Solitary bone plasmacytoma: Long-term clinical outcomes in a single center.

BACKGROUND: A solitary plasmacytoma is classified into a solitary plasmacytoma of the bone (SBP) and a solitary extramedullary (soft tissue mass) plasmacytoma, based on the site of the lesion. Despite the high local control rate with radiotherapy, approximately half of patients' conditions progress to multiple myeloma (MM) within 3-5 years after diagnosis, with SBP having a worse prognosis. PATIENTS AND METHODS: We retrospectively assessed the treatment and outcomes of patients with SBP in a hospital in China from 2008 to 2021. Twenty-four patients treated over 13 years with SBP were enrolled in this retrospective study. RESULTS: The most common sites for SBP were the axial skeleton and femur. The M protein was detected in 11 patients (46 %), of which 8 (33 %) had light chains, 2 (8 %) had immunoglobulin G kappa and 1 (4 %) had immunoglobulin D kappa. Flow cytometry revealed that 5 patients (21 %) had minimal bone marrow involvement. The treatment included chemotherapy, surgery, and radiotherapy in 18 (75 %), 12 (50 %), and 9 (38 %) patients, respectively, of whom 13 (54 %) received combined treatment. Over a median follow-up period of 67.2 months, 9 patients (38 %) developed MM in a median time of 101.5 months. The 5- and 10-year progression-free survival rates were 67.3 % and 37.4 %, respectively. One patient died due to pneumonia without progression and the other died due to relapse. CONCLUSION: This study confirmed the high rate of progression of SBP to MM, indicating a need for adjunct chemotherapy for the management of SBP.

Validation of the IMPEDE VTE score for prediction of venous thromboembolism in Chinese patients with multiple myeloma: A single-center retrospective cohort study.

Multiple myeloma (MM) significantly increases the risk of venous thromboembolism (VTE) within 6 months of treatment initiation. The IMPEDE VTE score is a VTE risk prediction model which is recently incorporated into the National Comprehensive Cancer Network (NCCN) guidelines, but it lacks validation among Asians, including Chinese MM patients. We performed a retrospective chart review of 405 Chinese with newly diagnosed MM who started therapy at Beijing Jishuitan Hospital between April 2013 to October 2022. The 6-month cumulative incidence of VTE was 3.8 % (95 % CI:1.6-7.6), 8.6 % (95 % CI: 5.3-21.9) and 40.5 % (95 % CI: 24.9-55.7) in the low-, intermediate- and high-risk groups (P < 0.001), respectively. The C-statistic of the IMPEDE VTE scores for predicting VTE within 6 months of treatment initiation was 0.74 (95 % CI: 0.65-0.83). Of note, in this single-center cohort study, we propose that the anticoagulant LMWH may be more effective than the antiplatelet aspirin in potentially preventing VTE in newly diagnosed MM patients. Our findings suggest that the IMPEDE VTE score is a valid evidence-based risk stratification tool in Chinese patients with newly diagnosed MM.

Tobacco smoking and nicotine vaping in persons with first episode psychosis.

Tobacco smoking is highly prevalent in persons with psychosis and is the leading cause of preventable mortality in this population. Less is known about tobacco smoking in persons with first episode psychosis (FEP) and there have been no estimates about the prevalence of nicotine vaping in FEP. This study reports rates of tobacco smoking and nicotine vaping in young people with FEP enrolled in Coordinated Specialty Care programs in Pennsylvania and Maryland. Using data collected from 2021 to 2023, we examined lifetime and recent smoking and vaping and compared smokers and vapers to nonusers on symptoms, functioning, and substance use. The sample included 445 participants aged 13-35 with recent psychosis onset. Assessments were collected by program staff. Overall, 28 % of participants engaged in either smoking or vaping within 30 days of the admission assessment. Smokers and vapers were disproportionately male, cannabis users, and had lower negative symptom severity than non-smokers. Vapers had higher role and social functioning. Both smoking and vaping were related to a longer time from psychosis onset to program enrollment. We compare these findings to previous studies and suggest steps for addressing smoking and vaping in this vulnerable population.

Performance comparison of two automated digital morphology analyzers for leukocyte differential in patients with malignant hematological diseases: Mindray MC-80 and Sysmex DI-60.

