Sequential CD7 CAR T-Cell Therapy and Allogeneic HSCT without GVHD Prophylaxis.

BACKGROUND: Patients with relapsed or refractory hematologic cancers have a poor prognosis. Chimeric antigen receptor (CAR) T-cell therapy as a bridge to allogeneic hematopoietic stem-cell transplantation (HSCT) has the potential for long-term tumor elimination. However, pre-HSCT myeloablation and graft-versus-host disease (GVHD) prophylaxis agents have toxic effects and could eradicate residual CAR T cells and compromise antitumor effects. Whether the integration of CAR T-cell therapy and allogeneic HSCT can preserve CAR T-cell function and improve tumor control is unclear. METHODS: We tested a novel "all-in-one" strategy consisting of sequential CD7 CAR T-cell therapy and haploidentical HSCT in 10 patients with relapsed or refractory CD7-positive leukemia or lymphoma. After CAR T-cell therapy led to complete remission with incomplete hematologic recovery, patients received haploidentical HSCT without pharmacologic myeloablation or GVHD prophylaxis drugs. Toxic effects and efficacy were closely monitored. RESULTS: After CAR T-cell therapy, all 10 patients had complete remission with incomplete hematologic recovery and grade 4 pancytopenia. After haploidentical HSCT, 1 patient died on day 13 of septic shock and encephalitis, 8 patients had full donor chimerism, and 1 patient had autologous hematopoiesis. Three patients had grade 2 HSCT-associated acute GVHD. The median follow-up was 15.1 months (range, 3.1 to 24.0) after CAR T-cell therapy. Six patients remained in minimal residual disease-negative complete remission, 2 had a relapse of CD7-negative leukemia, and 1 died of septic shock at 3.7 months. The estimated 1-year overall survival was 68% (95% confidence interval [CI], 43 to 100), and the estimated 1-year disease-free survival was 54% (95% CI, 29 to 100). CONCLUSIONS: Our findings suggest that sequential CD7 CAR T-cell therapy and haploidentical HSCT is safe and effective, with remission and serious but reversible adverse events. This strategy offers a feasible approach for patients with CD7-positive tumors who are ineligible for conventional allogeneic HSCT. (Funded by the National Natural Science Foundation of China and the Key Project of Science and Technology Department of Zhejiang Province; ClinicalTrials.gov numbers, NCT04599556 and NCT04538599.).

miR-375-3p/YWHAZ/ß-catenin axis regulates migration, invasion, EMT in gastric cancer cells.

YWHAZ (14-3-3ζ) plays crucial roles in regulating proliferation, apoptosis, migration, and invasion of gastric cancer (GC) cells. However, its extensive roles and potential mechanisms in GC cells remain unknown, and need to be researched deeply. In this study, we focus on the role of miR-375/YWHAZ axis in migration, invasion and epithelial-to-mesenchymal transition (EMT) of GC cells. YWHAZ level was assessed by western blot and qPCR assays in GC cells. Scratch and transwell assays were used to determine the migration and invasion of GC cells. The protein levels of correlative molecules were detected by western blot. The regulation of miR-375 on the expression of its target gene YWHAZ was verified by dual-luciferase report system. According to the results, knockdown of YWHAZ inhibited the migration, invasion and EMT of GC cells. Moreover, silencing of YWHAZ restrained the activation of wnt/ß-catenin signalling pathway. YWHAZ was confirmed to be a target gene of miR-375, and its expression was regulated by miR-375 in GC cells. Transfection of miR-375 inhibitor promoted the migration, invasion, EMT and activation of wnt/ß-catenin pathway in GC cells, which was suppressed by inhibition of YWHAZ. Taken together, this study suggests that miR-375/YWHAZ axis may be served as a novel therapeutic target for GC patients.

Application of the Hepatic Transit Time (HTT) in Evaluation of Portal Vein Pressure in Gastroesophageal Varices Patients.

