Brain radiotherapy and anlotinib control primary cardiac angiosarcoma with metastases: A case report.

RATIONALE: Primary cardiac angiosarcoma (PCA) is a rare and fatal disease with a poor prognosis. Whether the survival of PCA patients can be prolonged with additional treatment following complete surgical excision is controversial. PATIENT CONCERNS: In this case study, a 52-year-old male complained of chest tightness and pain for 7 days before admission into the hospital. Subsequently, he revisited the hospital because of dizziness and headache. DIAGNOSES: Initially, the patient was diagnosed with PCA in the right atrium by thoracic computed tomography (CT). Palliative resection identified brain, lung, and liver metastases. INTERVENTION: The patient accepted multimodal combination therapy, including first-line chemotherapy and then second-line anlotinib concurrent with brain radiotherapy and immunotherapy. OUTCOME: Although anlotinib combined with brain radiotherapy controlled the growth of intracranial lesions, progression-free survival (PFS) was only 5 months, and the overall survival (OS) was only 12 months. LESSON: The treatment for metastatic PCA needs an in-depth exploration.

Dual-modal radiomics nomogram based on contrast-enhanced ultrasound to improve differential diagnostic accuracy and reduce unnecessary biopsy rate in ACR TI-RADS 4-5 thyroid nodules.

BACKGROUND: American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TI-RADS, TR) 4 and 5 thyroid nodules (TNs) demonstrate much more complicated and overlapping risk characteristics than TR1-3 and have a rather wide range of malignancy possibilities (> 5%), which may cause overdiagnosis or misdiagnosis. This study was designed to establish and validate a dual-modal ultrasound (US) radiomics nomogram integrating B-mode ultrasound (BMUS) and contrast-enhanced ultrasound (CEUS) imaging to improve differential diagnostic accuracy and reduce unnecessary fine needle aspiration biopsy (FNAB) rates in TR 4-5 TNs. METHODS: A retrospective dataset of 312 pathologically confirmed TR4-5 TNs from 269 patients was collected for our study. Data were randomly divided into a training dataset of 219 TNs and a validation dataset of 93 TNs. Radiomics characteristics were derived from the BMUS and CEUS images. After feature reduction, the BMUS and CEUS radiomics scores (Rad-score) were built. A multivariate logistic regression analysis was conducted incorporating both Rad-scores and clinical/US data, and a radiomics nomogram was subsequently developed. The performance of the radiomics nomogram was evaluated using calibration, discrimination, and clinical usefulness, and the unnecessary FNAB rate was also calculated. RESULTS: BMUS Rad-score, CEUS Rad-score, age, shape, margin, and enhancement direction were significant independent predictors associated with malignant TR4-5 TNs. The radiomics nomogram involving the six variables exhibited excellent calibration and discrimination in the training and validation cohorts, with an AUC of 0.873 (95% CI, 0.821-0.925) and 0.851 (95% CI, 0.764-0.938), respectively. The marked improvements in the net reclassification index and integrated discriminatory improvement suggested that the BMUS and CEUS Rad-scores could be valuable indicators for distinguishing benign from malignant TR4-5 TNs. Decision curve analysis demonstrated that our developed radiomics nomogram was an instrumental tool for clinical decision-making. Using the radiomics nomogram, the unnecessary FNAB rate decreased from 35.3 to 14.5% in the training cohort and from 41.5 to 17.7% in the validation cohorts compared with ACR TI-RADS. CONCLUSION: The dual-modal US radiomics nomogram revealed superior discrimination accuracy and considerably decreased unnecessary FNAB rates in benign and malignant TR4-5 TNs. It could guide further examination or treatment options.

Optimizing surgical outcomes for elderly gallstone patients with a high body mass index using enhanced recovery after surgery protocol.

