 1-year overall survival (OS) rate for 5 patients who received CAR-T bridged HSCT was 100%, the 1-year DFS rate was 100%; the 1-year OS rate for the 4 patients who received CAR-T therapy was 75%, and the 1-year DFS rate was 75%. Patients who received CAR-T bridged to HSCT had no significant prolongation of myeloid and platelet engraftment median time compared with patients who received CAR-T alone, and the incidence of acute graft-versus-host disease or extensive chronic graft-versus-host disease did not increase. Overall, the present clinical trial demonstrated that CAR-T therapy bridging to HSCT is a feasible, safe and effective method to treat adult patients with R/R B-ALL.