[Clinical characteristics of myeloid tumors combined with the proliferation of large granular lymphocytes].

Myeloid neoplasms (MNs) belong to a group of hematological malignancies characterized by the abnormal biological functions of hematopoietic stem progenitor cells. The abnormal immune and hematopoietic microenvironment of patients with MN interact with malignant clonal hematopoietic stem cells, promoting the occurrence and development of their diseases. MN large granular lymphocyte proliferation (MN-LGLP) is a special and rare clinical phenomenon in this type of disease. Currently, research on this disease in domestic and international cohorts is limited. This study analyzes the clinical and laboratory characteristics of this type of patient and explores the impact of LGLP on the clinical characteristics and survival of patients with MN. Patients with MN-LGLP are prone to neutropenia and splenomegaly. The presence of LGLP is not a risk factor affecting the survival of patients with MN-LGLP. STAG, ASXL1, and TET2 are the most common accompanying gene mutations in MN-LGLP, and patients with MN-LGLP and STAG2 mutations have poor prognoses.

[Analysis of risk factors for venous thromboembolism in patients with polycythemia vera and establishment of a prediction model].

Objective: To investigate the risk factors of venous thrombosis in patients with polycythemia vera (PV) and establish a prediction model for venous thrombosis. Methods: PV patients with JAK2V617F gene mutation positive in the Second Hospital of Tianjin Medical University from September 2017 to November 2023 were retrospectively included. The patients were divided into groups according to whether they had venous thrombosis. After matching age and gender factors with propensity scores, 102 patients were included in the venous thrombosis group [46 males, 56 females, with a median age M (Q1, Q3) of 52 (44, 60) years] and 204 cases were included in the group without venous thrombosis [92 males, 112 females, with a median age of 52 (44, 59) years]. The clinical and laboratory characteristics, disease progression and incidence of gene mutation were compared between the two groups. The follow-up cohort ended on November 20, 2023, with a median follow-up [M (Q1, Q3)] of 11 (1, 53) years. Multivariate Cox risk model was used to analyze the influencing factors of venous thrombosis in PV patients, and establish a scoring system for the venous thrombosis risk factor prediction model of PV patients. Receiver operating characteristic (ROC) curve was used to evaluate the predictive efficiency of the model. Results: Hemoglobin concentration, the ratio of hematopoietic volume≥55%, neutrophil to lymphocyte ratio≥5, hypertension, subcostal spleen≥5 cm and secondary myelofibrosis in venous thrombosis group were higher than those in non-venous thrombosis group (all P<0.05). In addition, the proportion of history of thromboembolism, V617F gene mutation load (V617F%)≥50%, diabetes mellitus, ASXL1 mutation and secondary reticular silver staining≥3 in the venous thrombosis group were higher than those in the non-venous thrombosis group (all P<0.05). The proportion of PV patients with 3 or more gene mutations was 44.1% (45/102) in venous thrombosis group, which was higher than that of PV patients without venous thrombosis 29.9% (61/204) (P=0.014). The proportion of ASXL1 gene mutation in venous thrombosis group was 17.6% (18/102), which was higher than the 4.9% (10/204) in non-venous thrombosis group (P<0.001). Multivariate Cox risk model analysis showed that previous thromboembolism history (HR=2.031, 95%CI: 1.297-3.179, P=0.002), V617F%≥50% (HR=2.141, 95%CI: 1.370-3.347, P=0.001), ASXL1 mutation (HR=4.632, 95%CI: 1.497-14.336, P=0.008), spleen subcostal≥5 cm (HR=1.771, 95%CI: 1.047-2.996, P=0.033) are the risk factors of venous thrombosis in PV patients. According to HR values, a score system for predicting risk of venous thrombosis in PV patients was established: previous history of thromboembolism, V617F%≥50% and spleen subcostoal≥5 cm were assigned 1 point respectively, and ASXL1 mutation was assigned 2 points. Low risk group: score 0, medium risk group: score 1-2, high risk group: score≥3. The ROC curve analysis of the model for predicting venous thrombosis in PV patients showed that the area under the curve (AUC) was 0.807 (95%CI: 0.755-0.860), with the sensitivity of 88.2% and the specificity of 59.8% when the Youden index was 0.48. Conclusions: Previous thromboembolism history, V617F%≥50%, ASXL1 mutation, spleen subcostoal≥5 cm are risk factors of venous thrombosis in PV patients. The established prediction model has good prediction efficiency.

