Objective: To evaluate the efficacy and safety of different medical treatment in advanced or unresectable angiosarcoma. Methods: This study was a single-center retrospective clinical study. Fifty-five advanced or unresectable angiosarcoma patients treated in Sun-Yat Sen University Cancer Center from January 2005 to August 2020 were enrolled. There were 34 patients who received first-line doxorubicin-based chemotherapy (doxorubicin group), 12 patients received first-line doxorubicin or liposome doxorubicin plus paclitaxel or albumin bound paclitaxel chemotherapy (combination therapy group), and 4 patients received first-line paclitaxel-based treatment (paclitaxel group). There were 6 patients who received anti-angiogenesis targeted therapy, another 2 patients received anti-PD-1 antibody plus anti-angiogenesis targeted therapy. Targeted therapy and immunotherapy plus targeted therapy included 5 cases of first-line therapy and 3 cases of second-line therapy. The therapeutic effect was evaluated by RECIST 1.1 standard. The adverse reactions were evaluated by CTCAE4.0 standard. Kaplan-Meier survival analysis was evaluated with Log rank test. Cox proportional hazard model was used to analyze the influencing factors. Results: There were 18 patients achieved partial response (PR) in 34 patients in the doxorubicin group, median progression-free survival (mPFS) was 4.5 months, and median overall survival (mOS) was 15 months. Four patients achieved PR in 12 patients in the combination therapy group, mPFS and mOS were 4 months and 19 months. Two patients achieved PR in 4 patients in the paclitaxel group, mPFS and mOS were 3 months and 9 months. However, only 1 in 6 patients achieved PR for anti-angiogenesis targeted therapy, mPFS and mOS were 3 months and 16 months. Two patients who received anti-PD-1 immunotherapy combined with anti-angiogenesis targeted therapy acquired PR for 17 months and more than 16 months. Median PFS (7.5 months) were longer in those with primary liver, lung and spleen angiosarcoma than in those with other primary site (3.0 months, P=0.028). The mOS (20 months) was longer in females than that in males (12 months, P=0.045). Primary tumor site, sex, age and treatment were not independent prognostic factors for angiosarcoma patients (P>0.05). Grade 3-4 cardiac toxicity was found in 2 patients in the combination therapy group. Conclusions: Doxorubicin-based and paclitaxel-based chemotherapy are the most important treatment for advanced angiosarcoma. Potential efficacy for targeted therapy combined with anti-PD-1 immunotherapy are showed in some patients with long duration of response and moderate adverse event.
Male ; Female ; Humans ; Hemangiosarcoma ; Retrospective Studies ; Paclitaxel/adverse effects* ; Doxorubicin/therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols/adverse effects*

This study aimed to investigate the effect and mechanisms of Ephedra Herb (EH) extract on adriamycin-induced nephrotic syndrome (NS), providing an experimental basis for the clinical treatment of NS. Hematoxylin and eosin staining, creatinine, urea nitrogen, and kidn injury molecule-1 were used to evaluate the activities of EH extract on renal function. The levels of inflammatory factors and oxidative stress were detected by kits. The levels of reactive oxygen species, immune cells, and apoptosis were measured by flow cytometry. A network pharmacological approach was used to predict the potential targets and mechanisms of EH extract in the treatment of NS. The protein levels of apoptosis-related proteins and CAMKK2, p-CAMKK2, AMPK, p-AMPK, mTOR and p-mTOR in the kidneys were detected by Western blot. The effective material basis of EH extract was screened by MTT assay. The AMPK pathway inhibitor (compound C, CC) was added to investigate the effect of the potent material basis on adriamycin-induced cell injury. EH extract significantly improved renal injury and relieve inflammation, oxidative stress, and apoptosis in rats. Network pharmacology and Western blot results showed that the effect of EH extract on NS may be associated with the CAMKK2/AMPK/mTOR signaling pathway. Moreover, methylephedrine significantly ameliorated adriamycin-induced NRK-52e cell injury. Methylephedrine also significantly improved the phosphorylation of AMPK and mTOR, which were blocked by CC. In sum, EH extract may ameliorate renal injury via the CAMKK2/AMPK/mTOR signaling pathway. Moreover, methylephedrine may be one of the material bases of EH extract.
Rats ; Animals ; Doxorubicin/adverse effects* ; Nephrotic Syndrome ; AMP-Activated Protein Kinases/metabolism* ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism* ; Apoptosis

