Guanine nucleotide exchange factor RABGEF1 facilitates TNF-induced necroptosis by targeting cIAP1.

Necroptosis is a form of regulated cell death that depends on the receptor-interacting serine-threonine kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL). The molecular mechanisms underlying distinct instances of necroptosis have only recently begun to emerge. In the present study, we characterized RABGEF1 as a positive regulator of RIPK1/RIPK3 activation in vitro. Based on the overexpression and knockdown experiments, we determined that RABGEF1 accelerated the phosphorylation of RIPK1 and promoted necrosome formation in L929 cells. The pro-necrotic effect of RABGEF1 is associated with its E3 ubiquitin ligase activity and guanine nucleotide exchange factor (GEF) activity. We further confirmed that RABGEF1 interacts with cIAP1 protein by inhibiting its function and plays a regulatory role in necroptosis, which can be abolished by treatment with the antagonist Smac mimetic (SM)-164. In conclusion, our study highlights a potential and novel role of RABGEF1 in promoting TNF-induced cell necrosis.

Efficacy and prognostic factors of allogeneic hematopoietic stem cell transplantation treatment for adolescent and adult Tlymphoblastic leukemia /lymphoma: a large cohort multicenter study in China.

T lymphoblastic leukemia /lymphoma (T-ALL/LBL) is a rare and highly aggressive neoplasm of lymphoblasts. We evaluated 195 T-ALL/LBL adolescent and adult patients who received ALL-type chemotherapy alone (chemo,n = 72) or in combination with autologous hematopoietic stem cell transplantation(auto-HSCT,n = 23) or allogeneic hematopoietic stem cell transplantation(allo-HSCT,n = 100) from January 2006 to September 2020 in three Chinese medical centers. 167 (85.6%) patients achieved overall response (ORR) with 138 complete response (CR) patients (70.8%) and 29 partial response (PR) patients (14.8%). Until October 1, 2023, no difference was found in 5-year overall survival (5-OS) and 5-year progression free survival(5-PFS) between allo-HSCT and auto-HSCT (5-OS 57.9% vs. 36.7%, P = 0.139, 5-year PFS 49.4% vs. 28.6%, P = 0.078) for patients who achieved CR, for patients who achieved PR, allo-HSCT recipients had higher 5-OS compared with chemo alone recipients (5-OS 23.8% vs. 0, P = 0.042). For patients undergoing allo-HSCT, minimal residual disease (MRD) negative population showed better 5-OS survival compared with MRD positive patients (67.8% vs. 19.6%, p = 0.000). There were no significant differences between early T-cell precursor (ETP), NON-ETP patients with or without expression of one or more myeloid-associated or stem cell-associated (M/S+) markers (NON-ETP with M/S+, NON-ETP without M/S+) groups in allo-HSCT population for 5-OS. (62.9% vs. 54.5% vs.48.4%, P > 0.05). Notch mutations were more common in patients with non-relapsed/refractory disease than relapsed/refractory disease (χ² =4.293, P = 0.038). In conclusion, Allo-HSCT could be an effective consolidation therapy not just for patients with CR, but also for those who achieved PR. The prognosis is significantly improved by obtaining MRD negative prior to allogeneic transplantation.

Prediction of the bioaccessibility and accumulation of cadmium in the soil-rice-human system based on optimized DGT and BCR coupled models.