BACKGROUND: The MC-80 (Mindray, Shenzhen, China), a newly available artificial intelligence (AI)-based digital morphology analyzer, is the focus of this study. We aim to compare the leukocyte differential performance of the Mindray MC-80 with that of the Sysmex DI-60 and the gold standard, manual microscopy. METHODS: A total of 100 abnormal peripheral blood (PB) smears were compared across the MC-80, DI-60, and manual microscopy. Sensitivity, specificity, predictive value, and efficiency were calculated according to the Clinical and Laboratory Standards Institute (CLSI) EP12-A2 guidelines. Comparisons were made using Bland-Altman analysis and Passing-Bablok regression analysis. Additionally, within-run imprecision was evaluated using five samples, each with varying percentages of mature leukocytes and blasts, in accordance with CLSI EP05-A3 guidelines. RESULTS: The within-run coefficient of variation (%CV) of the MC-80 for most cell classes in the five samples was lower than that of the DI-60. Sensitivities for the MC-80 ranged from 98.2% for nucleated red blood cells (NRBC) to 28.6% for reactive lymphocytes. The DI-60's sensitivities varied between 100% for basophils and reactive lymphocytes, and 11.1% for metamyelocytes. Both analyzers demonstrated high specificity, negative predictive value, and efficiency, with over 90% for most cell classes. However, the DI-60 showed relatively lower specificity for lymphocytes (73.2%) and lower efficiency for blasts and lymphocytes (80.1% and 78.6%, respectively) compared with the MC-80. Bland-Altman analysis indicated that the absolute mean differences (%) ranged from 0.01 to 4.57 in MC-80 versus manual differential and 0.01 to 3.39 in DI-60 versus manual differential. After verification by technicians, both analyzers exhibited a very high correlation (r = 0.90-1.00) with the manual differential results in neutrophils, lymphocytes, and blasts. CONCLUSIONS: The Mindray MC-80 demonstrated good performance for leukocyte differential in PB smears, notably exhibiting higher sensitivity for blasts identification than the DI-60.

Vitamin D deficiency linked to abnormal bone and lipid metabolism predicts high-risk multiple myeloma with poorer prognosis.

Purpose: Vitamin D deficiency is frequent in patients with multiple myeloma (MM), however, its prognostic relevance in MM was rather inconclusive. We first investigated the association of vitamin D deficiency with abnormal bone and lipid metabolism in newly diagnosed multiple myeloma (NDMM), and next assessed the impact of serum ratio of vitamin D to carboxy-terminal telopeptide of type I collagen (ß-CTX) on progression-free survival (PFS) and overall free survival (OS) in patients with NDMM. Methods: The data of 431 consecutive patients with NDMM at Beijing Jishuitan Hospital from September 2013 to December 2022 were collected and retrospectively reviewed through our electronic medical record system. The measurement of 25-hydroxyvitamin D in the blood is an indicator of an individual's overall vitamin D status. Results: The serum levels of vitamin D were negatively correlated with ß-CTX in NDMM patients. Of note, positive correlation between vitamin D and cholesterol levels in the serum was found in this study. The cohort (n = 431) was divided into two groups based on the serum ratio of vitamin D to ß-CTX. Compared to the group with a higher vitamin D to ß-CTX ratio, the group with a lower vitamin D to ß-CTX ratio (n = 257, 60%) exhibited hypocholesterolemia, inferior PFS and OS, along with increased cases of ISS stage-III and R-ISS stage-III, a higher number of plasma cells in the bone marrow, and elevated serum calcium levels. Consistent with this, multivariate analysis confirmed that the vitamin D to ß-CTX ratio was an independent unfavorable indicator for survival in NDMM patients. Conclusion: Our data demonstrated the ratio of vitamin D to ß-CTX in the serum is a unique biomarker for NDMM patients to identify the high-risk cases with poor prognosis, which is superior to vitamin D itself for predicting PFS and OS in NDMM. Also, it is worth mentioning that our data on the connection between vitamin D deficiency and hypocholesterolemia might help clarify novel mechanistic aspects of myeloma development.

Risk-benefit ratio of percutaneous kyphoplasty and percutaneous vertebroplasty in patients with newly diagnosed multiple myeloma with vertebral fracture: a single-center retrospective study.

