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Abstract Hemophagocytic lymphohistiocytosis (HLH) is a rapidly progressing, life-threatening syndrome characterized by excessive immune activation, often presenting as a complex cytokine storm. This hyperactive immune response can lead to multi-organ failure and systemic damage, resulting in an extremely short survival period if left untreated. Over the past decades, although HLH has garnered increasing attention from researchers, there have been few advancements in its treatment. The cytokine storm plays a crucial role in the treatment of HLH. Investigating the detailed mechanisms behind cytokine storms offers insights into targeted therapeutic approaches, potentially aiding in early intervention and improving the clinical outcome of HLH patients. To date, there is only one targeted therapy, emapalumab targeting interferon-γ, that has gained approval for primary HLH. This review aims to summarize the current treatment advances, emerging targeted therapeutics and underlying mechanisms of HLH, highlighting its newly discovered targets potentially involved in cytokine storms, which are expected to drive the development of novel treatments and offer fresh perspectives for future studies. Besides, multi-targeted combination therapy may be essential for disease control, but further trials are required to determine the optimal treatment mode for HLH.

Abstract Cancer immunotherapies, represented by immune checkpoint inhibitors (ICIs), have reshaped the treatment paradigm for both advanced non-small cell lung cancer and small cell lung cancer. Programmed death receptor-1/programmed death receptor ligand-1 (PD-1/PD-L1) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) are some of the most common and promising targets in ICIs. Compared to ICI monotherapy, which occasionally demonstrates treatment resistance and limited efficacy, the dual blockade immunotherapy targeting PD-1/PD-L1 and CTLA-4 operates at different stages of T cell activation with synergistically enhancing immune responses against cancer cells. This emerging dual therapy heralds a new direction for cancer immunotherapy, which, however, may increase the risk of drug-related adverse reactions while improving efficacy. Previous clinical trials have explored combination therapy strategy of anti-PD-1/PD-L1 and anti-CTLA-4 agents in lung cancer, yet its efficacy remains to be unclear with the inevitable incidence of immune-related adverse events. The recent advent of bispecific antibodies has made this sort of dual targeting more feasible, aiming to alleviate toxicity without compromising efficacy. Thus, this review highlights the role of dual blockade immunotherapy targeting PD-1/PD-L1 and CTLA-4 in treating lung cancer, and further elucidates its pre-clinical mechanisms and current advancements in clinical trials. Besides, we also provide novel insights into the potential combinations of dual blockade therapies with other strategies to optimize the future treatment mode for lung cancer.

BackgroundMetachronous second primary lung cancer (MSPLC) is not that rare but is seldom studied. ObjectiveWe aim to compare real-world survival outcomes between different surgery strategies and radiotherapy for MSPLC. MethodsThis retrospective study analyzed data collected from patients with MSPLC between 1988 and 2012 in the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) analyses and machine learning were performed to compare variables between patients with MSPLC. Survival curves were plotted using the Kaplan-Meier method and were compared using log-rank tests. ResultsA total of 2451 MSPLC patients were categorized into the following treatment groups: 864 (35.3%) received radiotherapy, 759 (31%) underwent surgery, 89 (3.6%) had surgery plus radiotherapy, and 739 (30.2%) had neither treatment. After PSM, 470 pairs each for radiotherapy and surgery were generated. The surgery group had significantly better survival than the radiotherapy group (P