BACKGROUND: Rehabilitation of elderly patients with a high body mass index (BMI) after cholecystectomy carries risks and requires the adoption of effective perioperative management strategies. The enhanced recovery after surgery (ERAS) protocol is a comprehensive treatment approach that facilitates early patient recovery and reduces postoperative complications. AIM: To compare the effectiveness of traditional perioperative management methods with the ERAS protocol in elderly patients with gallbladder stones and a high BMI. METHODS: This retrospective cohort study examined data from 198 elderly patients with a high BMI who underwent cholecystectomy at the Shanghai Fourth People's Hospital from August 2019 to August 2022. Among them, 99 patients were managed using the traditional perioperative care approach (non-ERAS protocol), while the remaining 99 patients were managed using the ERAS protocol. Relevant indicator data were collected for patients preoperatively, intraoperatively, and postoperatively, and surgical outcomes were compared between the two groups. RESULTS: The comparison results between the two groups of patients in terms of age, sex, BMI, underlying diseases, surgical type, and preoperative hospital stay showed no statistically significant differences. However, the ERAS group had a significantly shorter preoperative fasting time than the non-ERAS group (4.0 ± 0.9 h vs 7.6 ± 0.9 h). Regarding intraoperative indicators, there were no significant differences between the two groups of patients. However, in terms of postoperative recovery, the ERAS protocol group exhibited significant advantages over the non-ERAS group, including a shorter hospital stay, lower postoperative pain scores and postoperative hunger scores, and higher satisfaction levels. The readmission rate was lower in the ERAS protocol group than in the non-ERAS group (3.0% vs 8.1%), although the difference was not significant. Furthermore, there were significant differences between the two groups in terms of postoperative nausea and vomiting severity, postoperative abdominal distention at 24 h, and daily life ability scores. CONCLUSION: The findings of this study demonstrate that the ERAS protocol confers significant advantages in postoperative outcomes following cholecystectomy, including reduced readmission rates, decreased postoperative nausea and vomiting, alleviated abdominal distension, and enhanced functional capacity. While the protocol may not exhibit significant improvement in early postoperative symptoms, it does exhibit advantages in long-term postoperative symptoms and recovery. These findings underscore the importance of implementing the ERAS protocol in the postoperative management of cholecystectomy patients, as it contributes to improving patients' recovery and quality of life while reducing health care resource utilization.

Donor-derived CD19 CAR-T Cells versus Chemotherapy Plus Donor Lymphocyte Infusion for Treatment of Recurrent CD19-positive B-ALL After Allogeneic Hematopoietic Stem Cell Transplantation.

OBJECTIVE: This study aimed to compare the efficacy of anti-CD19 chimeric antigen receptor T cells (CAR-T cells) versus chemotherapy plus donor lymphocyte infusion (chemo-DLI) for treating relapsed CD19-positive B-cell acute lymphoblastic leukemia (B-ALL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: Clinical data of 43 patients with B-ALL who relapsed after allo-HSCT were retrospectively analyzed. Twenty-two patients were treated with CAR-T cells (CAR-T group), and 21 with chemotherapy plus DLI (chemo-DLI group). The complete remission (CR) and minimal residual disease (MRD)-negative CR rates, leukemia-free survival (LFS) rate, overall survival (OS) rate, and incidence of acute graft-versus-host disease (aGVHD), cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were compared between the two groups. RESULTS: The CR and MRD-negative CR rates in the CAR-T group (77.3% and 61.5%) were significantly higher than those in the chemo-DLI group (38.1% and 23.8%) (P=0.008 and P=0.003). The 1- and 2-year LFS rates in the CAR-T group were superior to those in the chemo-DLI group: 54.5% and 50.0% vs. 9.5% and 4.8% (P=0.0001 and P=0.00004). The 1- and 2-year OS rates in the CAR-T versus chemo-DLI group were 59.1% and 54.5% vs. 19% and 9.5% (P=0.011 and P=0.003). Six patients (28.6%) with grade 2-4 aGVHD were identified in the chemo-DLI group. Two patients (9.1%) in the CAR-T group developed grade 1-2 aGVHD. Nineteen patients (86.4%) developed CRS in the CAR-T group, comprising grade 1-2 CRS in 13 patients (59.1%) and grade 3 CRS in 6 patients (27.3%). Two patients (9.1%) developed grade 1-2 ICANS. CONCLUSION: Donor-derived anti-CD19 CAR-T-cell therapy may be better, safer, and more effective than chemo-DLI for B-ALL patients who relapse after allo-HSCT.

Poor pretransplantation minimal residual disease clearance as an independent prognostic risk factor for survival in myelodysplastic syndrome with excess blasts: A multicenter, retrospective cohort study.

