Clinical features and current treatment status of essential thrombocythemia in older adults: a multicenter real-world study in China.

Approximately half of patients diagnosed with essential thrombocythemia (ET) are older adults (aged ≥ 60 years), but to date, little is known about the clinical and molecular characteristics of older patients diagnosed according to the 2016 World Health Organization criteria. We retrospectively collected clinical and molecular data from 282 older (≥ 60 years) and 621 younger ET patients (18-59 years) in China from March 1, 2012 to November 1, 2021 and summarized the clinical characteristics and treatment of these older ET patients. Compared to younger patients, older patients had a higher incidence of the JAK2V617F mutation (P = 0.001), a lower incidence of CALR mutations (P = 0.033) and a higher rate of epigenetic mutations (P < 0.001), TP53 mutations (P = 0.005), and RNA splicing mutations (P < 0.001). Older patients had not only a higher incidence of thrombosis but also a higher incidence of bleeding events. Furthermore, older patients had a significantly higher mortality rate after disease progression (P = 0.050) or after thrombotic events (P = 0.013). Risk factors for thrombosis or prognosis were significantly different between older patients and the entire ET cohort. In older patients, non-driver mutations contributed significantly to thrombotic complications and a poor prognosis, while the JAK2V617F mutation was a risk factor for overall survival but not for thrombotic events. The application of interferon in older ET patients was not inferior to that of hydroxyurea in terms of efficacy and safety. Older patients presented unique characteristics different from those of younger patients, which could provide new information for formulating more appropriate treatment and follow-up strategies.

Adverse events in lymphoma patients treated with phosphoinositide 3 kinase Inhibitor in clinical trials: a meta-analysis.

BACKGROUND: Malignant lymphomas are one of the most common cancers worldwide and with high biologic heterogeneity, while the phosphoinositide 3 kinase (PI3K)/mTOR pathway is crucial in maintaining cell growth and survival both in physiological and in pathological conditions (i.e., lymphoma). PI3K inhibitors have been proven to be effective in several subtypes of lymphomas. However, the high incidence of treatment-related adverse events as well as the special safety profile in PI3K inhibitors draws great attention. Thus, this meta-analysis was conducted to compare adverse events in PI3K inhibitors to conventional regimens in lymphoma patients. METHODS: Articles were retrieved from PubMed, Cochrane, and Embase to identify randomized controlled trials and phase III clinical trials that used PI3K inhibitors comparing with non-PI3K inhibitors in lymphoma patients. To achieve the appropriate results, we calculated the risk ratio and 95% confidence intervals. RESULTS: Four trials with 1399 patients that met our criteria were included. The PI3K inhibitors group significantly increased the risk of all-grade adverse events (AEs) (RR 0.95, 95% CI: 0.92-0.98) and high-grade AEs (RR 0.63, 95% CI: 0.57-0.70), compared with the non-PI3K inhibitors group. Besides, the incidence of neutropenia (RR 0.81, 95% CI: 0.74-0.90), pneumonia (RR 0.62, 95% CI: 0.46-0.83), and diarrhea (RR 0.40, 95% CI: 0.32-0.49) were significantly high in the PI3Ki group, while the incidence of anemia (RR 0.78, 95% CI: 0.50-1.20) and thrombocytopenia (RR 0.85, 95% CI: 0.51-1.42) had no statistic significant. CONCLUSION: PI3K inhibitors increased the risk of certain AEs in lymphoma patients.

Multilevel defects in the hematopoietic niche in essential thrombocythemia.

