Bendamustine in the treatment of patients with indolent non-Hodgkin lymphoma refractory or relapse to rituximab treatment: An open-label, single-agent, multicenter study in China.

BACKGROUND: The optimal treatment strategy for refractory or relapse (R/R) indolent non-Hodgkin lymphoma (iNHL) has not been fully identified. This study aims to investigate the efficacy and tolerance of bendamustine hydrochloride developed in native Chinese corporation in the treatment of patients with R/R iNHL. METHODS: A total of 101 patients from 19 centers were enrolled in this study from July 2016 to February 2019. Bendamustine hydrochloride (120 mg/m2 ) was given on days 1 and 2 of each 21-day treatment cycle for six planned cycles or up to eight cycles if tolerated. Parameters of efficacy and safety were analyzed. RESULTS: The median age of the patients was 53.44 (range, 24.4-74.6) years old. A total of 56 (55.44%) patients completed at least six treatment cycles, and the relative dose intensity was 93.78%. The overall response rate was 72.28%, and the median duration of response was 15.84 months (95% confidence interval [CI], 13.77-27.48 months). Median progression-free survival was 16.52 months (95% CI, 14.72-23.41 months), and the median overall survival was not reached. Grade 3 or 4 hematologic toxicities included neutropenia (77.22%), thrombocytopenia (29.70%), and anemia (15.84%). The most frequent nonhematologic adverse events (any grade) included nausea, vomiting, fatigue, fever, decreased appetite, and weight loss. Seven patients died during the trial, and four cases may be related to the investigational drug. CONCLUSIONS: This study reveals that bendamustine hydrochloride is a feasible treatment option for the indolent B-cell non-Hodgkin lymphoma patient who has not remitted or relapsed after treatment with rituximab. All adverse events were predictable and manageable.

Comparison of efficacy and safety of ripertamab (SCT400) versus rituximab (Mabthera® ) in combination with CHOP in patients with previously untreated CD20-positive diffuse large B-cell lymphoma: A randomized, single-blind, phase III clinical trial.

This study compared the efficacy, safety and immunogenicity of ripertamab (SCT400) and rituximab (Mabthera® ) combined with CHOP as the first-line treatment for Chinese patients with CD20-positive diffuse large B cell lymphoma (DLBCL). This is a randomized, patient-blind, multicenter, active-control, non-inferiority study with parallel design. Patients were randomly (2:1) to receive ripertamab combined with CHOP (S-CHOP) or rituximab (Mabthera® ) combined with CHOP (R-CHOP) for up to 6 cycles. The primary endpoint was the Independent Review Committee (IRC) assessed objective response rate (ORR) in full analysis set (FAS) and the per protocol set (PPS). A total of 364 patients (243 in the S-CHOP and 121 in the R-CHOP groups) were enrolled in this study. In FAS, IRC-assessed ORRs were 93.8% (95% confidence interval (CI) 90.0%, 96.5%) and 94.2% (95% CI: 88.4%, 97.6%) in the S-CHOP and R-CHOP groups (p = 0.9633), respectively. The ORR difference between the two groups -0.4% (95% CI: -5.5%, 4.8%) met the pre-specified non-inferiority margin of -12%. There were no significant differences between the S-CHOP and R-CHOP groups in 1-year progression-free survival rates (81.1% vs. 83.2%, p = 0.8283), 1 year event-free survival rates (56.2% vs. 58.1%, p = 0.8005), and 3-year overall survival rates (81.0% vs. 82.8%, p = 0.7183). The results in PPS were consistent with those in FAS. The rates of treatment-emergent adverse events (TEAEs) and ≥ grade 3 TEAEs were 97.9% and 99.2%, 85.2% and 86.0% in the S-CHOP and R-CHOP groups, respectively in safety set. The percentage of anti-drug antibodies positive patients in the S-CHOP group was numerically lower than the R-CHOP group (10.9% vs. 16.0%). This study demonstrated that S-CHOP was not inferior to R-CHOP in the first-line treatment of Chinese patients with CD20-positive DLBCL in efficacy, safety and immunogenecity. S-CHOP could be an alternative first-line standard treatment regimen for this patient population.

Association between MPO-463G > A polymorphism and cancer risk: evidence from 60 case-control studies.

