1.Interpretation of 2024 ESC guidelines for the management of peripheral arterial and aortic diseases
Kai TANG ; Mingyao LUO ; Chang SHU
Chinese Journal of Clinical Thoracic and Cardiovascular Surgery 2025;32(01):14-23
In recent years, the worldwide incidence rate of peripheral arterial and aortic diseases has increased year by year, significantly increasing the cardiovascular mortality and incidence rate of the whole population. In the past, peripheral arterial and aortic diseases were often more prone to missed diagnosis and delayed treatment compared to coronary artery disease. The 2024 ESC guidelines for the management of peripheral arterial and aortic diseases for the first time combines peripheral arterial and aortic diseases, integrating and updating the 2017 guidelines for peripheral arterial disease and the 2014 guidelines for aortic disease. The aim is to provide standardized recommendations for the management of systemic arterial diseases, ensuring that patients can receive coherent and comprehensive diagnosis and treatment, thereby improving prognosis. This article interprets the main content of the guideline in order to provide reference and assistance for the clinical diagnosis and treatment of peripheral arterial and aortic diseases in China at the current stage.
2.Optimizing 5-aminosalicylate for moderate ulcerative colitis: expert recommendations from the Asia-Pacific, Middle East, and Africa Inflammatory Bowel Disease Coalition
Filiz AKYÜZ ; Yoon Kyo AN ; Jakob BEGUN ; Satimai ANIWAN ; Huu Hoang BUI ; Webber CHAN ; Chang Hwan CHOI ; Nazeer CHOPDAT ; Susan J CONNOR ; Devendra DESAI ; Emma FLANAGAN ; Taku KOBAYASHI ; Allen Yu-Hung LAI ; Rupert W LEONG ; Alex Hwong-Ruey LEOW ; Wai Keung LEUNG ; Julajak LIMSRIVILAI ; Virly Nanda MUZELLINA ; Kiran PEDDI ; Zhihua RAN ; Shu Chen WEI ; Jose SOLLANO ; Michelle Mui Hian TEO ; Kaichun WU ; Byong Duk YE ; Choon Jin OOI
Intestinal Research 2025;23(1):37-55
The lack of clear definition and classification for “moderate ulcerative colitis (UC)” creates ambiguity regarding the suitability of step-up versus top-down treatment approaches. In this paper, experts address crucial gaps in assessing and managing moderate UC. The Asia-Pacific, Middle East, and Africa Inflammatory Bowel Disease Coalition comprised 24 experts who convened to share, discuss and vote electronically on management recommendations for moderate UC. Experts emphasized that the goal of treating UC is to attain clinical, biomarker, and endoscopic remission using cost-effective strategies such as 5-aminosalicylates (5-ASAs), well-tolerated therapy that can be optimized to improve outcomes. Experts agreed that 5-ASA therapy could be optimized by maximizing dosage (4 g/day for induction of remission), combining oral and topical administration, extending treatment duration beyond 8 weeks, and enhancing patient adherence through personalized counselling and reduced pill burden. Treatment escalation should ideally be reserved for patients with predictors of aggressive disease or those who do not respond to 5-ASA optimization. Premature treatment escalation to advanced therapies (including biologics and oral small molecules) may have long-term health and financial consequences. This paper provides consensus-based expert recommendations and a treatment algorithm, based on current evidence and practices, to assist decision-making in real-world settings.