The role of the bone marrow niche in essential thrombocythemia (ET) remains unclear. Here, we observed multilevel defects in the hematopoietic niche of patients with JAK2V617F-positive ET, including functional deficiency in mesenchymal stromal cells (MSC), immune imbalance, and sympathetic-nerve damage. Mesenchymal stromal cells from patients with JAK2V617F-positive essential thrombocythemia had a transformed transcriptome. In parallel, they showed enhanced proliferation, decreased apoptosis and senescence, attenuated ability to differentiate into adipocytes and osteocytes, and insufficient support for normal hematopoiesis. Additionally, they were inefficient in suppressing immune responses. For instance, they poorly inhibited proliferation and activation of CD4-positive T cells and the secretion of the inflammatory factor soluble CD40-ligand. They also poorly induced formation of mostly immunosuppressive T-helper 2 cells (Th2) and the secretion of the anti-inflammatory factor interleukin-4 (IL-4). Furthermore, we identified WDR4 as a potent protein with low expression and which was correlated with increased proliferation, reduced senescence and differentiation, and insufficient support for normal hematopoiesis in MSC from patients with JAK2V617F-positive ET. We also observed that loss of WDR4 in MSC cells downregulated the interleukin-6 (IL-6) level through the ERK-GSK3ß-CREB signaling based on our in vitro studies. Altogether, our results show that multilevel changes occur in the bone marrow niche of patients with JAK2V617F-positive ET, and low expression of WDR4 in MSC may be critical for inducing hematopoietic related changes.

Interleukin 35 may contribute to the loss of immunological self-tolerance in patients with primary immune thrombocytopenia.

Primary immune thrombocytopenia (ITP) is an autoimmune disorder. Interleukin-35 (IL35) can suppress T cell proliferation and elicit the development of inducible regulatory T cells (Tregs). Previous studies have shown decreased plasma IL35 levels and dysfunctional T cells in patients with ITP. In this study, we determined whether decreased IL35 levels correlate with T cell dysfunction in ITP patients. Plasma IL35 levels were found to be lower in ITP patients than in healthy controls, were positively correlated with platelet levels and the percentage of peripheral circulating Tregs, and negatively correlated with the levels of T helper-1 cells in ITP patients. We also evaluated the effects of IL35 on cytokines contributing to T cell proliferation. IL35 promoted the secretion of interleukin 10 (IL10) and transforming growth factor-ß1 but reduced the levels of interferon-γ and IL17A (also termed IL17). Moreover, IL35 inhibited the proliferation of CD4+ and CD8+ T cells but induced the differentiation and proliferation of Tregs in ITP. In summary, IL35 appears to contribute to the loss of immunological self-tolerance in ITP patients by modulating T cells and immunoregulatory cytokines.

[Liver safety of biosimilar of recombinant tumor necrosis factor-α receptor-antibody fusion protein in Spondyloarthritis patients under different status of HBV infection: a prospective observational study].

OBJECTIVE: To investigate the influence of recombinant human tumor necrosis factor α receptor-antibody fusion protein (rhTNFR: Fc) to the Hepatitis B virus (HBV) infection status and liver function of Spondyloarthritis (SpA) patients under different HBV infection status. METHODS: Active SpA patients with normal liver function were enrolled in Sun Yat-sen Memorial hospital from February 2012 to August 2014. All were treated with rhTNFR: Fc based therapy (monotherapy or combined therapy) for at least 12 weeks. SpA disease activity, HBV infection status and liver function were evaluated at each interview (baseline, 4(th) and 12(th) week, as primary endpoint). Part of the patients were evaluated at 24(th) week with or without extended rhTNFR: Fc treatment(as secondary endpoint) based on their choice. RESULTS: Eighty-one patients who completed 12-week follow-up visit were divided into chronic HBV carrier group (n=21), past HBV exposure group (n=25) and free of HBV infection group (n=35). Alanine transaminase (ALT) elevated (no more than 3-fold of normal) in 3 patients from 3 groups respectively at 4th week. During 24-week follow-up, none in past HBV exposure group or in free of HBV infection group developed HBV reactivation or HBV infection; and 4 patients in chronic HBV carrier group developed HBV reactivation without more than 2-fold of normalelevation of ALT. Among 7 patients with negative baseline HBV-DNA and without antiviral prophylaxis, 2 patients developed HBV reactivation at 10(th) 24(th) week of rhTNFR: Fc therapy respectively and 1 patient developed reactivation at 16(th) week (12-week rhTNFR: Fc+ thalidomide therapy and following 4-week thalidomide monotherapy), whose HBV-DNA load returned to normal spontaneously or after antiviral therapy. Four chronic HBV carriers with low-load of baseline HBV-DNA did not develop reactivation. One of 9 chronic HBV carriers with high-load of baseline HBV-DNA developed reactivation due to resistance of antiviral prophylaxis. CONCLUSIONS: Short-term rhTNFR: Fc based therapy may induce mild and transient HBV reactivation, usually without hepatitis.

