OBJECTIVE:To analyze the prognostic value of del(1p32) in patients with newly diagnosed multiple myeloma (MM). METHODS:The clinical data of 341 newly diagnosed MM attended in Jiangsu Province Hospital were retrospective analyzed. Clinical characteristic combined with genetic features, especially del(1p32), were analyzed for survival and prognostic of patients. RESULTS:Among the 341 patients with newly diagnosed MM, 24(7.0%) patients were del(1p32) positive. The progression-free survival (PFS) and overall survival (OS) were significantly shorter in MM patients with del(1p32) than those without del(1p32) (PFS: P < 0.001;OS: P < 0.001). The COX proportional-hazards model showed that del (1p32) was an independent risk factor for PFS and OS of patients with MM. The patients with both 1q21 gain/amplification and del(1p32), as "double-hit chromosome 1", have worse prognosis than those with only 1q21 gain/amplification or only del(1p32) (PFS: P < 0.001; OS: P < 0.001). CONCLUSION:Del(1p32) is an independent risk factor for PFS and OS of patients with MM. Del(1p32) detection should be widely used in the prognostic analysis for newly diagnosed MM patients.

Multiple myeloma (MM) is a highly heterogeneous and incurable disease. Inflammation plays a vital role in cancer genesis and progression. However, the relationship between inflammatory response-related genes (IRRGs) and the prognosis of MM patients remains unknown. We constructed a IRRGs prognosis model by least absolute shrinkage and selection operator regression analysis. Moreover, clinical multivariate regression was performed to identify clinical implications. Gene set enrichment analysis was implemented to conduct its biological properties. CIBERSORT deconvolution algorithm was utilized to calculate the immune cell infiltration in different risk groups. The flow cytometry was utilized to perform protein expression of prognostic gene. A Six-IRRGs (VCAM1, RGS1, KIT, CD81, BLNK, and BIRC3) prognostic risk model was successfully constructed and validated. The risk model was an independent predictor for overall survival. Enrichment analysis revealed autophagy and PI3K–Akt signaling pathways were enriched in the high-risk group. Furthermore, we found CD81 widely impacted on the infiltration of immune cells, especially on monocytes and macrophages2. At last, the role of CD81 in MM was confirmed to be an adverse prognostic factor in clinical. Our study explores the potential application value of IRRGs in MM. These findings may provide new insights into the treatment for MM patients.

Abnormal activation of FAK is associated with tumor development and metastasis. Through interactions with other intracellular signalling molecules, FAK influences cytoskeletal remodelling, modulation of adhesion signalling, and activation of transcription factors, promoting migration and invasion of tumor cells. However, the exact mechanism that regulates these processes remains unresolved. Herein, our findings indicate that the S-palmitoylation of FAK is crucial for both its membrane localization and activation. The palmitoylation of FAK in U251 and T98G cells was assessed by an acyl-PEG exchange (APE) assay and a metabolic incorporation assay. Cellular palmitoylation was inhibited using 2-bromopalmitate, and the palmitoylation status and cellular localization of FAK were determined. A metabolic incorporation assay was used to identify the potential palmitoyl acyltransferase and the palmitoylation site of FAK. Cell Counting Kit-8 (CCK8) assays, colony formation assays, and Transwell assays were conducted to assess the impact of ZDHHC5 in GBM. Additionally, intracranial GBM xenografts were utilized to investigate the effects of genetically silencing ZDHHC5 on tumor growth. Inhibiting FAK palmitoylation leads to its redistribution from the membrane to the cytoplasm and a decrease in its phosphorylation. Moreover, ZDHHC5, a protein-acyl-transferase (PAT), catalyzes this key modification of FAK at C456. Knockdown of ZDHHC5 abrogates the S-palmitoylation and membrane distribution of FAK and impairs cell proliferation, invasion, and epithelial-mesenchymal transition (EMT). Taken together, our research reveals the crucial role of ZDHHC5 as a PAT responsible for FAK S-palmitoylation, membrane localization, and activation. These results imply that targeting the ZDHHC5/FAK axis has the potential to be a promising strategy for therapeutic interventions for glioblastoma (GBM).