BACKGROUND: Though a number of studies have been conducted to explore the association between myeloperoxidase (MPO)-463G > A polymorphism and cancer risk, the results remain inconsistent. Therefore, we performed a meta-analysis to derive a more systematic estimation of this relationship. METHOD: Relevant studies were searched by PubMed, EMBASE, CNKI, Google Scholar, Ovid, and Cochrane library prior to December 2015. The strength of the association between MPO-463G > A polymorphism and cancer risk was estimated by odds ratios (OR) with 95% confidence interval (95%CI). Cumulative analysis was used to evaluate the stability of results through time. RESULTS: The current analysis consisted of 16,858 cases and 21,756 controls from 60 studies. Pooled results showed that MPO-463G > A polymorphism were associated with the overall decreased cancer susceptibility in all the genetic models included in this study (additive model: OR = 0.84, 95%CI = 0.76-0.94; allele genetic model: OR = 0.90, 95%CI = 0.840-0.954; recessive genetic model: OR = 0.89, 95%CI = 0.83-0.95). However, in the stratified analysis of cancer type, the significant results were only found in lung cancer (dominant model: OR = 0.93, 95%CI = 0.87-0.99) and digestive system cancer groups (dominant model: OR = 0.67 0.53-0.84; allele frequency model = 0.71, 95%CI = 0.57-0.87), but not in the blood system cancer or breast cancer group. When we further stratified the digestive system cancer group into digestive tract and digestive gland cancer groups, results showed a significant association between allele A of MPO-463G > A and digestive gland cancer in all the genetic models (allele frequency model: OR = 0.63, 95%CI = 0.40-0.99; additive model: OR = 0.41, 95%CI = 0.23-0.73; recessive model: OR = 0.51, 95%CI = 0.29-0.89; dominant model: OR = 0.58, 95%CI = 0.35-0.96), digestive tract cancers in allele frequency model (OR = 0.75, 95%CI = 0.59-0.95), and dominant model (OR = 0.72, 95%CI = 0.56-0.92). When stratified by ethnicity, results demonstrated that the genotype A might be a protect factor for both Caucasians and Asians. In group analysis according to source of controls, significant results were found in population from hospital in all the genetic models. In cumulative analysis, result of allele contrast showed a declining trend and increasingly narrower 95% overall, while the inclination toward non-significant association with lung cancer risk. CONCLUSIONS: This meta-analysis suggested that MPO-463G > A polymorphism was associated with the overall reduced cancer susceptibility significantly. It might be a more reliable predictor of digestive system cancer instead of lung cancer, blood system cancer, and breast cancer. In cumulative analysis, the stable trend indicated that evidence was sufficient to show the association between MPO-463G > A polymorphism and cancer risk.

Meta-analysis of the prognostic and clinical value of tumor-associated macrophages in adult classical Hodgkin lymphoma.

BACKGROUND: The prognostic significance of tumor-associated macrophages (TAM) in adult classical Hodgkin lymphoma (cHL) remains controversial. Here, we report a meta-analysis of the association of CD68 and CD163 infiltration on the clinical outcome of adult cHL. METHODS: A comprehensive search to identify relevant articles was performed in PubMed, Embase, and Google Scholar on January 31, 2016. Using the fixed effect or random effects model of DerSimonian and Laird, hazard ratios (HR) or odds ratios (OR) with 95 % confidence intervals (CIs) were used as the effect size estimate. RESULTS: Twenty-two eligible studies with a total of 2959 patients were identified. Our analysis indicated that a high density of CD68+ TAMs in the tumor microenvironment of adult cHL predicted poor overall survival (OS) (HR: 2.41; 95 % CI, 1.92-3.03), shorter progression-free survival (PFS) (HR: 1.78; 95 % CI, 1.45-2.18), and poor disease-specific survival (HR: 2.71; 95 % CI, 1.38-5.29). High density of CD163+ TAMs in the tumor microenvironment of adult cHL also predicted poor OS (HR: 2.75; 95 % CI, 1.58-4.78) and poor PFS (HR: 1.66; 95 % CI, 1.22-2.27). In addition, we demonstrated that a high density of either CD68+ or CD163+ TAMs was associated with the presence of Epstein-Barr virus in neoplastic cells (ORCD68: 3.13; 95 % CI, 2.02-4.84; ORCD163: 2.88; 95 % CI, 1.55-5.34). A high density of either CD68+ or CD163+ TAMs tend to be associated with a more advanced clinical stage (ORCD68: 1.25; 95 % CI, 0.93-1.67; OR CD163: 1.19; 95 % CI, 0.86-1.63), B-symptoms (ORCD68: 1.35; 95 % CI, 0.90-2.01; ORCD163: 2.19; 95 % CI, 0.96-5.03), higher International Prognostic Factors Project Score (ORCD68: 1.20; 95 % CI, 0.67-2.15; ORCD163: 2.00; 95 % CI, 0.92-4.35), and bulky disease (ORCD68: 1.47; 95 % CI, 0.88-2.47; ORCD163: 1.19; 95 % CI, 0.72-1.96). CONCLUSIONS: Our analyses suggest that a high density of either CD68+ or CD163+ TAMs is a robust predictor of adverse outcomes in adult cHL. Increased TAMs should be taken into account to further improve prognostic stratification and the planning of appropriate therapeutic strategies.

[Total trans-oral endoscopic thyroidectomy and cervical lymphadenectomy: a human cadavers surgery study].