The compensation effect of competence frustration and its behavioral manifestations.

The frustration of competence, one of the three basic psychological needs proposed by self-determination theory, has been widely demonstrated to negatively influence one's motivation and well-being in both work and life. However, research on the recovery mechanism of competence is still in the nascent stage. In this study, a two-stage behavioral experiment was conducted to examine the restoration of competence and the potential moderating role of resilience. Results showed that individuals who were asked to recall experience of competence frustration performed better on subsequent tasks, manifesting their behavioral efforts of competence restoration. However, resilience does not play a significant moderating role in competence restoration. Through convergent behavioral evidence, findings of this study demonstrate the compensation effect of competence frustration.

Prognostic implications of cGAS and STING gene expression in acute myeloid leukemia.

Acute myeloid leukemia (AML) is one of the most threatening hematological malignances. cGAS-STING pathway plays an important role in tumor immunity and development. However, the prognostic role of cGAS-STING pathway in AML remains unknown. Firstly, The expression of cGAS and STING was analyzed by bioinformatics analysis. Subsequently, Bone marrow samples were collected from 120 AML patients and 15 healthy individuals in an independent cohort. The cGAS and STING expression was significantly elevated in AML patients compared with healthy controls. Patients with high cGAS and STING expression had a higher NRAS/KRAS mutation rate and lower complete remission (CR) rate. High cGAS and STING expression was significantly associated with lower overall survival (OS) and disease-free survival (DFS). Our findings revealed that the expression levels of cGAS and STING in AML are elevated. High expression of cGAS and STING correlated with worse OS and DFS and may be a useful biomarker for inferior prognosis in AML patients.

Ultrasound-based deep learning radiomics nomogram for risk stratification of testicular masses: a two-center study.

OBJECTIVE: To develop an ultrasound-driven clinical deep learning radiomics (CDLR) model for stratifying the risk of testicular masses, aiming to guide individualized treatment and minimize unnecessary procedures. METHODS: We retrospectively analyzed 275 patients with confirmed testicular lesions (January 2018 to April 2023) from two hospitals, split into training (158 cases), validation (68 cases), and external test cohorts (49 cases). Radiomics and deep learning (DL) features were extracted from preoperative ultrasound images. Following feature selection, we utilized logistic regression (LR) to establish a deep learning radiomics (DLR) model and subsequently derived its signature. Clinical data underwent univariate and multivariate LR analyses, forming the "clinic signature." By integrating the DLR and clinic signatures using multivariable LR, we formulated the CDLR nomogram for testicular mass risk stratification. The model's efficacy was gauged using the area under the receiver operating characteristic curve (AUC), while its clinical utility was appraised with decision curve analysis(DCA). Additionally, we compared these models with two radiologists' assessments (5-8 years of practice). RESULTS: The CDLR nomogram showcased exceptional precision in distinguishing testicular tumors from non-tumorous lesions, registering AUCs of 0.909 (internal validation) and 0.835 (external validation). It also excelled in discerning malignant from benign testicular masses, posting AUCs of 0.851 (internal validation) and 0.834 (external validation). Notably, CDLR surpassed the clinical model, standalone DLR, and the evaluations of the two radiologists. CONCLUSION: The CDLR nomogram offers a reliable tool for differentiating risks associated with testicular masses. It augments radiological diagnoses, facilitates personalized treatment approaches, and curtails unwarranted medical procedures.