OBJECTIVES: To analyze the clinical significance of using hepatic transit time (HTT) to evaluate portal vein pressure in gastroesophageal varices patients. METHODS: For the observation group, we enrolled 50 gastroesophageal varices patients who had received esophagogastric variceal embolization in our hospital between January 2015 and February 2018. Patients without liver disease populated the control group and were recruited during the same time period. All patients underwent contrast-enhanced sonography. In the observation group, free portal pressure (FPP) was detected during esophagogastric variceal embolization with ultrasound guidance. Differences in hepatic artery-hepatic vein transit time (HA-HVTT), portal vein-hepatic vein transit time (PV-HVTT), and parenchyma-hepatic vein transit time (PA-HVTT) were compared between groups. Correlations between HA-HVTT, PV-HVTT, PA-HVTT, and FPP in the observation group were analyzed using the Pearson coefficient and linear regression analysis. RESULTS: HA-HVTT (t = 5.078; P < .001), PV-HVTT (t = 12.163; P < .001), and PA-HVTT (t = 2.649; P = .009) within the observation group were significantly lower than those of the control group. The areas under the curve of HTT were 0.771 (HA-HVTT), 0.951 (PV-HVTT), and 0.652 (PA-HVTT), and the sensitivity and specificity of PV-HVTT at 7.99 seconds were 86.0% and 88.0%, respectively. The HA-HVTT (r = -0.799; P < .001), PV-HVTT (r = -0.554; P < .001), and PA-HVTT (r = -0.735; P < .001) negatively correlated to FPP in the observation group. Linear regression analysis showed y = -0.410x + 7.254 (HA-HVTT and FPP), y = -0.335x + 4.983 (PV-HVTT and FPP), and y = -0.566x + 4.997 (PA-HVTT and FPP) in the observation group. CONCLUSION: Compared with the control patients, the HTT of patients with portal hypertension-esophagogastric varices was significantly shorter, and showed an inverse relationship with FPP.

Pancreatic Elastography From Acoustic Radiation Force Impulse Imaging for Evaluation of Diabetic Microangiopathy.

OBJECTIVE: The purposes of this study were to compare pancreatic shear-wave velocity (SWV) in subjects with and those without diabetic microvascular complications and to investigate the feasibility of pancreatic SWV in evaluating diabetic microangiopathy. SUBJECTS AND METHODS: SWV measurements were prospectively performed in 115 patients with diabetes mellitus and 115 healthy persons by use of acoustic radiation force impulse imaging. Patients with diabetes were divided into subgroups with and without microangiopathy. Pancreatic SWV was compared in three groups. Factors associated with increased SWV were studied. RESULTS: Pancreatic SWV increased significantly in the subgroups with diabetes mellitus compared with the control group (p < 0.01). Especially, the SWV in the pancreatic body was significantly higher when microangiopathy was present (p < 0.01). In patients with diabetes, microangiopathy (standardized ß = 0.208, p = 0.022), age (standardized ß = 0.265, p = 0.004), and total cholesterol level (standardized ß = 0.223, p = 0.011) were positively and markedly correlated with high SWV in the pancreatic body. CONCLUSION: The increased SWV in the pancreatic body was significantly related to the presence of microangiopathy. It is feasible to use SWV in the pancreatic body to evaluate diabetic microangiopathy.

A wide-necked extracranial internal carotid artery saccular aneurysm with ipsilateral proximal compression.

Extracranial internal carotid artery aneurysms (EICAA) are rare and can elicit various neurologic symptoms. Here, we present a case of a saccular EICAA compressing its proximal parent internal carotid artery (ICA). Ultrasonography demonstrated the proximal ICA stenosis and the "tardus-parvus" Doppler waveform downstream. The patient underwent aneurysmectomy and graft interposition. The histologic analysis highly supported an atypical fibromuscular dysplasia. Although this patient only showed a neck mass, the reduced ipsilateral cerebral blood supply was a potential cause for neurologic symptoms. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 45:116-120, 2017.

A new approach to overcoming resistance to immunotherapy: nanotechnology.

Immunotherapy for immune response has ushered in a new era of cancer treatment. In recent years, new immunotherapeutic agents have been introduced into clinical trials and even approved for marketing. However, the widespread use of immunotherapeutic agents faces an unavoidable challenge: immunotherapy does not work at all for some patients, or has good efficacy in the initial phase, but immunotherapy resistance develops within a short period of time, and immunotherapy can also cause serious adverse effects such as autoimmune inflammation and non-specific inflammation. How to enable patients to overcome drug resistance, reduce the toxic side effects of drugs, enhance patient compliance and improve patient survival has become a problem that clinicians have to face. The advent of nanotechnology provides an encouraging platform for immunotherapy. It can not only improve the bioavailability and stability of drugs and reduce toxic side effects, but also reduce resistance to immunotherapy. Here, we discuss these research advances and discuss potential challenges and future directions.