The indications for percutaneous kyphoplasty (PKP) and percutaneous vertebroplasty (PVP) are painful vertebral compression fractures. Our study is to assess the risk-benefit ratio of PKP/PVP surgery in the patients with newly diagnosed multiple myeloma (NDMM) without receiving antimyeloma therapy. The clinical data of 426 consecutive patients with NDMM admitted to our center from February 2012 to April 2022 were retrospectively analyzed. The baseline data, postoperative pain relief, the proportion of recurrent vertebral fractures, and survival time were compared between the PKP/PVP surgical group and the nonsurgical group in the NDMM patients. Of the 426 patients with NDMM, 206 patients had vertebral fractures (206/426, 48.4%). Of these, 32 (32/206, 15.5%) underwent PKP/PVP surgery for misdiagnosis of simple osteoporosis prior to diagnosis of MM (surgical group), and the other 174 (174/206, 84.5%) did not undergo surgical treatment prior to definitive diagnosis of MM (non-surgical group). The median age of patients in the surgical and nonsurgical groups was 66 and 62 years, respectively (p = 0.01). The proportion of patients with advanced ISS and RISS stages was higher in the surgical group (ISS stage II + III 96.9% vs. 71.8%, p = 0.03; RISS stage III 96.9% vs. 71%, p = 0.01). Postoperatively, 10 patients (31.3%) never experienced pain relief and 20 patients (62.5%) experienced short-term pain relief with a median duration of relief of 2.6 months (0.2-24.1 months). Postoperative fractures of vertebrae other than the surgical site occurred in 24 patients (75%) in the surgical group, with a median time of 4.4 months postoperatively (0.4-86.8 months). Vertebral fractures other than the fracture site at the first visit occurred in 5 patients (2.9%) in the nonoperative group at the time of diagnosis of MM, with a median time of 11.9 months after the first visit (3.5-12.6 months). The incidence of secondary fractures was significantly higher in the surgical group than in the nonsurgical group (75% vs. 2.9%, p = 0.001). The time interval between the first visit and definitive diagnosis of MM was longer in the surgical group than in the nonsurgical group (6.1 months vs. 1.6 months, p = 0.01). At a median follow-up of 32 months (0.3-123 months), median overall survival (OS) was significantly shorter in the surgical group than in the nonsurgical group (48.2 months vs. 66 months, p = 0.04). Application of PKP/PVP surgery for pain relief in NDMM patients without antimyeloma therapy has a limited effect and a high risk of new vertebral fractures after surgery. Therefore, patients with NDMM may need to have their disease controlled with antimyeloma therapy prior to any consideration for PKP/PVP surgery.

Clinical and genomic characterization of Chinese patients with functional high-risk multiple myeloma: A real-world validation study.

Objective: Precise risk stratification is increasingly essential in the management of multiple myeloma (MM) as some standard-risk (SR) patients still exhibit similar poor outcomes as genetically high-risk (GHR) patients in the era of novel agents. It has recently been demonstrated that functional high-risk (FHR) patients, those with suboptimal response to first-line induction therapy or early relapse within 12 months, have identifiable molecular characteristics from the SR group in the CoMMpass dataset. However, these findings lack practical validation in the real world. Methods: MM cells purified by CD138 microbeads from newly diagnosed MM (NDMM) patients received fluorescence in situ hybridization and sequencing with a 92-gene Panel. Cytogenetic abnormalities defined GHR patients with t(4;14) or t(14;16) or complete loss of functional P53 or 1q21 gain and International Staging System (ISS) stage 3. SR group was patients who did not fulfill any criteria for GHR or FHR. Results: There were 145 patients with NDMM, 78 in the SR group, 56 in the GHR group, and 11 in the FHR group. In the FHR group, eight patients were suboptimal responses to induction therapy, and three relapsed within 12 months. We found that male patients, patients with extra-medullary plasmacytoma (EMD), circulating clonal plasma cells (CPC) ≥0.05%, and P53 mono-allelic inactivation were significantly higher in the FHR group compared to the SR group. After a median follow-up of 21.0 months, the median progression-free survival (PFS) and overall survival (OS) were 5.0 months, 19.1 months and 36.6 months in the FHR, GHR, and SR groups, respectively. Compared to the SR group, FHR patients had a higher frequency of mutations in MKI67, ERN1, and EML4. GO analysis showed that mutations in FHR were enriched for oxidative stress, chromosomal segregation, and hypoxia tolerance. Conclusion: The FHR found in the SR NDMM patient group has unique clinical features, including being male, with EMD and CPC, and genetic characteristics of mutations affecting oxidative stress, chromosome segregation, and hypoxia tolerance. In contrast to previous reports, our data suggested that patients with P53 mono-allelic inactivation should be classified in the GHR group rather than the FHR group.

Clinical characteristics and prognostic significance of immunoglobulin isotype switch in patients with multiple myeloma.

