BACKGROUND: The level of measurable residual disease (MRD) before and after transplantation is related to inferior transplant outcomes, and post-hematopoietic stem cell transplantation measurable residual disease (post-HSCT MRD) has higher prognostic value in determining risk than pre-hematopoietic stem cell transplantation measurable residual disease (pre-HSCT MRD). However, only a few work has been devoted to the risk factors for positive post-HSCT MRD in patients with acute lymphoblastic leukemia (ALL). This study evaluated the risk factors for post-HSCT MRD positivity in patients with ALL who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: A total of 1683 ALL patients from Peking University People's Hospital between January 2009 and December 2019 were enrolled to evaluate the cumulative incidence of post-HSCT MRD. Cox proportional hazard regression models were built for time-to-event outcomes. Multivariable analysis was performed to determine independent influencing factors from the univariable analysis. RESULTS: Both in total patients and in T-cell ALL or B-cell ALL, pediatric or adult, human leukocyte antigen-matched sibling donor transplantation or haploidentical SCT subgroups, positive pre-HSCT MRD was a risk factor for post-HSCT MRD positivity ( P  <0.001 for all). Disease status (complete remission 1 [CR1] vs . ≥CR2) was also a risk factor for post-HSCT MRD positivity in all patients and in the B cell-ALL, pediatric, or haploidentical SCT subgroups ( P  = 0.027; P  = 0.003; P  = 0.035; P  = 0.003, respectively). A risk score for post-HSCT MRD positivity was developed using the variables pre-HSCT MRD and disease status. The cumulative incidence of post-HSCT MRD positivity was 12.3%, 25.1%, and 38.8% for subjects with scores of 0, 1, and 2-3, respectively ( P  <0.001). Multivariable analysis confirmed the association of the risk score with the cumulative incidence of post-HSCT MRD positivity and relapse as well as leukemia-free survival and overall survival. CONCLUSION Our results indicated that positive pre-MRD and disease status were two independent risk factors for post-HSCT MRD positivity in patients with ALL who underwent allo-HSCT.
Humans ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology* ; Neoplasm, Residual ; Hematopoietic Stem Cell Transplantation/methods* ; Male ; Female ; Risk Factors ; Adolescent ; Adult ; Child ; Child, Preschool ; Young Adult ; Middle Aged ; Infant ; Transplantation, Homologous ; Proportional Hazards Models ; Retrospective Studies

Hepatic stellate cells (HSCs) are the primary fibrogenic cells in the liver, and their activation plays a crucial role in the development and progression of hepatic fibrosis. Here, we report that retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a key modulator of HSC activation and liver fibrosis. RXRα exerts its effects by modulating calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ)-mediated activation of AMP-activated protein kinase-alpha (AMPKα). In addition, we demonstrate that K-80003, which binds RXRα by a unique mechanism, effectively suppresses HSC activation, proliferation, and migration, thereby inhibiting liver fibrosis in the CCl₄ and amylin liver NASH (AMLN) diet animal models. The effect is mediated by AMPKα activation, promoting mitophagy in HSCs. Mechanistically, K-80003 activates AMPKα by inducing RXRα to form condensates with CaMKKβ and AMPKα via a two-phase process. The formation of RXRα condensates is driven by its N-terminal intrinsic disorder region and requires phosphorylation by CaMKKβ. Our results reveal a crucial role of RXRα in liver fibrosis regulation through modulating mitochondrial activities in HSCs. Furthermore, they suggest that K-80003 and related RXRα modulators hold promise as therapeutic agents for fibrosis-related diseases.