Real-world experience with venetoclax-based therapy for patients with myeloid sarcoma.

BACKGROUND: The treatment of myeloid sarcoma (MS) is challenging and has not markedly improved patient prognosis. The introduction of venetoclax (VEN) has changed the treatment of MS, and venetoclax-based therapy has been described as very promising in several case reports. METHODS: In this retrospective study, we analyzed the treatment outcomes of 14 patients with MS treated with venetoclax-based therapy at The First Affiliated Hospital of Xiamen University from January 2020 to October 2023 RESULTS: The cohort consisted of 7 (50%) women and 7 (50%) men with an average age of 37.5 years. Four patients (28.6%) had isolated MS de novo, 2 (14.2%) were diagnosed synchronously with AML, and 8 (57.2%) had isolated extramedullary relapse. The most common sites for MS in our cohort were the skin and lung, followed by the spinal canal, soft tissue, bone and kidney. Five patients were affected at more than three sites. Nine patients received VEN in combination with azacytidine, and 5 patients received VEN in combination with other agents. The median number of venetoclax therapies administered was 2 cycles (range: 1-10 cycles). A response was observed in all patients included in the study, with 8 patients (57.2%) achieving a CR and 3 patients (21.4%) achieving a PR, corresponding to an ORR (including CR and PR) of 78.6%. The median follow-up time for all patients was 13 months (range 1-44 months), and the 1 year OS for all patients was 67.7%. CONCLUSIONS: Venetoclax-based therapy shows excellent efficacy and safety in MS patients in the "real world" at a single institution, and a corresponding prospective study is needed to verify this conclusion.

Lactate acid promotes PD-1+ Tregs accumulation in the bone marrow with high tumor burden of Acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) displayed poor response to programmed death-1 (PD-1) blockade therapy. Regulatory T cells (Tregs) was one of major immunosuppressive components in Tumor microenvironment and plays a vital role in the resistance of immunotherapy. Coinhibitory receptors regulate function of regulatory Tregs and are associated with resistance of PD-1 blockade. However, the coinhibitory receptors expression and differentiated status of Tregs in AML patients remain to be unclear. METHODS: Phenotypic determination of Tregs and CD8+ T cells in bone marrow of healthy donors and AML patients was performed by flow cytometry. Coculture experiments of AML and Tregs in vitro were performed and the concentrations of lactate acid (LA) in the supernatant were examined by ELISA. RESULTS: More Tregs differentiated into effector subsets in AML patients. However, PD-1 and T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) expression on Tregs were comparable in healthy donors and AML patients. Further analysis showed that PD-1+ and PD-1+TIGIT+Tregs are more abundant in the bone marrow of patients with higher leukemic load. Moreover, PD-1+ Tregs accumulation was associated with higher level of senescent CD4+ T cells and increased frequencies of exhausted CD4+ as well as CD8+ T cells. Notably, neither Tregs nor their effector subsets were decreased among patients in complete remission. PD-1 expression was significantly downregulated in Tregs after achieving complete remission. Mechanistically, both AML cell line (KG-1α) and primary AML blasts produced high concentration of LA. Blockade of LA by lactate transporter inhibitor abrogated the upregulation of PD-1 by AML cells. CONCLUSION: PD-1+ Tregs accumulation in bone marrow in higher leukemic burden setting was linked to lactate acid secreted by AML blasts and decreased after disease remission. Our findings provided a novel insight into Tregs in AML and possible mechanism for resistance of PD-1 blockade in AML.

Differentiation of testicular seminomas from nonseminomas based on multiphase CT radiomics combined with machine learning: A multicenter study.