Chimeric antigen receptor (CAR)-T therapy has emerged as a promising treatment for hematologic malignancies. However, cytopenia remains one of the most frequent and challenging adverse effects of this therapy. We conducted a retrospective analysis of 26 patients with relapsed/refractory aggressive B-cell lymphoma who received CAR-T therapy at our center. Subsequently, to investigate measures to address cytopenias following CAR-T therapy, we isolated and generated murine CAR-T cells and bone marrow-derived mesenchymal stem cells (MSCs), establishing a murine syngeneic CAR-T therapy model. We assessed the impact of MSC infusion on hematopoietic recovery post-CAR-T therapy by evaluating complete blood count, bone marrow hematopoietic stem cells and their subpopulations, bone marrow histomorphology, and hematopoiesis-related genes. All patients experienced cytopenias to varying degrees, with complete lineage involvement in half of the patients. Grade ≥ 3 cytopenias were observed in 88.46

IntroductionThe emergence of chimeric antigen receptor (CAR)-T therapy targeting B cell maturation antigen (BCMA) has improved the prognosis of patients with multiple myeloma (MM); however, the majority of patients eventually experience relapse.MethodsIn this study, employing the latest single-cell RNA sequencing technology, we examined 24 bone marrow or peripheral blood samples collected throughout the course of anti-BCMA CAR-T therapy, analyzing a total of 59,725 bone marrow cells and 72,479 peripheral blood cells.ResultsOur findings reveal that tumor cells in relapsed patient exhibit higher expression levels of HSP90B1 and HSPA5, and demonstrate significantly enriched pathways regarding endoplasmic reticulum stress and unfolded protein response. In the analysis of T cells, we observed that patient with impaired effector function and increased expression of immune checkpoints in endogenous T cell are more susceptible to relapse. Notably, T cells from both the bone marrow microenvironment and peripheral blood share highly similar biological characteristics.DiscussionOverall, this study provides a comprehensive atlas of endogenous immune cells, particularly in the relatively long term, after CAR-T therapy. It offers clinical evidence for a deeper understanding of the internal environment post CAR-T treatment and for identifying mechanisms underlying relapse.

The selenium-containing enzyme GPX4 moonlights as a central regulator of ferroptosis, an iron-dependent, nonapoptotic form of regulated cell death caused by lipid peroxidation. Yet, little is known about the mechanisms underlying the regulation of its post-transcriptional modifications. Here, we identify the tripartite motif-containing protein TRIM26 as an E3 ubiquitin ligase of GPX4. TRIM26 directly interacts with GPX4 through its Ring domain and catalyzes the ubiquitination of GPX4 at K107 and K117, which promotes the switch in polyubiquitination of GPX4 from K48 to K63, thus enhancing GPX4 protein stability. Moreover, PLK1-mediated S127 phosphorylation of TRIM26 enhances the interaction between TRIM26 and GPX4. Inhibition of TRIM26 phosphorylation causes a reduction in GPX4 K63-linked polyubiquitination and diminishes GPX4 protein levels in tumor cells. Further investigation revealed that TRIM26 is overexpressed in glioma cells. TRIM26 silencing dramatically impedes ferroptosis resistance and tumorigenesis in glioma in vivo and in vitro. Clinically, TRIM26 expression shows a direct correlation with GPX4 and PLK1 levels in glioma samples and is associated with poor outcome in patients with glioma. Collectively, these findings define the role of GPX4 K63-linked polyubiquitination in ferroptosis and suggest a potential strategy for glioma treatment.

