OBJECTIVE: To explore the efficacy and safety of venetoclax combined with demethylating drugs and intense chemotherapy in the treatment of acute myeloid leukemia (AML). METHODS: The clinical data of 76 patients with AML treated in Qilu Hospital of Shandong University Dezhou Hospital from January 2019 to March 2024 were retrospectively analyzed. Patients were divided into observation group and control group. 38 patients in the observation group received venetoclax combined with demethylating drugs (decitabine or azacytidine) and 38 patients in the control group with the "3+7" intensive chemotherapy regimen. The primary endpoints of clinical observation were complete remission (CR), CR with incomplete hematologic recovery (CRi), partial remission (PR), non remission (NR), and overall response rate (ORR). Secondary endpoints were overall survival (OS) and drug safety. RESULTS: After 2 courses of treatment, the CR+CRi rate in observation group and control group was 71.05% and 65.79%, respectively, and the ORR was 81.58% and 78.95%, respectively. After all courses of treatment, CR+CRi rate in the observation group and the control group was 73.68% and 78.95%, respectively, and the ORR was 81.58% and 84.21%, respectively, with no statistical significance between the two groups (P >0.05). After 1 course of treatment, there were statistically significant differences in the proportion and degree of myelosuppression, the duration of neutropenia and the duration of thrombocytopenia between the two groups (P < 0.05), while there were no statistically significant differences in the occurrence of neutropenia with fever between the two groups (P >0.05). The incidence of non-hematological adverse reactions was highest in infection (mainly pulmonary infection) and gastrointestinal reaction. Among the many adverse reactions, there were statistically significant differences in the infection and hypokalemia between the two groups (P < 0.05), the incidence of hypokalemia in observation group and control group was 42.11% and 15.79%, respectively, and the infection rate in observation group and control group was 73.68% and 94.74%, respectively. The median OS was 13.13(1.67-53.63) months in the observation group and 16.60(0.57-59.67) months in the control group. CONCLUSION The combination of venetoclax and demethylating drugs has a low degree of myelosuppression, but a long recovery time, a response rate as good as that of intensive chemotherapy, and a lower infection rate. However, the incidence of hypokalemia is low in the intensive chemotherapy regimen, and the regimen significantly improves the long-term outcome of patients.
Humans ; Leukemia, Myeloid, Acute/drug therapy* ; Sulfonamides/therapeutic use* ; Bridged Bicyclo Compounds, Heterocyclic/administration & dosage* ; Retrospective Studies ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Female ; Male ; Decitabine/therapeutic use* ; Azacitidine/therapeutic use* ; Middle Aged ; Treatment Outcome ; Adult ; Aged ; Remission Induction

OBJECTIVE: To investigate platelet count trajectories after induction therapy with venetoclax combined with azacitidine (VA regimen) in newly diagnosed AML patients and further analyze its clinical significance. METHODS: Clinical date of 50 newly diagnosed AML patients who received VA treatment from March 2020 to July 2023 in Department of Hematology of the First Hospital of Lanzhou University were retrospectively collected. The platelet trajectories after induction chemotherapy were constructed by using group-based trajectory modeling. To study the association between diverse trajectories of platelet counts and compound complete remission (cCR) rate, overall response rate (ORR), minimal residual disease (MRD) negative rate and overall survival (OS) rate. The Cox proportional hazard model was used to evaluate the relationship between platelet trajectory and OS. The logistic regression was used to analyze the influence of individual characteristics on platelet trajectory. RESULTS: Two platelet trajectories were identified based on the model, including platelet slowly increased group (n=31, 62.0%) and platelet rapidly increased group (n=19, 38.0%). There were statistically significant differences in cCR rate, ORR and OS rate between platelet slowly increased group and platelet rapidly increased group (all P < 0.05). The Cox regression analysis showed that platelet rapidly increased group was associated with a decreased risk of mortality compared with platelet slowly increased group (HR=0.153, 95%CI : 0.045-0.527, P =0.003). Logistic regression analysis showed that IDH1/2 mutation (OR =3.908, 95%CI : 1.023-14.923, P =0.046) and platelet transfusion (OR =0.771, 95%CI : 0.620-0.959, P =0.020) were independent influencing factors of platelet trajectory. CONCLUSION The dynamic trajectory of platelet counts in newly diagnosed AML patients who received VA treatment can serve as a significant indicator to observe the efficacy and prognosis. The platelet rapidly increased is an independent protective factor for good prognosis. TheIDH1 /2 mutation and platelet transfusion are independent influencing factors of platelet trajectory.
Humans ; Leukemia, Myeloid, Acute/blood* ; Sulfonamides/administration & dosage* ; Azacitidine/therapeutic use* ; Platelet Count ; Retrospective Studies ; Bridged Bicyclo Compounds, Heterocyclic/administration & dosage* ; Male ; Female ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Induction Chemotherapy ; Survival Rate