BACKGROUND: Differentiating seminomas from nonseminomas is crucial for formulating optimal treatment strategies for testicular germ cell tumors (TGCTs). Therefore, our study aimed to develop and validate a clinical-radiomics model for this purpose. METHODS: In this study, 221 patients with TGCTs confirmed by pathology from four hospitals were enrolled and classified into training (n = 126), internal validation (n = 55) and external test (n = 40) cohorts. Radiomics features were extracted from the CT images. After feature selection, we constructed a clinical model, radiomics models and clinical-radiomics model with different machine learning algorithms. The top-performing model was chosen utilizing receiver operating characteristic (ROC) curve analysis. Decision curve analysis (DCA) was also conducted to assess its practical utility. RESULTS: Compared with those of the clinical and radiomics models, the clinical-radiomics model demonstrated the highest discriminatory ability, with AUCs of 0.918 (95 % CI: 0.870 - 0.966), 0.909 (95 % CI: 0.829 - 0.988) and 0.839 (95 % CI: 0.709 - 0.968) in the training, validation and test cohorts, respectively. Moreover, DCA confirmed that the combined model had a greater net benefit in predicting seminomas and nonseminomas. CONCLUSION: The clinical-radiomics model serves as a potential tool for noninvasive differentiation between testicular seminomas and nonseminomas, offering valuable guidance for clinical treatment.

An investigation on 3-hydroxybenzaldehyde for exploring terahertz low-frequency vibration modes with quasi-harmonic approximation method.

3-Hydroxybenzaldehyde (3-HBA) was investigated in the range of 0.6-2.8 THz by terahertz time-domain spectroscopy (THz-TDS) and solid-state density functional theory (ss-DFT) with first-principles calculation. Four distinct peaks were found respectively, and among them, the intensity disparity between experiment and simulation spectra at 2.04 THz was recognized as the biggest inconsistency. Considering thermal behavior can be responsible for this, quasi-harmonic approximation (QHA) method was introduced to mimic the unit cell volume expansion. According to vibrational modes analysis, it was ascertained that the biggest vibrational modes discrepancy was also located at 2.04 THz. Molecules in 0% and 4% unit cell expansion exhibit an opposite rotational direction in a-b plane compared with 2% unit cell expansion. Noncovalent intermolecular interactions were investigated with independent gradient model (IGM), and the result indicates that hydrogen bonding is the dominating noncovalent interaction of 3-HBA. While calculating systematic potential energy to the displaced bonds stretching involving hydrogen atoms, it was found the anomalous potential energy variation to the bond stretching provides a possible explanation for the rotation direction divergence, that is, the rotation direction divergence can be related to some hydrogen atoms seeking lower overall potential energy around their equilibrium positions during bond stretching in response to the variational intermolecular van der Waals force. This research combined THz-TDS with the quasi-harmonic approximation method, elucidating the principle of vibrational characteristics in different volumes, which is beneficial to the investigation of the terahertz low-frequency vibration to thermal behavior as a reference in biochemistry and other fields.

CD4 T cells in chronic myeloid leukemia present MHC class II-dependent and IFN-γ-dependent cytotoxic capacity.

At present, many therapeutic schemes have been used to improve the prognosis of patients with chronic myeloid leukemia (CML), but response remains poor in a small group of patients. CD4 T cell-mediated cytotoxicity has been found in various autoimmune diseases. This study analyzed the characteristics of CD4 T cell mediated cytotoxicity in CML patients and healthy people. The cytotoxicity of CD4 T cells was tested in using two CML cell lines, including the MHC class II-deficient K562 cells and the MHC class II-expressing KU812 cells. CD4 T cell-mediated lysis was minimal in K562 cells but was much higher in KU812 cells. In CML patients, the level of CD4 T cell-mediated lysis was limited to a certain level. Interestingly, pre-treating KU812 cells with IFN-γ could significantly elevate the expression of MHC class II and elevate the level of CD4 T cell-mediated lysis. Overall, these data indicated CD4 T cells could become a potential candidate for cytotoxic elimination of CML cells.

Loss of CD28 expression associates with severe T-cell exhaustion in acute myeloid leukemia.