[Clinical significance of IL-18 and IL-18-binding protein in bone marrow of patients with myelodysplastic syndrome].

Objective: To analyze the level and clinical significance of IL-18 and IL-18-binding protein (BP) in the bone marrow of patients with myelodysplastic syndrome (MDS) . Methods: A total of 43 newly diagnosed patients with MDS who were admitted to the Department of Hematology, Tianjin Medical University General Hospital, from July 2020 to February 2021 were randomly selected. The control group consisted of 14 patients with acute myeloid leukemia (AML) and 25 patients with iron-deficiency anemia (IDA). The levels of IL-18 and IL-18 BP in the bone marrow supernatant were measured, and their correlations with MDS severity, as well as the functionality of CD8(+) T cells and natural killer cells, was analyzed. Results: The levels of IL-18, IL-18 BP, and free IL-18 (fIL-18) in the bone marrow supernatant of patients with MDS were higher than in the IDA group. The level of fIL-18 was linearly and negatively correlated with the MDS-International Prognostic Scoring System (IPSS) score. IL-18 receptor (IL-18Rα) expression on CD8(+) T cells in the MDS group was lower than in the IDA group, and the levels of fIL-18 and IL-18Rα were positively correlated with CD8(+) T-cell function in the MDS group. Conclusion: IL-18 BP antagonizes IL-18, leading to a decrease in fIL-18 in the bone marrow microenvironment of patients with MDS, affecting CD8(+) T-cell function, which is closely related to MDS severity; therefore, it may become a new target for MDS treatment.

[Evaluation of the efficacy and safety of intravenous infusion of ferric derisomaltose in the treatment of iron deficiency anemia: a single-center retrospective analysis].

Objective: To investigate the clinical efficacy and safety of ferric derisomaltose injection versus iron sucrose injection in the treatment of iron deficiency anemia (IDA) . Methods: A total of 120 patients with iron deficiency anemia admitted from June 2021 to March 2023 were given intravenous iron supplementation with ferric derisomaltose to assess the efficacy and safety of hemoglobin (HGB) elevation before and after treatment. Simultaneously, the clinical effects of iron supplementation with iron sucrose were compared to those of inpatient patients during the same period. Results: Baseline values were comparable in both groups. Within 12 weeks of treatment, the elevated HGB level in the ferric derisomaltose group was higher than that of the iron sucrose group, with a statistical difference at all time points, and the proportion of HGB increased over 20 g/L in the patients treated for 4 weeks was higher (98.7%, 75.9% ). During the treatment with ferric derisomaltose and iron sucrose, the proportion of mild adverse reactions in the ferric derisomaltose group was slightly lower than that of the iron sucrose group, and neither group experienced any serious adverse reactions. The patients responded well to the infusion treatment, with no reports of pain or pigmentation at the injection site. Conclusion: The treatment of IDA patients with ferric derisomaltose has a satisfactory curative effect, with the advantages of rapidity, accuracy, and safety. Therefore, it is worthy of widespread clinical use.

[Physical activity and its influencing factors in patients with diabetes mellitus: a comparative study between China and the United Kingdom].