Immunoglobulin (Ig) isotype switching in multiple myeloma (MM) is a rare form of clonal evolution. The aim of this study was to investigate the clinical features and prognostic significance of Ig isotype switching by observing Ig transformation in patients with relapse. A retrospective analysis was performed on 506 patients with newly diagnosed MM who were treated at our hospital from February 2005 to February 2020. The patients who experienced relapse were divided into the following four groups according to Ig phenotype: original paraprotein, complete isotype switching, light chain escape (LCE),and non-secretory clinical relapse. For comparative purposes with the original paraprotein group, the last three groups were pooled as the transformation group. Among the 506 included patients, 376 (74.3%) relapsed. Among them, 13/376 (3.5%) patients exhibited Ig isotype switching, including 3 with complete isotype switching, 3 with LCE, and 7 with non-secretory clinical relapse. Eleven remained sensitive to therapy, exhibiting at least a partial response. Seven patients survived for at least 20 months after relapse. The median overall survival time of the LCE, clinical relapse, and complete isotype switching groups were 6, 20, and 76 months, respectively, after recurrence. The clinical manifestations and Ig phenotypes of MM recurrence were different from those at the initial diagnosis in the 13 patients exhibiting Ig isotype switching. These differences vividly conveyed the heterogeneity of the clonal populations and provides direct clinical evidence for MM clonal evolution.

Pre-mobilization platelet count predicts stem cell yield during mobilization in patients with multiple myeloma.

Background: Autologous hematopoietic stem cell (HSC) transplantation remains the recommended treatment for eligible patients with multiple myeloma (MM). Increasing the number of transplanted CD34+ cells shorten the time to hematopoietic reconstitution and increases the overall survival of patients. With the harvest of a sufficient CD34+ cell number being crucial, this study aimed to predict the factors that affect stem cell collection. Methods: We conducted a retrospective study of 110 patients who were newly diagnosed with MM and underwent autologous HSC collection at Beijing Jishuitan Hospital between March 2016 and July 2022. Multiple factors were analyzed using the Mann-Whitney U tests for between-group comparisons. Differences were considered statistically significant at P â€‹< â€‹0.05. Results: We found that patient age affected stem cell collection significantly; for patients younger than 55 years, the number of CD34+ cells harvested may be â€‹≥ â€‹2 â€‹× â€‹106/L, is unlikely to reach 5 â€‹× â€‹106/L. Platelet count at initial mobilization was a predictor of the number of CD34+ cells collected. Collection may fail when the platelet count at initial mobilization is below 177 â€‹× â€‹109/L and may be excellent when it is higher than 199 â€‹× â€‹109/L. Conclusions: This finding could guide us to predict the approximate number of CD34+ cells collected in advance during autologous transplant mobilization for MM and to decide in advance whether to apply plerixafor to improve the number of HSCs collected.

Hypoxia-induced LINC00674 facilitates hepatocellular carcinoma progression by activating the NOX1/mTOR signaling pathway.

The hypoxic tumor microenvironment, a fundamental feature of solid tumors, drives hepatocellular carcinoma (HCC) progression through regulating the transcriptional activities of protein-coding and noncoding genes. However, long noncoding RNA (lncRNA)-mediated HCC progression in hypoxic microenvironment remains largely unknown yet. In this study, we found that LINC00674 was upregulated under hypoxic conditions in a HIF-1-dependent manner, and the occupancy of HIF-1 to HRE of LINC00674 gene promoter was essential for its transcription. In addition, LINC00674 level was increased in HCC cell lines and tissues. Clinically, statistical analysis showed that LINC00674 expression was significantly associated with tumor size, venous infiltration, tumor stage and poor prognosis of HCC. Functionally, loss-of-function assays revealed that LINC00674 knockdown inhibited the migration, proliferation and invasion of HCC cells. Furthermore, LINC00674 silencing prominently repressed the mTOR signaling pathway. LINC00674 overexpression-enhanced HCC cell proliferation, migration and invasion were markedly abolished by an mTOR inhibitor rapamycin. NADPH oxidase 1 (NOX1) was positively regulated by LINC00674 in HCC cells. NOX1 knockdown markedly reversed LINC00674-upregulated the p-mTOR level and HCC cells' malignant behaviors. Finally, we found that LINC00674 knockdown attenuated the growth of HCC cells in vivo. Our finding demonstrated that LINC00674 was a new HIF-1 target gene, and hypoxia-induced LINC00674 exerted a pro-proliferative and pro-metastatic role in HCC, possibly by activating the NOX1/mTOR signaling pathway. This study suggested LINC00674 as a promising therapeutic target for HCC.

Vγ2 x PD-L1, a Bispecific Antibody Targeting Both the Vγ2 TCR and PD-L1, Improves the Anti-Tumor Response of Vγ2Vδ2 T Cell.