OBJECTIVE: To find an approach for trans-oral endoscopic thyroidectomy (TOET) and cervical lymphadenectomy using conventional endoscopic surgical instruments on frozen fresh cadavers. METHODS: Six frozen fresh cadavers were used in three groups of trans-oral trocar installation experiments: oral vestibule installation, sublingual region installation, and combined bi-vestibular and sublingual installation. TOET (with pretrachealis method to thyroid fixation removal) and cervical lymphadenectomy were performed experiments on another 6 frozen fresh cadavers using the best access approach found in the aforementioned experiments. RESULTS: In oral vestibule trocar installations, the trocars caused large lacerated wound and damaged air tightness. In sublingual installations, only one trocar could be installed in the sublingual area because the space in sublingual area was limited. In combined bi-vestibular and sublingual installations, no gland, vessel or nerve was damaged. Combined bi-vestibular and sublingual access were selected as the surgical approach on the basic of analysis the merits of each approach. TOET and cervical lymphadenectomy in area III, IV, VI, VII were performed without making any accessory damage through combined bi-vestibular and sublingual access approach. CONCLUSIONS: TOET is feasible. Combined bi-vestibular and sublingual approach is available for TOET. Part of the cervical lymph nodes could be resected. Pretrachealis approach to thyroid fixation removal can still be used.

Clinical risk factors and Risk assessment model for Anastomotic leakage after Rectal cancer resection.

BACKGROUND: Anastomotic leakage (AL) is the most serious complication after rectal cancer surgery. Risk factors associated with AL have been documented in previous studies; however, the consensus is still lacking. In this retrospective study, we aimed to identify risk factors for AL after rectal cancer resection and to create an accurate and effective tool for predicting the risk of this complication. METHODS: The study cohort comprised of 276 patients with rectal cancer who had undergone anterior resection between 2015 and 2020. Twenty-four selected variables were assessed by univariate and multivariate logistic regression analyses to identify independent risk factors of AL. A risk assessment model for predicting the risk of AL was established on the basis of the regression coefficients of each identified independent risk factor. RESULTS: Anastomotic leakage occurred in 20 patients (7.2%, 20/276). Multivariate analysis identified the following variables as independent risk or protective factors of AL: perioperative ileus (P < 0.001, odds ratio [OR] = 14.699), tumor size ≥5 cm (P = 0.025, OR = 3.925), distance between tumor and anal verge <7.5 cm (P = 0.045, OR = 3.512), obesity (P = 0.032, OR = 7.256), and diverting stoma (P = 0.008, OR = 0.143). A risk assessment model was constructed and patients were allocated to high-, medium-, and low-risk groups on the basis of risk model scores of 5-7, 2-4, and 0-1, respectively. The incidences of AL in these three groups were 61.5%, 11.9%, and 2.0%, respectively (P < 0.001). CONCLUSIONS: Our risk assessment model accurately and effectively identified patients at high risk of AL and could be useful in aiding decision-making aimed at minimizing adverse outcomes associated with leakage.

[The Mechanism of miR-1294 Targeting SOX15 to Regulate Wnt/ß-catenin Signaling Pathway and Promote the Proliferation of Acute Lymphoblastic Leukemia Cells in Children].

OBJECTIVE: To explore the effect of abnormal miRNA expression on the proliferation of pediatric acute lymphoblastic leukemia (ALL) cells and its related mechanism. METHODS: 15 children with ALL and 15 healthy subjects were collected from the Second Affiliated Hospital of Hainan Medical University from July 2018 to March 2021. MiRNA sequencing was performed on their bone marrow cells, and validated using qRT-PCR. MiR-1294 and miR-1294-inhibitory molecule (miR-1294-inhibitor) were transfected into Nalm-6 cells, and the proliferation of Nalm-6 cells was detected by CCK-8 and colony formation assays. Western blot and ELISA were used to detect apoptosis of Nalm-6 cells. Biological prediction of miR-1294 was performed to find the target gene, which was verified by luciferase reporter assay. Si-SOX15 was transfected into Nalm-6 cells, Western blot was used to detect the expression of Wnt signaling pathway-related proteins and to verify the effect of si-SOX15 on the proliferation and apoptosis of Nalm-6 cells. RESULTS: Compared with healthy subjects, 22 miRNAs were significantly upregulated in bone marrow cells of ALL patients, of which miR-1294 was the most significantly upregulated. In addition, the expression level of SOX15 gene was significantly reduced in bone marrow cells of ALL patients. Compared with the NC group, the miR-1294 group showed increased protein expression levels of Wnt3a and ß-catenin, faster cell proliferation, and more colony-forming units, while caspase-3 protein expression level and cell apoptosis were reduced. Compared with the NC group, the miR-1294-inhibitor group showed reduced protein expression levels of Wnt3a and ß-catenin, slower cell proliferation, and fewer colony-forming units, while caspase-3 protein expression level was increased and apoptosis rate was elevated. miR-1294 had a complementary base-pair with the 3'UTR region of SOX15 , and miR-1294 directly targeted SOX15 . The expression of miR-1294 was negatively correlated with SOX15 in ALL cells. Compared with the si-NC group, the si-SOX15 group showed increased protein expression levels of Wnt3a and ß-catenin, accelerated cell proliferation, and decreased caspase-3 protein expression level and cell apoptosis rate. CONCLUSION: MiR-1294 can target and inhibit SOX15 expression, thus activating the Wnt/ß-Catenin signaling pathway to promote the proliferation of ALL cells, inhibit cell apoptosis, and ultimately affect the disease progression.