OBJECTIVE: To investigate the short-term efficacy and safety of low-dose venetoclax combined with CHG (cytarabine+homoharringtonine+G-CSF) priming regimen in patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy. METHODS: The data of 14 patients with AML or high-risk MDS admitted to the department of hematology/oncology of the First Hospital of Tsinghua University and 2 cooperative institutions from July 2022 to August 2023 were retrospectively analyzed. All the patients were treated with low-dose venetoclax combined with CHG priming regimen and the early induction (one course) efficacy and adverse reactions were observed. RESULTS: Among the 14 patients, 10 were males and 4 were females, with a median age of 69.5 (46-83) years. After 1 cycle of induction chemotherapy, the complete remission (CR) rate was 64.3% (9/14) and overall response rate (ORR) was 78.6% (11/14). Among the 10 patients with adverse prognosis according to cytogenetics and molecular genetics, the CR rate was 50.0% (5/10), and ORR was 70.0% (7/10). In 7 patients with TP53 mutation, the CR rate was 42.9% (3/7) and ORR was 71.4% (5/7). In the 6 patients with complex karyotype, CR rate was 33.3% (2/6) and ORR was 66.7% (4/6). While the CR rate and ORR of 8 non-complex karyotype patients were both 87.5% (7/8), and the difference in CR rate between patients with complex karyotype and non-complex karyotype was statistically significant ( P < 0.05). The adverse reactions of chemotherapy were tolerable, without early treatment-related deaths. CONCLUSION Low-dose venetoclax combined with CHG priming regimen can be used as an effective treatment for AML and high-risk MDS patients who are ineligible for intensive chemotherapy, and it is safe and worthy of clinical application.
Humans ; Leukemia, Myeloid, Acute/drug therapy* ; Aged ; Male ; Female ; Sulfonamides/therapeutic use* ; Middle Aged ; Myelodysplastic Syndromes/drug therapy* ; Bridged Bicyclo Compounds, Heterocyclic/therapeutic use* ; Aged, 80 and over ; Retrospective Studies ; Cytarabine/administration & dosage* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Homoharringtonine/therapeutic use*

OBJECTIVE: To retrospectively analyze the clinical data of newly diagnosed acute myeloid leukemia (AML) patients treated with venetoclax combined with azacitidine (Ven/Aza) or standard "3+7" regimen and similar regimens, collect real-world study data, compare the treatment response and adverse events between the two regimens, as well as perform survival analysis. METHODS: To retrospectively analyze the efficacy, survival, and adverse reactions of newly diagnosed AML patients treated with Ven/Aza (24 cases) and "3+7" regimens (117 cases ) in our hospital from September 2009 to March 2023, as well as factors influencing outcomes. A propensity score matching (PSM) was performed on age and Eastern Cooperative Oncology Group performance status (ECOG PS) to obtain a 1:1 matched cohort of 20 pairs, and the efficacy and survival before and after the matching were compared. RESULTS: The median age of patients in the Ven/Aza group was 69 years, while that in the "3+7" group was 56 years (P <0.001). Objective remission rate (ORR) was 62.5% in Ven/Aza group and 74.8% in "3+7" group (P >0.05). The median overall survival (OS) in the Ven/Aza group was 522 days, while that in the "3+7" group was 1 002 days (P >0.05). After controlling the two variables of age and ECOG PS, a PSM cohort of 20 pairs was obtained, in which the ORR was 65% in Ven/Aza group and 60% in "3+7" group (P >0.05). The median OS was 522 days and 629 days, and median progression-free survival (PFS) was 531 days and 198 days between the two groups, respectively. There were no statistically significant differences in OS and PFS between the two groups (both P >0.05). Additionally, the incidence of adverse events in the Ven/Aza group was significantly reduced. CONCLUSION The overall cohort shows that the "3+7" regimen has advantages in efficacy and survival, but Ven/Aza regimen is relatively safer. After performing PSM on age and ECOG PS, the Ven/Aza group showed improved efficacy, and a longer median PFS compared to "3+7" group.
Humans ; Leukemia, Myeloid, Acute/drug therapy* ; Retrospective Studies ; Sulfonamides/administration & dosage* ; Azacitidine/administration & dosage* ; Bridged Bicyclo Compounds, Heterocyclic/administration & dosage* ; Aged ; Middle Aged ; Male ; Female ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Treatment Outcome