Cost-effectiveness analysis of toripalimab for metastatic or recurrent triple-negative breast cancer.

Background: Toliparibizumab in combination with nab-paclitaxel (T+N) has excellent efficacy inmetastatic or recurrent triple-negative breast cancer (TNBC), but the optimal choice of sequence of therapy is unclear given the trade-offs between quality of life and cost. Cost-effectiveness analyses can quantify these tradeoffs, leading to more informed decisions. Our objective was to assess the societal cost-effectiveness of the T+N regimen for metastatic or recurrent TNBC. Methods: Clinical data were extracted from a multicenter, randomized, double-blind trial, TORCHLIGHT (NCT04085276). Patients were randomized into the T+N group or placebo plus nab-paclitaxel (P+N) group. 531 patients from 53 study locations were randomly assigned (T+N, n=353; P+N, n=178) into intend to treat (ITT) population; 200 and 100 patients, respectively had programmed death protein 1 (PD-L1) positive TNBC. A Markov model was established with a 21-day cycle length. Costs were acquired from local hospitals, effect parameters included quality-adjusted life year (QALY) and incremental cost-effectiveness ratio (ICER). Results: The cost differences were 47,538.3 CNY in ITT population (T+N, 143,725.67 CNY; P+N group, 96,187.37 CNY) and 29,258.84 CNY in PD-L1+ subgroup (T+N, 100,128.28 CNY; P+N group, 70,869.45 CNY). Meanwhile, the IEs were 0.03409 in the ITT population (T+N, 0.55323 QALY; P+N, 0.51914 QALY) and 0.03409 in the PD-L1+ subgroup (T+N, 0.42327 QALY; P+N, 0.37628 QALY). The ICERs between T+N and P+N groups were 1,394,548.41 CNY/QALY in the ITT population and 622,663.98 CNY/QALY in the PD-L1+ subgroup. We also analyzed the cost-effectiveness of toripalimab could be received in the Chinese medical insurance catalog. If toripalimab could be reimbursed at an 80% rate, the cost differences were changed to 16,598.99 CNY in ITT population (T+N, 112,786.36 CNY; P+N group, 96,187.37 CNY) and 7,704.58 CNY in PD-L1+ subgroup (T+N, 78,574.03 CNY; P+N group, 70,869.45 CNY). Meanwhile, the IEs remained unchanged. The ICERs between T+N and P+N groups were changed to 486,935.82 CNY/QALY in the ITT population and 163,962.96 CNY/QALY in the PD-L1+ subgroup. Sensitivity analyses indicated the stability of the model and the impact of utility. Conclusion: At current drug prices, the T+N group is not more cost-effective than the P+N group, but after incorporating toripalimab into medical insurance, the T+N group will be more cost-effective for patients with PD-L1+ metastatic or recurrent triple-negative breast cancer.

A preliminary study of changes in carotid artery elasticity in type 2 diabetes mellitus.

BACKGROUND: Carotid stiffening is found to be present in patients with type 2 diabetes mellitus (T2DM) together with endothelial dysfunction and it remains unclear about the role of carotid elasticity in the development of diabetic vascular damage. The aim of the study was to investigate changes and significance of carotid artery elasticity in diabetic patients with or without microvascular complications using velocity vector imaging (VVI) analysis. METHODS: Fifty participants were enrolled and divided into health Control group, the uncomplicated DM (uDM) group and the complicated DM (cDM) group. All of them underwent carotid ultrasound examinations. VVI was used to evaluate the common carotid artery (CCA) elasticity and intima-media thickness (IMT) was also measured. Flow-mediated dilation (FMD) was performed to detect the vascular endothelial function. Then differences and correlations of variables between three groups were compared and analyzed. RESULTS: CCA elasticity measured by VVI decreased significantly between three groups (p < 0.05), while FMD decreased significantly only in cDM group (p < 0.01) and only IMT in cDM group was significantly thicker than that of Control group (p < 0.05). Representative VVI variables were independently, negatively related to the known duration and microalbuminuria (p < 0.05). All VVI variables were significantly correlated with FMD (0.5 ≤ |r | <0.8, p < 0.001), and just a small part of VVI variables were significantly correlated with IMT (0.3 ≤ |r | <0.5, p < 0.05). CONCLUSION: Compared with FMD, CCA elasticity measured by VVI showed more obvious changes in diabetic patients with different levels of vascular damage and may be considered as an alternative indicator in evaluating arterial status of T2DM.