OBJECTIVE: To investigate the effect of honokiol (HKL) for reducing doxorubicin (DOX)-induced cardiotoxicity in H9c2 cells and the underlying mechanisms. METHODS: H9c2 cells were divided into control group, DOX group, HKL + DOX group, and HKL+compound C+DOX group. After 24 h of corresponding treatment, the cells were examined for morphological changes and cell viability using CCK-8 assay. The mRNA expressions of the inflammatory factors including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) were detected by RT-PCR, and the protein levels of cleaved caspase-3, cytochrome c, NOD-like receptor pyrin domain containing 3 (NLRP3), caspase-1, apoptosis-associated speck-like protein containing a CARD (ASC), p-AMPK and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) were detected with Western blotting; the expressions of NLRP3 and p-AMPK also detected with immunofluorescence staining. RESULTS: DOX treatment caused swelling and significantly lowered the viability of H9c2 cells (P < 0.05), resulting also in increased mRNA expressions of TNF-α, IL-6 and IL-1β (P < 0.05) and protein expressions of cleaved caspase-3, cytochrome c, NLRP3, caspase-1 and ASC (P < 0.05) but reduced protein levels of p-AMPK and Nrf2 (P < 0.05); fluorescence staining showed significantly increased NLRP3 expression and decreased expression of p-AMPK in DOX-treated cells (P < 0.05). All these changes in COX-treated cells were significantly alleviated by HKL treatment (P < 0.05). The application of compound C obviously mitigated the protective effects of HKL against DOX-induced cardiotoxicity in H9c2 cells. CONCLUSIONS HKL can alleviate DOX-induced cardiotoxicity by inhibiting pyroptosis in H9c2 cells, and this effect is mediated by activation of AMPK to regulate Nrf2 signaling.
AMP-Activated Protein Kinases/metabolism* ; Allyl Compounds ; Biphenyl Compounds ; Cardiotoxicity/pathology* ; Caspase 3/metabolism* ; Cytochromes c ; Doxorubicin/adverse effects* ; Humans ; Interleukin-6/metabolism* ; Myocytes, Cardiac ; NF-E2-Related Factor 2/metabolism* ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Phenols ; Pyroptosis ; RNA, Messenger/metabolism* ; Tumor Necrosis Factor-alpha/metabolism*

As a new type of anthracyclines, pegylated liposomal doxorubicin (PLD) is widely used in the treatment of a variety of malignant tumors, including soft tissue sarcoma, ovarian cancer, breast cancer, multiple myeloma, and so on. Compared with traditional anthracyclines, PLD can significantly decrease the incidences of adverse events such as cardiac toxicity and alopecia. However, the use of PLD will be accompanied with toxic side effects such as hand-foot syndrome, oral mucositis, and infusion reaction. This consensus will mainly focus on the mechanism, prevention and treatment of adverse events of PLD, in order to improve the therapeutic efficacy of PLD and life quality of patients.
Antibiotics, Antineoplastic ; adverse effects ; therapeutic use ; Consensus ; Doxorubicin ; adverse effects ; analogs & derivatives ; therapeutic use ; Drug-Related Side Effects and Adverse Reactions ; prevention & control ; Female ; Hand-Foot Syndrome ; complications ; Humans ; Neoplasms ; drug therapy ; Polyethylene Glycols ; adverse effects ; therapeutic use ; Practice Guidelines as Topic ; Stomatitis ; complications