BACKGROUND: Minimal residual disease (MRD) is an important prognostic factor for survival in adults with acute leukemia. The role of pretransplantation MRD status in myelodysplastic syndrome with excess blasts (MDS-EB) is unknown. This study retrospectively analyzed the relationship between pretransplantation MRD status and long-term survival. MATERIALS AND METHODS: Patients with MDS-EB who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) from March 5, 2005, to November 8, 2020, were included. The relationship between pretransplantation MRD status and long-term survival was analyzed using univariate and multivariate logistic regression models. RESULTS: Of 220 patients with MDS-EB who underwent allo-HSCT, 198 were eligible for inclusion in this multicenter, retrospective cohort study. Complete remission was attained in 121 (61.1%) patients, and 103 patients underwent detection of MRD pretransplantation, with 67 patients being MRD-positive and 36 patients being MRD-negative. The median follow-up time was 16 months, the median age was 41 years (6-65 years), and 58% of the patients were men. The 3-year disease-free survival (DFS) and overall survival (OS) probabilities for all patients were 70.1% and 72.9%, respectively. For patients in complete remission, the 3-year DFS and OS probabilities were 72.2% and 74.8%, respectively. Further analysis found that the 3-year DFS rates of MRD-negative and MRD-positive patients were 85.6% and 66.5% (p = .045), respectively, whereas the 3-year OS rates were 91.3% and 66.4% (p = .035), respectively. Univariate and multivariate analyses showed that poor pretransplantation MRD clearance was an independent prognostic risk factor for DFS and OS. CONCLUSION: Poor pretransplantation MRD clearance is an independent prognostic risk factor for long-term survival after allo-HSCT for patients with MDS-EB. PLAIN LANGUAGE SUMMARY: Poor minimal residual disease clearance pretransplanation is an independent prognostic risk factor for long-term survival after allogeneic hematopoietic stem cell transplantation for patients with myelodysplastic syndrome with excess blasts.

Novel third-generation tyrosine kinase inhibitor for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia: a case study.

Although Philadelphia chromosome-positive acute leukemia (Ph + -ALL) has been revolutionized with tyrosine kinase inhibitors (TKIs), resistance and mutation are universal events during treatment with first-generation and second-generation TKIs. The present third-generation TKI has a dose-dependent, increased risk of serious cardiovascular events and the sensitivity is poor for patients with ≥2 mutations accompanied by the T315I mutation. Thus, novel and well-tolerated TKIs should be explored. This study analyzes the efficacy and advert effects of olverembatinib, a novel third TKI, in the treatment of newly diagnosed adult Ph + -ALL in induction therapy. Four adult patients with newly diagnosed Ph + -ALL were treated with olverembatinib as the first-line treatment. For induction therapy, these patients received 40 mg of oral olverembatinib quaque omni die for 28 days, 1 mg/kg/d of prednisone for 14 days, then tapered and stopped at 28 days and vindesine 4 mg/d at days 1, 8 and 15. After induction therapy, these patients received median or high-dose of cytarabine and methotrexate combined with oral olverembatinib as consolidation therapy. Then the allogeneic hematopoietic stem cell transplantation (allo-HSCT) was performed. All patients reached complete remission with a complete cytogenetic response after induction therapy. Two patients reached major molecular remission and one with complete molecular remission. Before allo-HSCT, all the patients achieved complete molecular remission. All the patients have survived disease-free for 3-6 months. No severe advert effects were observed. It is well-tolerated and effective for olverembatinib in the treatment of newly diagnosed adult patients with Ph + -ALL. A prospective study should be performed to further testify the role.

Integrative analysis of platelet-related genes for the prognosis of esophageal cancer.