3.Optimizing 5-aminosalicylate for moderate ulcerative colitis: expert recommendations from the Asia-Pacific, Middle East, and Africa Inflammatory Bowel Disease Coalition
Filiz AKYÜZ ; Yoon Kyo AN ; Jakob BEGUN ; Satimai ANIWAN ; Huu Hoang BUI ; Webber CHAN ; Chang Hwan CHOI ; Nazeer CHOPDAT ; Susan J CONNOR ; Devendra DESAI ; Emma FLANAGAN ; Taku KOBAYASHI ; Allen Yu-Hung LAI ; Rupert W LEONG ; Alex Hwong-Ruey LEOW ; Wai Keung LEUNG ; Julajak LIMSRIVILAI ; Virly Nanda MUZELLINA ; Kiran PEDDI ; Zhihua RAN ; Shu Chen WEI ; Jose SOLLANO ; Michelle Mui Hian TEO ; Kaichun WU ; Byong Duk YE ; Choon Jin OOI
Intestinal Research 2025;23(1):37-55
The lack of clear definition and classification for “moderate ulcerative colitis (UC)” creates ambiguity regarding the suitability of step-up versus top-down treatment approaches. In this paper, experts address crucial gaps in assessing and managing moderate UC. The Asia-Pacific, Middle East, and Africa Inflammatory Bowel Disease Coalition comprised 24 experts who convened to share, discuss and vote electronically on management recommendations for moderate UC. Experts emphasized that the goal of treating UC is to attain clinical, biomarker, and endoscopic remission using cost-effective strategies such as 5-aminosalicylates (5-ASAs), well-tolerated therapy that can be optimized to improve outcomes. Experts agreed that 5-ASA therapy could be optimized by maximizing dosage (4 g/day for induction of remission), combining oral and topical administration, extending treatment duration beyond 8 weeks, and enhancing patient adherence through personalized counselling and reduced pill burden. Treatment escalation should ideally be reserved for patients with predictors of aggressive disease or those who do not respond to 5-ASA optimization. Premature treatment escalation to advanced therapies (including biologics and oral small molecules) may have long-term health and financial consequences. This paper provides consensus-based expert recommendations and a treatment algorithm, based on current evidence and practices, to assist decision-making in real-world settings.
4.Optimizing 5-aminosalicylate for moderate ulcerative colitis: expert recommendations from the Asia-Pacific, Middle East, and Africa Inflammatory Bowel Disease Coalition
Filiz AKYÜZ ; Yoon Kyo AN ; Jakob BEGUN ; Satimai ANIWAN ; Huu Hoang BUI ; Webber CHAN ; Chang Hwan CHOI ; Nazeer CHOPDAT ; Susan J CONNOR ; Devendra DESAI ; Emma FLANAGAN ; Taku KOBAYASHI ; Allen Yu-Hung LAI ; Rupert W LEONG ; Alex Hwong-Ruey LEOW ; Wai Keung LEUNG ; Julajak LIMSRIVILAI ; Virly Nanda MUZELLINA ; Kiran PEDDI ; Zhihua RAN ; Shu Chen WEI ; Jose SOLLANO ; Michelle Mui Hian TEO ; Kaichun WU ; Byong Duk YE ; Choon Jin OOI
Intestinal Research 2025;23(1):37-55
The lack of clear definition and classification for “moderate ulcerative colitis (UC)” creates ambiguity regarding the suitability of step-up versus top-down treatment approaches. In this paper, experts address crucial gaps in assessing and managing moderate UC. The Asia-Pacific, Middle East, and Africa Inflammatory Bowel Disease Coalition comprised 24 experts who convened to share, discuss and vote electronically on management recommendations for moderate UC. Experts emphasized that the goal of treating UC is to attain clinical, biomarker, and endoscopic remission using cost-effective strategies such as 5-aminosalicylates (5-ASAs), well-tolerated therapy that can be optimized to improve outcomes. Experts agreed that 5-ASA therapy could be optimized by maximizing dosage (4 g/day for induction of remission), combining oral and topical administration, extending treatment duration beyond 8 weeks, and enhancing patient adherence through personalized counselling and reduced pill burden. Treatment escalation should ideally be reserved for patients with predictors of aggressive disease or those who do not respond to 5-ASA optimization. Premature treatment escalation to advanced therapies (including biologics and oral small molecules) may have long-term health and financial consequences. This paper provides consensus-based expert recommendations and a treatment algorithm, based on current evidence and practices, to assist decision-making in real-world settings.