Logs are valuable information for oil and gas fields as they help to determine the lithology of the formations surrounding the borehole and the location and reserves of subsurface oil and gas reservoirs. However, important logs are often missing in horizontal or old wells, which poses a challenge in field applications. To address this issue, conventional methods involve supplementing the missing logs by either combining geological experience and referring data from nearby boreholes or reconstructing them directly using the remaining logs in the same borehole. Nevertheless, there is currently no quantitative evaluation for the quality and rationality of the constructed log. In this paper, we utilize data from the 2020 machine learning competition of the Society of Petrophysicists and Logging Analysts (SPWLA), which aims to predict the missing compressional wave slowness (DTC) and shear wave slowness (DTS) logs using other logs in the same borehole. We employ the natural gradient boosting (NGBoost) algorithm to construct an Ensemble Learning model that can predicate the results as well as their uncertainty. Furthermore, we combine the SHAP (SHapley Additive exPlanations) method to investigate the interpretability of the machine learning model. We compare the performance of the NGBosst model with four other commonly used Ensemble Learning methods, including Random Forest, GBDT, XGBoost, LightGBM. The results show that the NGBoost model performs well in the testing set and can provide a probability distribution for the prediction results. This distribution allows petrophysicists to quantitatively analyze the confidence interval of the constructed log. In addition, the variance of the probability distribution of the predicted log can be used to justify the quality of the constructed log. Using the SHAP explainable machine learning model, we calculate the importance of each input log to the predicted results as well as the coupling relationship among input logs. Our findings reveal that the NGBoost model tends to provide greater slowness prediction results when the neutron porosity (CNC) and gamma ray (GR) are large, which is consistent with the cognition of petrophysical models. Furthermore, the machine learning model can capture the influence of the changing borehole caliper on slowness, where the influence of borehole caliper on slowness is complex and not easy to establish a direct relationship. These findings are in line with the physical principle of borehole acoustics. Finally, by using the explainable machine learning model, we observe that although we did not correct the effect of borehole caliper on the neutron porosity log through preprocessing, the machine learning model assigned a greater importance to the influence of the caliper, achieving the same effect as caliper correction.

ChatGPT (OpenAI), a cutting-edge natural language processing model, holds immense promise for revolutionizing medical education. With its remarkable performance in language-related tasks, ChatGPT offers personalized and efficient learning experiences for medical students and doctors. Through training, it enhances clinical reasoning and decision-making skills, leading to improved case analysis and diagnosis. The model facilitates simulated dialogues, intelligent tutoring, and automated question-answering, enabling the practical application of medical knowledge. However, integrating ChatGPT into medical education raises ethical and legal concerns. Safeguarding patient data and adhering to data protection regulations are critical. Transparent communication with students, physicians, and patients is essential to ensure their understanding of the technology’s purpose and implications, as well as the potential risks and benefits. Maintaining a balance between personalized learning and face-to-face interactions is crucial to avoid hindering critical thinking and communication skills. Despite challenges, ChatGPT offers transformative opportunities. Integrating it with problem-based learning, team-based learning, and case-based learning methodologies can further enhance medical education. With proper regulation and supervision, ChatGPT can contribute to a well-rounded learning environment, nurturing skilled and knowledgeable medical professionals ready to tackle health care challenges. By emphasizing ethical considerations and human-centric approaches, ChatGPT’s potential can be fully harnessed in medical education, benefiting both students and patients alike.

Abstract Background There is no standard first‐line immunochemotherapy regimen for transplant‐ineligible patients with mantle cell lymphoma (MCL) currently, and the efficacy of various treatment remains unclear. Methods We conducted a Bayesian network meta‐analysis (NMA) of all eligible randomized controlled trials. Pairwise comparisons and ranking of different first‐line treatment options were performed. Results Nine studies were included in the NMA, involving a total of 2897 MCL patients. The BR‐Ibrutinib+R regimen showed the best progression‐free survival (PFS), with a surface under the cumulative ranking curve (SUCRA) of 0.89 and probability of being the best treatment (PbBT) of 69%. The VR‐CAP regimen was the most potential intervention to improve overall survival (OS), with a SUCRA of 0.89 and PbBT of 63%. Compared with the R‐CHOP regimen, the BR regimen achieved a better PFS (hazard ratio [HR] 0.45 [95% credible interval 0.2–0.96]). The BR‐Ibrutinib+R regimen (HR 0.14 [0.02–0.99]), BR+R regimen (HR 0.19 [0.034–0.99]), and BR regimen (HR 0.3 [0.08–1.03]) were superior to CHOP regimen with better PFS. The R‐FC regimen (HR 2.27 [1.01–5.21]) or FC regimen (HR 3.17 [1.15–8.71]) was inferior to the VR‐CAP regimen with a worse OS. Conclusions Our study presents the most promising first‐line treatment strategy for transplant‐ineligible MCL patients in terms of PFS and OS, which provides innovative treatment strategy for MCL treatment.