Introduction Circulating plasma cells (CPC) have been reported to be one of the indicators of high-risk multiple myeloma (MM), yet the prognostic significance of CPC in Chinese population and the genetic mechanisms underlying CPC formation have not been fully elucidated. Methods Patients with newly diagnosed MM were included in this study. We used multi-parameter flow cytometry (MFC) for CPC quantification and next-generation sequencing (NGS) technology for mutational landscape mapping to identify the correlation of CPC level with clinical characteristics and the mutations. Results A total of 301 patients were enrolled in this investigation. We demonstrated that CPC quantification could effectively mirror the tumor load, and CPC ≥ 0.105% at diagnosis or detectable CPC after therapy indicates poor treatment response and adverse outcome, and the introduction of CPC into the R-ISS enables a more accurate risk stratification. Interestingly, we noticed an elevated percentage of light-chain MM in patients with higher CPC. Mutational landscape revealed that patients harboring mutations in TP53, BRAF, DNMT3A, TENT5C, and IL-6/JAK/STAT3 pathway-related genes tended to have higher CPC levels. Gene enrichment analysis demonstrated that pathways involving chromosome regulation and adhesion may be potential mechanisms accounting for CPC formation. Discussion Accordingly, quantification of CPC may provide a less-invasive and reliable approach for identifying high-risk MM in Chinese population.

To the Editor: Multiple myeloma (MM), the second most common hematological malignancy, is caused by clonal proliferation of plasma cells and presents characteristics including anemia, bone pain, renal insufficiency, and hypercalcemia. The adhesion of myeloma cells to the bone marrow (BM) microenvironment results in the mainly intramedullary involvement of MM, and sometimes, however, plasma cells can disseminate and infiltrate into extramedullary (EM) sites, called extramedullary disease (EMD). The prevalence of EMD in MM is 6% to 8% at initial diagnosis and can be as high as 10% to 30% during disease progression/relapse.[1] An increasing incidence of EMD has been reported over the decades, possibly owing to advances in imaging as well as the growing secondary EMD resulting from prolonged survival. EMD is a highly aggressive disease entity with a poor response to treatment even in the era of novel agents; hence the exploration of pathogenesis and characteristics of extramedullary myeloma (EMM) is of significance.[2] The EM invasion of MM cells reflects the altered biology of MM cells, particularly the ability to grow independently of the BM microenvironment. These alterations may be triggered by genomic instability. Previous studies revealed that P53 deletion, RAS mutation, and FAK upregulation may account for the EM migration of MM cells.[2] Since cytogenetic aberrations are relevant to the biological nature of tumor cells, they will ultimately determine the clinical outcome of MM. The revised International Staging System (R-ISS) and Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART), both widely used for prognostic categorizing in MM, take cytogenetic aberrations as predictive markers for prognosis. Nevertheless, current studies on EMM mainly investigated the chromosomal abnormalities in BM rather than EM lesions, and little is known about the cytogenetic differences between medullary and EM lesions. Accordingly, we analyzed the cytogenetic characteristics of lesions from different locations and of different types in patients with EMM and further explored the role of cytogenetic aberration in the pathogenesis and prognosis of EMM in this work. To the best of our knowledge, this is one of the most extensive studies comparing chromosomal abnormalities on paired samples in EMM. To reveal the chromosomal abnormalities of EMD, 1q21 gain/amplification, P53 deletion, and immunoglobulin heavy chain (IgH) gene translocation were detected by fluorescence in situ hybridization (FISH) in paired samples of BM and EM lesions from EMM patients. A total of 30 patients diagnosed with EMM from May 2017 to November 2020 in the First Affiliated Hospital of Nanjing Medical University were enrolled, and this study was conducted in accordance with the Declaration of Helsinki and was approved by the institutional review boards of the First Affiliated Hospital of Nanjing Medical University Ethics Committee (No. 2020-SR-589). Informed consent was obtained from all patients before enrollment. In all cases, standard tissue FISH was performed on paraffin-embedded sections as follows: paraffin-embedded sections were dewaxed, rehydrated, heat-treated, and digested in pepsin solution, followed by incubating with respective FISH probes (Vysis 1q21 CKS1B SpectrumOrange/1p32 CDKN2C SpectrumGreen FISH Probe Kit, Vysis P53/CEP17 FISH Probe Kit, LSI IGH Dual Color Break Apart Rearrangement Probe, Vysis LSI IGH/FGFR3 Dual Color Dual Fusion Probes, Vysis LSI IGH/CCND1 Dual Color Dual Fusion Probes and Vysis LSI IGH/MAF Dual Color Dual Fusion Probes [all purchased from Abbott Molecular Inc., IL, USA], MAFB/IGH Fusion Probes [purchased from Guangzhou LBP Medicine Science & Technology Co., Ltd., Guangzhou, China]) in the hybridization oven overnight. Chromosomal abnormalities were identified by counting 100 non-overlapping tumor cells. The cut-off used for IgH break apart or translocation was 10%, and 30% for deletion or gain/amplification. The presence of three copies of 1q21 was defined as 1q21 gain, while the presence of four or more copies was 1q21 amplification. Among the 30 patients, including 13 males and 17 females, with a median age of 56 years (ranged from 39–78 years), 26 patients were diagnosed with EMD at the onset of MM, and four patients developed EMD during progression. FISH analysis showed a higher frequency of chromosomal abnormalities in EM sites than BM (93.33% vs. 70.00%, P = 0.0195). It is noteworthy that 13 patients presented additional abnormalities in EM lesions compared with their BM counterparts, of which 11 patients had one additional abnormality (one with 1q21 amplification, seven with P53 deletion, and three with IgH translocation), and two patients possessed two additional aberrations (both got 1q21 amplification, accompanied with P53 deletion or IgH translocation). As a result, the incidence of 1q21 amplification (33.33% [10/30] vs. 23.33% [7/30], P = 0.3901), P53 deletion (33.33% [10] vs. 6.67% [2], P = 0.0098), and IgH translocation (43.33% [13] vs. 30.00% [9], P = 0.2839) in EM lesions was higher than those in BM [Figure 1A and Supplementary Table 1, https://links.lww.com/CM9/B258].Figure 1: Incidence and prognostic impact of medullary and EM chromosome abnormalities in patients with EM myeloma. (A) Incidence of chromosomal abnormalities in BM and EM lesions. Pie chart depicts the proportional incidence of 1q21 amplification (outer donut), P53 deletion (interim donut), and IgH translocation (inner pie). (B, C) Kaplan-Meier survival curves for PFS (B) and OS (C) regarding different EM 1q21 copy numbers. (D, E) Kaplan-Meier survival curves for PFS (D) and OS (E) of DH/TH and non-DH/TH patients based on medullary chromosomal abnormalities in BM lesions. (F, G) Kaplan-Meier survival curves for PFS (F) and OS (G) of DH/TH and non-DH/TH patients based on EM chromosomal abnormalities in EM lesions. (H, I) Kaplan-Meier survival curves for PFS (H) and OS (I) regarding different R-ISS stages stratified by medullary chromosomal abnormalities in BM lesions. (J, K) Kaplan-Meier survival curves for PFS (J) and OS (K) regarding different R-ISS stages stratified by medullary chromosomal abnormalities in EM lesions. ∗ P < 0.05. BM: Bone marrow; DH: Double-hit; EM: Extramedullary; IgH: Immunoglobulin heavy chain gene; OS: Overall survival; PFS: Progression-free survival; R-ISS: Revised International Staging System; TH: Triple-hit.Clinically, EMD is divided into two categories. One is extramedullary-bone associated (EM-B), in which plasma cells in BM extend into contiguous soft tissues via disruption of cortical bones. The other one is extramedullary-extraosseous (EM-E), referring to extraosseous soft tissue masses resulting from hematogenous dissemination and involves almost all systems throughout the body, with an even worse outcome than EM-B.[2] To find out the cytogenetic differences between EM-B and EM-E lesions, we compared the chromosomal abnormalities according to the type of lesions (19 with EM-B and 11 with EM-E). It tended to show a higher incidence of 1q21 amplification (45.45% [5] vs. 26.32% [5], P = 0.4253) in EM-E than those in EM-B, yet no statistical differences were reached. The incidences of P53 deletion (27.27% [3] vs. 36.84% [7], P = 0.7020) and IgH translocation (45.45% [5] vs. 42.11% [8], P = 1.0000) were similar in the two groups [Supplementary Table 2, https://links.lww.com/CM9/B258]. Chromosomal abnormalities are common in MM and abundant studies have revealed the critical role of P53, 1q21, and IgH in the outcome of MM as well as EMM. Since little is known about the prognostic implications of EM chromosomal abnormalities in EMM, we followed up all the patients with a median follow-up time