The potent cytotoxic property of Vγ2Vδ2 T cells makes them attractive for adoptive T cell transfer therapy. The transfusing of the expanded Vγ2Vδ2 T cells into cancer patients shows well-tolerated, but the clinical response rates are required to be improved, implying that there is still an unmet efficacy with low toxicity for this novel anti-tumor therapy. In this study, we test the anti-tumor efficacy of a Y-body-based bispecific antibody (bsAb) Vγ2 x PD-L1 that preferentially redirects Vγ2Vδ2 T cells to combat PD-L1 positive tumor cells. With nanomolar affinity levels to Vγ2Vδ2 T cells and PD-L1+ tumor cells, Vγ2 x PD-L1 bridges a Vγ2Vδ2 T cell with a SKOV3 tumor cell to form a cell-to-cell conjugation. In a PD-L1-dependent manner, the bsAb elicits effective activation (CD25+CD69+), IFNγ releasing, degranulation (CD107a+), and cytokine production (IFNγ+ and TNFα+) of expanded Vγ2Vδ2 T cells. The activations of the Vγ2Vδ2 T cells eliminate PD-L1-expressing human cancer cell lines, including H1975, SKOV3, A375, H1299, and H2228 cells, but not PD-L1 negative cells including HEK-293 (293) cells and healthy PBMCs. Finally, we show that combining Vγ2 x PD-L1 with adoptively transferring Vγ2Vδ2 T cells inhibits the growth of existing tumor xenografts and increases the number of Vγ2Vδ2 T cells into the tumor bed. Vγ2 x PD-L1 represents a promising reagent for increasing the efficacy of adoptively transferred Vγ2Vδ2 T cells in the treatment of PD-L1 positive malignant tumors.

Machine Learning-Based Overall Survival Prediction of Elderly Patients With Multiple Myeloma From Multicentre Real-Life Data.

Objective: To use machine learning methods to explore overall survival (OS)-related prognostic factors in elderly multiple myeloma (MM) patients. Methods: Data were cleaned and imputed using simple imputation methods. Two data resampling methods were implemented to facilitate model building and cross validation. Four algorithms including the cox proportional hazards model (CPH); DeepSurv; DeepHit; and the random survival forest (RSF) were applied to incorporate 30 parameters, such as baseline data, genetic abnormalities and treatment options, to construct a prognostic model for OS prediction in 338 elderly MM patients (>65 years old) from four hospitals in Beijing. The C-index and the integrated Brier score (IBwere used to evaluate model performances. Results: The 30 variables incorporated in the models comprised MM baseline data, induction treatment data and maintenance therapy data. The variable importance test showed that the OS predictions were largely affected by the maintenance schema variable. Visualizing the survival curves by maintenance schema, we realized that the immunomodulator group had the best survival rate. C-indexes of 0.769, 0.780, 0.785, 0.798 and IBS score of 0.142, 0.112, 0.108, 0.099 were obtained from the CPH model, DeepSurv, DeepHit, and the RSF model respectively. The RSF model yield best scores from the fivefold cross-validation, and the results showed that different data resampling methods did affect our model results. Conclusion: We established an OS model for elderly MM patients without genomic data based on 30 characteristics and treatment data by machine learning.

Evaluation of Pharmacokinetics and Safety With Bioequivalence of Anastrozole in Healthy Chinese Volunteers: Bioequivalence Study Findings.

Anastrozole is a third-generation aromatase inhibitor that exerts potent anti-breast cancer effects. This trial aimed to explore the pharmacokinetics (PK) and safety with bioequivalence of orally administered anastrozole provided by 2 sponsors in healthy volunteers.Two separate open-label, randomized, single-dose, crossover-design studies consisting of a fasting study (n = 23) and a fed study (n = 23, 1 participant withdrew before taking medication) were conducted. In each study, healthy volunteers were randomized to receive the test product (Haizheng Pharmaceutical Group) followed by the reference drug (AstraZeneca Pharmaceuticals LP), or vice versa. Each study subject received a 1-mg anastrozole tablet with a 21-day washout. The plasma concentrations of anastrozole were measured with liquid chromatography-tandem mass spectrometry, and PK parameters were determined by noncompartmental analysis. Forty-six healthy female volunteers were enrolled. For patients enrolled in the fasting study, the mean age was 55.0 years, mean weight was 57.1 kg, mean body mass index was 23.6 kg/m2 , and mean height was 155.5 cm. For patients enrolled in the fed study, the mean age was 54.2 years, mean weight was 55.9 kg, mean body mass index was 23.9 kg/m2, and mean height was 152.8 cm. All PK end points met the predefined criteria for PK equivalence. In fasting subjects, the median maximum plasma concentration was 23.4 and 22.6 at 1 hour for test and reference formulations, respectively. The maximum plasma concentration in fed subjects was 18.7 and 18.5 at 4 hours for test and reference formulations, respectively. Both fasting and fed studies achieved plausible bioequivalence. Anastrozole was well tolerated and exhibited a favorable safety profile at the prescribed doses. The severity of observed adverse events assessed according to the Common Terminology Criteria for Adverse Events (version CTCAE4.03) was mild, and some of the adverse events were not caused by anastrozole. Furthermore, the results of our study under fasting and fed conditions demonstrated bioequivalence of the test and reference products.