Long non-coding RNA SNHG17 may function as a competitive endogenous RNA in diffuse large B-cell lymphoma progression by sponging miR-34a-5p.

We investigated the functional mechanism of long non-coding small nucleolar host gene 17 (SNHG17) in diffuse large B-cell lymphoma (DLBCL). lncRNAs related to the prognosis of patients with DLBCL were screened to analyze long non-coding small nucleolar host gene 17 (SNHG17) expression in DLBCL and normal tissues, and a nomogram established for predicting DLBCL prognosis. SNHG17 expression in B-cell lymphoma cells was detected using qPCR. The effects of SNHG17 with/without doxorubicin on the proliferation and apoptosis of DoHH2 and Daudi were detected. The effects of combined SNHG17 and doxorubicin were analyzed. The regulatory function of SNHG17 in DLBCL was investigated using a mouse tumor xenotransplantation model. RNA sequencing was used to analyze the signaling pathways involved in SNHG17 knockdown in B-cell lymphoma cell lines. The target relationships among SNHG17, microRNA, and downstream mRNA biomolecules were detected. A higher SNHG17 level predicted a lower survival rate. SNHG17 was highly expressed in DLBCL patient tissues and cell lines. We established a prognostic model containing SNHG17 expression, which could effectively predict the overall survival rate of DLBCL patients. SNHG17 knockdown inhibited the proliferation and induced the apoptosis of B-cell lymphoma cells, and the combination of SNHG17 and doxorubicin had a synergistic effect. SNHG17, miR-34a-5p, and ZESTE gene enhancer homolog 2 (EZH2) had common hypothetical binding sites, and the luciferase reporter assay verified that miR-34a-5p was the direct target of SNHG17, and EZH2 was the direct target of miR-34a-5p. The carcinogenic function of SNHG17 in the proliferation and apoptosis of DLBCL cells was partially reversed by a miR-34a-5p inhibitor. SNHG17 increases EZH2 levels by inhibiting miR-34a-5p. Our findings indicate SNHG17 as critical for promoting DLBCL progression by regulating the EZH2 signaling pathway and sponging miR-34a-5p. These findings provide a new prognostic marker and therapeutic target for the prognosis and treatment of DLBCL.

The Oral PI3Kδ Inhibitor Linperlisib for the Treatment of Relapsed and/or Refractory Follicular Lymphoma: A Phase II, Single-Arm, Open-Label Clinical Trial.

PURPOSE: To investigate the efficacy and safety of the novel orally active PI3Kδ inhibitor in relapsed and/or refractory patients with follicular lymphoma (FL) who had received at least two prior systemic treatments. PATIENTS AND METHODS: Histologically confirmed relapsed and/or refractory patients with FL with disease progression after receiving second-line or greater systemic therapy were enrolled. Linperlisib was administered at 80 mg every day, orally in a 28-day cycle until disease progression or intolerable toxicity occurred. The primary outcome for the study was the objective response rate (ORR), with secondary outcomes including the duration of response (DOR), progression-free survival (PFS), overall survival (OS), disease control rate, and drug safety profile. RESULTS: Of 114 screened relapsed and/or refractory patients with FL, 84 were enrolled in the full analysis set (FAS). The ORR of the 84 FAS patients was 79.8% [95% confidence interval (CI), 69.6-87.8, 67 patients], with 13 patients (15.5%) achieving a complete response and 54 patients (64.3%) with a partial response. The median DOR was 12.3 months (95% CI, 9.3-15.9). The median PFS was 13.4 months (95% CI, 11.1-16.7). The 12-month OS rate was 91.4% (95% CI, 82.7-95.8) and a median OS not reached by 42 months. The most frequent (>3%) treatment-related adverse events Grade ≥3 were infectious pneumonia (19.0%), neutropenia (15.5%), decreased lymphocyte count (4.8%), decreased leukocyte count (4.8%), increased lipase (3.6%), decreased platelet count (3.6%), hypertriglyceridemia (3.6%), and interstitial lung disease (3.6%). CONCLUSIONS: Linperlisib demonstrated compelling clinical activity and manageable tolerability for relapsed and/or refractory patients with FL who had received at least two prior systemic therapies.