OBJECTIVE To evaluate the cost-utiliby of capivasertib combined with fulvestrant for the second-line treatment of hormone receptor-positive/human epidermal growth factor receptor-2-negative （HR+/HER2－） advanced breast cancer from the perspective of the Chinese healthcare system. METHODS A partitioned survival model was constructed using clinical data from the CAPItello-291 trial. Costs and quality-adjusted life years （QALYs） were used as the output indicators of the model， and the incremental cost-effectiveness ratio （ICER） was used as the evaluation indicator of the model. Using three times the per capita gross domestic product （GDP） of China in 2024 as the willingness-to-pay threshold （WTP）， this study analyzed the cost-utility of capivasertib combined with fulvestrant versus fulvestrant monotherapy in the treatment of HR+/HER2－ advanced breast cancer， and conducted sensitivity analysis and scenario analysis under conditions where the price of capivasertib was reduced by 50%， 60%， 70% and 95%， respectively. RESULTS The results of the basic analysis showed that compared with the fulvestrant monotherapy regimen， the ICER of capivasertib combined with fulvestrant was 843 038.46 yuan/QALY， which was higher than the WTP（287 247 yuan/QALY）. The one-way sensitivity analysis revealed that the top three factors with the most substantial influence on ICER were the utility value in the progression disease state， the price of capivasertib， and the utility value inthe progression free survival state. Probabilistic sensitivity analysis demonstrated the robustness of the basic analysis results. Scenario analysis revealed that even if the price of capivasertib were reduced by 95%， capivasertib combined with fulvestrant did not exhibit cost-effectiveness at the current WTP. CONCLUSION At a WTP of three times China’s GDP per capita in 2024， compared to fulvestrant monotherapy， capivasertib combined with fulvestrant as the second-line treatment for HR+/ HER2－ advanced breast cancer is not cost-effective.

Objective:We aimed to analyse the trend of incidence and mortality of stomach cancer in Shandong province from 2012 to 2022 and predict the development trend from 2023 to 2030.Methods:Data on incidence and mortality of stomach cancer in Shandong province from 2012 to 2022 were obtained from Shandong Cancer Registry. The incidence, age-specific incidence, mortality and age-specific mortality in different years, sexes and urban and rural areas were calculated, the rates were standardized based on the age composition of the Chinese standard population in 2000. The average annual percent change (AAPC) of incidence and mortality was calculated using Joinpoint software. The Bayesian age-period-cohort model was used to predict the trend of stomach cancer incidence and mortality from 2023 to 2030.Results:From 2012 to 2022, the stomach cancer age-standardized incidence rate (ASIR) and age-standardized mortality rate (ASMR) showed a decreasing trend. The ASIR decreased from 27.47/100 000 in 2012 to 16.06/100 000 in 2022 (AAPC=-5.10%, P＜0.001), and the ASMR decreased from 17.69/100 000 to 11.09/100 000 (AAPC=-5.52%, P＜0.001). The ASIR and ASMR of male, female, urban and rural population also showed downward trends. The incidence and mortality rates of men were always higher than those of women, and the difference between urban and rural areas is gradually narrowing. In 2022, the ASIR (16.09/100 000 in urban and 16.03/100 000 in rural) and the ASMR (11.10/100 000 in urban and 11.08/100 000 in rural) of stomach cancer between urban and rural areas were nearly identical. The Bayesian age-period-cohort model predicted that the ASIR of stomach cancer in Shandong would further decrease from 2023 to 2030 (AAPC=-0.51%, P=0.001), but the change tended to be smooth. The incidences in male (AAPC=-1.46%, P=0.010) and rural areas (AAPC=-1.21%, P＜0.001) were still expected to have a little room for decline. The trend of incidences in female and urban areas were not statistically significant. The trend of mortality was consistent with the incidence. Conclusions:The stomach cancer incidence and mortality in Shandong shows a decreasing trend and it is expected to decrease further by 2030. However, the trend tends to be smooth, and the disease burden should be reduced as early as possible for high-risk population and high-risk factors of stomach cancer.