Antitumor therapy for breast cancer: Focus on tumor-associated macrophages and nanosized drug delivery systems.

BACKGROUND: In breast cancer (BC), tumor-associated macrophages (TAMs) are an important component of the tumor microenvironment and are closely related to poor prognosis. A growing number of studies have focused on the role of TAMs in BC progression and therapeutic strategies targeting TAMs. As an emerging treatment, the application of nanosized drug delivery systems (NDDSs) in the treatment of BC by targeting TAMs has attracted much attention. AIMS: This review is to summarize the characteristics and treatment strategies targeting TAMs in BC and to clarify the applications of NDDSs targeting TAMs in the treatment of BC by targeting TAMs. MATERIALS & METHODS: The existing results related to characteristics of TAMs in BC, BC treatment strategies by targeting TAMs, and the applications of NDDSs in these strategies are described. Through analyzing these results, the advantages and disadvantages of the treatment strategies using NDDSs are discussed, which could provide advices on designing NDDSs for BC treatment. RESULTS: TAMs are one of the most prominent noncancer cell types in BC. TAMs not only promote angiogenesis, tumor growth and metastasis but also lead to therapeutic resistance and immunosuppression. Mainly four strategies have been used to target TAMs for BC therapy, which include depleting macrophages, blocking recruitment, reprogramming to attain an anti-tumor phenotype, and increasing phagocytosis. Since NDDSs can efficiently deliver drugs to TAMs with low toxicity, they are promising approaches for targeting TAMs in tumor therapy. NDDSs with various structures can deliver immunotherapeutic agents and nucleic acid therapeutics to TAMs. In addition, NDDSs can realize combination therapies. DISCUSSION: TAMs play a critical role in the progression of BC. An increasing number of strategies have been proposed to regulate TAMs. Compared with free drugs, NDDSs targeting TAMs improve drug concentration, reduce toxicity and realize combination therapies. However, in order to achieve better therapeutic efficacy, there are still some disadvantages that need to be considered in the design of NDDSs. CONCLUSION: TAMs play an important role in the progression of BC, and targeting TAMs is a promising strategy for BC therapy. In particular, NDDSs targeting TAMs have unique advantages and are potential treatments for BC.

Nogo-B receptor increases glycolysis and the paclitaxel resistance of estrogen receptor-positive breast cancer via the HIF-1α-dependent pathway.

Chemotherapy can improve the prognosis and overall survival of breast cancer patients, but chemoresistance continues a major problem in clinical. Most breast cancer is estrogen receptor (ER) positive but responds less to neoadjuvant or adjuvant chemotherapy than ER-negative breast cancer. The Nogo-B receptor (NgBR) increases the chemoresistance of ER-positive breast cancer by facilitating oncogene signaling pathways. Here, we further investigated the potential role of NgBR as a novel target to overcome glycolysis-dependent paclitaxel resistance in ER-positive breast cancer. NgBR knockdown inhibited glycolysis and promoted paclitaxel-induced apoptosis by attenuating HIF-1α expression in ER-positive breast cancer cells via NgBR-mediated estrogen receptor alpha (ERα)/hypoxia-inducible factor-1 alpha (HIF-1α) and nuclear factor-kappa B subunit (NF-κB)/HIF-1α signaling pathways. A ChIP assay further confirmed that NgBR overexpression not only facilitates ERα binding to HIF-1α and GLUT1 genes but also promotes HIF-1α binding to GLUT1, HK2, and LDHA genes, which further promotes glycolysis and induces paclitaxel resistance. In conclusion, our study suggests that NgBR expression is essential for maintaining the metabolism and paclitaxel resistance of ER-positive breast cancer, and the NgBR can be a new therapeutic target for improving chemoresistance in ER-positive breast cancer.