Abstract The outbreak of coronavirus disease 2019 (COVID-19) posed an unprecedented challenge on public health systems. Despite the measures put in place to contain it, COVID-19 is likely to continue experiencing sporadic outbreaks for some time, and individuals will remain susceptible to recurrent infections. Chimeric antigen receptor (CAR)-T recipients are characterized by durable B-cell aplasia, hypogammaglobulinemia and loss of T-cell diversity, which lead to an increased proportion of severe/critical cases and a high mortality rate after COVID-19 infection. Thus, treatment decisions have become much more complex and require greater caution when considering CAR T-cell immunotherapy. Hence, we reviewed the current understanding of COVID-19 and reported clinical experience in the management of COVID-19 and CAR-T therapy. After a panel discussion, we proposed a rational procedure pertaining to CAR-T recipients with the aim of maximizing the benefit of CAR-T therapy in the post COVID-19 pandemic era.

ObjectiveBispecific antibody (BsAbs) therapy represents a promising immunotherapeutic approach with manageable toxicity and noteworthy preliminary efficacy in treating patients with relapsed or refractory multiple myeloma (RRMM). The objective of this systematic review and meta-analysis was to compare the efficacy and safety of B-cell maturation antigen (BCMA)-targeted BsAbs and non-BCMA-targeted BsAbs in the treatment of RRMM patients.MethodsPubMed/MEDLINE, Web of Science, EMBASE, Cochrane Library and meeting libraries were searched from inception to August 16th, 2023. The efficacy evaluation included the complete objective response rate (ORR), complete response (CR) rate, stringent CR (sCR) rate, partial response (PR) rate, and very good PR (VGPR) rate. The efficacy evaluation included any grade adverse events (AEs) and grade ≥ 3 AEs.ResultsFourteen studies with a total of 1473 RRMM patients were included. The pooled ORR of the entire cohort was 61%. The non-BCMA-targeted BsAbs group displayed a higher ORR than the BCMA-targeted BsAbs group (74% vs. 54%, P < 0.01). In terms of hematological AEs, BCMA-targeted BsAbs therapy exhibited higher risks of neutropenia (any grade: 48% vs. 18%, P < 0.01; grade ≥ 3: 43% vs. 15%, P < 0.01) and lymphopenia (any grade: 37% vs. 8%, P < 0.01; grade ≥ 3: 31% vs. 8%, P = 0.07). Regarding non-hematological AEs, there were no significant differences in the risks of cytokine release syndrome (CRS, any grade: 64% vs. 66%, P = 0.84; grade ≥ 3: 1% vs. 1%, P = 0.36) and infections (any grade: 47% vs. 49%, P = 0.86; grade ≥ 3: 24% vs. 20%, P = 0.06) between the two groups. However, non-BCMA-targeted BsAbs therapy was associated with a higher risk of immune effector cell-associated neurotoxicity syndrome (ICANS, any grade: 11% vs. 2%, P < 0.01) and lower risks of fatigue (any grade: 14% vs. 30%, P < 0.01) and pyrexia (any grade: 14% vs. 29%, P < 0.01).ConclusionThis analysis suggest that non-BCMA-targeted BsAbs therapy may offer a more favorable treatment response and tolerability, while BCMA-targeted BsAbs therapy may be associated with diminished neurotoxic effects.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42018090768.