Sugemalimab Monotherapy for Patients With Relapsed or Refractory Extranodal Natural Killer/T-Cell Lymphoma (GEMSTONE-201): Results From a Single-Arm, Multicenter, Phase II Study.

PURPOSE: Relapsed or refractory extranodal natural killer/T-cell lymphoma (R/R ENKTL) is a rare and aggressive type of non-Hodgkin lymphoma with limited treatment options. This phase II study evaluated the efficacy and safety of sugemalimab, an anti-PD-L1 monoclonal antibody, in R/R ENKTL. METHODS: Eligible patients received sugemalimab 1,200 mg intravenously once every 3 weeks for up to 24 months or until progression, death, or study withdrawal. The primary end point was objective response rate (ORR) assessed by an independent radiologic review committee. Key secondary end points included ORR assessed by the investigators, complete response rate, duration of response, and safety. RESULTS: At the data cutoff (February 23, 2022), 80 patients were enrolled and followed for a median of 18.7 months. At baseline, 54 (67.5%) had stage IV disease and 39 (48.8%) had received ≥2 lines of prior systemic therapy. Independent radiologic review committee-assessed ORR was 44.9% (95% CI, 33.6 to 56.6); 28 (35.9%) patients achieved a complete response and seven (9.0%) achieved a partial response, with a 12-month duration of response rate of 82.5% (95% CI, 62.0 to 92.6). Investigator-assessed ORR was 45.6% (95% CI, 34.3 to 57.2), and 24 (30.4%) patients achieved a complete response. Most treatment-emergent adverse events were grade 1-2 in severity, and grade ≥ 3 events were reported in 32 (40.0%) patients. CONCLUSION: Sugemalimab showed robust and durable antitumor activity in R/R ENKTL. Treatment was well tolerated with expected safety profile for this drug class.

Long non-coding RNA (LncRNA) CHROMR promotes the expression of the CNNM1 gene by adsorbing hsa-miR-1299 to obtain drug resistance in diffuse large B lymphoma cells.

Background: Long non-coding RNA (LncRNA) play roles in different diseases, LncRNA is differentially expressed in diffuse large B cell lines with varying degrees of resistance to rituximab. Methods: In the GEO database (GSE159852), we found that CHROMR (cholesterol induced regulator of metabolism RNA) may be differentially expressed in different rituximab-resistant diffuse large B lymphoma cell lines. We also verified the expression level in cell lines and verified the role of CHROMR in acquiring cell drug resistance through various biological function experiments. We predict that there may be a potential regulatory mechanism for CHROMR and validated it. Results: We found that CHROMR was differentially expressed in different rituximab-resistant cell lines. When the rituximab-sensitive cell line SU_DHL_4 was stimulated by rituximab, flow experiments demonstrated that overexpression of CHROMR could reduce the level of cell apoptosis and the proportion of arrested cells in the G2/M phase of the cell cycle. cck8 experiments demonstrated that overexpression of CHROMR increased cell proliferation. Western Blot (WB) experiments confirmed that overexpression of CHROMR reduced the expression of apoptosis-related proteins. Dual-luciferase and recovery experiments suggested that CHROMR acted through the CHROMR/hsa-miR-1299/CNNM1 pathway. Conclusions: lncRNA CHROMR promotes the expression of the CNNM1 gene by adsorbing hsa-miR-1299 to obtain drug resistance in diffuse large B lymphoma cells.

SGK1 mutation status can further stratify patients with germinal center B-cell-like diffuse large B-cell lymphoma into different prognostic subgroups.

There are over a 100 driver gene mutations in patients with diffuse large B-cell lymphoma (DLBCL), but their clinical significance remains unclear. Here, we first analyzed the DLBCL dataset from the UK-based Haematological Malignancy Research Network. Patients were divided into high- and low-risk groups based on whether lymphoma progressed within 24 months. Genes showing significantly different frequencies between groups were selected. Survival data for patients with the selected mutant genes were analyzed. The results were validated using two other large databases to evaluate the relationship between the selected mutant genes and prognosis. The mutation frequencies of 11 genes (MYD88[L265P], SGK1, MPEG1, TP53, SPEN, NOTCH1, ETV6, TNFRSF14, MGA, CIITA, and PIM1) significantly differed between the high- and low-risk groups. The relationships between these mutant genes and patient survival were analyzed. Patients who harbored SGK1 (serum and glucocorticoid-inducible kinase 1) mutations exhibited the best prognosis. Most patients with SGK1 mutation are germinal center B-cell (GCB) subtype. Among patients with GCB DLBCL, those harboring SGK1 mutations exhibited better prognosis than those without SGK1 mutations. Most SGK1 mutations were single-base substitutions, primarily scattered throughout the catalytic domain-encoding region. Multiple SGK1 mutations were identified in a single patient. Thus, SGK1 mutations are a marker of good prognosis for DLBCL and occur predominantly in the GCB subtype of DLBCL. SGK1 mutation status can further stratify patients with GCB DLBCL into different prognostic subgroups.