Deletion of Slc26a6 alters the stoichiometry of apical Cl-/HCO-3 exchange in mouse pancreatic duct.

To define the stoichiometry and molecular identity of the Cl(-)/HCO(3)(-) exchanger in the apical membrane of pancreatic duct cells, changes in luminal pH and volume were measured simultaneously in interlobular pancreatic ducts isolated from wild-type and Slc26a6-null mice. Transepithelial fluxes of HCO(3)(-) and Cl(-) were measured in the presence of anion gradients favoring rapid exchange of intracellular HCO(3)(-) with luminal Cl(-) in cAMP-stimulated ducts. The flux ratio of Cl(-) absorption/HCO(3)(-) secretion was ∼0.7 in wild-type ducts and ∼1.4 in Slc26a6(-/-) ducts where a different Cl(-)/HCO(3)(-) exchanger, most likely SLC26A3, was found to be active. Interactions between Cl(-)/HCO(3)(-) exchange and cystic fibrosis transmembrane conductance regulator (CFTR) in cAMP-stimulated ducts were examined by measuring the recovery of intracellular pH after alkali-loading by acetate prepulse. Hyperpolarization induced by luminal application of CFTRinh-172 enhanced HCO(3)(-) efflux across the apical membrane via SLC26A6 in wild-type ducts but significantly reduced HCO(3)(-) efflux in Slc26a6(-/-) ducts. In microperfused wild-type ducts, removal of luminal Cl(-), or luminal application of dihydro-4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid to inhibit SLC26A6, caused membrane hyperpolarization, which was abolished in Slc26a6(-/-) ducts. In conclusion, we have demonstrated that deletion of Slc26a6 alters the apparent stoichiometry of apical Cl(-)/HCO(3)(-) exchange in native pancreatic duct. Our results are consistent with SLC26A6 mediating 1:2 Cl(-)/HCO(3)(-) exchange, and the exchanger upregulated in its absence, most probably SLC26A3, mediating 2:1 exchange.

Activatable "Matryoshka" nanosystem delivery NgBR siRNA and control drug release for stepwise therapy and evaluate drug resistance cancer.

Drug resistance is always a challenge in conquering breast cancer clinically. Recognition of drug resistance and enhancing the sensitivity of the tumor to chemotherapy is urgent. Herein, a dual-responsive multi-function "Matryoshka" nanosystem is designed, it activates in the tumor microenvironment, decomposes layer by layer, and release gene and drug in sequence. The cell is re-educated by NgBR siRNA first to regain the chemosensitivity through regulating the Akt pathway and inhibit ERα activation, then the drugs loaded in the core are controlled released to killing cells. Carbonized polymer dots are loaded into the nanosystem as an efficient bioimaging probe, due to the GE11 modification, the nanosystem can be a seeker to recognize and evaluate drug-resistance tumors by photoacoustic imaging. In the tumor-bearing mouse, the novel nanosystem firstly enhances the sensitivity to chemotherapy by knockdown NgBR, inducing a much higher reduction in NgBR up to 52.09%, then effectively inhibiting tumor growth by chemotherapy, tumor growth in nude mouse was inhibited by 70.22%. The nanosystem also can inhibit metastasis, prolong survival time, and evaluate tumor drug resistance by real-time imaging. Overall, based on regulating the key molecules of drug resistance, we created visualization nanotechnology and formatted new comprehensive plans with high bio-safety for tumor diagnosis and treatment, providing a personalized strategy to overcome drug resistance clinically.

Roles of Endothelial Motilin Receptor and Its Signal Transduction Pathway in Motilin-Induced Left Gastric Artery Relaxation in Dogs.