BACKGROUND: Every year, esophageal cancer is responsible for 509000 deaths and around 572000 new cases worldwide. Although esophageal cancer treatment options have advanced, patients still have a dismal 5-year survival rate. AIM: To investigate the relationship between genes associated to platelets and the prognosis of esophageal cancer. METHODS: We searched differentially expressed genes for changes between 151 tumor tissues and 653 normal, healthy tissues using the "limma" package. To develop a prediction model of platelet-related genes, a univariate Cox regression analysis and least absolute shrinkage and selection operator Cox regression analysis were carried out. Based on a median risk score, patients were divided into high-risk and low-risk categories. A nomogram was created to predict the 1-, 2-, and 3-year overall survival (OS) of esophageal cancer patients using four platelet-related gene signatures, TNM stages, and pathological type. Additionally, the concordance index, receiver operating characteristic curve, and calibration curve were used to validate the nomogram. RESULTS: The prognosis of esophageal cancer was associated to APOOL, EP300, PLA2G6, and VAMP7 according to univariate Cox regression analysis and least absolute shrinkage and selection operator regression analysis. Patients with esophageal cancer at high risk had substantially shorter OS than those with cancer at low risk, according to a Kaplan-Meier analysis (P < 0.05). TNM stage (hazard ratio: 2.187, 95% confidence interval: 1.242-3.852, P = 0.007) in both univariate and multivariate Cox regression and risk score were independently correlated with OS (hazard ratio: 2.451, 95% confidence interval: 1.599-3.756, P < 0.001). CONCLUSION: A survival risk score model and independent prognostic variables for esophageal cancer have been developed using APOOL, EP300, PLA2G6, and VAMP7. OS for esophageal cancer might be predicted using the nomogram based on TNM stage, pathological type, and risk score. The nomogram demonstrated strong predictive ability, as shown by the concordance index, receiver operating characteristic curve, and calibration curve.

Comprehensive analysis of the relationship between cuproptosis-related genes and esophageal cancer prognosis.

BACKGROUND: Esophageal cancer is one of the most common malignant tumors of the digestive system, with a 5-year survival rate of 15% to 50%. Cuproptosis, a unique kind of cell death driven by protein lipoylation, is strongly connected to mitochondrial metabolism. The clinical implications of cuproptosis-related genes in esophageal cancer, however, are mainly unknown. AIM: To identify cuprotosis-related genes that are differentially expressed in esophageal cancer and investigate their prognostic significance. METHODS: With |log fold change| > 1 and false discovery rate < 0.05 as criteria, the Wilcox test was used to evaluate the differentially expressed genes between 151 tumor tissues and 151 normal esophageal tissues. Cuproptosis-related genes were selected to be linked with prognosis using univariate Cox regression analysis. Genes were separated into high- and low- expression groups based on their cutoff value of gene expression, and the correlation between the two groups and overall survival or progression-free survival was investigated using the log-rank test. The C-index, calibration curve, and receiver operator characteristic (ROC) curve were used to assess a nomogram containing clinicopathological characteristics and cuproptosis-related genes. RESULTS: Pyruvate dehydrogenase A1 (PDHA1) was found to be highly correlated with prognosis in univariate Cox regression analysis (hazard ratio = 22.96, 95% confidence interval = 3.09-170.73; P = 0.002). According to Kaplan-Meier survival curves, low expression of PDHA1 was associated with a better prognosis (log-rank P = 0.0007). There was no significant correlation between PDHA1 expression and 22 different types of immune cells. Tumor necrosis factor superfamily member 15 (TNFSF15) (P = 3.2 × 10-6; r = 0.37), TNFRSF14 (P = 8.1 × 10-8; r = 0.42), H long terminal repeat-associating 2 (P = 6.0 × 10-8; r = 0.42) and galectin 9 (P = 3.1 × 10-6; r = 0.37) were all found to be considerably greater in the high PDHA1 expression group, according to an analysis of genes related to 47 immunological checkpoints. The low PDHA1 expression group had significantly lower levels of cluster of differentiation 44 (CD44) (P = 0.00028; R = -0.29), TNFRSF18 (P = 1.2 × 10-5; R = -0.35), programmed cell death 1 ligand 2 (P = 0.0032; R = -0.24), CD86 (P = 0.018; R = -0.19), and CD40 (P = 0.0047; R = -0.23), and the differences were statistically significant. We constructed a prognostic nomogram incorporating pathological type, tumor-node-metastasis stage, and PDHA1 expression, and the C-index, calibration curve, and ROC curve revealed that the nomogram's predictive performance was good. CONCLUSION: Cuproptosis-related genes can be used as a prognostic predictor for esophageal cancer patients, providing novel insights into cancer treatment.

T-cell lymphoblastic lymphoma with extensive thrombi and cardiac thrombosis: A case report and review of literature.