Carcinoma, Hepatocellular/therapy* ; Cerebral Infarction ; Chemoembolization, Therapeutic/adverse effects* ; Doxorubicin ; Humans ; Liver Neoplasms/drug therapy* ; Pharmaceutical Preparations ; Treatment Outcome

Metastasis is one of the main reasons causing death in cancer patients. It was reported that chemotherapy might induce metastasis. In order to uncover the mechanism of chemotherapy-induced metastasis and find solutions to inhibit treatment-induced metastasis, the relationship between epithelial-mesenchymal transition (EMT) and doxorubicin (DOX) treatment was investigated and a redox-sensitive small interfering RNA (siRNA) delivery system was designed. DOX-related reactive oxygen species (ROS) were found to be responsible for the invasiveness of tumor cells in vitro, causing enhanced EMT and cytoskeleton reconstruction regulated by Ras-related C3 botulinum toxin substrate 1 (RAC1). In order to decrease RAC1, a redox-sensitive glycolipid drug delivery system (chitosan-ss-stearylamine conjugate (CSO-ss-SA)) was designed to carry siRNA, forming a gene delivery system (CSO-ss-SA/siRNA) downregulating RAC1. CSO-ss-SA/siRNA exhibited an enhanced redox sensitivity compared to nonresponsive complexes in 10 mmol/L glutathione (GSH) and showed a significant safety. CSO-ss-SA/siRNA could effectively transmit siRNA into tumor cells, reducing the expression of RAC1 protein by 38.2% and decreasing the number of tumor-induced invasion cells by 42.5%. When combined with DOX, CSO-ss-SA/siRNA remarkably inhibited the chemotherapy-induced EMT in vivo and enhanced therapeutic efficiency. The present study indicates that RAC1 protein is a key regulator of chemotherapy-induced EMT and CSO-ss-SA/siRNA silencing RAC1 could efficiently decrease the tumor metastasis risk after chemotherapy.
Amines/chemistry* ; Antineoplastic Agents/adverse effects* ; Breast Neoplasms/pathology* ; Chitosan/chemistry* ; Doxorubicin/adverse effects* ; Drug Delivery Systems ; Epithelial-Mesenchymal Transition/drug effects* ; Female ; Humans ; MCF-7 Cells ; Neoplasm Metastasis/prevention & control* ; Oxidation-Reduction ; RNA, Small Interfering/administration & dosage* ; Reactive Oxygen Species/metabolism* ; rac1 GTP-Binding Protein/physiology*

PURPOSE: Dose-dense chemotherapy (DD-CT) is a preferred (neo)adjuvant regimen in early breast cancer (BC). Although the results of reported randomized trials are conflicting, a recent meta-analysis showed improved overall and disease-free survival with DD-CT compared to conventional schedules. However, no DD-CT safety data for Korean BC patients are available. This phase II study was conducted to evaluate the safety and efficacy of pegteograstim in Korean BC patients receiving DD-CT. MATERIALS AND METHODS: Patients with operable (stage I-III), histologically confirmed BC received four cycles of intravenous doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) on day 1 every 2 weeks as neoadjuvant or adjuvant therapy. Pegteograstim (6.0 mg) was administered subcutaneously on day 2 of each cycle. The primary endpoint was the incidence of febrile neutropenia (FN). The secondary endpoints were safety and tolerability. RESULTS: Of 63 patients, one (1.6%) developed FN during all cycles of DD-CT. Dose delay was observed in four patients (6.3%) and dose reduction in two (3.2%) during DD-CT. Frequent adverse events (AEs) were nausea, alopecia, generalized muscle weakness, myalgia, mucositis, anorexia, dyspepsia, and diarrhea; most AEs were related to chemotherapy. Grade 3-4 AEs were reported in five of 63 patients (7.9%), and all grade 3 and 4 AEs were related to chemotherapy. Adverse drug reactions possibly linked to pegteograstim were abdominal pain, bone pain, myalgia, generalized muscle weakness, and headache in five of 63 patients (7.9%). CONCLUSION: Dose-dense AC (doxorubicin/cyclophosphamide) chemotherapywith pegteograstim support is a tolerable and safe regimen in Korean early BC patients.
Abdominal Pain ; Alopecia ; Anorexia ; Appointments and Schedules ; Breast Neoplasms ; Breast ; Cyclophosphamide ; Diarrhea ; Disease-Free Survival ; Doxorubicin ; Drug Therapy ; Drug-Related Side Effects and Adverse Reactions ; Dyspepsia ; Febrile Neutropenia ; Headache ; Humans ; Incidence ; Mucositis ; Muscle Weakness ; Myalgia ; Nausea