Conventional combination therapies have not resulted in considerable progress in the treatment of acute myeloid leukemia (AML). Elderly patients with AML and poor risk factors have grave prognosis. Midostaurin has been recently approved for the treatment of FLT-3-mutated AML. Venetoclax, a BCL-2 inhibitor, has been approved for the treatment of relapsed and/or refractory chronic lymphoid leukemia. Clinical trials on applying venetoclax in combination with cytarabine and other agents to treat various hematological malignancies are currently underway. Here, we present a case of a male patient with poor performance status and who developed AML following allogeneic hematopoietic stem cell transplant for high-risk myelodysplasia. The patient with high risk AML achieved complete response to the combined treatment regimen of low-dose cytarabine and venetoclax. Furthermore, we reviewed current clinical trials on the use of venetoclax for hematological malignancies.
Aged ; Bridged Bicyclo Compounds, Heterocyclic ; administration & dosage ; Combined Modality Therapy ; Cytarabine ; administration & dosage ; Fatal Outcome ; Hematopoietic Stem Cell Transplantation ; Humans ; Leukemia, Myeloid, Acute ; drug therapy ; genetics ; Male ; Recurrence ; Remission Induction ; Sulfonamides ; administration & dosage

OBJECTIVE: To evaluate the utility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) using macromolecular contrast agent (P792) for assessment of vascular disrupting drug effect in rabbit VX2 liver tumor models. MATERIALS AND METHODS: This study was approved by our Institutional Animal Care and Use Committee. DCE-MRI was performed with 3-T scanner in 13 VX2 liver tumor-bearing rabbits, before, 4 hours after, and 24 hours after administration of vascular disrupting agent (VDA), using gadomelitol (P792, n = 7) or low molecular weight contrast agent (gadoterate meglumine [Gd-DOTA], n = 6). P792 was injected at a of dose 0.05 mmol/kg, while that of Gd-DOTA was 0.2 mmol/kg. DCE-MRI parameters including volume transfer coefficient (K(trans)) and initial area under the gadolinium concentration-time curve until 60 seconds (iAUC) of tumors were compared between the 2 groups at each time point. DCE-MRI parameters were correlated with tumor histopathology. Reproducibility in measurement of DCE-MRI parameters and image quality of source MR were compared between groups. RESULTS: P792 group showed a more prominent decrease in K(trans) and iAUC at 4 hours and 24 hours, as compared to the Gd-DOTA group. Changes in DCE-MRI parameters showed a weak correlation with histologic parameters (necrotic fraction and microvessel density) in both groups. Reproducibility of DCE-MRI parameters and overall image quality was not significantly better in the P792 group, as compared to the Gd-DOTA group. CONCLUSION: Dynamic contrast-enhanced magnetic resonance imaging using a macromolecular contrast agent shows changes of hepatic perfusion more clearly after administration of the VDA. Gadolinium was required at smaller doses than a low molecular contrast agent.
Animals ; Antineoplastic Agents/therapeutic use ; Benzophenones/therapeutic use ; Disease Models, Animal ; Heterocyclic Compounds/administration & dosage/*chemistry ; Liver Neoplasms/drug therapy/pathology/*radiography ; *Magnetic Resonance Imaging ; Male ; Organometallic Compounds/administration & dosage/*chemistry ; Rabbits ; Reproducibility of Results ; Valine/analogs & derivatives/therapeutic use

OBJECTIVETo evaluate the efficacy and safety of patient-controlled intravenous analgesia (PCIA) of dezocine combined with sufentanil in burn patients after escharectomy or tangential excision followed by autologous skin grafting.

METHODSSixty burn patients hospitalized in Department of Burns and Plastic Surgery of our hospital from February 2011 to December 2013, conforming to the study criteria and going to have escharectomy or tangential excision followed by autologous skin grafting, were divided into sufentanil group (S, n = 30) and dezocine+sufentanil group (DS, n = 30) according to the random number table. Patients in group S were given 150 mL normal saline containing 2.5 µg/kg sufentanil citrate and 6 mg tropisetron after skin grafting for 48 hours. Patients in group DS were given 150 mL normal saline containing 0.25 mg/kg dezocine, 1.5 µg/kg sufentanil citrate, and 6 mg tropisetron for 48 hours. Visual Analog Scale (VAS), Bruggrmann Comfort Scale (BCS), and Ramsay Sedation Scale were used to evaluate the sedative effect or analgesic effect, and their scores were recorded at administration hour (AH) 2, 6, 12, 24, and 48. The times of efficient injection and incidence of adverse effect within the 48 AH were recorded. Data were processed with analysis of variance for repeated measurement, t test, chi-square test, and Fisher's exact test.