Objective: To compare the differences in low-level physical activity (PA) and related influencing factors in patients with diabetes mellitus in China and the United Kingdom (UK). Methods: Using baseline survey data from the China Kadoorie Biobank and the UK Biobank, we analyzed the association between diabetes mellitus and low-level PA using logistic regression, with the participants' self-reported whether they had diabetes mellitus as the independent variable, and low-level PA as the dependent variable. Results: We included 509 254 Chinese adults and 359 763 British adults in the analysis. After adjusting for multiple factors, we found that both Chinese and British patients with diabetes mellitus were at elevated risk for low-level PA, with corresponding ORs (95%CIs) of 1.15 (1.12-1.19) and 1.37 (1.32-1.41), respectively. Patients with diabetes mellitus with longer disease duration and poorer glycemic control were at greater risk of having low-level of PA. Female, rural-distributed, employed, never-smoking Chinese diabetics, and male, urban-distributed, retired/unemployed, quit-smoking British diabetics were more likely to have low-level PA. Conclusions: Chinese and British patients with diabetes mellitus were more likely to have low-level PA compared with the general population, but the risk of low-level PA for patients in both countries varied by population characteristics. Therefore, PA guidelines and intervention measures should be based on the characteristics of individuals in the target countries and regions, which could improve PA levels among patients with diabetes mellitus.

[Comparative study on physical activity and its influencing factors in patients with chronic pulmonary obstructive disease between China and the United Kingdom].

Objective: To compare physical activity and its influencing factors in patients with chronic obstructive pulmonary disease (COPD) between China and the United Kingdom. Methods: We analyzed baseline data from China Kadoorie Biobank and the United Kingdom Biobank among COPD patients who were diagnosed with a one-second rate (FEV1/FVC) less than 70%. Physical activity level was calculated as metabolic equivalent (MET) and divided into three levels: low, medium, and high, according to tertiles stratified by gender and age. Multiple logistic regression was used to estimate ORs and 95%CIs for COPD and Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade about physical activity level, and subgroup analysis was conducted. Results: A total of 506 073 Chinese adults and 231 884 British adults were included. After adjusting for potential confounders, COPD was associated with lower physical activity levels in both Chinese and British COPD patients, with OR (95%CI) of 1.07(1.03-1.10) and 1.03(1.01-1.06) compared with non COPD patients, respectively. The GOLD grade was inversely correlated with physical activity level, particularly in a dose-response manner in the CKB population (trend test P<0.001). The negative relationship was stronger among the elderly, people with less education and lower economic status, and those with a smoking or chronic disease history. Chinese rural COPD patients were at high risk of decline of physical activity. Conclusions: Physical activity is inversely related to COPD, with a dose-response connection to GOLD grade. Therefore, physical activity maintenance and improvement should be encouraged and promoted in COPD patients, especially in high-risk groups.

[Clinical and laboratory features of SF3B1-mutated myeloproliferative neoplasms].

Objective: To explore the clinical and laboratory characteristics of SF3B1 gene mutations in myeloproliferative neoplasms (MPN) patients. Methods: The clinical data of 273 MPN patients who were diagnosed MPN and treated in the Second Hospital of Tianjin Medical University from November 2017 to March 2023 were retrospectively analyzed. There were 133 males and 140 females, with a median age M(Q1,Q3)of 56(46, 67) years. The molecular biology and cytogenetic characteristics were detected by second-generation sequencing (NGS) and R+G banding techniques, and the clinical and laboratory characteristics of patients with SF3B1 gene mutation were analyzed. Results: SF3B1 gene mutations were found in 13 patients (4.8%, 13/273).The types of SF3B1 mutations included missense (92.3%, 12/13) and nonsense mutations (7.7%, 1/13).Compared to the non-mutant cohort, patients in SF3B1 mutant cohort had older ages [68(51, 76) vs 56(45, 66)years,P=0.025], higher proportion of splenomegaly [46.2%(6/13) vs 15.8%(41/259),P=0.014]and secondary tumor [23.1%(3/13)vs 3.8%(10/260), P=0.018]with higher proportion of bone marrow blast [0.5%(0, 1.5%) vs 0(0, 0.5%),P=0.002] and lower hemoglobin[(104±36) vs (137±40) g/L,P=0.004] and hematocrit [31%(22%, 40%) vs 41%(35%, 52%),P=0.003]. All of the 10 patients in the SF3B1 mutant cohort whose ring sideroblast (RS) could be evaluated showed no RS formation. The overall survival, thrombosis-free survival and leukemia free survival of MPN patients in SF3B1 mutant cohort were 4.0 (2.0, 6.0), 2.0 (0.5, 4.5) and 4.0 (2.0, 6.0) years, respectively, while patients in the non-mutant cohort were 6.0 (3.0, 10.0), 5.0 (1.0, 8.0), 6.0 (3.0, 10.0) years, respectively, there were no statistical significance between two groups (Z=3.69, 1.66, 2.05, all P>0.05).The secondary tumor free survival of SF3B1 mutant cohort patients was 4.0 (2.0, 6.0) years, which was lower than that of non-mutant cohort patients [5.5 (3.0, 10.0) years, Z=18.18, P<0.001). Conclusions: MPN patients with SF3B1 gene mutations are older, more prone to splenomegaly and secondary tumors. They also have a higher proportion of bone marrow blast, lower hemoglobin and hematocrit, and show no RS formation.