BACKGROUND: T-lymphoblastic lymphoma (T-LBL), a neoplasm of immature T-cell precursors or lymphoblasts, is a clinically aggressive disease. In general, patients with T-LBL have a poor prognosis and often have high-risk clinical features, such as mediastinal masses, central nervous system infiltration, or other indications of high tumor burden; however, extensive thrombi are not common. CASE SUMMARY: A 27-year-old woman presented to the Department of General Surgery with cervical lymph node enlargement accompanied by cough, wheezing, and palpitation for 3 mo. A complete blood count showed a white blood cell count of 1.6 × 109/L, a hemoglobin concentration of 135 g/L, and a platelet count of 175 × 109/L. A biopsy sample of the lymph node mass indicated T-cell lymphoblastic lymphoma, and the bone marrow immunophenotype indicated early T-cell precursor acute lymphoblastic leukemia (ETP-ALL). Abdominal and chest enhanced computed tomography showed thrombi in the superior vena cava, inferior vena cava, right hepatic vein, azygos vein, and right atrium. The ultrasonic cardiogram showed a thrombus in the right atrium of 5.23 cm × 4.21 cm. The patient was first treated with low-dose dexamethasone and low-molecular-weight heparin followed by 2 cycles of chemotherapy. Then, the ultrasonic cardiogram showed that thrombus in the right atrium had disappeared and the patient had achieved complete cytological remission. The maintenance therapy of the patient included chidamide 30 mg/wk, and she survived for 6 mo. CONCLUSION: The incidence of venous thromboembolism is high in lymphoma; however, extensive thrombi with heart thrombosis is rare. Chemotherapy is the major method of treatment for lymphoma with thrombosis. We successfully treated a patient with T-LBL complicated by extensive thrombi, including a large right atrial thrombus, with combined chemotherapy containing liposomal doxorubicin, and the patient achieved complete remission. Maintenance therapy with chidamide was also effective.

Donor-derived CD19 CAR-T cell therapy of relapse of CD19-positive B-ALL post allotransplant.

Safety and efficacy of allogeneic anti-CD19 chimeric antigen receptor T cells (CAR-T cells) in persons with CD19-positive B-cell acute lymphoblastic leukemia (B-ALL) relapsing after an allotransplant remain unclear. Forty-three subjects with B-ALL relapsing post allotransplant received CAR-T cells were analyzed. 34 (79%; 95% confidence interval [CI]: 66, 92%) achieved complete histological remission (CR). Cytokine release syndrome (CRS) occurred in 38 (88%; 78, 98%) and was ≥grade-3 in 7. Two subjects died from multiorgan failure and CRS. Nine subjects (21%; 8, 34%) developed ≤grade-2 immune effector cell-associated neurotoxicity syndrome (ICANS). Two subjects developed ≤grade-2 acute graft-versus-host disease (GvHD). 1-year event-free survival (EFS) and survival was 43% (25, 62%). In 32 subjects with a complete histological remission without a second transplant, 1-year cumulative incidence of relapse was 41% (25, 62%) and 1-year EFS and survival, 59% (37, 81%). Therapy of B-ALL subjects relapsing post transplant with donor-derived CAR-T cells is safe and effective but associated with a high rate of CRS. Outcomes seem comparable to those achieved with alternative therapies but data from a randomized trial are lacking.

Photodynamic antimicrobial chemotherapy in mice with Pseudomonas aeruginosa-infected wounds.

This study examined the antibacterial effect of protoporphyrin IX-ethylenediamine derivative (PPIX-ED)-mediated photodynamic antimicrobial chemotherapy (PPIX-ED-PACT) against Pseudomonas aeruginosa in vitro and in vivo. PPIX-ED potently inhibited the growth of Pseudomonas aeruginosa by inducing reactive oxygen species production via photoactivation. Atomic force microscopy revealed that PPIX-ED-PACT induced the leakage of bacterial content by degrading the bacterial membrane and wall. As revealed using acridine orange/ethidium bromide staining, PPIX-ED-PACT altered the permeability of the bacterial membrane. In addition, the antibacterial effect of PPIX-ED-PACT was demonstrated in an in vivo model of P. aeruginosa-infected wounds. PPIX-ED (100 µM) decreased the number of P. aeruginosa colony-forming units by 4.2 log10. Moreover, histological analysis illustrated that the wound healing rate was 98% on day 14 after treatment, which was 10% higher than that in the control group. According to the present findings, PPIX-ED-PACT can effectively inhibit the growth of P. aeruginosa in vitro and in vivo.

