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

A boy aged 6 years and 3 months developed upper respiratory tract infection and pyrexia 2 months ago and was given oral administration of nimesulide by his parents according to directions. Half an hour later, the boy experienced convulsions and cardiopulmonary arrest, and emergency examination found hypoketotic hypoglycemia, metabolic acidosis, significant increases in serum aminotransferases and creatine kinase, and renal damage. Recovery of consciousness and vital signs was achieved after cardiopulmonary resuscitation, but severe mental and movement regression was observed. The boy had a significant reduction in free carnitine in blood and significant increases in medium- and long-chain fatty acyl carnitine, urinary glutaric acid, 3-hydroxy glutaric acid, isovalerylglycine, and ethylmalonic acid, suggesting the possibility of multiple acyl-CoA dehydrogenase deficiency. After the treatment with vitamin B2, L-carnitine, and bezafibrate, the boy gradually improved, and reexamination after 3 months showed normal biochemical parameters. The boy had compound heterozygous mutations in the ETFDH gene, i.e., a known mutation, c.341G>A (p.R114H), from his mother and a novel mutation, c.1484C>G (p.P495R), from his father. Finally, he was diagnosed with multiple acyl-CoA dehydrogenase deficiency. Reye syndrome and sudden death symptoms were caused by nimesulide-induced acute metabolic crisis. It is concluded that inherited metabolic diseases may be main causes of Reye syndrome and sudden death, and biochemical and genetic analyses are the key to identifying underlying diseases.
Acyl-CoA Dehydrogenase ; Administration, Oral ; Carnitine ; Child ; Death, Sudden ; Humans ; Male ; Respiratory Tract Infections ; Reye Syndrome ; Sulfonamides

Cytokines are believed to be involved in a "vicious circle" of progressive interactions in bone metastasis. Iguratimod is a novel anti-rheumatic drug which is reported to have the capability of anti-cytokines. In this study, a rat model was constructed to investigate the effect of iguratimod on bone metastasis and it was found that iguratimod alleviated cancer-induced bone destruction. To further explore whether an anti-tumor activity of iguratimod contributes to the effect of bone resorption suppression, two human breast cancer cell lines MDA-MB-231 and MCF-7 were studied. The effect of iguratimod on tumor proliferation was detected by CCK-8 assay and flow cytometry. The effects of iguratimod on migration and invasion of cancer cells were determined by wound-healing and Transwell assays. Results showed that high dose (30 μg/mL) iguratimod slightly suppressed the proliferation of cancer cells but failed to inhibit their migration and invasion capacity. Interestingly, iguratimod decreased the transcription level of IL-6 in MDA-MB-231 cells in a concentration-dependent manner. Moreover, iguratimod partially impaired NF-κB signaling by suppressing the phosphorylation of NF-κB p65 subunit. Our findings indicated that iguratimod may alleviate bone destruction by partially decreasing the expression of IL-6 in an NF-κB-dependent manner, while it has little effect on the tumor proliferation and invasion.
Animals ; Apoptosis ; drug effects ; Bone Neoplasms ; complications ; drug therapy ; pathology ; secondary ; Bone Resorption ; complications ; drug therapy ; pathology ; Breast Neoplasms ; complications ; drug therapy ; genetics ; pathology ; Carcinogenesis ; drug effects ; Cell Movement ; drug effects ; Cell Proliferation ; drug effects ; Chromones ; administration & dosage ; Female ; Humans ; Interleukin-6 ; biosynthesis ; genetics ; MCF-7 Cells ; Neoplasm Invasiveness ; genetics ; pathology ; Rats ; Sulfonamides ; administration & dosage ; Transcription Factor RelA ; biosynthesis ; genetics

OBJECTIVETo evaluate the clinical effect and safety of dapoxetine in the treatment of premature ejaculation (PE).

METHODSWe randomly assigned 116 PE patients to receive dapoxetine on demand at 30 mg qd (dapoxetine group, n = 60, aged 23-49 years) or oral tamsulosin at 20 mg qd (control group, n = 56, aged 24-46 years). After 4 weeks of medication, we compared the clinical global impression of change (CGIC) , PE profile (PEP) scores, intravaginal ejaculation latency time (IELT) , and adverse reactions between the two groups of patients.

RESULTSCompared with the baseline, the IELT was remarkably prolonged after treatment both in the dapoxetine group ([0.86 ± 0.17] vs [4.32 ± 2.23] min, P < 0.05) and the control ([0.88 ± 0.15] vs [4.17 ± 2.26] min, P < 0.05), with no statistically significant difference between the two groups (P > 0. 05). The post-treatment rate of CGIC in the dapoxetine group had no statistically significant difference from that in the control (85.00% vs 82.14%, P > 0.05). In comparison with pre-treatment, the patients of both the dapoxetine and control groups showed dramatically improved scores after medication in perceived control over ejaculation (0.85 ± 0.23 vs 2.13 ± 0.97 and 0.88 ± 0.21 vs 2.06 ± 0.34, both P < 0.05), ejaculation-related personal distress (1.15 ± 0.64 vs 2.89 ± 0.26 and 1.19 ± 0.53 vs 2.82 ± 0.69, both P < 0.05), satisfaction with sexual intercourse (0.81 ± 0.33 vs 2.58 ± 0.37 and 0.79 ± 0.28 vs 2.45 ± 0.32, both P < 0.05), and ejaculation-related interpersonal difficulty (2.05 ± 0.61 vs 3.24 ± 0.35 and 2.03 ± 0.65 vs 3.18 ± 0.76, both P < 0.05), with no significant differences between the two groups (P > 0.05). The incidence of adverse reactions was significantly lower in the dapoxetine than in the control group (3.33% vs 30.36%, P < 0.05).