of 35 months (ranged from 3.5–59 months) for survival analysis. We have noticed that the increase of 1q21 copy number detected in EM lesions retained negative effects on both progression-free survival (PFS) (P < 0.0001) and overall survival (OS) (P = 0.0185) [Figures 1B and 1C]. There seemed to be a trend for worse outcome of patients with EM P53 deletion, but the differences were not statistically significant. No significant differences were found in survival between patients with and without EM IgH translocation [Supplementary Figure 1, https://links.lww.com/CM9/B258]. Aberration of chromosome 1q21 is the most frequent chromosomal abnormalities in our cohort. Previous studies showed that 1q21 gain and amplification account for approximately 35% and 10% in MM, respectively, both of which suggest a poor outcome, especially for 1q21 amplification.[3] One of our previous studies discovered that 1q21 amplification occurs more frequently in EMM patients.[4] In the current work, the frequency of 1q21 amplification is higher in EM lesions than that in BM and higher in EM-E than EM-B. Therefore, it is possible that 1q21 amplification is a contributing factor to EMD development. We also noted that the increase of EM 1q21 copy number negatively affected both PFS and OS, reaffirming the predictive value of EM chromosomal abnormalities in EMM patients. The deletion of the P53 gene, which is located at chromosome 17p13 and plays a critical role in suppressing tumorigenesis, occurs in about 7% of MM patients and indicates a high risk of progression and death. It has been reported that EMM patients are more likely to have P53 deletion than those without EMD, and that P53 deletion may dampen the adhesion of MM cells to the BM stroma and augment the invasion of tumor cells.[2,5] In the present study, we have observed a statistically higher incidence of P53 deletion in EM lesions as compared with their BM counterparts in EMM, further illustrating a potential role of P53 deletion in facilitating the EM invasion of myeloma cells. The IgH gene is on chromosome 14q32, and the translocation of IgH is observed in about half of MM patients, frequently involving the genes of 11q13 (CCND1), 4p16 (MMSET/FGFR3), 16q23 (MAF), and 20q11 (MAFB).[2] Notably, although IgH translocations are mainly considered to be the initial or primary genetic events in MM, it accumulates with disease progression. The higher percentage of IgH translocation in EM lesions compared to BM suggests the acquisition of mutations during disease progression. These acquired chromosomal abnormalities may alter the biological properties of myeloma cells, thereby driving their migration from the BM to EM organs, where EMD occurs. To further investigate the prognostic value of EM cytogenetics, we introduced EM chromosomal abnormalities into the existing R-ISS and mSMART systems. According to the latest mSMART, the presence of any two high-risk factors involving t (4;14), t (14;16), t (14;20), del (17p), and gain (1q) is double-hit (DH) myeloma, whereas the presence of three or more high-risk factors is triple-hit (TH) myeloma. While dividing patients according to the presence of DH/TH based on intra- or EM chromosomal abnormalities, DH/TH tended to confer a worse survival, yet no statistical differences were reached between groups except for OS based on EM chromosomal abnormalities (P = 0.0290) [Figures 1D–1G]. When it comes to the R-ISS system, we were excited to notice that R-ISS stages based on EM chromosomal abnormalities demonstrating a robust discrimination for the prognosis of EMM (P = 0.0121 for PFS and P = 0.0192 for OS), whereas no significant differences were found between stages based on medullary cytogenetics [Figures 1H–1K]. Therefore, for EMM patients, EM chromosomal abnormalities showed significant predictive implications, possibly due to the direct regulation of tumor cells by cytogenetic alterations in EM plasmacytomas. In conclusion, this study demonstrates EM lesions harbored more chromosomal abnormalities than their BM counterparts in patients with EMM and the EM chromosomal abnormalities possess significant prognostic implications. The introduction of EM cytogenetics into the existing R-ISS and mSMART systems allows for more accurate risk stratification for EMM. Acknowledgments We thank Dr. Xiao Li and Dr. Ying Ding for the technical support of this study. Funding This work was supported by grants from the National Natural Science Foundation of China (No. 82070223) and Social Development Project of Jiangsu Science and Technology Plan (No. BE2022810). Conflicts of interest None.