5.Comparison of predictive accuracy and clinical applicability among four vancomycin individualized dosing tools
Shu CHEN ; Yanqin LU ; Yun SHEN ; Chang CAO ; Kunming PAN ; Xiaoyu LI ; Qianzhou LYU
China Pharmacy 2025;36(22):2822-2827
OBJECTIVE To compare the predictive accuracy and clinical applicability of four vancomycin individualized dosing tools (SmartDose, ClinCalc, Gulou, Pharmado) and provide a basis for rational clinical medication use. METHODS A retrospective cohort study was conducted, enrolling 479 adult patients who received vancomycin therapy and underwent steady-state trough concentration monitoring in Zhongshan Hospital, Fudan University (Xiamen Branch) from January 1, 2022, to June 30, 2024. The predictive accuracy of each tool was evaluated using indicators, such as mean error (ME), mean absolute error (MAE), mean percentage error (MPE), mean absolute percentage error (MAPE), the proportion of patients with an absolute percentage error (APE) of less than 30%, the 95% limits of agreement, and the overall relative percentage difference between predicted and measured values. Using indicators such as accessibility, patient management, and recommendation of multiple treatment options, the clinical panxso@163.com applicability of the tools for all patients was evaluated; using the discrepancy in accuracy between the predicted and actual measured blood drug concentrations as an indicator, the clinical applicability was assessed for patients in different renal function subgroups (hyperfunction, normal, mild impairment, moderate impairment, and severe impairment). RESULTS In terms of accuracy, SmartDose demonstrated the best overall performance with an MAPE of 46.40% and a proportion of APE <30% (46.56%). Bland-Altman analysis indicated that SmartDose had the smallest overall relative percentage difference (-7.25%), although the 95% limits of agreement were broad for all tools, with differences between the upper and lower limits exceeding 200%. In terms of applicability, all four dosing tools were freely accessible and demonstrated good availability; SmartDose and Pharmado provided the most comprehensive solutions, offering features such as patient management, multiple regimen recommendations, and drug concentration-time curve plotting. Stratified analysis based on renal function revealed that Pharmado showed optimal prediction for hyperfiltration patients (mean difference: 0.11 mg/L). SmartDose and ClinCalc showed relatively better performance in normal and mild renal impaiment (mean difference: 0.37, 0.51 mg/L and -1.13, -1.33 mg/L,respectively). SmartDose performed best in moderate renal impairment (mean difference: -2.60 mg/L). Pharmado and Gulou had smaller prediction biases in severe renal impairment (mean differences: 1.52 mg/L and -0.23 mg/L, respectively). CONCLUSIONS The four individualized dosing tools demonstrated limited accuracy in the initial prediction of vancomycin concentrations. Among them, SmartDose demonstrates the highest overall prediction accuracy and possesses comprehensive clinical management features. It is recommended that Pharmado be preferred for patients with renal hyperfiltration; SmartDose or ClinCalc can be used for patients with normal or mildly impaired renal function; SmartDose is recommended for patients with moderately impaired renal function; Pharmado or Gulou may be considered for patients with severely impaired renal function.
6.Forty years of construction and innovative development of scientific regulation system of traditional Chinese medicine in China.
Jun-Ning ZHAO ; Zhi-Shu TANG ; Hua HUA ; Rong SHAO ; Jiang-Yong YU ; Chang-Ming YANG ; Shuang-Fei CAI ; Quan-Mei SUN ; Dong-Ying LI
China Journal of Chinese Materia Medica 2025;50(13):3489-3505
Since the promulgation of the first Drug Administration Law of the People's Republic of China 40 years ago in 1984, China has undergone four main stages in the traditional Chinese medicine(TCM) regulation: the initial establishment of TCM regulation rules(1984-1997), the formation of a modern TCM regulatory system(1998-2014), the reform of the review and approval system for new TCM drugs(2015-2018), and the construction of a scientific regulation system for TCM(2019-2024). Over the past five years, a series of milestone achievements of TCM regulation in China have been achieved in the six aspects, including its strategic objectives and the establishment of a science-based regulatory system, the reform of the review and approval system for new TCM drugs, the optimization and improvement of the TCM standard system and its formation mechanism, comprehensive enhancement of regulatory capabilities for TCM safety, international harmonization of TCM regulation and its role in promoting innovation. Looking ahead, centered on advancing TCMRS to establish a sound regulatory framework tailored to the unique characteristics of TCM, TCM regulation will evolve into new reform patterns, advancing and extending across eight critical fronts, including the legal framework and policy architecture, the review and approval system for new TCM drugs, the quality standard and management system of TCM, the comprehensive quality & safety regulation and traceability system, the research and transformation system for TCMRS, AI-driven innovations in TCM regulation, the coordination between high-quality industrial development and high-level regulation, and the leadership in international cooperation and regulatory harmonization. In this way, a unique path for the development of modern TCM regulation with Chinese characteristics will be pioneered.