[Analysis of Clinical Characteristics and Prognostic Factors of Patients with Limited-Stage Mantle Cell Lymphoma].

OBJECTIVE: To investigate the clinical characteristics, prognostic factors, and treatment outcomes of patients with limited-stage (Ann Arbor stage I or II) mantle cell lymphoma (MCL). METHODS: Examining consecutive the clinical characteristics, treatment outcomes and prognostic factors of 47 patients with stage I or II MCL diagnosed in Affiliated Tumor Hospital of Guangxi Medical University from January 2005 to June 2020 were analyzed retrospectively. RESULTS: The median age of patients was 62(37-78) years old. 36 patients were male, accounting for 76.6% of the whole. Among these, 74.5% (n=35) of the diagnoses were estimated at II stage. According to Mantle cell lymphoma International Prognostic Index (MIPI), 28 patients (59.6%) were classified as low risk. Patients who received first-line treatment and could be evaluated received rituximab combined chemotherapy, chemotherapy alone, cytarabine containing chemotherapy or chemotherapy combined with local radiotherapy, the different first-line therapies did not affect the complete response (CR) rate of patients (P＞0.05). The median follow-up time was 81.5 months, the 5-year progression-free survival (PFS) was 37.4% and the 5-year overall survival (OS) rate was 80.6%. Multivariate analysis showed that Ki-67＞30% (P＜0.05) the independent adverse prognostic factor for PFS and OS. CONCLUSION: Limited-stage MCL is rare. Patients with limited-stage MCL had a better outcome than those with III-IV stage MCL. Patients with limited-stage MCL whose Ki-67≤30% had better PFS and OS.

Application Value of Combined Detection of NLR, PNI, D-Dimer, CD3+ T Lymphocytes, and CEA in Colorectal Cancer Screening.

Objective: To investigate the application value of combined detection of neutrophil-lymphocyte ratio (NLR), prognostic nutrition index (PNI), D-dimer (D-D), CD3+ T lymphocytes (CD3+ T), and carcinoembryonic antigen (CEA) in colorectal cancer screening. Methods: The study cohort comprised 187 colorectal cancer patients and 100 mixed hemorrhoids patients as controls from January 2019 to August 2021 at the Fifth Affiliated Hospital of Sun Yat-sen University. Comparing the levels of NLR, PNI, D-D, CD3+ T, and CEA between the two groups of subjects, drawing receiver operating characteristic (ROC) curve evaluates the efficacy of single and combined detection for colorectal cancer screening. Results: Compared with the control group, the levels of NLR, D-D, and CEA in the colorectal cancer group were significantly increased, while the levels of PNI and CD3+ T were significantly decreased (P < 0.05). ROC curve analysis showed that the combined detection of NLR, PNI, D-D, CD3+ T, and CEA for colorectal cancer screening had an AUCROC of 0.943, a sensitivity of 84.49%, a specificity of 91.00%, and a Youden index of 0.75, and its screening efficacy was significantly superior to that of a single detection (P < 0.001). Conclusion: The combined detection of NLR, PNI, D-D, CD3+ T, and CEA has a high clinical application value for colorectal cancer and can provide a reference for early screening and auxiliary diagnosis of colorectal cancer.

Gene set-based identification of two immune subtypes of diffuse large B cell lymphoma for guiding immune checkpoint blocking therapy.

Background: Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma in adults. Tumour microenvironment is closely related to tumour prognosis and immune checkpoint blocking therapy (ICBT). This study aimed to investigate the immunological and prognostic characteristics of the tumour microenvironment (TME), as well as the regulatory mechanisms. Methods: Gene expression profiles and clinical data of patients with DLBCL were obtained from GEO database. ESTIMATE, CIBERSORT, and ssGSEA analyses were used to explore microenvironment characteristics and regulatory mechanism of the immune subtypes, which were identified by consistent clustering. The differences in enriched pathways were showed by GSEA. Hub genes associated with CD8+ T cells, which were identified by WCGNA, were exhibited biological functions through GO and KEGG. Immune-related gene scores (IRGSs) based on hub genes were used to evaluate the prediction of immune subtypes and ICBT, and retrospective analysis was used for validation. Finally, prognostic genes were screened to construct risk models. Results: Consensus clustering divided patients with DLBCL into two subtypes with significant heterogeneities in prognosis and immune microenvironment. Low immune infiltration was associated with poor prognosis. Subtype C1 with high immune infiltration was enriched in multiple immune pathways. We observed that two common mutated genes (B2M and EZH2) in DLBCL were closely related to MHC-I and microenvironment. Our further analysis manifested that MYD88L265P may be the main cause of TLR signalling pathway activation in subtype C1. Hub genes (SH2D1A, CD8A, GBP2, ITK, CD3D, RORA, IL1R2, CD28, CD247, CD3G, PRKCQ, CXCR6, and CD3E) in relation with CD8+ T cells were used to establish IRGS, which was proved an accurate predictor of immune subtypes, and patients in high-IRGS group were more likely to benefit from ICBT. Retrospective analysis showed that absolute lymphocyte count (ALC) was higher in the group that responded to the PD-1 inhibitor. Finally, the risk model was constructed based on two genes (CD3G and CD3D), and the low-risk group showed better prognosis. Conclusion: DLBCL immune classifications with highly heterogeneity are a powerful predictor of prognosis and ICBT. The IRGS is proved to be a reliable tool to distinguish immune subtypes as a substitute for gene expression profile.