Meta-analysis exploring the effectiveness and safety of different doses of estrogen in the treatment of osteoporosis in perimenopausal women in China.

OBJECTIVE: This study aims to systematically evaluate the effectiveness and safety of using different doses of estrogen in the treatment of perimenopausal osteoporosis in China. MATERIALS AND METHODS: Computer searches of the Cochrane Library, PubMed, Embase, CBM, CNKI, WanFang Date, and VIP databases were conducted. Randomized Controlled Trials (RCTs) on different doses of estrogen for the treatment of osteoporosis in Chinese perimenopausal women were searched for the period 01/01/2000-06/09/2022. Document screening and data extraction were completed independently by 2 researchers and assessed using the Cochrane recommended risk bias assessment tool for RCTs. The software used for analysis in this study was Stata, version 16.0. RESULTS: A total of 10 RCTs with a cumulative total of 804 patients were included. Meta-analysis results showed that low doses of estrogen were more effective in improving patient outcomes [OR=0.521, 95% CI (0.300-0.907), z = 2.31, p ≤ 0.05] and bone mineral density [SMD = -0.218, 95% CI (-0.42,-0.016), z = 2.11, p ≤ 0.05] was not superior. For bone metabolism and sex hormone indicators, the standard dose group had a slight advantage, but the difference was small (p > 0.05) and not statistically significant. With regard to safety, the incidence of adverse reactions was higher with the standard dose of estrogen. CONCLUSIONS: In China, standard doses of estrogen are used for clinical effectiveness. However, vigilance must be maintained for potential safety concerns that may arise during treatment.

[Research status and challenges of advanced myeloproliferative neoplasms].

Classical myeloproliferative neoplasms (MPN), also known as Ph-MPN, includes polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). Secondary myelofibrosis (sMF) and secondary acute myeloid leukemia (sAML) are important disease progressions of MPN. After MPN disease progression, hematopoietic stem cells undergo new clonal evolution, leading to drug resistance, poor treatment effect and poor survival of patients. In recent years, the exploration of the mechanism of disease progression and the precise diagnosis and treatment of MPN have attracted much attention. This article summarizes the research status of MPN disease progression, including the pathogenesis, risk stratification, and precision treatment, in order to provide reference for exploring new diagnosis and treatment methods of MPN disease progression.

[Efficacy and safety of pegylated interferon alpha-2b for patients with myeloproliferative neoplasm].