Amp 1q21 is more predictable with dismal survival than gain 1q21 of newly diagnosed multiple myeloma in real-world analysis.

INTRODUCTION: The gain/amplification (amp) of 1q21 is one of the most common high-risk chromosome abnormality (HRCA) in multiple myeloma (MM). The prognostic value of 1q21+ remains to be controversial on the status of gain or amp and the combination of other HRCAs. METHODS: In this retrospective study, we included 318 newly diagnosed MM (NDMM) patients who had fluorescence in situ hybridization (FISH) data and treated with novel agents in our department. RESULTS: Our study noted MM patients with amp 1q21 were more likely accompanied with t(4;14), t(14;16), and t(14;20). Patients with amp 1q21 presented with elder age, advanced Revised International Staging System (R-ISS) stages, anemia, and more plasma cells in bone marrow compared to patients with gain 1q21 alone and no 1q21+. Moreover, amp 1q21 alone correlated with shorter progression-free survival (PFS) (22.8m vs. 40.5m vs. 39.6m) and overall survival (OS) (45.2m vs. NA vs. 83.5m) compared with gain 1q21 alone and no FISH abnormalities. Although the high ratio of proteasome inhibitor and immunomodulatory drugs used in patients with amp 1q21, the overall response (ORR) was the lowest compared with no 1q21+ and gain 1q21. Multivariate analysis defined amp 1q21 as an independent prognostic marker for NDMM patients, rather than gain 1q21. CONCLUSION: The amp 1q21 predict inferior treatment response and survival, especially coexisted with high-risk IgH translocation.

Correlation analysis of coronary artery tortuosity and calcification score.

BACKGROUND: Coronary artery tortuosity (CAT) is regarded as a variation of vascular anatomy, and its relationship with coronary artery calcification (CAC) score is still not well clarified. Studying the correlation between coronary artery calcification scores and CAT to determine specific prevention and intervention populations seems to have more meaningful. METHODS: The study is a cross-sectional retrospective study, including 1280 patients. CAT is defined as the presence of at least three consecutive curvatures of more than 45°measured during systole or diastole of a major epicardial coronary artery. Multivariable regression analysis was used to adjust the clinical parameters directly affecting CAT. RESULTS: Of these individuals, 445 (35%) were evaluated having CAT, of which females are higher than males (59.1% vs. 40.9%). Moderate CAC score (101-400) (odds ratio (OR) 1.49, 95% confidence interval [95%CI] 1.05-2.10, P = 0.025) revealed significantly associated with CAT on univariable analysis. However, multivariable analysis after adjusting for confounding factors only indicated that CAT was positively correlated with female (OR 1.68, 95%CI 1.30-2.17, P < 0.001), hypertension (OR 1.35, 95% CI 1.04-1.75, P = 0.024), and age (OR 1.02, 95% CI 1.01-1.03, P = 0.001), while was negatively associated with body mass index (BMI) 24-27.9(OR 0.76, 95% CI 0.58-1.00, P = 0.044), and BMI > 28 (OR 0.46, 95% CI 0.31-0.68, P < 0.001). Further analysis stratified by gender showed that compared with non-CAT, CAT was significantly linked with moderate CAC score (OR 1.79, 95% CI 1.00-3.20, P = 0.048), hypertension (OR 1.54, 95% CI 1.07-2.22, P = 0.021), and high-density lipoprotein (HDL) (OR 1.86, 95% CI 1.07-3.24, P = 0.028), while was negatively related to BMI > 28 (OR 0.51, 95% CI 0.31-0.84, P = 0.008) in female patients. CONCLUSIONS: CAT is more likely to be found in females, connected with hypertension, age, and BMI. No significant correlation is found between the presence of tortuosity and calcium score or diameter stenosis on multivariable analysis. Whereas the CAT is associated with moderate CAC score in correlation analysis when women are selected as the main group.