Cadmium, as a typical heavy metal, has the potential to induce soil pollution and threaten human health through the soil-plant-human pathway. The conventional evaluation method based on the total content in soil cannot accurately represent the content migrated from the food chain to plants and the human body. Previous studies focused on the process of plant enrichment of heavy metals in soil, and very few studies directly predicted human exposure or risk through the labile state of Cd in soil. Hence, a relatively accurate and convenient prediction model of Cd release and translocation in the soil-rice-human system was developed. This model utilizes available Cd and soil parameters to predict the bioavailability of Cd in soil, as well as the in vitro bioaccessibility of Cd in cooked rice. The bioavailability of Cd was determined by the Diffusive Gradients in Thin-films technology and BCR sequential extraction procedure, offering in-situ quantification, which presents a significant advantage over traditional monitoring methods and aligns closely with the actual uptake of heavy metals by plants. The experimental results show that the prediction model based on the concentration of heavy metal forms measured by BCR sequential extraction procedure and diffusive gradients in thin-films technique can accurately predict the Cd uptake in rice grains, gastric and gastrointestinal phase (R2=0.712, 0.600 and 0.629). This model accurately predicts Cd bioavailability and bioaccessibility across the soil-rice-human pathway, informing actual human Cd intake, offering scientific support for developing more effective risk assessment methods.

Treatment Response Assessment in Multiple Myeloma: Histogram Analysis of Total Tumor Apparent Diffusion Coefficient based on Whole-body Diffusion-weighted MR Imaging.

BACKGROUND: The International Myeloma Working Group (IMWG) consensus criteria for response assessment in multiple myeloma (MM) has methodological limitations. Whole-body diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) histogram analysis may be complementary to response assessment of MM. PURPOSE: To explore the role of histogram analysis of the ADC based on the total tumor volume (ttADC) in response assessment in patients with newly diagnosed MM (NDMM). STUDY TYPE: Retrospective. POPULATION: Thirty-six patients with NDMM. FIELD STRENGTH/SEQUENCE: 3.0T/single-shot DWI echo planar imaging (EPI) sequence with an integrated slice-by-slice shimming (iShim) technique. ASSESSMENT: Baseline (median: 1 day before treatment) and post-treatment (median: five cycles of therapy) whole-body DWI were analyzed. A region of interest (ROI) containing lesions on every section of baseline image was drawn to derive the per-patient total tumor data. Post-treatment image analysis was based on the same ROI as the corresponding baseline. Histogram metrics were extracted from both ROIs. Patients were categorized into the very good partial response or better (VGPR+) group and the less than VGPR group per the IMWG response criteria for response assessment. Progression-free survival (PFS) was also calculated. STATISTICAL TESTS: Mann-Whitney test and Fisher's exact or Chi-squared tests, Receiver operating characteristic (ROC) analysis and DeLong test, Kaplan-Meier analysis and Cox proportional hazards model. A two-tailed P-value <0.05 was considered statistically significant. RESULTS: Thirty patients were categorized into the VGPR+ group and six into the less than VGPR group. The ttADC histogram changes between post-treatment and baseline metrics (ΔttADC) revealed significant differences in all percentile values between the VGPR+ and less than VGPR groups. For distinguishing VGPR+, ΔttADC_5th percentile had the largest area under the curve (AUC) (0.950, 95% CI 0.821-0.995). Patients with lower ΔttADC_5th percentile values (cutoff point, 188.193) showed significantly longer PFS (HR = 34.911, 95% CI 6.392-190.677). DATA CONCLUSION: ttADC histogram may facilitate response assessment in patients with NDMM. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 4.

Proposed risk-scoring model for estimating the prognostic impact of 1q gain in patients with newly diagnosed multiple myeloma.

1q gain (+1q) is the most common high-risk cytogenetic abnormality (HRCA) in patients with multiple myeloma (MM). However, its prognostic value remains unclear in the era of novel agents. Here, we retrospectively analyzed the impact of +1q on the outcomes of 934 patients newly diagnosed with MM. +1q was identified in 53.1% of patients and verified as an independent variate for inferior overall survival (OS) (hazard ratio, 1.400; 95% confidence interval, 1.097-1.787; p = .007). Concurrence of other HRCAs (particularly t(14;16) and del(17p)) further exacerbated the outcomes of patients with +1q, suggesting prognostic heterogeneity. Thus, a risk-scoring algorithm based on four risk variates (t(14;16), hypercalcemia, ISS III, and high LDH) was developed to estimate the outcomes of patients with +1q. Of the patients, 376 evaluable patients with +1q were re-stratified into low (31.6%), intermediate (61.7%), and high risk (6.7%) groups, with significantly different progression-free survival and OS (p < .0001), in association with early relapse of the disease. The prognostic value of this model was validated in the CoMMpass cohort. While attaining undetectable MRD largely circumvented the adverse impact of +1q, it scarcely ameliorated the outcome of the patients with high risk, who likely represent a subset of patients with extremely poor survival. Hence, patients with +1q are a heterogeneous group of high-risk patients, therefore underlining the necessity for their re-stratification. The proposed simple risk-scoring model can estimate the outcomes of patients with +1q, which may help guide risk-adapted treatment for such patients.