Introduction: Despite accumulated evidence in T-cell exhaustion in acute myeloid leukemia (AML), the immunotherapeutic targeting exhausted T cells such as programmed cell death protein 1 (PD-1) blockade in AML failed to achieve satisfying efficacy. Characteristics of exhausted T cells in AML remained to be explored. Methods: Phenotypic analysis of T cells in bone marrow (BM) using flow cytometry combining senescent and exhausted markers was performed in de novo AML patients and healthy donors as well as AML patients with complete remission (CR). Functional analysis of T-cell subsets was also performed in de novo AML patients using flow cytometry. Results: T cells experienced a phenotypic shift to terminal differentiation characterized by increased loss of CD28 expression and decrease of naïve T cells. Additionally, lack of CD28 expression could help define a severely exhausted subset from generally exhausted T cells (PD-1+TIGIT+). Moreover, CD28- subsets rather than CD28+ subsets predominantly contributed to the significant accumulation of PD-1+TIGIT+ T cells in AML patients. Further comparison of de novo and CR AML patients showed that T-cell exhaustion status was improved after disease remission, especially in CD28+ subsets. Notably, higher frequency of CD28-TIGIT-CD4+ T cells correlated with the presence of minimal residual disease in AML-CR group. However, the correlation between CD28- exhausted T cells and cytogenetic risk or white blood cell count was not observed, except for that CD28- exhausted CD4+ T cells correlated with lymphocyte counts. Intriguingly, larger amount of CD28-TGITI+CD8+ T cells at diagnosis was associated with poor treatment response and shorter leukemia free survival. Discussion: In summary, lack of CD28 expression defined a severely exhausted status from exhausted T cells. Accumulation of CD28- exhausted T cells was linked to occurrence of AML, and correlated to poor clinical outcome. Our data might facilitate the development of combinatory strategies to improve the efficacy of PD-1 blockade in AML.

Relationship between incompetent perforator veins and pigmentation below the knee in patients with chronic venous disease.

OBJECTIVE: The aim of the present study was to evaluate the correlation between incompetent perforator veins (PVs) and venous pigmentation. METHODS: A total of 203 limbs of patients with chronic venous disease were studied. The limbs were classified into two groups: C2 group (varicose veins) and C4a group (skin changes with pigmentation). The PVs of the lower legs were examined using Doppler ultrasound. The diameter, reflux duration, and peak velocities were measured and analyzed. The pigmentation area in the lower leg was also studied. RESULTS: Pigmentation in the lower legs was significantly associated with venous insufficiency of the PVs. The prevalence of PVs insufficiency was higher for the C4a patients compared with the C2 patients (96 of 164 [58.3%] vs 4 of 39 [10.3%]; P < .001). The presence of incompetent PVs was associated with an increased risk of pigmentation (OR, 8.977; 95% CI, 2.824-28.537; P < .001). The higher the patients' pigmentation severity (higher VCSS), the greater the prevalence of perforator venous insufficiency (P < .001). The PVs in the areas of pigmentation were larger in diameter, required longer to reach peak velocity, and had higher peak velocities than the PVs in nonpigmented limbs (P < .01 for all). We found a linear relationship between the pigmentation area and the diameter of the PV, reflux time, and peak velocity (r = 0.272, r = 0.172, and r = 0.664, respectively; P < .05). CONCLUSIONS: Incompetent PVs are a significant risk factor for venous pigmentation and, therefore, are potentially suitable for surgical correction.

Evaluation of CRISPR-Based Assays for Rapid Detection of SARS-CoV-2: A Systematic Review and Meta-Analysis.