Rare and complex diseases pose significant challenges to both patients and healthcare providers. These conditions often present with atypical symptoms, making diagnosis and treatment a formidable task. In recent years, artificial intelligence and natural language processing technologies have shown great promise in assisting medical professionals in diagnosing and managing such conditions. This paper explores the role of ChatGPT, an advanced artificial intelligence model, in improving the diagnosis and treatment of rare and complex diseases. By analyzing its potential applications, limitations, and ethical considerations, we demonstrate how ChatGPT can contribute to better patient outcomes and enhance the healthcare system's overall effectiveness.

Background: Small cell lung cancer (SCLC) is characterized by extreme invasiveness and lethality. There have been very few developments in its diagnosis and treatment over the past decades. It is urgently needed to explore potential novel biomarkers and drug targets for SCLC.Methods: Two-sample Mendelian Randomization (MR) was performed to investigate causal associations between SCLC and plasma proteins using genome-wide association studies (GWAS) summary statistics of SCLC from Transdisciplinary Research Into Cancer of the Lung Consortium (nCase = 2,791 vs. nControl = 20,580), and was validated in another cohort (nCase = 2,664 vs. nControl = 21,444). 734 plasma proteins and their genetic instruments of cis-acting protein quantitative trait loci (pQTL) were used, whereas external plasma proteome data was retrieved from deCODE database. Bidirectional MR, Steiger filtering and phenotype scanning were applied to further verify the associations.Results: Seven significant (p < 6.81 × 10−5) plasma protein-SCLC pairs were identified by MR analysis, including ACP5 (OR = 0.76, 95% CI: 0.67–0.86), CPB2 (OR = 0.90, 95% CI: 0.86–0.95), GSTM3 (OR = 0.45, 95% CI: 0.33–0.63), SHMT1 (OR = 0.74, 95% CI: 0.64–0.86), CTSB (OR = 0.79, 95% CI: 0.71–0.88), NTNG1 (OR = 0.81, 95% CI: 0.74–0.90) and FAM171B (OR = 1.40, 95% CI: 1.21–1.62). The external validation confirmed that CPB2, GSTM3 and NTNG1 had protective effects against SCLC, while FAM171B increased SCLC risk. However, the reverse causality analysis revealed that SCLC caused significant changes in plasma levels of most of these proteins, including decreases of ACP5, CPB2, GSTM3 and NTNG1, and the increase of FAM171B.Conclusion: This integrative analysis firstly suggested the causal associations between SCLC and plasma proteins, and the identified several proteins may be promising novel drug targets or biomarkers for SCLC.

Abstract Hematologic malignancies are one of the most common cancers, and the incidence has been rising in recent decades. The clinical and molecular features of hematologic malignancies are highly heterogenous, and some hematologic malignancies are incurable, challenging the treatment, and prognosis of the patients. However, hematopoiesis and oncogenesis of hematologic malignancies are profoundly affected by epigenetic regulation. Studies have found that methylation-related mutations, abnormal methylation profiles of DNA, and abnormal histone deacetylase expression are recurrent in leukemia and lymphoma. Furthermore, the hypomethylating agents and histone deacetylase inhibitors are effective to treat acute myeloid leukemia and T-cell lymphomas, indicating that epigenetic regulation is indispensable to hematologic oncogenesis. Epigenetic regulation mainly includes DNA modifications, histone modifications, and noncoding RNA-mediated targeting, and regulates various DNA-based processes. This review presents the role of writers, readers, and erasers of DNA methylation and histone methylation, and acetylation in hematologic malignancies. In addition, this review provides the influence of microRNAs and long noncoding RNAs on hematologic malignancies. Furthermore, the implication of epigenetic regulation in targeted treatment is discussed. This review comprehensively presents the change and function of each epigenetic regulator in normal and oncogenic hematopoiesis and provides innovative epigenetic-targeted treatment in clinical practice.