More accurate prediction of treatment response than mean apparent diffusion coefficient value in multiple myeloma using whole body MRI histogram analysis.

Aim: To assess baseline histogram parameters from apparent diffusion coefficient (ADC) images in predicting early treatment response in newly diagnosed multiple myeloma (NDMM) patients. Methods: The histogram parameters of lesions in 68 NDMM patients were obtained with the Firevoxel software. The presence of deep response after two cycles of induction was recorded. Results: Some parameters were significantly different between the two groups, for example, ADC 75% in lumbar spine (p = 0.026). No significant difference in mean ADC for any anatomic site was found (all p > 0.05). The combination of ADC 75, ADC 90 and ADC 95% in lumbar spine; ADC skewness and ADC kurtosis in rib achieved a sensitivity of 100% in predicting deep response. Conclusion: Histogram analysis of ADC images can describe NDMM heterogeneity and accurately predict treatment response.

Purine nucleoside analogs plus rituximab are an effective treatment choice for hairy cell leukemia-variant.

Both characteristics and optimal treatment strategy for hairy cell leukemia-variant (HCL-v) remain elusive due to its rarity. We retrospectively analyzed the clinical features of HCL-v and the efficacy of first-line treatment options in a large Chinese cohort. In this study, we recruited 33 HCL-v patients (23 males and 10 females) with a median age of 59 years (range, 34-79 years). The chief complaints included abdominal mass and relative signs (67%) and abnormal complete blood count (27%). Immunophenotyping showed monoclonal B-cells positive for pan B-cell antigens and CD11c, weakly positive for CD103 and CD200, while negative for CD5, CD10, CD25, CD123, and annexin A1. No BRAF V600E mutation was detected, but TP53 abnormality was recurrent. Treatment choices included interferon-α (IFN-α) in 11 patients, chlorambucil (CLB) in 5 patients, single purine nucleoside analogs (PNA) in 3 patients, PNA plus rituximab (PNA + R) in 9 patients, and others in 3 patients. Four patients who received IFN-α or CLB treatment also underwent splenectomy. Patients who received PNA + R had a higher complete response rate (88% versus 5%, P < 0.001) and longer progression-free survival (PFS, 3-year PFS rate 42% [95% CI 1-84] vs. 16% [95% CI 3-40], P = 0.042) than those who received other regimens. Overall, HCL-v is an indolent lymphoma with unique characteristics. The PNA + R regimen is the preferred choice in the first-line treatment for HCL-v.

Prediction of Early Treatment Response in Multiple Myeloma Using MY-RADS Total Burden Score, ADC, and Fat Fraction From Whole-Body MRI: Impact of Anemia on Predictive Performance.