PURPOSE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen of coronavirus disease 2019. Diagnostic methods based on the clustered regularly interspaced short palindromic repeats (CRISPR) have been developed to detect SARS-CoV-2 rapidly. Therefore, a systematic review and meta-analysis were performed to assess the diagnostic accuracy of CRISPR for detecting SARS-CoV-2 infection. MATERIALS AND METHODS: Studies published before August 2021 were retrieved from four databases, using the keywords "SARS-CoV-2" and "CRISPR." Data were collected from these publications, and the sensitivity, specificity, negative likelihood ratio (NLR), positive likelihood ratio (PLR), and diagnostic odds ratio (DOR) were calculated. The summary receiver operating characteristic curve was plotted for analysis with MetaDiSc 1.4. The Stata 15.0 software was used to draw Deeks' funnel plots to evaluate publication bias. RESULTS: We performed a pooled analysis of 38 independent studies shown in 30 publications. The reference standard was reverse transcription-quantitative PCR. The results indicated that the sensitivity of CRISPR-based methods for diagnosis was 0.94 (95% CI 0.93-0.95), the specificity was 0.98 (95% CI 0.97-0.99), the PLR was 34.03 (95% CI 20.81-55.66), the NLR was 0.08 (95% CI 0.06-0.10), and the DOR was 575.74 (95% CI 382.36-866.95). The area under the curve was 0.9894. CONCLUSION: Studies indicate that a diagnostic method based on CRISPR has high sensitivity and specificity. Therefore, this would be a potential diagnostic tool to improve the accuracy of SARS-CoV-2 detection.

Secondary myeloma in patients with chronic lymphoblastic leukemia: A case report and analysis of data from SEER database.

Both chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) are common hematological malignancies originating from mature B cells of different differentiation stage. However, it is quite rare that MM could develop after CLL diagnosed. We reported a 66-year-old female progressed forward myeloma 3 years after she was diagnosed as CLL and conducted an analysis to investigate the epidemiology and clinical features among these patients based on the Surveillance, Epidemiology, and End Results (SEER) database. Our data demonstrated that CLL patients were 19% less likely to develop myeloma than general U.S. population (standardized incidence ratio 0.81; 95% confidence interval 0.62-1.03), although without statistical difference. The median overall survival from CLL diagnosed was 90 (58.1-121.9) months, which was the same as general CLL patients according to historical data. But the outcomes of secondary MM was much poorer than general MM patients. Age and gender were independent factors that impact the survival among these patients.

Rheumatoid arthritis and risk of lung cancer: Meta-analysis and Mendelian randomization study.

OBJECTIVE: Observational studies suggest that rheumatoid arthritis (RA) may be associated with lung cancer (LC) risk, while the evidence is inconsistent. We conducted a meta-analysis and a Mendelian randomization study to investigate the association and causality between RA and the LC risk. METHODS: We conducted a systematic search of cohort studies and performed a meta-analysis (PROSPERO ID CRD42020159082) to calculate the relative risks (RRs) and their 95% confidence intervals (95%CIs). Subgroup analyses based on sex and initiation year of follow-up were carried out. E-values of each study were calculated to evaluate if existing studies were sensitive to unmeasured confounding. Furthermore, we investigated the correlation between genetically predisposed RA and LC risk using summary statistics from the International Lung Cancer Consortium (11,348 cases and 15,861 controls) and 90 RA-related single nucleotide polymorphisms from European and East Asian descent as instrumental variables. A two-sample Mendelian randomization (MR) analysis was performed to detect the findings based on LC and histological subtypes. Sensitivity analyses were performed to test the robustness of our findings. RESULTS: In the meta-analysis of 11 cohort studies involving 183,888 patients, an increased risk of LC was observed among RA patients (RR = 1.44, 95%CI = 1.31-1.57). Subgroup analyses suggested that male patients have a relatively higher LC risk than female patients, and an increased incidence of LC in RA patients was found from 1950 to 2010. Conversely, in the MR analysis, we found that genetically predisposed RA was associated with a decreased risk of LC overall, while neither causally associated with the risk of lung adenocarcinoma nor squamous cell lung cancer. Nevertheless, genetically predisposed RA was associated with a decreased LC risk among the East Asian population, but not in Europeans. These results were robust against extensive sensitivity analyses. CONCLUSION: Our meta-analysis suggested that although RA was associated with a relatively higher LC risk, the causal relationship between genetically predisposed RA and LC risk was not supported by the MR study. Further studies are warranted to elucidate the possible association between RA and the risk of LC, as well as its underlying mechanisms.