BACKGROUND:Bortezomib resistance hampers the long-term survival of multiple myeloma (MM) patients. Our previous study has proved that downregulated lncRNA MEG3 is associated with the poor clinical outcome in MM. However, the effect of MEG3 on the sensitivity of bortezomib in MM and its possible molecular mechanism remains muddled.METHODS:In this study, CCK8 and flow cytometry techniques were used to assess cell viability in MEG3 overexpressed MM cells after bortezomib treatment. The expression of autophagy-related protein LC3 and p62 were distinguished by Western blot, and the mCherry-GFP-LC3 puncta reflecting autophagy level was observed under fluorescence microscope. RNA immunoprecipitation (RIP) technology was used to detect the binding relationship of MEG3 and ATG2B to PTBP1.RESULTS:Increased toxicity of bortezomib and diminished autophagy level were found in MEG3 overexpressed MM cells. Mechanistically, we discovered that RNA-binding protein PTBP1 could bind to MEG3 and ATG2B by RIP assay. Upregulation of MEG3 promoted PTBP1 expression and inhibited the expression level of ATG2B, suggesting that MEG3 recruited PTBP1 and then decayed ATG2B expression.CONCLUSION:In summary, our study illustrated that MEG3 increased bortezomib sensitivity by hindering autophagy through the PTBP1/ATG2B axis, providing a new therapeutic target for bortezomib-resistant MM patients.

Abstract Multiple myeloma (MM) is one of the most common hematological malignancies and remains incurable to date. Clonal plasma cells can be detected in the peripheral blood of most MM patients, and previous studies have shown an association between the quantification of circulating plasma cells (CPC) and prognosis. However, the significance of CPC for response assessment and prognosis prediction as well as the mechanism underlying CPC formation in Chinese population has not been fully elucidated. In this investigation, we used multi-parameter flow cytometry (MFC) for CPC quantification and next-generation sequencing (NGS) technology for mutational landscape mapping to identify the correlation of CPC level with clinical characteristics and the mutations. As a result, we demonstrated that CPC quantification could effectively mirror the tumor load, and CPC≥0.105% at diagnosis or detectable CPC after therapy indicates poor treatment response and adverse outcome, and it is verified that the introduction of CPC level into the R-ISS system enables a more accurate risk stratification. We also noticed an elevated percentage of light-chain MM in patients with high CPC, this is the first time, to the best of our knowledge, to report the subtype pattern regarding CPC. Mutational landscape revealed that TP53 mutations and pathways involving chromatin or chromosome regulation and adhesion may be potential mechanisms accounting for CPC formation. Accordingly, the detection of CPC by MFC may provide a less-invasive, convenient and, more importantly, reliable approach for risk stratification and disease monitoring in Chinese population.

Background Cytopenia is one of the most common adverse events following the CAR-T cell infusion, affecting the quality of life and potentially leading to life-threatening bleeding and infection. This study aimed to systematically review the cytopenias following anti-CD19 CAR-T therapy and further analyse the contributing factors.Methods Databases including PubMed, MEDLINE, Embase and Cochrane were systematically searched on 8 May 2022. A random-effect meta-analysis was used to estimate the incidence of cytopenia, and subgroup analyses were applied to explore heterogeneity.Results A total of 68 studies involving 2950 patients were included in this study. The overall incidence of all grade anaemia, thrombocytopenia, neutropenia, leukopoenia, lymphocytopenia and febrile neutropenia was 65%, 55%, 78%, 62%, 70% and 27%, respectively, and the corresponding cytopenias of grade 3 or worse were 33%, 31%, 61%, 45%, 46%, and 21%, respectively. Subgroup analysis showed increased incidence of cytopenias in subgroups with lower median age, proportion of males (<65%) and proportion of bridging therapy (<80%) and in the subgroup with a median line of prior therapy ≥3. In terms of disease and therapeutic target, cytopenias were more frequent in ALL patients and in dual-target CAR-T therapies (targeting CD19 in combination with other targets). Furthermore, CAR-T products manufactured by lentiviral vectors and those with the costimulatory domain of CD28 were more likely to cause haematological toxicity. No significant differences were observed in cytopenia between patients treated with CAR-T products with murine and humanized scFv.Conclusion In conclusion, neutropenia is the most frequent cytopenia after CAR-T therapy, both in all grades or grade ≥3. The incidence of cytopenias following CAR-T therapy is influenced by the age, sex, disease and number of prior therapy lines of the patients, as well as the target and costimulatory domain of CAR-T cells, and viral vectors used for manufacturing.KEY MESSAGESNeutropenia is the most frequent cytopenia after CAR-T therapy.The clinical characteristics of the patients, the design of CAR-T cells and the protocol of CAR-T treatment can influence the occurrence of cytopenias following the CAR-T therapy.