CONCLUSIONDapoxetine is effective for the treatment of PE, with its advantages of prolonging the intravaginal ejaculation latency time, improving the quality of sexual life, and low incidence of adverse reactions.

Adult ; Benzylamines ; administration & dosage ; therapeutic use ; Coitus ; Double-Blind Method ; Ejaculation ; Humans ; Male ; Middle Aged ; Naphthalenes ; administration & dosage ; therapeutic use ; Patient Satisfaction ; Premature Ejaculation ; drug therapy ; Serotonin Uptake Inhibitors ; administration & dosage ; therapeutic use ; Sexual Behavior ; Sulfonamides ; administration & dosage ; therapeutic use ; Treatment Outcome ; Young Adult

BACKGROUNDThe medium-to-long-term use of antimuscarinics alone or in combination with an α-blocker in men with an enlarged prostate is still controversial. This double-blind, placebo-controlled, randomized clinical trial aimed to investigate the efficacy and safety of medium-to-long-term use of tolterodine extended release (ER) with or without tamsulosin in patients with benign prostate hyperplasia (BPH) and larger prostate size.

METHODSTotally, 152 patients (age ≥50 years) with BPH, International Prostate Symptom Score (IPSS) ≥12, quality-of-life (QoL) score ≥3, and total prostate volume ≥25 ml were enrolled in this study. The patients were randomized into four groups (n = 38 in each) to receive tolterodine ER placebo plus tamsulosin placebo, 0.2 mg tamsulosin plus tolterodine ER placebo, 4 mg tolterodine ER plus tamsulosin placebo, or tolterodine ER plus tamsulosin once daily for 24 weeks. IPSS (total, storage, and voiding subscales), QoL, maximum urinary flow rate (Qmax), and postvoid residual volume (PVR) were collected at baseline, and at weeks 4, 12, and 24.

RESULTSCompared with placebo, tolterodine ER plus tamsulosin significantly improved total IPSS (-7.15, -12.20, and -14.66 vs. -3.51, -5.78, and -7.23), storage IPSS (-3.56, -5.63, and -6.66 vs. -1.52, -1.21, and -2.43), voiding IPSS (-2.88, -5.10, and -6.48 vs. -1.52, -3.03, and -2.97), QoL (-1.21, -2.40, and -3.21 vs. -0.39, -1.41, and -1.60), Qmax (2.21, 7.97, and 9.72 ml/s vs. 2.15, 2.44, and 2.73 ml/s), and PVR (-17.88, -26.97, and -27.89 ml vs. -12.03, -11.16, and -16.73 ml) at weeks 4, 12, and 24, respectively; the differences were all statistically significant (P < 0.05). Adverse events (AEs) were not increased with treatment progression. Tolterodine ER alone did not improve total IPSS (-4.61, -6.79, and -5.70), voiding IPSS (-0.64, -1.83, and -1.45), QoL (-0.69, -1.21, and -1.41), or Qmax(-0.79, 2.83, and 1.11 ml/s), compared with placebo (all P > 0.05). However, a gradual increase in PVR (10.03, 10.41, and 12.89 ml) and more urinary AEs suggestive of urinary retention (11/38 vs. 4/38) were observed.

CONCLUSIONMedium-to-long-term use of tolterodine ER plus tamsulosin should be recommended in patients with BPH and an enlarged prostate volume.

TRIAL REGISTRATIONwww.chictr.org.cn, ChiCTR-TRC-09000596; http://www.chictr.org.cn/showproj.aspx?proj=8939.

Adrenergic alpha-Antagonists ; administration & dosage ; therapeutic use ; Aged ; Double-Blind Method ; Drug Administration Schedule ; Female ; Humans ; Male ; Middle Aged ; Prostate ; drug effects ; pathology ; Prostatic Hyperplasia ; drug therapy ; Quality of Life ; Sulfonamides ; administration & dosage ; therapeutic use ; Tolterodine Tartrate ; administration & dosage ; therapeutic use ; Treatment Outcome

Fontan surgery is a widely used palliative procedure that significantly improves the survival period of patients with complex congenital heart disease (CHD). However, it does not decrease postoperative complication rate. Previous studies suggested that elevated mean pulmonary artery pressure (mPAP) and vascular resistance lead to decreased exercise tolerance and myocardial dysfunction. Therapy with endothelial receptor antagonists (Bosentan) has been demonstrated to improve the patients' prognosis. A double-blind, randomized controlled trial was performed to explore the efficacy of Bosentan in treating patients who underwent the Fontan procedure. Eligible participants were randomly divided into Bosentan group and control group. Liver function was tested at a local hospital and the results were reported to the phone inspector every month. If the results suggested abnormal liver function, treatment would be adjusted or terminated. All the participants finished the follow-up study, with no patients lost to follow-up. Unblinding after 2-year follow-up, no mortality was observed in either group. However, secondary end-points were found to be significantly different in the comparable groups. The cardiac function and 6-min walking distance in the Bosentan group were significantly superior to those in the control group (P=0.018 and P=0.027). Bosentan could improve New York Heart Association (NYHA) functional status and improve the results of the 6-min walking test (6MWT) in Fontan patients post-surgery, and no other benefits were observed. Furthermore, a primary meta-analysis study systematically reviewed all the similar clinical trails worldwide and concluded an overall NYHA class improvement in Fontan patients who received Bosentan treatments.
Adolescent ; Child ; Double-Blind Method ; Female ; Follow-Up Studies ; Fontan Procedure ; Heart Defects, Congenital ; drug therapy ; pathology ; surgery ; Humans ; Liver ; drug effects ; pathology ; Male ; Palliative Care ; Prognosis ; Sulfonamides ; administration & dosage ; Treatment Outcome