Objective: To identify the risk factors and clinical features associated with the interstitial pneumonia in diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (RCHOP) or rituximab, cyclophosphamide, liposomal doxorubicin, vincristine and prednisone (RCDOP) regimens. Methods: A retrospective study was conducted in 836 patients with DLBCL admitted to the Department of Hematology at Ruijin Hospital from 2013 to 2018. Among them, 114 patients were treated with RCDOP regimen. Using the method of propensity score matching according to age, gender, IPI score of patients, 114 patients treated with RCHOP regimen were selected as controls. Clinical data, including comorbidities, gender, age, B symptoms, international prognostic index (IPI) score, disease stage, serum lactic dehydrogenase (LDH) and β(2) microglobulin (β(2)-MG) level were collected and the risk factors of interstitial pneumonia were further analyzed. Results: The interstitial pneumonia developed more frequently in RCDOP group than RCHOP group (28.95% vs 2.60%, P<0.01) . As the dose of liposomal doxorubicin elevated from 25-30 mg/m(2) to 35-40 mg/m(2), the incidence of interstitial pneumonia accordingly increased from 17.30% to 38.71% (P<0.05) . By multivariate analysis, disease stage was an independent factor of interstitial pneumonitis. Conclusions: Front line regimens containing liposomal doxorubicin in DLBCL patients link to a higher incidence of dose-dependent interstitial pneumonia. Prevention and surveillance should be emphasized in future studies.
Antineoplastic Combined Chemotherapy Protocols/adverse effects* ; Cyclophosphamide ; Doxorubicin ; Humans ; Lung Diseases, Interstitial/chemically induced* ; Lymphoma, Large B-Cell, Diffuse/drug therapy* ; Prednisone ; Retrospective Studies ; Rituximab ; Vincristine

OBJECTIVES: To investigate the effect of Astragalus injection on cardiomyocyte apoptosis, endoplasmic reticulum stress and connexin protein in cardiomyopathy rats induced by adriamycin. METHODS: Thirty-six male Wister rats were randomly divided into control group (=12), adriamycin(ADR) group (=12) and Astragalus group (=12). The normal saline (10 ml/kg body weight) was injected intraperitoneally in control group rats, ADR (2 mg/kg body weight) was injected intraperitoneally in ADR group rats, ADR (10 ml/kg body weight) and Astragalus injection (10 ml/kg body weight) were injected intraperitoneally in rats of astragalus group, one time a week, totle 3 times. By the end of the 7 week, the left ventricular end-diastolic diameter(LVEDD), left ventricular end-systolic diameter (LVESD) and left ventricular ejection fraction (LVEF) were measured by echocardiography. Then the rats in the three groups were sacrificed and the left ventricle section was stained by HE, Masson, uranyl acetate/lead citrate respectively, the cardiomyopathy and ultrastructural changes were observed under light microscope and transmission electron microscope. The apoptosis of rat cardiomyocyte were analyzed by TUNEL. The expression of connexin Cx43 and p-Cx43 was detected by immunohistochemistry. The expression of glucose-regulated protein 78 (Grp78),activating transcription factor 4 (ATF-4) and C/EBP homologous protein (CHOP) were detected by real time PCR. RESULTS: Compared with control group, LVEDD, LVESD increased and LVEF decreased, myocardial fibers were disordered and edematous, infiltrated by lymphocytes, the mitochondria were destroyed and vacuolized, and the number of cardiomyocyte apoptosis was increased(<0.01) in ADR group. The expression of Grp78, ATF-4, CHOP and p-Cx43 were increased, and the expression of Cx43 was decreased in ADR group. However, compared with ADR group, LVEDD, LVESD decreased and LVEF increased, the cardiomyopathy and ultrastructural changes were significantly improved, the number of cardiomyocyte apoptosis was significantly decreased (<0. 01); the expression of Grp78, ATF-4, CHOP and p-Cx43 decreased (<0.01); the expression of Cx43 increased in Astragalus group (<0.01). CONCLUSIONS Astragalus injection may effectively improve the myocardial damage induced by adriamycin, its mechanism may be related to the inhibition of endoplasmic reticulum stress (ERS) and the decrease of phosphorylation of CX43 in cardiomyopathy rats induced by adriamycin.
Animals ; Apoptosis ; Astragalus Plant ; chemistry ; Cardiomyopathies ; chemically induced ; drug therapy ; Doxorubicin ; adverse effects ; Drugs, Chinese Herbal ; pharmacology ; Endoplasmic Reticulum Stress ; drug effects ; Male ; Myocytes, Cardiac ; cytology ; drug effects ; Random Allocation ; Rats ; Rats, Wistar