BACKGROUND. The recently released Myeloma Response Assessment and Diagnosis System (MY-RADS) for multiple myeloma (MM) evaluation using whole-body MRI (WB-MRI) describes the total burden score. However, assessment is confounded by red bone marrow hyperplasia in anemia. OBJECTIVE. The purpose of this study is to assess the utility of the MY-RADS total burden score, ADC, and fat fraction (FF) from WB-MRI in predicting early treatment response in patients with newly diagnosed MM and to compare the utility of these measures between patients with and without anemia. METHODS. This retrospective study included 56 patients (40 men, 16 women; mean age, 57.4 ± 9.6 [SD] years) with newly diagnosed MM who underwent baseline WB-MRI including DWI and modified Dixon sequences. Two radiologists recorded total burden score using MY-RADS and measured the ADC and FF of diffuse and focal disease sites. Mean values across sites were derived. Interobserver agreement was evaluated, and the mean assessments of the readers were used for further analyses. Presence of deep response after four cycles of induction chemotherapy was recorded. Patients were classified as having anemia if their hemoglobin level was less than 100 g/L. The utility of WBMRI parameters in predicting deep response was assessed. RESULTS. A total of 24 of 56 patients showed deep response, and 25 of 56 patients had anemia. Interobserver agreement, which was expressed using intraclass correlation coefficients, ranged from 0.95 to 0.99. Among patients without anemia, those with deep response compared with those without deep response had a lower total burden score (9.0 vs 18.0), a lower ADC (0.79 × 10-3 mm2/s vs 1.08 × 10-3 mm2/s), and a higher FF (0.21 vs 0.10) (all p < .001). The combination of these three parameters (optimal cutoffs: ≤ 15 for total burden score, ≤ 0.84 × 10-3 mm2/s for ADC, and > 0.16 for FF) achieved sensitivity of 93.8%, specificity of 93.3%, and accuracy of 93.5% for predicting deep response. In patients with anemia, none of the three parameters were significantly different between patients with and without deep response (all p > .05), and the combination of parameters achieved sensitivity of 56.3%, specificity of 100.0%, and accuracy of 72.0%. CONCLUSION. Low total burden score, low ADC, and high FF from WB-MRI may predict deep response in patients with MM, although only among those without anemia. CLINICAL IMPACT. WB-MRI findings may help guide determination of prognosis and initial treatment selection in MM.

Acute pancreatitis in pregnancy: a 10-year, multi-center, retrospective study in Beijing.

OBJECTIVE: Acute pancreatitis in pregnancy (APIP) is a rare and serious complication during pregnancy. It has acute onset and is difficult to diagnose and treat. The aim of the present study was to describe the etiology, clinical manifestations, and maternofetal outcomes of APIP. METHODS: We retrospectively reviewed 32 pregnant women who were treated at three tertiary care hospitals in Beijing, China. The correlation between the causes of APIP, severity, laboratory indices, and outcomes was analyzed. RESULTS: The most common causes of APIP were hypertriglyceridemia (56.2%,18/32) and gallstones (28.1%, 9/32). Hypertriglyceridemia-induced APIP was associated with a higher rate of severe acute pancreatitis (P = 0.025). Serum level of triglycerides showed a positive correlation with the severity of APIP (P = 0.039). The most frequent presentation of APIP was abdominal pain (93.7%, 30/32). There were no maternal or fetal deaths in our study. Apgar scores at 1 min, 5 min, and 10 min of the premature neonates was correlated with the severity of APIP of the mother (P = 0.022; 0.002; 0.002). CONCLUSION: High level of triglycerides may serve as a useful marker of the severity of APIP. The severity of APIP was associated with higher risk of neonate asphyxia. Appropriate timing of termination of pregnancy is a key imperative for APIP patients.

Undetectable minimal residual disease is an independent prognostic factor in splenic marginal zone lymphoma.