RESULTSThere were no obvious differences in the scores of VAS and BCS between two groups at each time point (with t values from -0.426 to 0.864, P values above 0.05). The scores of Ramsay Sedation Scale in group S at AH 2, 6, 12, 24, and 48 were respectively (3.2 ± 0.6), (3.2 ± 0.5), (3.3 ± 0.7), (3.2 ± 0.4), and (3.3 ± 0.4) points, which were higher than those in group DS [(2.4 ± 0.6), (2.5 ± 0.5), (2.4 ± 0.6), (2.4 ± 0.4), and (2.4 ± 0.5) points, with t values from 5.302 to 8.391, P values below 0.001]. The times of efficient injection within the 48 AH was 6.8 ± 0.7 in group S and 6.5 ± 0.9 in group DS, showing no significantly statistical difference (t = 1.260, P > 0.05). Respiratory depression was not observed in both groups; the incidence of pruritus was the same, and that of urine retention was similar between the 2 groups within the 48 AH (with P values above 0.05). Within the 48 AH, the incidence of nausea and vomiting in group S was 26.7% (8/30), which was obviously higher than that in group DS (6.7%, 2/30, P < 0.05); the incidence of drowsiness in group S was 20.0% (6/30), which was significantly higher than that in group DS (no patient, P < 0.05).

CONCLUSIONSDezocine combined with sufentanil can provide effective postoperative analgesia with little adverse effect for PCIA in burn patients after escharectomy or tangential excision followed by autologous skin grafting, therefore it can be widely used.

Analgesia, Patient-Controlled ; adverse effects ; Analgesics, Opioid ; administration & dosage ; Bridged Bicyclo Compounds, Heterocyclic ; administration & dosage ; adverse effects ; Burns ; surgery ; Female ; Humans ; Hypnotics and Sedatives ; administration & dosage ; Infusions, Intravenous ; Male ; Pain, Postoperative ; drug therapy ; Reconstructive Surgical Procedures ; Skin Transplantation ; Sufentanil ; administration & dosage ; adverse effects ; Tetrahydronaphthalenes ; administration & dosage ; adverse effects ; Treatment Outcome

The present study is to establish Caco-2/HT29-MTX co-cultured cells and investigate the transport capability of PLGA nanoparticles with different surface chemical properties across Caco-2/HT29-MTX co-cultured cells. PLGA-NPs, mPEG-PLGA-NPs and chitosan coated PLGA-NPs were prepared by nanoprecipitation method using poly(lactic-co-glycolic acid) as carrier material with surface modified by methoxy poly(ethylene glycol) and chitosan. The particle size and zeta potential of nanoparticles were measured by dynamic light scattering. Coumarin 6 was used as a fluorescent marker in the transport of nanoparticles investigated by confocal laser scanning microscopy. The transport of furanodiene (FDE) loaded nanoparticles was quantitively determined by high performance liquid chromatography. Colchicine and nocodazole were used in the transport study to explore the involved endocytosis mechanisms of nanoparticles. Distribution of the tight junction proteins ZO-1 was also analyzed by immunofluorescence staining. The results showed that the nanoparticles dispersed uniformly. The zeta potential of PLGA-NPs was negative, the mPEG-PLGA-NPs was close to neutral and the CS-PLGA-NPs was positive. The entrapment efficiency of FDE in all nanoparticles was higher than 75%. The transport capability of mPEG-PLGA-NPs across Caco-2/HT29-MTX co-cultured cells was higher than that of PLGA-NPs and CS-PLGA-NPs. Colchicine and nocodazole could significantly decrease the transport amount of nanoparticles. mPEG-PLGA-NPs could obviously reduce the distribution of ZO-1 protein than PLGA-NPs and CS-PLGA-NPs. The transport mechanism of PLGA-NPs and mPEG-PLGA-NPs were indicated to be a combination of endocytosis and paracellular way, while CS-PLGA-NPs mainly relied on the endocytosis way. PEG coating could shield the surface charge and enhance the hydrophilicity of PLGA nanoparticles, which leads mPEG-PLGA-NPs to possess higher anti-adhesion activity. As a result, mPEG-PLGA-NPs could penetrate the mucus layer rapidly and transport across Caco-2/HT29-MTX co-cultured cells.
Biological Transport ; Caco-2 Cells ; Chitosan ; chemistry ; Coated Materials, Biocompatible ; chemistry ; Coculture Techniques ; Drug Carriers ; Furans ; administration & dosage ; chemistry ; metabolism ; HT29 Cells ; Heterocyclic Compounds, 2-Ring ; administration & dosage ; chemistry ; metabolism ; Humans ; Lactic Acid ; chemistry ; Nanoparticles ; Particle Size ; Polyethylene Glycols ; chemistry ; Polyglycolic Acid ; chemistry ; Zonula Occludens-1 Protein ; metabolism