Objective:We aimed to analyse the trend of incidence and mortality of stomach cancer in Shandong province from 2012 to 2022 and predict the development trend from 2023 to 2030.Methods:Data on incidence and mortality of stomach cancer in Shandong province from 2012 to 2022 were obtained from Shandong Cancer Registry. The incidence, age-specific incidence, mortality and age-specific mortality in different years, sexes and urban and rural areas were calculated, the rates were standardized based on the age composition of the Chinese standard population in 2000. The average annual percent change (AAPC) of incidence and mortality was calculated using Joinpoint software. The Bayesian age-period-cohort model was used to predict the trend of stomach cancer incidence and mortality from 2023 to 2030.Results:From 2012 to 2022, the stomach cancer age-standardized incidence rate (ASIR) and age-standardized mortality rate (ASMR) showed a decreasing trend. The ASIR decreased from 27.47/100 000 in 2012 to 16.06/100 000 in 2022 (AAPC=-5.10%, P＜0.001), and the ASMR decreased from 17.69/100 000 to 11.09/100 000 (AAPC=-5.52%, P＜0.001). The ASIR and ASMR of male, female, urban and rural population also showed downward trends. The incidence and mortality rates of men were always higher than those of women, and the difference between urban and rural areas is gradually narrowing. In 2022, the ASIR (16.09/100 000 in urban and 16.03/100 000 in rural) and the ASMR (11.10/100 000 in urban and 11.08/100 000 in rural) of stomach cancer between urban and rural areas were nearly identical. The Bayesian age-period-cohort model predicted that the ASIR of stomach cancer in Shandong would further decrease from 2023 to 2030 (AAPC=-0.51%, P=0.001), but the change tended to be smooth. The incidences in male (AAPC=-1.46%, P=0.010) and rural areas (AAPC=-1.21%, P＜0.001) were still expected to have a little room for decline. The trend of incidences in female and urban areas were not statistically significant. The trend of mortality was consistent with the incidence. Conclusions:The stomach cancer incidence and mortality in Shandong shows a decreasing trend and it is expected to decrease further by 2030. However, the trend tends to be smooth, and the disease burden should be reduced as early as possible for high-risk population and high-risk factors of stomach cancer.

Objective:To analyze the clinical characteristics and outcomes of patients with invasive fungal sinusitis (invasive fungal rhinosinusitis, IFR) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and explored the risk factors for IFR after allo-HSCT.Methods:Nineteen patients with IFR after allo-HSCT at Peking University People’s Hospital from January 2012 to December 2021 were selected as the study group, and 95 patients without IFR after allo-HSCT during this period were randomly selected as the control group (1:5 ratio) .Results:Nineteen patients, including 10 males and 9 females, had IFR after allo-HSCT. The median age was 36 (10–59) years. The median IFR onset time was 68 (9–880) days after allo-HSCT. There were seven patients with acute myeloid leukemia, five with acute lymphoblastic leukemia, two with myelodysplastic syndrome, two with chronic myeloid leukemia, one with acute mixed-cell leukemia, one with multiple myeloma, and one with T-lymphoblastic lymph node tumor. There were 13 confirmed cases and 6 clinically diagnosed cases. The responsible fungus was Mucor in two cases, Rhizopus in four, Aspergillus in four, and Candida in three. Five patients received combined treatment comprising amphotericin B and posaconazole, one patient received combined treatment comprising voriconazole and posaconazole, nine patients received voriconazole, and four patients received amphotericin B. In addition to antifungal treatment, 10 patients underwent surgery. After antifungal treatment and surgery, 15 patients achieved a response, including 13 patients with a complete response and 2 patients with a partial response. Multivariate analysis revealed that neutropenia before transplantation ( P=0.021) , hemorrhagic cystitis after transplantation ( P=0.012) , delayed platelet engraftment ( P=0.008) , and lower transplant mononuclear cell count ( P=0.012) were independent risk factors for IFR after allo-HSCT. The 5-year overall survival rates in the IFR and control groups after transplantation were 29.00%±0.12% and 91.00%±0.03%, respectively ( P<0.01) . Conclusion:Although IFR is rare, it is associated with poor outcomes in patients undergoing allo-HSCT. The combination of antifungal treatment and surgery might be effective.