The role of minimal residual disease (MRD) in splenic marginal zone lymphoma (SMZL) has not been well studied. We prospectively designed a study to evaluate undetectable MRD (uMRD) by multiparameter flow cytometry as a prognostic factor. Residual disease level of <0·01% was defined as uMRD. A total of 71 newly diagnosed patients with bone marrow involvement were enrolled and all received rituximab-based therapy. The overall response rate (ORR) was 98·5% (70/71), with a complete remission (CR) rate of 54·9% (39/71). There were a total of 295 MRD detections in bone marrow and 77·4% patients (55/71) had uMRD. The 5-year progression-free survival (PFS) [(74·8 ± 6·5)% vs. (31·4 ± 12·6)%, P < 0·001] and 5-year overall survival (OS) [(87·2 ± 5·6)% vs. (68·9 ± 13·4)%, P = 0·035] were significantly higher in uMRD patients than in MRD-positive patients. The 5-year PFS in partial remission (PR) patients with positive MRD was significantly poorer than that of PR patients with uMRD [(21·1 ± 12·9)% vs. (83·3 ± 8·8)%, P = 0·005]. Multivariate prognostic analysis revealed that uMRD was an independent good prognostic factor for PFS (hazard ratio 0·162, 95% confidence interval 0·041-0·635; P = 0·009). All these results highlight uMRD as an independent prognostic factor in patients with SMZL, especially for patients who only achieve PR.

Regulation of survivin protein stability by USP35 is evolutionarily conserved.

Survivin is the key component of the chromosomal passenger complex and plays important roles in the regulation of cell division. Survivin has also been implicated in the regulation of apoptosis and tumorigenesis. Although the survivin protein has been reported to be degraded by a ubiquitin/proteasome-dependent mechanism, whether there is a DUB that is involved in the regulation of its protein stability is largely unknown. Using an expression library containing 68 deubiquitinating enzymes, we found that ubiquitin-specific-processing protease 35 (USP35) regulates survivin protein stability in an enzymatic activity-dependent manner. USP35 interacted with and promoted the deubiquitination of the survivin protein. USP38, an ortholog of USP35 encoded by the human genome, is also able to regulate survivin protein stability. Moreover, we found that the deubiquitinating enzyme DUBAI, the Drosophila homolog of human USP35, is able to regulate the protein stability of Deterin, the Drosophila homolog of survivin. Interestingly, USP35 also regulated the protein stability of Aurora B and Borealin which are also the component of the chromosomal passenger complex. By regulating protein stabilities of chromosomal passenger complex components, USP35 regulated cancer cell proliferation. Taken together, our work uncovered an evolutionarily conserved relationship between USP35 and survivin that might play an important role in cell proliferation.

Structural and biochemical characterization of inorganic pyrophosphatase from Homo sapiens.

Inorganic pyrophosphatase (PPase) plays an essential role in energy conservation and provides energy for many biosynthetic pathways. Here, we present two three-dimensional structures of PPase from Homo sapiens (Hu-PPase) at 2.38 Å and 3.40 Å in different crystallization conditions. One of the Hu-PPase structures complex of two magnesium metal ions was determined to be a monomer (Hu-PPase-mono) here, while the other one to be a dimer-dimer (Hu-PPase-dd). In each asymmetric unit of Hu-PPase-mono, there are four α-helices and ten ß-strands and folds as a barrel structure, and the active site contains two magnesium ions. Like PPases from many species, we found that Hu-PPase was able to undergo self-assembly. To our surprise, disruption of the self-assembly of Hu-PPase did not influence its enzymatic activity or the ability to promote cell growth. Our work uncovered that different structure forms of Hu-PPase and found that the pyrophosphatase activity of Hu-PPase is independent of its self-assembly.

Pegfilgrastim improves the outcomes of mobilization and engraftment in autologous hematopoietic stem cell transplantation for the treatment of multiple myeloma.