OBJECTIVETo investigate the impact of the mobilization with the antagonist of the stromal cell-derived factor receptor CXCR4 (AMD3100) (plerixafor), granulocyte-colony-stimulating factor (G-CSF) alone and in combination on the proliferation and cytotoxic functions of the murine splenic lymphocytes.

METHODSC57BL/6(H-2(b)) mice, as donors, were mobilized by, AMD3100, G-CSF alone or in combination (n = 10 mice in each group), and phosphate buffered saline (PBS). Then, the proliferation capacity of murine lymphocytes either in response to the phytohemagglutinin (PHA) stimulation or the mixed lymphocytes reaction (MLR) with allo-lymphocytes from the BALB/C(H-2(d)) mice were detected by CCK-8 method. The cytotoxic capacity of murine lymphocytes on Yac-1 tumor cells was examined by LDH assay.

RESULTSThe proliferation capacity and the responsiveness to alloantigen of the lymphocytes derived from the mice spleen mobilized by AMD3100, G-CSF alone or in combination were significantly lower than those by PBS control (P < 0.05), and those combination of AMD 3100 and G-CSF group were significantly lower than in other groups(P < 0.05). At the effector-target ration of 40:1, the cytotoxic capacity of murine lymphocytes in above mobilization groups was lower than in control group, but no statistically significant difference (P > 0.05).

CONCLUSIONBoth the proliferation capacity and the responsiveness to alloantigen of the murine lymphocytes decreases significantly after the mobilization with AMD3100, G-CSF alone or in combination, whereas no significant alternations are demonstrated on the cytotoxic capacity of murine lymphocytes. Further studies are needed to clarify the underlying mechanisms.

Animals ; Cell Proliferation ; Granulocyte Colony-Stimulating Factor ; adverse effects ; pharmacology ; Hematopoietic Stem Cell Mobilization ; methods ; Hematopoietic Stem Cell Transplantation ; methods ; Heterocyclic Compounds ; administration & dosage ; pharmacology ; Lymphocytes ; drug effects ; immunology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Receptors, CXCR4 ; drug effects ; Sincalide

Influenza virus is a virus causing upper respiratory tract infection disease with high morbidity and mortality. China is considered as an area with high rate of influenza morbidity. Prevention and treatment of influenza currently rely on vaccines and antiviral agents in the world. In addition, traditional Chinese medicines also have been used in clinical for influenza therapy. In vitro anti-influenza virus activities of 10 traditional Chinese medicines were studied by cytopathic effect (CPE). Qingre Jiedu oral liquid (factory H) had strong antiviral activity against influenza virus A/Guangdong Luohu/219/2006 (H1N1); Yinhuang oral liquid had strong antiviral activity against influenza virus A/Hanfang/359/95 and A/Yuefang/243/72 (H3N2). Qingkailing oral liquid (factory G) had strong antiviral activity against influenza virus A/Jifang/15/90 (H3N2). Qingre Jiedu oral liquid (factory H) had strong antiviral activity against influenza virus A/Jifang/15/90, A/Yuefang/243/72 (H3N2) and virus B.
Administration, Oral ; Animals ; Antiviral Agents ; administration & dosage ; pharmacology ; Bridged Bicyclo Compounds, Heterocyclic ; administration & dosage ; pharmacology ; Cell Line ; Chlorogenic Acid ; administration & dosage ; pharmacology ; Cytopathogenic Effect, Viral ; drug effects ; Dogs ; Drugs, Chinese Herbal ; administration & dosage ; pharmacology ; Flavonoids ; administration & dosage ; pharmacology ; Indoles ; administration & dosage ; pharmacology ; Influenza A Virus, H1N1 Subtype ; drug effects ; Influenza A Virus, H3N2 Subtype ; drug effects ; Influenza B virus ; drug effects ; Iridoids ; administration & dosage ; pharmacology