BackgroundIn recent years, with the continuous development of treatments for hematological malignancies (HMs), the remission and survival rates of patients with HMs have been significantly improved. However, because of severe immunosuppression and long-term recurrent neutropenia during treatment, the incidence and mortality of bloodstream infection (BSI) were all high in patients with HMs. Therefore, we analyzed pathogens’ distribution and drug-resistance patterns and developed a nomogram for predicting 30-day mortality in patients with BSIs among HMs.MethodsIn this retrospective study, 362 patients with positive blood cultures in HMs were included from June 2015 to June 2020 at West China Hospital of Sichuan University. They were randomly divided into the training cohort (n = 253) and the validation cohort (n = 109) by 7:3. A nomogram for predicting 30-day mortality after BSIs in patients with HMs was established based on the results of univariate and multivariate logistic regression. C-index, calibration plots, and decision curve analysis were used to evaluate the nomogram.ResultsAmong 362 patients with BSIs in HMs, the most common HM was acute myeloid leukemia (48.1%), and the most common pathogen of BSI was gram-negative bacteria (70.4%). The final nomogram included the septic shock, relapsed/refractory HM, albumin

BackgroundThe overall survival of peripheral T-cell lymphoma (PTCL) is dismal. Histone deacetylase (HDAC) inhibitors have exhibited promising treatment outcomes for PTCL patients. Therefore, this work aims to systematically evaluate the treatment outcome and safety profile of HDAC inhibitor-based treatment for untreated and relapsed/refractory (R/R) PTCL patients.MethodsThe prospective clinical trials of HDAC inhibitors for the treatment of PTCL were searched on the Web of Science, PubMed, Embase, ClinicalTrials.gov, and Cochrane Library database. The pooled overall response rate, complete response (CR) rate, and partial response rate were measured. The risk of adverse events was evaluated. Moreover, the subgroup analysis was utilized to assess the efficacy among different HDAC inhibitors and efficacy in different PTCL subtypes.ResultsFor untreated PTCL, 502 patients in seven studies were involved, and the pooled CR rate was 44% (95% CI, 39-48%). For R/R PTCL patients, there were 16 studies included, and the CR rate was 14% (95% CI, 11-16%). The HDAC inhibitor-based combination therapy exhibited better efficacy when compared with HDAC inhibitor monotherapy for R/R PTCL patients (P = 0.02). In addition, the pooled CR rate was 17% (95% CI, 13-22%), 10% (95% CI, 5-15%), and 10% (95% CI, 5-15%) in the romidepsin, belinostat, and chidamide monotherapy subgroups, respectively. In the R/R angioimmunoblastic T-cell lymphoma subgroup, the pooled ORR was 44% (95% CI, 35-53%), higher than other subtypes. A total of 18 studies were involved in the safety assessment of treatment-related adverse events. Thrombocytopenia and nausea were the most common hematological and non-hematological adverse events, respectively.ConclusionThis meta-analysis demonstrated that HDAC inhibitors were effective treatment options for untreated and R/R PTCL patients. The combination of HDAC inhibitor and chemotherapy exhibited superior efficacy to HDAC inhibitor monotherapy in the R/R PTCL setting. Additionally, HDAC inhibitor-based therapy had higher efficacy in angioimmunoblastic T-cell lymphoma patients than that in other subtypes.

In recent years, growing emphasis has been placed on amino acids and their role in hematologic malignancies. Cancer cell metabolism is altered during tumorigenesis and development to meet expanding energetic and biosynthetic demands. Amino acids not only act as energy-supplying substances, but also play a vital role via regulating key signaling pathways, modulating epigenetic factors and remodeling tumor microenvironment. Targeting amino acids may be an effective therapeutic approach to address the current therapeutic challenges. Here, we provide an updated overview of mechanisms by which amino acids facilitate tumor development and therapy resistance. We also summarize novel therapies targeting amino acids, focusing on recent advances in basic research and their potential clinical implications.