[The Significance of CD319 and CD269 in the Detection of Immunophenotyping and Minimal Residual Disease in Multiple Myeloma Patients].

OBJECTIVE: To investigate the expression of CD319 and CD269 in plasma cells of patients with multiple myeloma (MM) and the feasibility of using CD319 instead of CD38 as a gating antigen in immunophenotyping and minimal residual disease (MRD) monitoring. METHODS: The expression levels of CD319 and CD269 antigens in clonal bone marrow plasma cells of 387 patients were detected by CD38/CD138 gating strategy with 8-color flow cytometry, and the stability of antigens was also analyzed, and the sensitivity and correlation of two different gating strategies employing CD319/CD138 and CD38/CD138 were compared as well. The control group consisted of 53 cases with non-malignant blood disease matched by age and sex. RESULTS: Monoclonal plasma cells were detected in 303 of 387 MM patients, among which 277 cases (91.42%) were positive for CD269, and all cases were positive for CD319 (100%). In newly diagnosed MM (NDMM) and recurrent refractory MM (RRMM) patients, the expression levels of CD269 were 97.53% (0-99.92%) and 94.96% (0.22%-99.99%), respectively, while levels of CD319 were 99.90% (87.77%-100%) and 99.78% (63.12%-100%), respectively. The expression levels of CD269 and CD319 in the control group were 97.00% (77.00%-100%) and 100% (89.00%-100%), respectively. There were no significant differences in the expression levels of CD269 and CD319 among NDMM, RRMM and the control group. Patients acquiring therapeutic effects were divided into complete remission (CR) group, very good partial response (VGPR) group and partial response (PR) group. Gating with CD38/CD138, median MRD values were 0.76% (0-1.88%), 0.77% (0-4.96%) and 1.75% (0.09%-10.90%) in the three groups, respectively, while gating with CD319/CD138, median MRD values were 0.57% (0.18%-1.96%), 1.07% (0.12%-4.85%) and 1.77% (0.08%-8.22%), respectively. There was no significant difference in MRD level by the two gating strategies, but a good correlation between the two (r=0.808, P<0.05). In addition, in 4 patients treated by CD38 monoclonal antibody (DARA), the expression level of CD38 was observed to be down-regulated or even negative after treatment. When the MRD level was very low, CD38/CD138 gating resulted in false MRD-, while CD319/CD138 gating resulted in MRD+. CONCLUSION: CD319 and CD269 express stably and continuously in plasma cells of MM patients at different disease stages. CD319 can be used as an alternative of CD38 for immunophenotyping and MRD detection, especially for MRD detection after DARA treatment, while CD269 is suitable for detection before BCMA-CAR-T treatment.

DHA exhibits synergistic therapeutic efficacy with cisplatin to induce ferroptosis in pancreatic ductal adenocarcinoma via modulation of iron metabolism.

Pancreatic ductal adenocarcinoma (PDAC) is an extremely lethal cancer with limited treatment options. Cisplatin (DDP) is used as a mainstay of chemotherapeutic agents in combination with other drugs or radiotherapy for PDAC therapy. However, DDP exhibits severe side-effects that can lead to discontinuation of therapy, and the acquired drug resistance of tumor cells presents serious clinical obstacles. Therefore, it is imperative to develop a more effective and less toxic therapeutic strategy. We and others have previously discovered that dihydroartemisinin (DHA) represents a safe and promising therapeutic agent to preferentially induce cancer cell ferroptosis. In the present study, we find that DHA could intensively strengthen the cytotoxicity of DDP and significantly reduce its effective concentrations both in vitro and in vivo. Combination of DHA and DDP synergistically inhibits the proliferation and induces DNA damage of PDAC cells. Mechanically, the combinative treatment impairs mitochondrial homeostasis, characterized by destroyed mitochondrial morphology, decreased respiratory capacity, reduced ATP production, and accumulated mitochondria-derived ROS. Further studies show that ferroptosis contributes to the cytotoxic effects in PDAC cells under the challenge of DHA and DDP, together with catastrophic accumulation of free iron and unrestricted lipid peroxidation. Moreover, pharmacologic depleting of the free iron reservoir or reconstituted expression of FTH contributes to the tolerance of DHA/DDP-induced ferroptosis, while iron addition accelerates the ferroptotic cell death. In summary, these results provide experimental evidence that DHA acts synergistically with DDP and renders PDAC cells vulnerable to ferroptosis, which may act as a promising therapeutic strategy.