Objective: To evaluate the efficacy and safety of pegylated interferon alpha-2b (PEG-IFN-α2b) in the treatment of myeloproliferative neoplasm (MPN). Methods: Thirty-four MPN patients receiving PEG-IFN-α2b treatment in the Second Hospital of Tianjin Medical University from August 2019 to October 2022 were prospectively included. Among the patients, 9 were male and 25 were female, and the median age [M (Q1, Q3)] was 57 (19, 78) years. Patients' clinical characteristics were collected and the follow-up was performed. As of January 30, 2023, the follow-up period [M(Q1, Q3)] was 24 (16, 33) months. The efficacy, safety and changes in immune cell and cytokine levels after 12 and 24 months of treatment were analyzed. Results: During the follow-up period, 4 patients dropped out, and the efficacy was evaluable in 30 patients. Following 12 and 24 months of treatment, the complete hematologic response (CHR) rates were 57.1% (16/28) and 75.0% (18/24), respectively. The complete molecular response (CMR)+partial molecular response (PMR) rates were 27.3% (6/22) and 55.0% (11/20), respectively. The bone marrow histopathological overall response rates (ORR) were 34.6% (9/26) and 47.6% (10/21), respectively. At 12 and 24 months of treatment, the proportions of CD8+HLA-DR+T cells, effector T cell subpopulations, CD56bright natural killer (NK) cells, and plasmacytoid dendritic cells (pDC) were higher than the pre-treatment levels, while the proportion of CD56dim NK cells was lower than the pre-treatment level (all P<0.05). The levels of motif chemokine ligand 10 (CXCL10), tumor necrosis factor (TNF)-α and TNF-ß in bone marrow all increased from those prior to treatment, while the levels of vascular endothelial growth factor (VEGF) and interleukin (IL-4) decreased from those prior to treatment (all P<0.05). Among hematological adverse reactions, white blood cells decrease [47% (16/34)] was observed with high incidence. Among non-hematological adverse reactions, asthenia [44.1% (15/34)] and transaminases increase [32.3% (11/34)] were observed with high incidences. Conclusions: PEG-IFN-α2b has high hematologic, molecular, and bone marrow histopathological response rates in the treatment of MPN. It can reduce malignant clone loads and regulate the immune microenvironment and is safe and well tolerated overall.

[Analysis of risk factors for thromboembolism in patients with JAK2V617F gene mutation positive myeloproliferative neoplasms].

Objective: To analyze the risk factors of thrombosis in patients with JAK2V617F mutation positive myeloproliferative neoplasms (MPN). Methods: A total of 223 MPN patients with JAK2V617F mutation in the Second Hospital of Tianjin Medical University from September 2017 to May 2023 were retrospectively enrolled, including 111 males and 112 females, aged [M(Q1,Q3)] 57(21,66) years. According to the presence or absence of thromboembolism during follow-up, the patients were divided into thrombosis group (n=102) and non-thrombosis group (n=121). The clinical characteristics, laboratory characteristics, cytogenetics and other disease progression and survival of the two groups of patients were analyzed. As of March 31, 2023, the follow-up period [M (Q1, Q3)] was 6 (3, 10) years. The influencing factors of thrombosis in JAK2V617F positive MPN patients were analyzed by using the Cox risk model. Results: Among 223 JAK2V617F positive MPN patients, 144 were polycythemia vera (PV), 51 were essential thrombocythemia (ET) and 28 were primary myelofibrosis (PMF). The mutation rates of ASXL1 and BCORL1 genes in the thrombosis group were 19.6% (20/102) and 6.9% (7/102), respectively, which were higher than those in the non-thrombosis group [9.1% (11/121) and 0.8% (1/121)] (both P<0.05). The proportion of monocytes, C-reactive protein (CRP), interleukin-1ß (IL)-1ß, IL-8 and tumor necrosis factor-ß (TNF-ß) increased in the thrombosis group were higher than those in the non-thrombosis group (all P<0.05). Multivariate analysis showed that age≥60 years (HR=2.132, 95%CI: 1.376-3.303, P=0.001), history of thrombosis (HR=3.636, 95%CI: 2.121-6.202, P<0.001), ASXL1 mutation positive (HR=2.245, 95%CI: 1.093-3.231, P=0.022) and elevated TNF-ß (HR=2.009, 95%CI: 1.113-3.624, P=0.021) were risk factors for thrombosis in JAK2V617F positive MPN patients. Conclusions: In addition to age, history of thrombosis and positive ASXL1 mutation, elevated TNF-ß is also an influencing factor of thrombosis in JAK2V617F positive MPN patients. Intervention of inflammation may have a certain effect on the prevention and treatment of thrombosis.