BACKGROUND:Previous studies have demonstrated the preclinical pharmacological and toxicological consistency, and clinical pharmacokinetic equivalence of bevacizumab biosimilar LY01008 with reference bevacizumab (Avastin). This randomized controlled trial aimed to compare the efficacy and safety of LY01008 with Avastin in first-line treatment of Chinese patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC).METHODS:Stage IIIB-IV NSCLC patients with evaluable lesions, good physical status, and adequate organ functions from 67 centers across China were randomized in a ratio of 1:1 to receive LY01008 or Avastin 15 mg/kg intravenously in combination with paclitaxel/carboplatin (combined treatment) for 4-6 cycles, followed by maintenance monotherapy with LY01008 until disease progression, intolerable toxicity, or death. The primary endpoint was objective response rate (ORR) in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 confirmed by independent radiological review committees (IRRC). Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. This study was registered in ClinicalTrials.gov (NCT03533127).RESULTS:Between December 15th , 2017, and May 15th , 2019, a total of 649 patients were randomized to the LY01008 (n = 324) or Avastin (n = 325) group. As of September 25th , 2019 for primary endpoint analysis, 589 patients received ORR evaluation, with a median number of combined treatment cycles of 5 (range 1-6) and median duration of treatment of 3.0 (range 0.0-5.1) months. ORR of response-evaluable patients in the LY01008 and Avastin groups were 48.5% and 53.0%, respectively. The stratified ORR ratio was 0.91 (90% CI 0.80-1.04, within the prespecified equivalence margin of 0.75-1.33). Up to May 15th , 2020, with a median follow-up of 13.6 (range 0.8-28.4) months, no notable differences in DCR, median DoR, median PFS, median OS, and 1-year OS rate were observed between the LY01008 and Avastin groups. There were no clinically meaningful differences in safety and immunogenicity across treatment groups.CONCLUSIONS:LY01008 demonstrated similarity to Avastin in terms of efficacy and safety in Chinese patients with advanced or recurrent non-squamous NSCLC. LY01008 combined with paclitaxel/carboplatin is expected to become a new treatment option for unresectable, metastatic, or recurrent non-squamous NSCLC patients in the first-line setting.

OBJECTIVE:To investigate the prognostic value of cervical node features in patients with nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy (IMRT) and build a prognostic nomogram to predict the long-term survival.METHODS:In this study, 1752 patients after IMRT from 2008 to 2011 were recruited. The clinical and laboratory characteristics and the nodal features including the nodal number, maximum dimension diameter, extranodal extension (ENE), and cervical node necrosis (CNN) were retrospective analyzed. Univariate Cox and multivariate proportional hazard regression models were used to test the prognostic value of nodal features. Prognostic nomograms were established to predict survival.RESULTS:The 10-year distant metastases-free survival (DMFS) and disease-specific survival (DSS) rates were 86.5% and 80.8%, respectively. Multivariate analysis showed that age, sex, lactate dehydrogenase (LDH), CNN, ENE, T stage, and N stage were independent factors for DSS. Two nomograms-nomogram A (without nodal features) and nomogram B (with nodal features)-were built. The calibration curve for the probability of DSS showed good agreement between prediction by nomogram and the actual observation. The C-index of nomogram B was higher than that for nomogram A in predicting DSS (0.708 vs 0.676, P<0.01).CONCLUSION:The nodal features including ENE and CNN were negative prognostic factors for NPC, and the prognostic nomogram incorporating the nodal features was more accurate in predicting survival than the nomogram without nodal features.