Background: Motilin increases left gastric artery (LGA) blood flow in dogs via the endothelial motilin receptor (MLNR). This article investigates the signaling pathways of endothelial MLNR. Methods: Motilin-induced relaxation of LGA rings was assessed using wire myography. Nitric oxide (NO), and cyclic guanosine monophosphate (cGMP) levels were measured using an NO assay kit and cGMP ELISA kit, respectively. Results: Motilin concentration-dependently (EC50=9.1±1.2×10-8M) relaxed LGA rings precontracted with U46619 (thromboxane A2 receptor agonist). GM-109 (MLNR antagonist) significantly inhibited motilin-induced LGA relaxation and the production of NO and cGMP. N-ethylmaleimide (NEM; G-protein antagonist), U73122 [phospholipase C (PLC) inhibitor], and 2-aminoethyl diphenylborinate [2-APB; inositol trisphosphate (IP3) blocker] partially or completely blocked vasorelaxation. In contrast, chelerythrine [protein kinase C (PKC) inhibitor] and H89 [protein kinase A (PKA) inhibitor] had no such effect. Low-calcium or calcium-free Krebs solutions also reduced vasorelaxation. N-nitro-L-arginine methyl ester [L-NAME; nitric oxide synthase (NOS) inhibitor] and ODQ [soluble guanylyl cyclase (sGC) inhibitor] completely abolished vasodilation and synthesis of NO and cGMP. Indomethacin (cyclooxygenase inhibitor), 18α-glycyrrhetinic acid [18α-GA; myoendothelial gap junction (MEGJ) inhibitor], and K+ channel inhibition through high K+ concentrations or tetraethylammonium (TEA-Cl; KCa channel blocker) partially decreased vasorelaxation, whereas glibenclamide (KATP channel blocker) had no such effect. Conclusion: The current study suggests that motilin-induced LGA relaxation is dependent on endothelial MLNR through the G protein-PLC-IP3 pathway and Ca2+ influx. The NOS-NO-sGC-cGMP pathway, prostacyclin, MEGJ, and K+ channels (especially KCa) are involved in endothelial-dependent relaxation of vascular smooth muscle (VSM) cells.

Differential expression of motilin receptors on the endothelium of dog gastrointestinal arteries and motilin-induced motilin receptor dependent relaxation of corresponding arteries.

BACKGROUND: Motilin's role in the regulation of vascular tone and hemodynamic besides gastrointestinal motility is concerned. This study aimed to investigate the expression of motilin receptors in gastrointestinal arteries and motilin-induced relaxation. MATERIAL AND METHODS: The expression of motilin receptors in the left gastric artery (LGA), superior mesenteric artery (SMA), and inferior mesenteric artery (IMA) of adult dogs (1.5-5 years old) were analyzed by immunochemistry, RT-PCR, and western blotting. Motilin's effects on the gastrointestinal arteries were evaluated in a multi-wire myograph system. RESULTS: Immunohistochemical staining showed that motilin receptor was expressed on the membranes of endothelial cells with the fluorescence intensity LGA > SMA > IMA (P < 0.01). The motilin receptor's mRNA and protein expression levels shared the same distribution patterns as it in fluorescence intensity (P < 0.01). In isolated LGA preparations precontracted with U46619 (a thromboxaneA2 analog), motilin induced a concentration-dependent relaxation, and the EC50 was 8.8 × 10-8 ± 0.9 × 10-8 M. Motilin-induced relaxation on the three arteries also shared the same pattern as it in fluorescence intensity (P < 0.01) and inhibited by denuded-endothelium and GM-109 (a motilin receptor antagonist) but not by atropine (a muscarinic receptor antagonist). CONCLUSIONS: Motilin receptors are expressed differentially on the membranes of endothelial cells in dog gastrointestinal arteries with a significantly high expression in the LGA. Motilin-induced relaxation is endothelium- and motilin receptor-dependent. The motilin receptor expressed on the endothelial cell membrane of the LGA is the molecular basis for motilin regulating gastric blood flow under physiological conditions in dogs.

Acute myeloid leukemia with CPSF6-RARG fusion resembling acute promyelocytic leukemia with extramedullary infiltration.

Some subtypes of acute myeloid leukemia (AML) share morphologic, immunophenotypic, and clinical features of acute promyelocytic leukemia (APL), but lack a PML-RARA (promyelocytic leukemia-retinoic acid receptor alpha) fusion gene. Instead, they have the retinoic acid receptor beta (RARB) or retinoic acid receptor gamma (RARG) rearranged. Almost all of these AML subtypes exhibit resistance to all-trans retinoic acid (ATRA); undoubtedly, the prognosis is poor. Here, we present an AML patient resembling APL with a novel cleavage and polyadenylation specific factor 6 (CPSF6)-RARG fusion, showing resistance to ATRA and poor response to chemotherapy with homoharringtonine and cytarabine. Simultaneously, the patient also had extramedullary infiltration.