Humans
;
China
;
Drugs, Chinese Herbal/standards*
;
History, 20th Century
;
History, 21st Century
;
Medicine, Chinese Traditional/trends*
7.Mechanism of Tougu Xiaotong Capsules regulating Malat1 and mi R-16-5p ceRNA to alleviate "cholesterol-iron" metabolism disorder in osteoarthritis chondrocytes.
Chang-Long FU ; Yan-Ming LIN ; Shu-Jie LAN ; Chao LI ; Zi-Hong ZHANG ; Yue CHEN ; Ying-Rui TONG ; Yan-Feng HUANG
China Journal of Chinese Materia Medica 2025;50(15):4363-4371
From the perspective of competitive endogenous RNA(ceRNA) constructed by metastasy-associated lung adenocarcinoma transcript 1(Malat1) and microRNA 16-5p(miR-16-5p), the improvement mechanism of Tonggu Xiaotong Capsules(TGXTC) on the imbalance and disorder of "cholesterol-iron" metabolism in chondrocytes of osteoarthritis(OA) was explored. In vivo experiments, 60 8-week-old C57BL/6 mice were acclimatized and fed for 1 week and then randomly divided into two groups: blank group(12 mice) and modeling group(48 mice). The animals in modeling group were anesthetized by 5% isoflurane inhalation, which was followed by the construction of OA model. They were then randomly divided into model group, TGXTC group, Malat1 overexpression group, and TGXTC+Malat1 overexpression(TGXTC+Malat1-OE) group, with 12 mice in each group. The structural changes of mouse cartilage tissues were observed by Masson staining after the intervention in each group. RT-PCR was employed to detect the mRNA levels of Malat1 and miR-16-5p in cartilage tissues. Western blot was used to analyze the protein expression of ATP-binding cassette transporter A1(ABCA1), sterol regulatory element-binding protein(SREBP), cytochrome P450 family 7 subfamily B member 1(CYP7B1), CCAAT/enhancer-binding protein homologous protein(CHOP), acyl-CoA synthetase long-chain family member 4(ACSL4), and glutathione peroxidase 4(GPX4) in cartilage tissues. In vitro experiments, mouse chondrocytes were induced by thapsigargin(TG), and the combination of Malat1 and miR-16-5p was detected by double luciferase assay. The fluorescence intensity of Malat1 in chondrocytes was determined by fluorescence in situ hybridization. The miR-16-5p inhibitory chondrocyte model was constructed. RT-PCR was used to analyze the levels of Malat1 and miR-16-5p in chondrocytes under the inhibition of miR-16-5p. Western blot was adopted to analyze the regulation of TG-induced chondrocyte proteins ABCA1, SREBP, CYP7B1, CHOP, ACSL4, and GPX4 by TGXTC under the inhibition of miR-16-5p. The results of in vivo experiments showed that,(1) compared with model group, TGXTC group exhibited a relatively complete cartilage layer structure. Compared with Malat1-OE group, TGXTC+Malat1-OE group showed alleviated cartilage surface damage.(2) Compared with model group, TGXTC group had a significantly decreased Malat1 mRNA level and an increased miR-16-5p mRNA level in mouse cartilage tissues(P<0.01).(3) Compared with the model group, the protein levels of ABCA1 and GPX4 in the cartilage tissue of mice in the TGXTC group increased, while the protein levels of SREBP, CYP7B1, CHOP and ACSL4 decreased(P<0.01). The results of in vitro experiments show that,(1) dual-luciferase was used to evaluate that miR-16-5p has a targeting effect on the Malat1 gene.(2)Compared with TG+miR-16-5p inhibition group, TG+miR-16-5p inhibition+TGXTC group had an increased mRNA level of miR-16-5p and an decreased mRNA level of Malat1(P<0.01).(3) Compared with TG+miR-16-5p inhibition group, TG+miR-16-5p inhibition+TGXTC group exhibited increased expression of ABCA1 and GPX4 proteins and decreased expression of SREBP, CYP7B1, CHOP, and ACSL4 proteins(P<0.01). The reasults showed that TGXTC can regulate the ceRNA of Malat1 and miR-16-5p to alleviate the "cholesterol-iron" metabolism disorder of osteoarthritis chondrocytes.