Abstract Janus kinase 2 (JAK2) hyperactivation by JAK2 V617F mutation leads to myeloproliferative neoplasms (MPNs) and targeting JAK2 could serve as a promising therapeutic strategy for MPNs. Here, we report that Flonoltinib Maleate (FM), a selective JAK2/FLT3 inhibitor, shows high selectivity for JAK2 over the JAK family. Surface plasmon resonance assays verified that FM had a stronger affinity for the pseudokinase domain JH2 than JH1 of JAK2 and had an inhibitory effect on JAK2 JH2V617F. The cocrystal structure confirmed that FM could stably bind to JAK2 JH2, and FM suppressed endogenous colony formation of primary erythroid progenitor cells from patients with MPNs. In several JAK2 V617F-induced MPN murine models, FM could dose-dependently reduce hepatosplenomegaly and prolong survival. Similar results were observed in JAK2 V617F bone marrow transplantation mice. FM exhibited strong inhibitory effects on fibrosis of the spleen and bone marrow. Long-term FM treatment showed good pharmacokinetic/pharmacodynamic characteristics with high drug exposure in tumor-bearing tissues and low toxicity. Currently, FM has been approved by the National Medical Products Administration of China (CXHL2000628), and this study will guide clinical trials for patients with MPNs.

BackgroundCopanlisib is an intravenously administered pan-class I PI3K inhibitor that has been demonstrated to have appreciable effects in the treatment of patients with lymphoma. The purpose of this meta-analysis was to evaluate the efficacy and safety of copanlisib for treating patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL).MethodsPubMed, Web of Science, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for relevant studies published prior to July 2022. The efficacy evaluation included complete response rate (CR), partial response rate (PR), rate of stable disease (SDR), overall response rate (ORR), disease control rate (DCR), rate of progressive disease (PDR), median progression-free survival (PFS), and median overall survival (OS). Any grade adverse events (AEs) and grade ≥3 AEs were synthesized to assess its safety.ResultsEight studies with a total of 652 patients with R/R B-NHL were identified. The pooled CR, PR, ORR, SDR, DCR, and PDR from all 8 articles were 13%, 40%, 57%, 19%, 86%, and 9%, respectively. The CR and ORR of combination therapy with rituximab were higher than those with copanlisib monotherapy for R/R B-NHL (34% vs. 6%, p

BackgroundWith approval of anti-PD-1/PD-L1, metastatic non-small cell lung cancer (NSCLC) has entered the era of immunotherapy. Since immune-related adverse events (irAEs) occur commonly in patients receiving anti-PD-1/PD-L1, the landscape of death causes may have changed in metastatic NSCLC. We aim to compare patterns of death causes in metastatic NSCLC between the pre-immunotherapy and immunotherapy era to identify the consequent landscape transition of death causes.MethodsIn this cohort study, 298,485 patients with metastatic NSCLC diagnosed between 2000 and 2018 were identified from the Surveillance, Epidemiology, and End Results Program. Unsupervised clustering with Bayesian inference method was performed for all patients’ death causes, which separated them into two death patterns: the pre-immunotherapy era group and the immunotherapy era group. Relative risk (RR) of each death cause between two groups was estimated using Poisson regression. Reduced death risk as survival time was calculated with locally weighted scatterplot smooth (Lowess) regression.ResultsTwo patterns of death causes were identified by unsupervised clustering for all patients. Thus, we separated them into two groups, the immunotherapy era (2015-2017, N=40,172) and the pre-immunotherapy era (2000-2011, N=166,321), in consideration of obscure availability to immunotherapy for patients diagnosed in 2012-2014, when the follow-up cutoff was set as three years. Although all-cause death risk had reduced (29.2%, 13.7% and 27.8% for death risks of lung cancer, non-cancer and other cancers), non-cancer deaths in the immunotherapy era (N=2,100, 5.2%; RR=1.155, 95%CI: 1.101-1.211, P