Pegylated liposomal doxorubicin for myeloid neoplasms.

Pegylated liposomal doxorubicin (Peg-Dox) treatment resulted in a good outcome for patients with lymphoma and multiple myeloma, with reduced cardiotoxicity and an improved pharmacokinetic profile when compared to those of conventional doxorubicin. However, the use of Peg-Dox in myeloid neoplasms remains poorly studied. In this study, we first tested the role of Peg-Dox in the killing of myeloid cell lines and of primary myeloid leukemia cells. Then, a Peg-Dox-based protocol was used to treat patients with myeloid neoplasms. The results showed that the Peg-Dox and Peg-Dox-based protocols had a similar killing ability in myeloid cell lines and in primary myeloid leukemia cells compared to that of conventional doxorubicin. The complete remission rate was 87.5% and 100% for patients with refractory/relapsed acute myeloid leukemia and myelodysplastic syndrome with excess blasts, respectively, after treatment with Peg-Dox. All patients developed grade 3 or 4 hematological toxicity and recovered approximately 2 weeks after completing chemotherapy. No deaths or other severe complications were reported. Our results showed that Peg-Dox can be used in the treatment of myeloid neoplasms with high rates of complete remission and with mild complications.

Preventive infusion of donor-derived CAR-T cells after haploidentical transplantation: Two cases report.

RATIONALE: Relapse is the main cause of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Unfortunately, there are no efficient methods to prevent relapse after allo-HSCT. Chimeric antigen receptor T (CAR-T) cells have achieved favorable outcomes in the treatment of refractory/relapsed acute lymphoblastic leukemia (ALL) because of their strong anti-leukemia activity. However, it is unclear whether the CAR-T cells constructed using viral systems can be used as preventive infusions to prevent relapse after haploidentical HSCT. PATIENT CONCERNS: Two patients with ALL with high risk received haploidentical HSCT. DIAGNOSES: Two patients were diagnosed with ALL with high risk. INTERVENTIONS: Patients received preventive infusion of donor-derived CAR-T cells constructed using viral systems on day 60 after haploidentical HSCT. OUTCOMES: The CAR-T cells were continually detected, and no graft versus host disease developed. The two patients survived with disease-free for 1 year and 6 months, respectively. LESSONS: Preventive infusion of donor-derived CAR-T cells after haploidentical HSCT may be safe and that immunosuppressors may not affect the proliferation of CAR-T cells.

Study on the Prognostic Value of Aberrant Antigen in Patients With Acute B Lymphocytic Leukemia.

BACKGROUND: Approximately 30% to 60% of patients with acute B-lymphocytic leukemia (B-ALL) show as refractory or relapsed, which is one of the major causes of death in patients with B-ALL, but the methods of the treatment for relapsed/refractory B-ALL (R/R B-ALL) are limited. The chimeric antigen receptors redirected T cells (CAR-T cells) have showed a strong anti-leukemia role for B-ALL. About 90% of patients with R/R B-ALL treated with CD19-CAR-T cells achieved complete remission. However, 60% to 70% of patients relapsed after CAR-T cells treatment, which may be related to target antigen reduction or escape. New products are urgently needed to prevent and treat antigenic escapes causing recurrence. PATIENTS AND METHODS: In this article, we retrospectively analyzed the immunophenotype of patients with B-ALL initially diagnosed in our center from January 2010 to December 2015 to determine whether aberrant antigen expression was associated with the prognosis of patients in order to find new targets for immunotherapy. RESULTS: The results show that disease-free and overall survival in patients without aberrant antigen expression were better than patients with aberrant antigen expression. The most common abnormal antigens were CD123, CD13, and CD56. Correlation analysis showed a negative correlation between aberrant CD123 expression and both disease-free and overall survival. CONCLUSION: Therefore, in the construction of CAR-T cells in patients with R/R B-ALL, conventional CD19 can be combined with aberrant antigens such as CD123 to form CARs with bi-specific antigens or multi-specific antigens may achieve the purpose of improving efficacy. However, more clinical trials are needed.

CHI3L1 promotes tumor progression by activating TGF-ß signaling pathway in hepatocellular carcinoma.