Autologous stem cell transplantation (ASCT) is the only curable therapy for multiple myeloma (MM), while its success primarily relies on mobilization to obtain sufficient hematopoietic stem/progenitor cells (HPC). Although the role of Pegfilgrastim (PEG), a novel PEGylated form of the recombinant G-CSF filgrastim (FIL), in mobilization has been demonstrated, it remains unclear whether this approach is cost-effective in MM treatment. Here, we performed a real-world analysis to evaluate the efficacy and cost of PEG for mobilization in a cohort of MM patients, of which 53% carried high-risk cytogenetic abnormalities. A total of 91 patients who received either a single dose of PEG (6 or 12 mg, n = 42) or multiple dosing of 10 µg/kg/day FIL (n = 49) after chemotherapy for HPC mobilization were included. The yield of MNCs and CD34+ cells per milliliter of blood collected via apheresis was significantly greater in the PEG group than that in the FIL group (P = 0.014 and P = 0.038). Mobilization with PEG yielded significantly higher median number of collected CD34+ cells than FIL (5.56 vs. 4.82 × 106/kg; P = 0.038). Moreover, the average time-to-recovery of leukocytes and platelets after transplantation was markedly shorter in the PEG group than that in the FIL group (leukocyte, 11.59 ± 1.98 vs 12.93 ± 2.83 days, P = 0.019; platelet, 12.86 ± 2.62 vs 14.80 ± 5.47, P = 0.085). However, the total cost of mobilization and apheresis using PEG or FIL was comparable (P = 0.486). Of note, mobilization with 12 mg PEG further shortened time-to-recovery of leukocytes (10.64 ± 0.51 vs. 12.04 ± 2.26 days, P = 0.05) and platelets (10.60 ± 2.89 vs. 13.33 ± 2.35 days, P = 0.031) compared with 6 mg PEG. Our results support a notion that PEG (especially 12 mg) combined with chemotherapy is a cost-effective and convenient regimen of mobilization, which might improve the outcome of ASCT in MM.

Sequential treatment escalation improves survival in patients with Waldenstrom macroglobulinemia.

Waldenstrom macroglobulinemia (WM) is a type of incurable, indolent B-cell lymphoma that is prone to relapse. Over time, treatment strategies have progressed from cytotoxic drugs to rituximab (R)- or bortezomib (V)-based regimens, and have now entered into an era of Bruton tyrosine kinase inhibitor (BTKi)-based regimens. However, the optimal treatment for the relapsed patients is still unclear. Herein, we analyzed the outcomes of the first- and second-line therapies in 377 patients with WM to illustrate the optimal choices for second-line therapy. After a median follow-up of 45.4 months, 89 patients received second-line therapy, and 53 patients were evaluated for response. The major response rates (MRR) of first- and second-line treatment were 65.1% and 67.9% (P = 0.678). The median progression-free survival (PFS) for the second-line therapy (PFS2) was shorter than that for the first-line therapy (PFS1) (56.3 vs 40.7 months, P = 0.03). However, PFS2 in targeted drugs group (R-/V-/BTKi-based regimens) was comparable to PFS1 (60.7 months vs 44.7 months, respectively, P = 0.21). Regarding second-line therapy, patients who underwent sequential treatment escalation-such as transitioning from cytotoxic drugs to R-/V-/BTKi-based regimens or from R-/V-based to BTKi-based regimens (escalation group) -had higher MRR (80.6% vs 47.1%, respectively, P = 0.023) and longer PFS2 (50.4 vs 23.5 months, respectively, P < 0.001) compared to the non-escalation group. Patients in the escalation group also had longer post-relapse overall survival compared with the non-escalation group (median, 50.4 vs 23.5 months, respectively, P = 0.039). Our findings indicate that sequential treatment escalation may improve the survival of patients with WM.

Dynamic monitoring of circulating tumor DNA reveals outcomes and genomic alterations in patients with relapsed or refractory large B-cell lymphoma undergoing CAR T-cell therapy.