Diagnostic accuracy of pelvic magnetic resonance imaging for the assessment of bone marrow involvement in diffuse large B-cell lymphoma.

PURPOSE: We investigated the efficacy of pelvic magnetic resonance imaging (MRI) in the diagnosis of bone marrow involvement (BMinv) in diffuse large B-cell lymphoma (DLBCL) patients. PATIENTS AND METHODS: This was a retrospective study of data from a previous study (NCT02733887). We included 171 patients who underwent bone marrow biopsy (BMB) and bone marrow smear (BMS), pelvic MRI, and whole-body positron emission tomography-computed tomography (PET/CT) from January 2016 to December 2019 at a single center. BMB/BMS and whole-body PET/CT results were used as reference standards against which we calculated the diagnostic value of pelvic MRI for BMinv in DLBCL patients. A chi-square test was used to compare detection rates, and a receiver operating characteristic curve was used to evaluate diagnostic value of pelvic MRI. Propensity-score matching was performed according to clinical information, and Kaplan-Meier curves were constructed to compare progression-free survival (PFS) and overall survival (OS) of patients. RESULTS: The BMinv detection rate of pelvic MRI (42/171) was higher (P = 0.029) than that of BMB/BMS (25/171), and similar to that of PET/CT (44/171; P = 0.901). The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of pelvic MRI were 83.33%, 98.37%, 94.15%, 95.24%, and 93.80%, respectively. Median PFS values were as follows: BMB/BMS-positive, 17.8 months vs. BMB/BMS-negative, 26.9 months (P = 0.092); PET/CT-positive, 24.8 months vs. PET/CT-negative, 33.0 months (P = 0.086); pelvic MRI-positive, 24.9 months vs. pelvic MRI-negative, 33.1 months (P<0.001). Median OS values were as follows: BMB/BMS-positive, 22.3 months vs. BMB/BMS-negative, 29.8 months (P = 0.240); PET/CT-positive, 27.9 months vs. PET/CT-negative, 33.9 months (P = 0.365); pelvic MRI-positive, 27.3 months vs. pelvic MRI-negative, 35.8 months (P = 0.062). CONCLUSION: Pelvic MRI is effective for detecting BMinv in DLBCL patients, providing a more accurate indication of PFS than BMB/BMS and PET/CT do. It may ultimately be used to improve the accuracy of clinical staging, guide patient treatment, and evaluate prognosis.

A new 7-gene survival score assay for pancreatic cancer patient prognosis prediction.

Gene expression features that are valuable for pancreatic ductal adenocarcinoma (PDAC) prognosis are still largely unknown. We aimed to explore pivotal molecular signatures for PDAC progression and establish an efficient survival score to predict PDAC prognosis. Overall, 163 overlapping genes were identified from three statistical methods, including differentially expressed genes (DEGs), coexpression network analysis (WGCNA), and target genes for miRNAs that were significantly related to PDAC patients' overall survival (OS). Then, according to the optimal value of the cross-validation curve (lambda = 0.031), 7 non-zero coefficients (ARNTL2, DSG3, PTPRR, ANLN, S100A14, ANKRD22, and TSPAN7) were selected to establish a prognostic prediction model of PDAC patients. We further confirmed the expression level of 7 genes using RT-PCR, western blot, and immunohistochemistry staining in PDAC patients' tissues. Our results showed that the ROC curve of the 7-mRNA model indicated good predictive ability for 1- and 2-year OS in three datasets (TCGA: 0.71, 0.69; ICGC: 0.8, 0.74; GEO batch: 0.61, 0.7, respectively). The hazard ratio (HR) of the low-risk group had a similar significant result (TCGA: HR = 0.3723; ICGC: HR = 0.2813; GEO batch: HR = 0.4999; all P < 0.001). Furthermore, Log-rank test results in three cohorts showed that the 7-mRNA assay excellently predicted the prognosis and metastasis, especially in TNM stage I&II subgroups of PDAC. In conclusion, the strong validation of our 7-mRNA signature indicates the promising effectiveness of its clinical application, especially in patients with TNM stages I&II.