Background and ObjectivesThis study aims to perform a comprehensive clinical analysis of patients with primary malignant pituitary tumors (PMPT) that involves incidence, demographics, treatments, long-term survival, and death causes.Materials and methodsPatients with PMPT were identified from registries of the Surveillance, Epidemiology, and End Results (SEER) database. Frequencies and average annual age-adjusted rate (AAR) were calculated for incidence trend analyses using Join-point regression. Univariate and multivariate Cox regression analyses were conducted to identify potential prognostic factors associated with patients' survival outcomes. Using the Kaplan–Meier method and log-rank test, survival curves were plotted and compared, respectively. Propensity score matching (PSM) was performed to balance baseline characteristics.ResultsThe AAR for PMPT was 0.233 (95%CI: 0.205–0.264) per 1,000,000 using nine SEER registries from 1975 to 2017. The incidence trend has declined over years but without significance (–1.04% per year, P = 0.10). Besides, older age may indicate a higher incidence rate for both pediatric and adult patients. From 18 SEER registries, a total of 501 PMPT patients were also identified. Univariate and multivariate Cox regression showed age, sex, tumor extent, and marital status were independent prognostic factors for malignant pituitary tumors. Via PSM, we found that patients who received surgery, radiotherapy, and chemotherapy did not demonstrate significantly different survival than those who did not.ConclusionThis study first conducts a comprehensive clinical analysis of patients with PMPT and provides guide effects on future study designs. More studies should be conducted to focus on its characteristics and therapy.

ObjectivesTo explore the clinical and prognostic characteristics of thymic lymphoma and the effects of current treatments on the prognosis.MethodsPatients diagnosed as primary thymic lymphoma between 1975 and 2018 from the nine states of the US were identified, including Atlanta, Connecticut, Detroit, Hawaii, Iowa, New Mexico, San Francisco-Oakland, Seattle–Puget Sound, and Utah. Incidence and mortality rates were analyzed using SEER*Stat 8.3.9 software. Univariate and multivariate Cox regressions were performed to identify prognostic factors. The Kaplan–Meier curve and log-rank test were used to compare overall survival (OS) among different treatments.ResultsA total of 233 patients diagnosed as thymic lymphoma were identified, and eight of them were lost to follow-up or died upon diagnosis. The incidence of thymic lymphoma was 2.032 per ten million (95% CI: 1.777–2.312), and the mortality rate was 0.649 per ten million (95% CI: 0.508–0.817). Among the 225 patients with definite follow-up, 98 were males and 127 were females, with a median age of 33 years. The Cox regression results showed that age and pathological type were independent risk prognostic factors. The 5-, 10-, and 20-year OS were 80.0%, 77.5%, and 70.9%, respectively. For Ann Arbor stage I and II patients, there was no significant difference between the surgical group (N = 78) and the non-operative group (N = 65; P = 0.270). The radiotherapy group (N = 79) had better OS than the non-radiotherapy group (N = 64) in the first 25 years, and the prognosis in the later years was not significantly different (P = 0.051). The chemotherapy group (N = 37) had a significantly better prognosis than the non-chemotherapy group (N = 37; P = 0.020). Patients who received postoperative radiotherapy (N = 45) or who only received radiotherapy (N = 34) seemed to have better OS than that of patients who only received surgery (N = 33), although the difference was not significant (P = 0.063).ConclusionsAge and pathological type were independent prognostic factors for thymic lymphoma. Surgical treatment had limited effects on OS, while both radiotherapy and chemotherapy could significantly improve the survival outcome.