OBJECTIVETo investigate the effects of Huaiqihuang Granules (, HQH), a mixture of Chinese herbs including Trametes robiniophila Murr, Fructus Lycii and Polygonatum sibiricum, on adriamycininduced nephropathy (ADRN) in rats and its underlying mechanisms.

METHODSRats with ADRN were divided into four groups: the sham group, the model group (distilled water), the low-dose HQH-treated (2 g/kg) group, and the high-dose HQH-treated (4 g/kg) group. Body weight and 24-h urinary protein (Upro) were checked every week. After 5-week intervention, at the end of the study, the rats were sacrificed and blood samples were collected for examination of biochemical parameters, including glomerular morphological makers, podocyte shape, cellular apoptosis, expressions of nephrin, inflammatory and apoptosis markers.

RESULTSHQH ameliorated the rat's general status, proteinuria, renal morphological appearance and glomerulosclerosis. The decreased expression of nephrin in ADRN rats was increased by HQH, as well as the impaired podocyte foot process fusion. Cytosolic levels of p65 and inhibitor of nuclear factor κBα (IκBα) were decreased in ADRN rats, and recovered by the treatment of HQH. Consistently, the induced expression of tumor necrosis factor α (TNF-α), phosphorylated nuclear factor κB p65 (p-NFκB p65) and IκBα in ADRN were markedly suppressed by HQH. In addition, induction of Bax, cleaved caspase-3 and cytochrome C in ADRN rats were suppressed by HQH, indicating the amelioration of apoptosis.

CONCLUSIONHQH could ameliorate renal impairments in ADRN rats by increasing nephrin expression, inhibiting NF-κB signaling pathway via the down-regulation of p-NF-κB p65 and p-IκBα, and suppression of glomerular and tubular apoptosis.

Animals ; Apoptosis ; drug effects ; Body Weight ; drug effects ; Caspase 3 ; metabolism ; Chromatography, High Pressure Liquid ; Cytochromes c ; metabolism ; Doxorubicin ; adverse effects ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Kidney ; drug effects ; pathology ; Kidney Diseases ; blood ; chemically induced ; complications ; drug therapy ; Kidney Glomerulus ; drug effects ; pathology ; ultrastructure ; Kidney Tubules ; drug effects ; pathology ; ultrastructure ; Male ; Membrane Proteins ; metabolism ; NF-KappaB Inhibitor alpha ; metabolism ; NF-kappa B ; metabolism ; Organ Size ; drug effects ; Proteinuria ; blood ; complications ; drug therapy ; Rats, Sprague-Dawley ; Signal Transduction ; drug effects ; Transcription Factor RelA ; metabolism ; Tumor Necrosis Factor-alpha ; metabolism ; bcl-2-Associated X Protein ; metabolism