Animals
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MicroRNAs/metabolism*
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RNA, Long Noncoding/metabolism*
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Chondrocytes/drug effects*
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Drugs, Chinese Herbal/pharmacology*
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Mice, Inbred C57BL
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Mice
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Osteoarthritis/drug therapy*
;
Iron/metabolism*
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Male
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Cholesterol/metabolism*
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Humans
;
Capsules
;
RNA, Competitive Endogenous
8.Study on the efficacy of automatic-controlled pressure cupping for lumbar disc herniation.
Bo-Chen PENG ; Min-Shan FENG ; Li LI ; Gui-Ju REN ; Yi-Zhen YUAN ; Li-Jie CHANG ; Shu-Ying REN ; Liu ZENG ; Guang-Wei LIU ; Li-Guo ZHU ; Na YUAN
China Journal of Orthopaedics and Traumatology 2025;38(11):1133-1138
OBJECTIVE:
To observe the clinical efficacy and safety of automatic pressure-controlled pressure cupping in patients with lumbar disc herniation, and compare it with traditional cupping.
METHODS:
A total of 100 patients diagnosed with lumbar disc herniation from January 2022 to August 2024 were selected and divided into two groups:the automatic pressure-controlled pressure cupping group (controlled pressure cupping group) and the traditional cupping group (control group), 50 cases in each group. In the controlled pressure cupping group, there were 18 males and 32 females, with an age of (51.98±12.69) years;in the control group, there were 16 males and 34 females, with an age of (51.32±12.05) years. The visual analogue scale(VAS), comfort score, and lumbar range of motion were observed before treatment and after the 1st, 3rd, and 7th treatments to evaluate the efficacy and safety.
RESULTS:
All patients completed the treatment intervention, with complete follow-up data collected. No adverse reactions or complications occurred during treatment and follow-up. After the 3rd treatment, the VAS score of the controlled pressure cupping group was (2.38±0.49), which was lower than that of the control group (2.94±0.68), with a statistically significant difference (P<0.001). In the controlled pressure cupping group, the VAS scores after the 1st, 3rd, and 7th treatments were significantly better than those before treatment (P=0.026);in the control group, the VAS scores after the 3rd and 7th treatments were better than those before treatment, but the difference was not statistically significant(P=0.182). Repeated-measures analysis of variance (ANOVA) on VAS scores at different time points in both groups showed that there were statistically significant differences in inter-group, time, and interaction effects (P<0.05). After the 1st treatment, in the controlled pressure cupping group, 0 patients felt comfortable, 42 patients (84%) felt mild discomfort, and 8 patients (16%) felt moderate discomfort;in the control group, 0 patients felt comfortable, 28 patients (56%) felt mild discomfort, and 22 patients(44%) felt moderate discomfort;the difference between the two groups was statistically significant(P=0.005). After the 3rd treatment, in the controlled pressure cupping group, 30 patients(60%) felt comfortable, 20 patients (40%) felt mild discomfort, and 0 patients felt moderate discomfort; in the control group, 9 patients (18%) felt comfortable, 41 patients (82%) felt mild discomfort, and 0 patients felt moderate discomfort;the difference between the two groups was statistically significant(P<0.001). There was no statistically significant difference in comfort between the two groups after the 7th treatment(P>0.001). There was no statistically significant difference in lumbar range of motion between the two groups before and after treatment(P>0.05);compared with before treatment, the lumbar range of motion of both groups after treatment was significantly improved, with statistically significant differences (P<0.001).
CONCLUSION
Automatic pressure-controlled pressure cupping can effectively relieve symptoms in patients with lumbar disc herniation, with excellent safety.
Humans
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Female
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Male
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Intervertebral Disc Displacement/physiopathology*
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Middle Aged
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Adult
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Lumbar Vertebrae/physiopathology*
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Cupping Therapy/methods*
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Pressure
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Aged
;
Treatment Outcome
9.Granulomatous primary central nervous system vasculitis in a child.