[Socioeconomic status and cecal adenocarcinoma mortality risk: an American population-based analysis].

OBJECTIVE: To explore the relationship between socioeconomic status (SES) and disease mortality in patients with cecal adenocarcinoma in America through the Surveillance, Epidemiology, and End results (SEER) database. METHODS: The SEER database was queried for patients with cecal adenocarcinoma in America diagnosed from 2011 to 2015. Factor analysis, cluster analysis, and univariate and multivariate Cox proportional hazard models were used for data analysis. Five social security factors were identified: factor 1, economic and educational disadvantage; factor 2, characteristics related to immigration (language isolation and foreign birth); factor 3, high relocation rate in the county; factor 4, high intra-state relocation rate; and factor 5, high domestic relocation rate. Five clusters defined by SES were identified. RESULTS: The number of all-cause deaths among 17 185 patients was 5948, and the number of survivors was 11, 237. In the multivariate Cox regression analysis, with cluster 1 (low poverty rate and high education level) as the reference, the hazard ratio (HR) of cluster 3 (high intra-county mobility rate) was 1.13 (95% CI: 1.04-1.21, P < 0.05), and the risk was 13% higher than that of cluster 1. The HR of cluster 4 (low language isolation, foreign birth, housing overcrowding, and intra-country mobility rates) was 1.15 (95% CI: 1.07- 1.24, P < 0.001) with a 15% higher risk than cluster 1. The HR of cluster 5 (economic and educational disadvantages, immigration-related characteristics, and low intra-country mobility) was 1.11 (95% CI: 1.03-1.20, P < 0.01) with a 11% higher risk. The factors related to SES indicators were based on the mortality of patients with cecal adenocarcinoma, indicating that low economic and education levels are risk factors for cecal adenocarcinoma. CONCLUSION: Low socioeconomic status is associated with an increased risk of death in patients with cecal adenocarcinoma in the United States and show different distribution patterns based on population. Improving health insurance policies and strengthening psychotherapy can provide guidance for improving prognosis f cecal adenocarcinoma patients.

[Abnormal expression of CXCR5+CD8+ T cells and CXCL13 in severe aplastic anemia patients and their correlation with hematological parameters].