Objectives:To determine the effect of glucose-6-phosphate-dehydrogenase (G6PD) deficiency on patients’ complications and prognosis following allogeneic stem cell hematopoietic transplantation (allo-HSCT) .Methods:7 patients with G6PD deficiency (study group) who underwent allo-HSCT at Peking University People's Hospital from March 2015 to January 2021 were selected as the study group, and thirty-five patients who underwent allo-HSCT during the same period but did not have G6PD deficiency were randomly selected as the control group in a 1∶5 ratio. Gender, age, underlying diseases, and donors were balanced between the two groups. Collect clinical data from two patient groups and perform a retrospective nested case-control study.Results:The study group consisted of six male patients and one female patient, with a median age of 37 (range, 2-45) years old. The underlying hematologic diseases included acute myeloid leukemia ( n=3), acute lymphocytic leukemia ( n=2), and severe aplastic anemia ( n=2). All 7 G6PD deficiency patients achieved engraftment of neutrophils within 28 days of allo-HSCT, while the engraftment rate of neutrophils was 94.5% in the control group. The median days of platelet engraftment were 21 (6–64) d and 14 (7–70) d ( P=0.113). The incidence rates of secondary poor graft function in the study group and control group were 42.9% (3/7) and 8.6% (3/35), respectively ( P=0.036). The CMV infection rates were 71.4% (5/7) and 31.4% (11/35), respectively ( P=0.049). The incidence rates of hemorrhagic cystitis were 57.1% (4/7) and 8.6% (3/35), respectively ( P=0.005), while the bacterial infection rates were 100% (7/7) and 77.1% (27/35), respectively ( P=0.070). The infection rates of EBV were 14.3% (1/7) and 14.3% (5/35), respectively ( P=1.000), while the incidence of fungal infection was 14.3% (1/7) and 25.7% (9/35), respectively ( P=0.497). The rates of post-transplant lymphoproliferative disease (PTLD) were 0% and 5.7%, respectively ( P=0.387) . Conclusions:The findings of this study indicate that blood disease patients with G6PD deficiency can tolerate conventional allo-HSCT pretreatment regimens, and granulocytes and platelets can be implanted successfully. However, after transplantation, patients should exercise caution to avoid viral infection, complications of hemorrhagic cystitis, and secondary poor graft function.

OBJECTIVE To investigate the effect of individualized repositioning maneuver in the treatment of posterior semicircular canal benign paroxysmal positional vertigo(PC-BPPV)with limited neck movement.METHODS There were 163 patients with PC-BPPV admitted to the Department of Otolaryngology of Xiaolan People's Hospital of Zhongshan from January,2019 to July,2022 who were selected and divided into observation group(57 cases)and control group(106 cases)according to whether there was neck movement limitation or not.The control group was divided into control group 1(51 cases)and control group 2(55 cases)based on different reduction methods.The control group 1 were treated with modified Epley maneuver,and the observation group and the control group 2 were treated with individualized Epley maneuver.The cure rate and effective rate were compared among the three groups.The scores of vestibular symptom index(VSI),Berg balance scale(BBS)and the dimension scores of vertigo handicap inventory(DHI)were compared among the three groups before and after treatment.RESULTS There was no significant difference in the cure rate(84.37%vs.81.82%vs.80.70%)and effective rate(11.76%vs.10.91%vs.12.28%)among the three groups(P>0.05).After treatment,the scores of each dimension of VSI and DHI of PC-BPPV patients of the three groups decreased(P<0.01),and the scores of BBS increased(P<0.01),and there was no statistically significant difference in the scores of VSI(23.19±3.88 vs.23.70±4.01 vs.23.46±3.92),BBS(45.56±5.02 vs.45.14±4.98 vs.44.84±5.11)and each dimension of DHI among the three groups(P>0.05),respectively.CONCLUSION The individual Epley maneuver can effectively improve the vertigo status of patients with PC-BPPV with limited neck movement.