Ya-Nan ZHANG ; Chang-Hong DING ; Shu-Hong REN ; Wei-Hua ZHANG ; Fang LIU ; Nan ZHANG ; Yu-Juan ZHANG
Chinese Journal of Contemporary Pediatrics 2025;27(9):1140-1142
A 14-year-old boy was admitted to the hospital due to a single episode of afebrile seizure and four hours of impaired consciousness. Three months prior to admission, he had a history of bilateral uveitis. Cerebrospinal fluid analysis revealed a mild elevation in white blood cell count. Cranial magnetic resonance imaging and contrast-enhanced scans showed multiple abnormal signals in both cerebral hemispheres, with punctate and nodular enhancement. Susceptibility-weighted imaging revealed multiple punctate hemorrhages within lesions in the bilateral frontal and left parietal lobes, suggestive of vasculitis. Brain biopsy demonstrated inflammatory granulomatous lesions. No secondary causes were identified, and the final diagnosis was granulomatous primary central nervous system vasculitis. The patient's condition improved after treatment with methylprednisolone sodium succinate and mycophenolate mofetil. This report describes a rare case of granulomatous central nervous system vasculitis in a child and provides valuable insights for the diagnosis and treatment of this disease.
Humans
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Male
;
Vasculitis, Central Nervous System/diagnosis*
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Adolescent
;
Magnetic Resonance Imaging
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Granuloma/diagnosis*
10.Clinical Characteristics and Prognostic Analysis of Newly Diagnosed Acute Myeloid Leukemia Patients with NRAS and KRAS Gene Mutations.
Zhang-Yu YU ; Bo CAI ; Yi WANG ; Yang-Yang LEI ; Bing-Xia LI ; Yu-Fang LI ; Yan-Ping SHI ; Jia-Xin CHEN ; Shu-Hong LIU ; Chang-Lin YU ; Mei GUO
Journal of Experimental Hematology 2025;33(3):682-690
OBJECTIVE:
To retrospectively analyze the clinical characteristics, co-mutated genes in newly diagnosed acute myeloid leukemia (AML) patients with NRAS and KRAS gene mutations, and the impact of NRAS and KRAS mutations on prognosis.
METHODS:
The clinical data and next-generation sequencing results of 80 newly diagnosed AML patients treated at our hospital from December 2018 to December 2023 were collected. The clinical characteristics, co-mutated genes of NRAS and KRAS , and the impact of NRAS and KRAS mutations on prognosis in newly diagnosed AML patients were analyzed.
RESULTS:
Among 80 newly diagnosed AML patients, NRAS mutations were detected in 20 cases(25.0%), and KRAS mutations were detected in 9 cases(11.3%). NRAS mutations predominantly occurred at codons 12 and 13 of exon 2, as well as codon 61 of exon 3, while KRAS mutations were most commonly occurred at codons 12 and 13 of exon 2, all of which were missense mutations. There were no statistically significant differences observed in terms of age, sex, white blood cell count(WBC), hemoglobin(Hb), platelet count(PLT), bone marrow blasts, first induction chemotherapy regimen, CR1/CRi1 rates, chromosome karyotype, 2022 ELN risk classification and allogeneic hematopoietic stem cell transplantation(allo-HSCT) among the NRAS mutation group, KRAS mutation group and NRAS/KRAS wild-type group (P >0.05). KRAS mutations were significantly correlated with PTPN11 mutations (r =0.344), whereas no genes significantly associated with NRAS mutations were found. Survival analysis showed that compared to the NRAS/KRAS wild-type group, patients with NRAS mutation had a relatively higher 5-year overall survival (OS) rate and relapse-free survival (RFS) rate, though the differences were not statistically significant (P =0.097, P =0.249). Compared to the NRAS/KRAS wild-type group, patients with KRAS mutation had a lower 5-year OS rate and RFS rate, with no significant differences observed (P =0.275, P =0.442). There was no significant difference in the 5-year RFS rate between the KRAS mutation group and NRAS mutation group (P =0.157), but the 5-year OS rate of patients with KRAS mutation was significantly lower than that of patients with NRAS mutation (P =0.037).
CONCLUSION
In newly diagnosed AML patients, KRAS mutation was significantly correlated with PTPN11 mutation. Compared to patients with NRAS/KRAS wild-type, those with NRAS mutation showed a more favorable prognosis, while patients with KRAS mutation showed a poorer prognosis; however, these differences did not reach statistical significance. Notably, the prognosis of AML patients with KRAS mutation was significantly inferior compared to those with NRAS mutation.
Humans
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Leukemia, Myeloid, Acute/diagnosis*
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Mutation
;
Prognosis
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Proto-Oncogene Proteins p21(ras)/genetics*
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GTP Phosphohydrolases/genetics*
;
Retrospective Studies
;
Membrane Proteins/genetics*
;
Female
;
Male
;
Middle Aged
;
Adult
;
Aged

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