BACKGROUND: Over 50% of patients with relapsed or refractory large B-cell lymphoma (r/r LBCL) receiving CD19-targeted chimeric antigen receptor (CAR19) T-cell therapy fail to achieve durable remission. Early identification of relapse or progression remains a significant challenge. In this study, we prospectively investigate the prognostic value of dynamic circulating tumor DNA (ctDNA) and track genetic evolution non-invasively, for the first time in an Asian population of r/r patients undergoing CAR19 T-cell therapy. METHODS: Longitudinal plasma samples were prospectively collected both before lymphodepletion and at multiple timepoints after CAR19 T-cell infusion. ctDNA was detected using a capture-based next-generation sequencing which has been validated in untreated LBCL. RESULTS: The study enrolled 23 patients with r/r LBCL and collected a total of 101 ctDNA samples. Higher pretreatment ctDNA levels were associated with inferior progression-free survival (PFS) (p=0.031) and overall survival (OS) (p=0.023). Patients with undetectable ctDNA negative (ctDNA-) at day 14 (D14) achieved an impressive 3-month complete response rate of 77.8% vs 22.2% (p=0.015) in patients with detectable ctDNA positive (ctDNA+), similar results observed for D28. CtDNA- at D28 predicted significantly longer 1-year PFS (90.9% vs 27.3%; p=0.004) and OS (90.9% vs 49.1%; p=0.003) compared with patients who remained ctDNA+. Notably, it is the first time to report that shorter ctDNA fragments (<170 base pairs) were significantly associated with poorer PFS (p=0.031 for D14; p=0.002 for D28) and OS (p=0.013 for D14; p=0.008 for D28) in patients with LBCL receiving CAR T-cell therapy. Multiple mutated genes exhibited an elevated prevalence among patients with progressive disease, including TP53, IGLL5, PIM1, BTG1, CD79B, GNA13, and P2RY8. Notably, we observed a significant correlation between IGLL5 mutation and inferior PFS (p=0.008) and OS (p=0.014). CONCLUSIONS: Our study highlights that dynamic ctDNA monitoring during CAR T-cell therapy can be a promising non-invasive method for early predicting treatment response and survival outcomes. Additionally, the ctDNA mutational profile provides novel insights into the mechanisms of tumor-intrinsic resistance to CAR19 T-cell therapy.

Total Tumor ADC Histogram Analysis: A New Tool for Predicting High-Risk Cytogenetic Abnormalities in Multiple Myeloma Patients.

RATIONALE AND OBJECTIVES: We explored the feasibility of using total tumor apparent diffusion coefficient (ttADC) histogram parameters to predict high-risk cytogenetic abnormalities (HRCA) in patients with multiple myeloma (MM) and compared the performance of an image prediction model based on these parameters with that of a combined prediction model based on these parameters and clinical indicators. METHODS: We retrospectively analyzed the parameters of the ttADC histogram based on whole-body diffusion-weighted images(WB-DWI) and clinical indicators in 92 patients with MM. The patients were divided into HRCA and non-HRCA groups according to the results of the fluorescence in situ hybridization. Logistic regression analysis was used to construct the image prediction and combined prediction models. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve was used to evaluate the performance of the models to identify HRCA. The DeLong test was used to compare the AUC differences of each prediction model. RESULTS: Logistic regression analysis results revealed that the ttADC histogram parameter, ttADC entropy < 7.959 (OR: 39.167; 95% confidence interval [CI]: 3.891-394.208; P < 0.05), was an independent risk factor for HRCA. The image prediction model consisted of ttADC entropy and ttADC SD. The combined prediction model included ttADC entropy along with patient clinical indicators such as biological sex and M protein percentage. The AUCs of the image prediction and combined prediction models were 0.739 and 0.811, respectively (P < .05). The image prediction model showed a sensitivity of 73.9% and a specificity of 68.1%. The combined prediction model showed 82.6% sensitivity and 72.5% specificity. CONCLUSIONS: Using ttADC histogram parameters based on WB-DWI images to predict HRCA in patients with MM is feasible, and combining ttADC parameters with clinical indicators can achieve better predictive performance.

Gemcitabine-based conditioning compared to BEAM/BEAC conditioning prior to autologous stem cell transplantation for non-Hodgkin lymphoma: No difference in outcomes.