Objective:To describe the trend of mortality and death spectrum in Shandong Province from 1970 to 2021 and provide basis for the targeted disease prevention and control.Methods:The data were collected from the death registration reports of Shandong and 3 national retrospective surveys of death causes in Shandong. The change in levels of overall and specific deaths in Shandong in different years were analyzed based on mortality rate, age-standardized mortality rate and constituent ratio of cause of death, differential decomposition was used to quantify the contribution of demographic and non-demographic factors to changes of mortality.Results:The crude mortality rate in residents in Shandong was basically stable from 1970 to 2021, and the mortality rate during 2020-2021 (732.73/100 000) was slightly higher than that during 1970-1974 (671.98/100 000). While the standardized mortality rate decreased significantly, and the mortality during 2020-2021 (183.39/100 000) decreased by 67.71% compared with that during 1970-1974 (568.00/100 000). The negative increase of population factors and the positive decrease of non-population factors reacted each other, so the mortality was relatively stable. Cardiac-cerebrovascular disease was always the leading cause of death, but the constituent ratio of death increased rapidly from 19.70% during 1970-1974 to 54.72% during 2020-2021. The rank in the causes of death changed from the fourth (11.46%) to the second (25.70%) for malignant tumor, from the seventh (5.85%) to the third (5.59%) for injury, from the second (12.87%) to the fourth (4.99%) for chronic respiratory diseases, from the third (12.27%) to the tenth (0.42%) for infectious diseases. The standardized mortality rates of the main causes of death decreased at different degrees, the standardized mortality rates of obstetrical disease, infectious disease, gastrointestinal disease and chronic respiratory disease decreased by more than 50.00%. The age distribution of deaths and the death spectrum in different age groups and in urban-rural populations changed significantly. During 2020-2021, the proportion of deaths in young people aged 0-14 years was 0.54%, which was 97.05% lower than that during 1970-1974, while the proportion of deaths in the elderly aged ≥75 years was 55.14%, which was 55.75% higher than that during 1970-1974. The rank of infectious diseases in the causes of death descended significantly in all age groups, but the ranks of injury, neuropsychiatric disease and malignant tumor rose significantly in adolescents, and the ranks of endocrine nutrition and metabolic disease rose in middle-aged and elderly people. The difference of death spectrum between urban area and rural area became less obvious and the main death causes in urban and rural residents were basically the same during 2020-2021.Conclusions:The death spectrum of residents in Shandong changed significantly. Chronic and non-communicable diseases, especially cardiac-cerebrovascular disease and malignant tumor, should be the focus in disease control and prevention. The prevention and control of diseases in Shandong made remarkable achievement during 1970-2021. However, in the context of population ageing, it is suggested to strengthen the treatment, prevention of diseases and injuries related to the health of the elderly and elderly health care in the future.

Objectives It was a preliminary exploration on rare disease management of comprehensive hospital based on the"Center-Multidisciplinary Team"structure.Methods By applying interrupted time series analysis,the characteristics and related medical service of rare disease patients discharged from sample hospitals from 2021 to 2023 were measured.Results The results showed that the hospital served 19 825 rare disease patients from 2021 to 2023.The proportion of patients whose main diagnosis were rare diseases was approximately 27％.The interrupted time series technique indicated that the expected proportion of rare disease patients increased instantly by 1.89 thousand points.The capability to diagnose has significantly improved,with a growing trend on volume of bioinformatics analysis services for rare diseases patients.Conclusion The rare disease management based on the"Center-Team"structure can increase the attention of medical staff to rare diseases,strengthen the diagnostic capacity of rare diseases,and make patient management more continuous and disciplinary co-operation more efficient without significantly increasing the input burden on hospitals.