Corrigendum: Different Patient Subgroup Different Maintenance, Proteasome Inhibitors or Immunomodulators Maintenance for Newly Diagnosed Multiple Myeloma: A 7-Year Single-Center Data in China.

[This corrects the article DOI: 10.3389/fonc.2021.665217.].

Different Patient Subgroup Different Maintenance, Proteasome Inhibitors or Immunomodulators Maintenance for Newly Diagnosed Multiple Myeloma: A 7-Year Single-Center Date in China.

INTRODUCTION: We analyzed different patient subgroups to determine optimal maintenance therapy in newly diagnosed multiple myeloma (NDMM) patients. METHODS: A total of 226 NDMM patients in our center were included in the study. The characteristics, survival, and adverse reactions were compared among patients who received maintenance therapy or not, and patients who received proteasome inhibitors (PIs) or immunomodulators (IMiDs) maintenance. The survival of different maintenance durations of bortezomib-based regimens was also analyzed. RESULTS: The maintenance therapy not only upgraded more patient responses (34.3 vs 13.3%, P = 0.006), but also significantly prolonged their progression-free survival (PFS) (median PFS: 41.1 vs 10.5 months, P < 0.001) and overall survival (OS) (median OS: not reached vs 38.6 months, P < 0.001). Compared with IMiDs, the PFS (median PFS: 43.7 vs 38.5 months, P = 0.034) and OS (median OS: not reached vs 78.5 months, P = 0.041) were both enhanced by PIs maintenance. Patients younger than 65 years who received PIs had a significantly prolonged OS (P = 0.032). Patients achieving only a partial response (PR) after induction and consolidation therapy had significantly longer PFS and OS after PIs maintenance compared to IMiDs (P = 0.007, 0.002). High-risk patients (ISS 2-3, DS 2-3, and RISS 2-3) given PIs maintenance benefit from a prolonged PFS (P = 0.002, 0.02, 0.06) and OS (P = 0.059, 0.047, 0.044, respectively) compared with IMiDs therapy. OS was significantly prolonged in patients who received ≥ 12 months of bortezomib-based maintenance therapy compared to those who were treated for < 12 months (P < 0.001), but no difference was observed in OS between patients who received 12 to 24 or ≥ 24 months of bortezomib-based maintenance therapy (P = 0.292). CONCLUSION: PIs maintenance was superior to IMiDs in overall PFS and OS. The beneficial effect was most evident in patients achieving PR after induction and consolidation therapy, and in high-risk patients. Moreover, younger patients also benefited from PIs maintenance with an increased OS. A bortezomib-based maintenance therapy duration of 12 to 24 months after induction and consolidation therapy produced satisfactory OS.

Identification of a 7-mRNA signature as a prognostic biomarker in pediatric osteosarcoma.

BACKGROUND: The aim of the present study was to establish a prognostic model for the survival of children with osteosarcoma (OS). METHODS: The mRNA expression and clinical characteristics of pediatric patients with OS were extracted from the Therapeutically Available Research to Generate Effective Treatments (TARGET) database. After genes with differential mRNA expression were identified, univariate and multivariate Cox analyses were performed, and a prognostic model of pediatric OS was established. The prognostic values of a 7-mRNA signature were evaluated using the receiver-operating characteristic (ROC) curve in pediatric patients with OS. RESULTS: A total of 19,496 differentially expressed mRNAs were identified, including 267 upregulated mRNAs and 104 downregulated mRNAs. After univariate and multivariate Cox analyses, seven mRNA species (SCGB3A1, MUC17, ADH1B, KRT83, RP1-37E16.12, FIGF, and SFTPD) were found to be closely associated with survival. These mRNA species were mainly enriched in glycolysis/gluconeogenesis, arachidonic acid metabolism, cytokine-cytokine receptor interaction, neuroactive ligand-receptor interaction, tight junction, and complement and coagulation cascade pathways. A predictive model using the sum of independent prognostic values of the seven mRNA species as the risk score was proposed. The risk score was calculated as follows: risk score = 0.242257 × SCGB3A1 + 0.168999 × MUC17 + 0.415514 × ADH1B + 0.488864 × KRT83 + 0.360864 × RP1-37E16.12 - 0.2991 × FIGF - 0.39576 × SFTPD. Pediatric patients with OS were assigned to low- and high-risk groups based on the risk score. The ROC curve analysis showed that the 7-mRNA prediction model performed well [area under the curve (AUC): 0.858]. CONCLUSIONS: A 7-mRNA signature has the potential to predict the prognosis of pediatric patients with OS, and therefore warrants further validation.