BACKGROUND: High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) remains an effective treatment for non-Hodgkin lymphoma (NHL). The limited availability of carmustine has prompted the exploration of novel alternative conditioning regimens. This study aimed to compare the efficacy and safety profile of GBM/GBC (gemcitabine, busulfan, and melphalan or cyclophosphamide) conditioning compared with the standard BEAM/BEAC regimens (carmustine, etoposide, cytarabine, and melphalan or cyclophosphamide) for ASCT in patients with NHL. METHODS: A retrospective analysis was conducted on 231 NHL patients, who underwent ASCT from October 2010 to October 2021 at the Institute of Hematology & Blood Disease Hospital, including both first-line and salvage settings. This resulted in the inclusion of 112 patients in the GBM/GBC arm and 92 in the BEAM/BEAC arm. Propensity score matching was employed to validate the results. RESULTS: Disease subtype distribution was similar between the GBM/GBC and BEAM/BEAC groups, with diffuse large B-cell lymphoma being the most common (58.9% vs. 58.7%), followed by PTCL (17.0% vs. 18.5%) and MCL (14.3% vs. 14.1%). At 3 months post-ASCT, complete response (CR) rates were comparable (GBM/GBC 93.5% vs. BEAM/BEAC 91.1%; p = 0.607). The 4-year progression-free survival (78.4% vs. 82.3%; p = 0.455) and 4-year overall survival (88.1% vs. 87.7%; p = 0.575) were also similar. Both groups exhibited low non-relapse mortality at 4 years (GBM/GBC 1.8% vs. BEAM/BEAC 3.5%; p = 0.790) with no transplant-related mortalities reported. The GBM/GBC cohort demonstrated a higher incidence of grade 3/4 oral mucositis and hepatic toxicity, whereas the BEAM/BEAC group had more frequent cases of bacteremia or sepsis (13 cases vs. 5 in GBM/GBC). CONCLUSIONS: The GBM/GBC regimen is effective and well-tolerated, offering outcomes that are highly comparable to those in NHL patients conditioned with BEAM/BEAC, as demonstrated in a prognostically matched cohort.

Combinational therapy of CAR T-cell and HDT/ASCT demonstrates impressive clinical efficacy and improved CAR T-cell behavior in relapsed/refractory large B-cell lymphoma.

BACKGROUND: Approximately two-thirds of patients with relapsed or refractory large B-cell lymphoma (R/R LBCL) do not respond to or relapse after anti-CD19 chimeric antigen receptor T (CAR T)-cell therapy, leading to poor outcomes. Previous studies have suggested that intensified lymphodepletion and hematological stem cell infusion can promote adoptively transferred T-cell expansion, enhancing antitumor effects. Therefore, we conducted a phase I/II clinical trial in which CNCT19 (an anti-CD19 CAR T-cell) was administered after myeloablative high-dose chemotherapy and autologous stem cell transplantation (HDT/ASCT) in patients with R/R LBCL. METHODS: Transplant-eligible patients with LBCL who were refractory to first-line immunochemotherapy or experiencing R/R status after salvage chemotherapy were enrolled. The study aimed to evaluate the safety and efficacy of this combinational therapy. Additionally, frozen peripheral blood mononuclear cell samples from this trial and CNCT19 monotherapy studies for R/R LBCL were used to evaluate the impact of the combination therapy on the in vivo behavior of CNCT19 cells. RESULTS: A total of 25 patients with R/R LBCL were enrolled in this study. The overall response and complete response rates were 92.0% and 72.0%, respectively. The 2-year progression-free survival rate was 62.3%, and the overall survival was 68.5% after a median follow-up of 27.0 months. No unexpected toxicities were observed. All cases of cytokine release syndrome were of low grade. Two cases (8%) experienced grade 3 or higher CAR T-cell-related encephalopathy syndrome. The comparison of CNCT19 in vivo behavior showed that patients in the combinational therapy group exhibited enhanced in vivo expansion of CNCT19 cells and reduced long-term exhaustion formation, as opposed to those receiving CNCT19 monotherapy. CONCLUSIONS: The combinational therapy of HDT/ASCT and CNCT19 demonstrates impressive efficacy, improved CNCT19 behavior, and a favorable safety profile. TRIAL REGISTRATION NUMBERS: ChiCTR1900025419 and NCT04690192.