A novel prognostic model for angioimmunoblastic T-cell lymphoma: A retrospective study of 55 cases.

OBJECTIVE: To explore prognostic factors and develop an accurate prognostic prediction model for angioimmunoblastic T-cell lymphoma (AITL). METHODS: Clinical data from Chinese patients with newly diagnosed AITL were retrospectively analysed. Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan-Meier method survival curves; prognostic factors were determined using a Cox proportional hazards model. The sensitivity and specificity of the predicted survival rates were compared using area under the curve (AUC) of receiver operating characteristic (ROC) curves. RESULTS: The estimated 5-year OS and PFS of 55 eligible patients with AITL were 22% and 3%, respectively. Multivariate analysis showed that the presence of pneumonia, and serous cavity effusions at initial diagnosis were significant prognostic factors for OS. Based on AUC ROC values, our novel prognostic model was superior to IPI and PIT based models and suggested better diagnostic accuracy. CONCLUSIONS: Our prognostic model based on pneumonia, and serous cavity effusions at initial diagnosis enabled a balanced classification of AITL patients into different risk groups.

CAR T cells targeting CD99 as an approach to eradicate T-cell acute lymphoblastic leukemia without normal blood cells toxicity.

CAR T cell therapy has shown dramatic clinical success in relapsed or refractory B-ALL and other hematological malignancies. However, the loss of specific antigens, cell fratricide, T cell aplasia, and normal T cell separation are challenges in treating T cell leukemia/lymphoma with CAR T therapy. CD99 is a promising antigen to target T-ALL and AML as it is strongly expressed on the majority of T-ALL and AML. Here, we isolated a low-affinity CD99 (12E7) antibody, which specifically recognizes leukemia cells over normal blood cells. Moreover, T cells transduced with an anti-CD99-specific CAR that contained the 12E7 scFv expanded with minor fratricide and without normal blood cells toxicity. We observed that our anti-CD99 CAR T cells showed robust cytotoxicity specifically against CD99+ T-ALL cell lines and primary tumor cells in vitro and significantly prolonged cell line-derived xenografts (CDXs) or patient-derived xenografts (PDXs) models survival in vivo. Together, our results demonstrate that anti-CD99 CAR T cells could specifically recognize and efficiently eliminate CD99+ leukemia cells.

Efficacy and safety of geptanolimab (GB226) for relapsed or refractory peripheral T cell lymphoma: an open-label phase 2 study (Gxplore-002).

BACKGROUND: Peripheral T cell lymphoma (PTCL) is a rare disease and recent approved drugs for relapsed/refractory (r/r) PTCL provided limited clinical benefit. We conducted this study to evaluate the efficacy and safety of geptanolimab (GB226), an anti-PD-1 antibody, in r/r PTCL patients. METHODS: We did this single-arm, multicenter phase 2 study across 41 sites in China. Eligible patients with r/r PTCL received geptanolimab 3 mg/kg intravenously every 2 weeks until disease progression or intolerable toxicity. All patients who received at least one dose of geptanolimab and histological confirmed PTCL entered full analysis set (FAS). The primary endpoint was objective response rate (ORR) in FAS assessed by the independent radiological review committee (IRRC) per Lugano 2014 criteria. RESULTS: Between July 12, 2018, and August 15, 2019, 102 patients were enrolled and received at least one dose of geptanolimab. At the data cutoff date (August 15, 2020), the median follow-up was 4.06 (range 0.30-22.9) months. For 89 patients in FAS, 36 achieved objective response (40.4%, 95% CI 30.2-51.4), of which 13 (14.6%) were complete response and 23 (25.8%) had partial response assessed by IRRC. The median duration of response (DOR) was 11.4 (95% CI 4.8 to not reached) months per IRRC. Patients with PD-L1 expression ≥ 50% derived more benefit from geptanolimab treatment compared to < 50% ones (ORR, 53.3% vs. 25.0%, p = 0.013; median PFS 6.2 vs. 1.5 months, p = 0.002). Grade ≥ 3 treatment-related adverse events occurred in 26 (25.5%) patients, and the most commonly observed were lymphocyte count decreased (n = 4) and platelet count decreased (n = 3). Serious adverse events were observed in 45 (44.1%) patients and 19 (18.6%) were treatment related. CONCLUSIONS: In this study, geptanolimab showed promising activity and manageable safety profile in patients with r/r PTCL. Anti-PD-1 antibody could be a new treatment approach for this patient population. TRIAL REGISTRATION: This clinical trial was registered at the ClinicalTrials.gov (NCT03502629) on April 18, 2018.