Remodeling of the tumor microenvironment using an engineered oncolytic vaccinia virus improves PD-L1 inhibition outcomes.

Immune checkpoint inhibitor (ICI) immunotherapies have vastly improved therapeutic outcomes for patients with certain cancer types, but these responses only manifest in a small percentage of all cancer patients. The goal of the present study was to improve checkpoint therapy efficacy by utilizing an engineered vaccinia virus to improve the trafficking of lymphocytes to the tumor, given that such lymphocyte trafficking is positively correlated with patient checkpoint inhibitor response rates. We developed an oncolytic vaccinia virus (OVV) platform expressing manganese superoxide dismutase (MnSOD) for use as both a monotherapy and together with anti-PD-L1. Intratumoral OVV-MnSOD injection in immunocompetent mice resulted in inflammation within poorly immunogenic tumors, thereby facilitating marked tumor regression. OVV-MnSOD administration together with anti-PD-L1 further improved antitumor therapy outcomes in models in which these monotherapy approaches were ineffective. Overall, our results emphasize the value of further studying these therapeutic approaches in patients with minimally or non-inflammatory tumors.

Bispecific Antibody PD-L1 x CD3 Boosts the Anti-Tumor Potency of the Expanded Vγ2Vδ2 T Cells.

Vγ2Vδ2 T cell-based immunotherapy has benefited some patients in clinical trials, but the overall efficacy is low for solid tumor patients. In this study, a bispecific antibody against both PD-L1 and CD3 (PD-L1 x CD3), Y111, could efficiently bridge T cells and PD-L1 expressing tumor cells. The Y111 prompted fresh CD8+ T cell-mediated lysis of H358 cells, but spared this effect on the fresh Vδ2+ T cells enriched from the same donors, which suggested that Y111 could bypass the anti-tumor capacity of the fresh Vγ2Vδ2 T cells. As the adoptive transfer of the expanded Vγ2Vδ2 T cells was approved to be safe and well-tolerated in clinical trials, we hypothesized that the combination of the expanded Vγ2Vδ2 T cells with the Y111 would provide an alternative approach of immunotherapy. Y111 induced the activation of the expanded Vγ2Vδ2 T cells in a dose-dependent fashion in the presence of PD-L1 positive tumor cells. Moreover, Y111 increased the cytotoxicity of the expanded Vγ2Vδ2 T cells against various NSCLC-derived tumor cell lines with the releases of granzyme B, IFNγ, and TNFα in vitro. Meanwhile, the adoptive transferred Vγ2Vδ2 T cells together with the Y111 inhibited the growth of the established xenografts in NPG mice. Taken together, our data suggested a clinical potential for the adoptive transferring the Vγ2Vδ2 T cells with the Y111 to treat PD-L1 positive solid tumors.

Hypercalcemia caused by humoral effects and bone damage indicate poor outcomes in newly diagnosed multiple myeloma patients.

BACKGROUND: Hypercalcemia of malignancy (HCM) is a serious metabolic complication, and the highest rates are in multiple myeloma (MM). The cause of hypercalcemia in newly diagnosed multiple myeloma (NDMM) remains unknown. We sought to evaluate the prognostic impact and mechanism of hypercalcemia in patients with symptomatic NDMM. METHODS: We studied all consecutive MM patients who were initially diagnosed and followed up at Beijing Jishuitan Hospital between February 2013 and December 2019; 357 patients were included in the retrospective analysis. RESULTS: A total of 16.8% of MM patients presented with hypercalcemia at the time of MM diagnosis. The presence of hypercalcemia was associated with higher serum levels of ß2 microglobulin, creatinine, phosphorus, uric acid, procollagen I N-terminal peptide, ß-carboxy-terminal cross-linking telopeptide of type I collagen and osteocalcin, lower serum levels of hemoglobin, parathyroid hormone (PTH), and advanced ISS and R-ISS stages. Multivariate analysis showed that serum PTH, hemoglobin, creatinine, and uric acid levels were the main factors affecting hypercalcemia. The presence of hypercalcemia was associated with significantly inferior survival (40 months vs 57 months, p < 0.05) based on univariate analysis, and it remained an independent poor prognostic factor (HR: 1.854, 95% CI: 1.006-3.415, adjusted p = 0.048) in a multivariate model that included age and R-ISS stage. CONCLUSION: This study shows that hypercalcemia is associated with poor survival and is caused by manifold factors with humoral effects and local bone destruction.