CHI3L1 (YKL40) is a secreted glycoprotein and elevated serum CHI3L1 level has been proved to be associated with poor prognosis in many human cancers. However, the mechanism of how CHI3L1 causes poor prognosis in cancers is still unknown. Here, considering that CHI3L1 is a liver specific/enriched protein, we use hepatocellular carcinoma as a model to study the function of CHI3L1. We showed that, both in vivo and in vitro, overexpression of CHI3L1 could promote liver cancer cells growth, migration and invasion. We then used RNA-seq to analyze the expression profiles of CHI3L1 overexpressed in two HCC cell lines and found that CHI3L1 overexpression affected genes that were involved in cell-cell adhesion, extracellular exosome and adherens junction. Western blot analysis further revealed that CHI3L1 could activate TGF-ß signal pathways. Our data added new understanding of the mechanism of CHI3L1's action. 1) CHI3L1 promoted cancer cell proliferation by regulating cell cycles; 2) CHI3L1 promoted cancer cell invasion and metastasis; 3) CHI3L1 regulate liver cancer potentially by regulating the TGF-ß signaling pathways; 4) CHI3L1 has direct kinase activities or activate kinase to phosphorylate SMAD2, SMAD3.

Targeting of the leukemia microenvironment by c(RGDfV) overcomes the resistance to chemotherapy in acute myeloid leukemia in biomimetic polystyrene scaffolds.

The bone marrow microenvironment provides a relative sanctuary from cytotoxic drugs for leukemia cells. The present niche models concentrate on a two-dimensional (2D) co-culture system in vitro, which does not imitate the in vivo environment, while the 3D scaffolds are more reflective of this. Osteopontin (Opn) secreted by bone marrow osteoblasts, may participate in protecting leukemia cells from apoptosis by binding to its receptor αvß3, which can be expressed on the surface of the leukemia MV4-11 cell line. However, the association between the Opn/αvß3 axis and leukemia cells is unknown. In the present study, experiments were conducted on 3D polystyrene scaffolds coated with osteoblasts and leukemia cells. The cells were exposed to cyclo(Arg-Gly-Asp-d-Phe-Val) [c(RGDfV)] (35 nmol/ml), which blocks αvß3, for a period of 24 h. Cytarabine was applied 24 h later. The adhesion, migration and apoptosis rates, and the cell cycle of the leukemia cells were analyzed after incubation for 24 and 48 h. In contrast to the 2D culture system, the stromal cells in the scaffolds secreted significantly more alkaline phosphatase and Opn (P<0.05). c(RGDfV) disrupted the adhesion and migration between the tumor cells and the matrix, induced the leukemia cells to leave the protective microenvironment and increased their sensitivity to cell cycle-dependent agents (P<0.05). In summary, the data certified that the 3D scaffolds are suitable for the growth of cells, and that c(RGDfV) inhibits the adhesion and migration abilities of leukemia cells in the endosteal niche. Therefore, blocking the function of Opn may be beneficial in the treatment of acute myeloid leukemia.

AMD3100 and G-CSF disrupt the cross-talk between leukemia cells and the endosteal niche and enhance their sensitivity to chemotherapeutic drugs in biomimetic polystyrene scaffolds.

BACKGROUND: The multidrug resistance of leukemia cells is closely related to the microenvironment. The present leukemia microenvironment models focus on two-dimensional co-culture system in vitro which does not mimic the in vivo cell growth, while the 3D polystyrene (PS) scaffolds have the advantage. Stromal cell derived factor-1 may be involved in the shielding of endosteal niche from leukemia cells by binding to its receptor CXCR4, but the relationship between SDF-1/CXCR4 axis and leukemia cells is unclear. DESIGN AND METHODS: The experiments were built on the 3D PS scaffolds coated with osteoblasts. Stromal cells and MV4-11 cells were plated on the scaffolds. Then G-CSF, AMD3100 and cytarabine were added. Adhesive rate, SDF-1 level, migration state, apoptosis rate, and cell cycle of leukemia cells were observed after incubation at 24h and 48h. RESULTS: G-CSF decreased the level of SDF-1 and inhibited the expression of CXCR4 and promoted stationary phase leukemia cells to enter the mitotic phase and enhanced the killing effect of chemotherapeutic drugs. AMD3100 disrupted the interaction between tumors and matrix, mobilized the leukemia cells to keep away from the protective microenvironment and strengthened the cytotoxic effect of Ara-C. The combination of G-CSF and AMD3100 had stronger effects on killing the leukemia cells induced by Ara-C. CONCLUSION: It demonstrates that AMD3100 and G-CSF may inhibit adhesion and migration abilities of leukemia cells with the bone marrow niche. Both of them inhibit the role of SDF-1/CXCR4 directly or indirectly. Thus inhibiting SDF-1/CXCR4 axis may be helpful to the treatment of refractory AML.