The diagnostic accuracy of liver fibrosis in non-viral liver diseases using acoustic radiation force impulse elastography: A systematic review and meta-analysis.

BACKGROUND: Acoustic radiation force impulse (ARFI) imaging is an ultrasound-based elastography method that has been studied in the staging of hepatic fibrosis, especially in chronic hepatitis. However, the diagnostic accuracy of ARFI in non-viral hepatopathies, such as autoimmune hepatitis and non-alcoholic fatty liver disease, has not been systematically determined. AIM: To systematically assess the diagnostic accuracy of ARFI in non-viral hepatopathies. METHODS: The databases of PubMed, Embase, Cochrane Library and clinicaltrials.gov were systematically searched for candidate studies reporting the diagnostic accuracy of ARFI for hepatic fibrosis. The pooled estimates of the sensitivity, specificity, diagnostic odds ratio, and positive and negative likelihood ratios were calculated with the summary receiver operating curve (sROC) performed using STATA software. RESULTS: In detail, a total of 29 diagnostic studies were included for further analysis. The quality of the included studies was relatively high using QUADAS method. The pooled sensitivity and specificity were 0.79 (0.73, 0.83) and 0.81 (0.75, 0.86), with AUROC 0.87 (0.83, 0.89) for the staging of significant fibrosis (F≥2). Meanwhile, for the staging of severe fibrosis (F≥3), the pooled sensitivity and specificity were 0.92 (0.87, 0.95) and 0.85 (0.80, 0.89), with AUROC 0.94 (0.92, 0.96). Furthermore, the pooled sensitivity and specificity were 0.89 (0.79, 0.95) and 0.89 (0.85, 0.92), with AUROC 0.94 (0.92, 0.96) for ARFI in staging cirrhosis (F = 4), which were similar to the data for severe fibrosis. No significant publication bias was present in this study. CONCLUSION: This meta-analysis demonstrated that ARFI exerted satisfactory diagnostic performance in staging non-viral hepatic fibrosis, especially severe fibrosis (F≥3) and cirrhosis (F = 4).

Quantification of pancreatic elasticity in type 2 diabetes: A new potential imaging marker for evaluation of microangiopathy.

PURPOSE: The aim of this study was to noninvasively explore pancreatic morphological and mechanical changes in diabetic patients with or without microangiopathy and to investigate the clinical correlations of pancreatic stiffness or size with diabetic microangiopathy. METHODS: A total of 213 type 2 diabetic patients with / without microangiopathy (91/122) were prospectively enrolled. Microangiopathy included diabetic retinopathy, diabetic nephropathy and diabetic peripheral neuropathy. Each subject underwent pancreatic ultrasonography and elastography. The shear wave velocity (SWV) and thickness of the head, body and tail were measured and compared. Receiver operating characteristic (ROC) curves was performed in the diagnosis of microangiopathy. Risk factors of the occurrence of more microvascular complications were explored. RESULTS: The SWV in pancreas increased significantly in patients with microangiopathy (P < 0.01) while the thickness was similar in all patients. The area under ROC curve for the SWV in pancreatic body was greatest (0.747) and the sensitivity, specificity were 73.0, 70.9 %. There was a significant shift towards the occurrence of more microvascular complications for patients with increasing of the SWV in pancreatic body (OR 39.25), long duration of diabetes (OR 1.077), aging (OR 1.039) and elevation of microalbuminuria (OR 1.004). CONCLUSIONS: The SWV in pancreatic body was significantly high in diabetic patients with microangiopathy and was prominently correlated with the number of microvascular complications. The SWV in pancreatic body may be considered as a potential marker for diabetic microangiopathy and its occurrence.