Objective: To analyze the expression of C-X-C chemokine receptor 5 (CXCR5)+CD8+ T cells and plasma C-X-C motif chemokine 13 (CXCL13) in severe aplastic anemia (SAA) patients and their correlations with hematological parameters. Methods: The clinical data of 35 SAA patients in the Hematology Department of Tianjin Medical University General Hospital from January 2018 to September 2021 were retrospectively analyzed. The patients were divided into two groups according to whether they had received the medication: untreated SAA group and recovery SAA group. In untreated group, there were 18 patients who had not received any medication, with 9 males and 9 females, and aged 51 (18-76) years. In recovery SAA group, there were 17 patients who were separated from component blood transfusion after the immunosuppressive treatment with anti-thymocyte globulin (ATG) combined with cyclosporine A (CsA), with 7 males and 10 females, and aged 46 (16-70) years. Meanwhile, 20 healthy controls were also selected, including 8 males and 12 females, and aged 45(15-72) years. Peripheral blood and bone marrow samples were collected from SAA patients, while peripheral blood samples were obtained from healthy controls. Flow cytometry was used to detect the percentage of CXCR5+CD8+ T cells in peripheral blood and bone marrow samples. The concentration of plasma CXCL13 was measured by enzyme-linked immunosorbent assay (ELISA). The correlations between the percentage of CXCR5+CD8+ T cells and the concentration of CXCL13, as well as the correlations between these two parameters and the hematological parameters were analyzed by Spearman correlation analysis. Results: The proportion of CXCR5+CD8+ T cells in the bone marrow of untreated SAA group was (4.9±2.9)%, which was higher than that of recovery SAA group (2.7±1.5)%, with a statistically significant difference (t=2.34, P=0.027). The proportion of CXCR5+CD8+ T cells in peripheral blood of untreated SAA group, recovery SAA group and healthy control group was (8.4±4.2)%, (3.8±2.3)% and (2.6±2.0)% respectively. The proportion of CXCR5+CD8+ T cells in peripheral blood of untreated SAA group was higher than that of recovery SAA group and healthy control group (both P<0.05). The plasma CXCL13 concentration in untreated SAA group was (97.2±46.8) ng/L, which was significantly higher than that in recovery SAA group [(54.9±20.9) ng/L] and healthy control group [(47.6±17.3) ng/L] (both P<0.05). The proportion of CXCR5+CD8+ T cells in peripheral blood of SAA patients was positively correlated with the concentration of plasma CXCL13 (r=0.545, P<0.001). The proportion of peripheral blood CXCR5+CD8+ T cells in SAA patients was negatively correlated with white blood cell count, platelets count, percentage of neutrophils, absolute neutrophils count, percentage of reticulocytes, absolute reticulocytes count, bone marrow myeloid cells, bone marrow erythroid cells and megakaryocytes count (r=-0.556, -0.392, -0.617, -0.615, -0.395, -0.543, -0.432, -0.484 and -0.523, all P<0.05). The proportion of peripheral blood CXCR5+CD8+ T cells was positively correlated with the percentage of peripheral blood lymphocytes and bone marrow lymphoid cells (r=0.593 and 0.556, both P<0.05). Meanwhile, the concentration of plasma CXCL13 in SAA patients was negatively correlated with white blood cell count, absolute neutrophils count, percentage of reticulocytes, absolute reticulocytes count and bone marrow myeloid cells (r=-0.447, -0.446, -0.498, -0.407 and -0.456, all P<0.05), but positively correlated with bone marrow lymphoid cells (r=0.384, P<0.05). Conclusions: The proportion of CXCR5+CD8+ T cells and the concentration of plasma CXCL13 increases in SAA patients. The proportion of CXCR5+CD8+ T cells in peripheral blood is positively correlated with the concentration of CXCL13. Moreover, the proportion of CXCR5+CD8+ T cells and the concentration of CXCL13 are correlated with many hematological parameters, which may play a critical role in the immune pathogenesis of SAA.

Docosahexaenoic Acid Reverses Epithelial-Mesenchymal Transition and Drug Resistance by Impairing the PI3K/AKT/ Nrf2/GPX4 Signalling Pathway in Docetaxel-Resistant PC3 Prostate Cancer Cells.

Drug resistance is a serious problem in cancer therapy. Growing evidence has shown that docosahexaenoic acid has anti-inflammatory and chemopreventive abilities. Studies have shown that autophagy inhibition and ferroptosis are promising therapeutic strategies for overcoming multidrug resistance. This study was aimed to examine whether docosahexaenoic acid (DHA) could reverse docetaxel resistance in prostate cancer cells. Cell survival was examined by MTT and colony formation. Protein expression was determined by Western blot. Reactive oxygen species (ROS) production was measured by flow cytometry. DHA displayed anti-cancer effects on proliferation, colony formation, migration, apoptosis, autophagy and epithelial mesenchymal transition. Glutathione-S-transferase π is an enzyme that plays an important role in drug resistance. DHA inhibited GSTπ protein expression and induced cytoprotective autophagy by regulating the PI3K/AKT signalling pathway in PC3R cells. DHA combined with PI3K inhibitor (LY294002) enhanced apoptosis by alleviating the expression of LC3B, (pro-) caspase- 3 and (uncleaved) PARP. DHA induced ferroptosis by attenuating the expression of glutathione peroxidase 4 (GPX4) and nuclear erythroid 2-related factor 2 (Nrf2). DHA-treated PC3R cells produced ROS. The ROS and cytotoxicity were reversed by treatment with ferrostatin-1. DHA combined with docetaxel inhibited EMT by regulating the expression of E-cadhein and N-cadherin. In summary, DHA reversed drug resistance and induced cytoprotective autophagy and ferroptosis by regulating the PI3K/AKT/Nrf2/GPX4 signalling pathway in PC3R cells. We propose that DHA could be developed as a chemosensitizer and that the PI3K/AKT /Nrf2/GPX4 signalling pathway might be a promising therapeutic target for overcoming cancer drug resistance.

Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer.

BACKGROUND: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. PATIENTS AND METHODS: One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. RESULTS: With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. CONCLUSION: With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals.

Final results of the global and Asia cohorts of KAMILLA, a phase IIIB safety trial of trastuzumab emtansine in patients with HER2-positive advanced breast cancer.

BACKGROUND: KAMILLA is a single-arm safety study of trastuzumab emtansine (T-DM1) in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (BC; NCT01702571). We report the final analysis of cohort 2 (Asia) within the context of published cohort 1 (Global) findings. METHODS: Patients had HER2-positive, locally advanced, or metastatic BC progressing after chemotherapy and anti-HER2 therapy or ≤6 months after adjuvant therapy. The primary objective was to further evaluate T-DM1 (3.6 mg/kg, administered intravenously every 3 weeks) safety/tolerability, including the following adverse events of primary interest (AEPIs): grade ≥3 AEPIs (hepatic events, allergic reactions, thrombocytopenia, hemorrhage events), all grade ≥3 treatment-related AEs, and all-grade pneumonitis. RESULTS: KAMILLA enrolled 2185 patients (cohort 1, n = 2003; cohort 2, n = 182) as of 31 July 2019. Of these, 2002 and 181 per cohort were treated and included in the safety population. Approximately 70% of patients had two or more previous treatment lines in the metastatic setting. Median T-DM1 exposure was 5.6 and 5.0 months per cohort; median follow-up was 20.6 and 15.1 months. The overall AEPI rate was higher in cohort 2 (93/181; 51.4%) versus cohort 1 (462/2002; 23.1%), mostly driven by a higher grade ≥3 thrombocytopenia rate in cohort 2. In cohort 2, grade ≥3 thrombocytopenia was not associated with grade ≥3 hemorrhagic events and most (128/138) fully resolved. Grade ≥3 treatment-related AEPI rates were 18.4% (cohort 1) and 48.6% (cohort 2), the latter mainly due to thrombocytopenia. Any-grade pneumonitis rates were 1.0% and 2.2%. No new safety signals were identified. Median (95% confidence interval) progression-free survival was 6.8 months (5.8-7.6 months) and 5.7 months (5.5-7.0 months) in cohorts 1 and 2, respectively; median overall survival was 27.2 months (25.5-28.7 months) and 29.5 months (21.1 months to non-estimable). In both cohorts, median progression-free survival and overall survival decreased with increasing prior therapy lines. CONCLUSIONS: Cohort 2 results aligned with previous findings in Asian patients, supporting the manageable safety profile and use of T-DM1 in advanced BC.

MiR-572 promotes the development of non-small cell lung cancer by targeting KLF2.

OBJECTIVE: The aim of this study was to uncover the role of miR-572 in regulating proliferative and migratory abilities in non-small cell lung cancer (NSCLC) and the possible mechanism. PATIENTS AND METHODS: Expression levels of miR-572 in 46 matched NSCLC and paracancerous samples were detected. The relationship between miR-572 level and clinical features of NSCLC was analyzed. Subsequently, the regulatory effects of miR-572 on proliferative and migratory abilities in lung cancer cells were assessed by functional experiments. Finally, the downstream genes of miR-572 were tested by luciferase assay, and their functions in the development of NSCLC were finally explored by rescue experiments. RESULTS: It was found that miR-572 was upregulated in NSCLC samples. High level of miR-572 predicted high rates of lymphatic and distant metastases, as well as poor prognosis in NSCLC. Besides, the knockdown of miR-572 suppressed proliferative and migratory abilities in A549 and SPC-A1 cells. KLF2 was identified to be the downstream gene of miR-572, which was involved in the regulation of NSCLC phenotypes influenced by miR-572. CONCLUSIONS: MiR-572 is closely linked to metastasis and prognosis in NSCLC patients, and it promotes the malignant development of NSCLC via targeting KLF2.