Subclinical hypothyroidism is associated with metabolic syndrome and clomiphene citrate resistance in women with polycystic ovary syndrome.

BACKGROUND: To evaluate the possible relationship between subclinical hypothyroidism (SCH) and metabolic syndrome (MS) and the response to clomiphene citrate (CC) stimulation in women with polycystic ovary syndrome (PCOS). METHODS: One hundred and ninety-six women with PCOS were divided into two groups: (1) the SCH group with 92 patients; (2) the euthyroid (EU) group with 104 patients. Physical characteristics and metabolic parameters as well as the reaction to CC stimulating test were compared between these two groups. RESULTS: (1) In the SCH group, significantly higher body mass index, Ferriman-Gallwey score, serum triglyceride, insulin and glucose of oral glucose tolerance test, homeostatic model assessment-insulin resistance (HOMA-IR) and significantly lower serum high-density lipoprotein cholesterol was observed in comparison with those in the EU group (p < 0.05). (2) The prevalence of CC resistance (30.4%), IR (43.5%) and MS (34.8%) in the SCH group was significantly higher than that in the EU group (p < 0.05). CONCLUSIONS: SCH was found associated with IR, MS and CC resistance in women with PCOS. PCOS patients with SCH may have a poorer treatment response to ovulation induction with CC.

ZnO-Based Nanoplatforms for Labeling and Treatment of Mouse Tumors without Detectable Toxic Side Effects.

ZnO quantum dots (QDs) were synthesized with polymer shells, coordinated with Gd(3+) ions and adsorbed doxorubicin (DOX) together to form a new kind of multifunctional ZnO-Gd-DOX nanoplatform. Such pH sensitive nanoplatforms were shown to release DOX to cancer cells in vitro and to mouse tumors in vivo, and reveal better specificity and lower toxicity than free DOX, and even better therapeutic efficacy than an FDA approved commercial DOX-loading drug DOX-Liposome Injection (DOXIL, NDA#050718). The ZnO-Gd-DOX nanoplatforms exhibited strong red fluorescence, which benefited the fluorescent imaging on live mice. Due to the special structure of ZnO-Gd-DOX nanoparticles, such nanoplatforms possessed a high longitudinal relaxivity r1 of 52.5 mM(-1) s(-1) at 0.55 T, which was superior to many other Gd(3+) based nanoparticles. Thus, both fluorescence labeling and magnetic resonance imaging could be applied simultaneously on the tumor bearing mice along with drug delivery. After 36 days of treatment on these mice, ZnO-Gd-DOX nanoparticles greatly inhibited the tumor growth without causing any appreciable abnormality in major organs. The most important merit of ZnO-Gd-DOX was that such a nanoplatform was biodegraded completely and showed no toxic side effects after H&E (hematoxylin and eosin) staining of tumor slices and ICP-AES (inductively coupled plasma atomic emission spectrometry) bioanalyses.

Are there any new insights for G-CSF and/or AMD3100 in chemotherapy of haematological malignants?

AML is a common life-threatening blood system malignancy. The treatment of AML continues to face greater challenges. An abnormal haematopoietic niche with high adhesion and proliferation might be the root cause of resistance and relapse. Most leukaemia cells are stored in the endosteal niche and recess in the G0 phase, and they are not sensitive to varieties of radiotherapies and chemotherapies. G-CSF and AMD3100 are increasingly used in priming chemotherapy. G-CSF can promote leukaemia cells to the cell cycle, which improves the complete remission rate of leukaemia patients. AMD3100, the novel CXCR4 antagonist, could also potentially promote leukaemia cells to cell cycle and improve the susceptibility of leukaemia cells to chemotherapeutic agents. The combination of them enhances anti-leukaemia effect. So in this review, we explore the function of G-CSF and/or AMD3100 in the priming chemotherapy of haematological malignants.