PurposeTo investigate clinical characteristics, management, and prognosis of Epstein-Barr virus (EBV)-positive lymphoma-associated hemophagocytic syndrome (LAHS) patients in real-world practice.MethodsThis was a retrospective, single-center cohort study. EBV-positive LAHS patients diagnosed from January 2010 to December 2021 in our center were enrolled. Clinical characteristics, treatment, overall response rate (ORR), and overall survival (OS) were investigated. Univariate and multivariate analysis of potential factors were conducted.ResultsOf the 51 patients, 44 were T/NK cell lymphoma; five were B cell lymphoma; two were Hodgkin lymphoma. EBV-positive T/NK cell LAHS patients were significantly younger and showed lower fibrinogen levels and C-reactive protein levels than EBV-positive B cell LAHS patients (P=0.033, P=0.000, and P=0.004, respectively). Combined treatment of anti-hemophagocytic lymphohistiocytosis (HLH) and anti-lymphoma treatment was conducted in 24 patients; anti-HLH treatment was conducted in 18 patients; anti-lymphoma treatment was conducted in three patients; glucocorticoid treatment was conducted in one patient. ORR was 47.8%, and the median OS was 61 (95% confidence interval 47.9-74.1) days for overall patients. Patients who received anti-HLH treatment and turned to anti-lymphoma treatment early displayed higher ORR and OS than those of anti-HLH patients (P=0.103, and P=0.003, respectively). Elevated alanine aminotransferase level was the independent risk factor of EBV-positive LAHS prognosis.ConclusionsPrognosis of EBV-positive LAHS patients was poor. Anti-lymphoma treatment should be initiated as soon as HLH was rapidly controlled.

Brain metastasis (BM) occurs commonly in patients with lung adenocarcinomas. Limited evidence indicates safety and efficacy of immunotherapy for this metastatic tumor, though immune checkpoint blockade has become the front-line treatment for primary advanced non-small cell lung cancer. We aim to comprehensively compare tumor microenvironments (TME) between primary tumors (PT) and BM at single-cell resolution. Single-cell RNA transcriptomics from tumor samples of PT (N = 23) and BM (N = 16) and bulk sequencing data were analyzed to explore potential differences in immunotherapeutic efficacy between PT and BM of lung adenocarcinomas. Multiple machine learning algorithms were used to develop and validate models that predict responses to immunotherapy using the external cohorts. We found obviously less infiltration of immune cells in BM than PT, characterized specifically by deletion of anti-cancer CD8+ Trm cells and more dysfunctional CD8+ Tem cells in BM tumors. Meanwhile, macrophages and dendritic cells within BM demonstrated more pro-tumoral and anti-inflammatory effects, represented by distinct distribution and function of SPP1+ and C1Qs+ tumor-associated microphages, and inhibited antigen presentation capacity and HLA-I gene expression, respectively. Besides, we also found the lack of inflammatory-like CAFs and enrichment of pericytes within BM tumors, which may be critical factors in shaping inhibitory TME. Cell communication analysis further revealed mechanisms of the immunosuppressive effects associated with the activation of some unfavorable pathways, such as TGFβ signaling, highlighting the important roles of stromal cells in the anti-inflammatory microenvironment, especially specific pericytes. Furthermore, pericyte-related genes were identified to optimally predict immunotherapeutic responses by machine learning models with great predictive performance. Overall, various factors contribute to the immunosuppressive TME within BM tumors, represented by the lack of critical anti-cancer immune cells. Meanwhile, pericytes may help shape the TME and targeting the associated mechanisms may enhance immunotherapy efficacy for BM tumors in patients with lung adenocarcinomas.

Background: Ibrutinib is an oral covalent Bruton’s tyrosine kinase inhibitor that has been approved for chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia and some other B-cell malignancies. Some studies have found an increased risk of bleeding with ibrutinib. Some studies, however, found no significant differences in the risk of major bleeding between patients treated with ibrutinib and those with other regimens. So, a systematic review and meta-analysis of randomized controlled trials (RCTs) were performed to estimate the risk of bleeding associated with ibrutinib in patients with B-cell malignancies.Methods: A systematic search of PUBMED, EMBASE, Central Register of Controlled Trials, and ClinicalTrials.gov was conducted from January 2000 to February 2020 to identify RCTs by comparing ibrutinib with other agents or placebo in B-cell malignancies. The RevMan software (version 5.3) was used to carry out this analysis, and the analyzed data were represented by risk ratios (RR) and 95% confidence intervals (CI).Results: There were 11 eligible RCTs (4,288 patients). All studies reported major bleeding, and seven studies reported overall bleeding (any-grade bleeding). Ibrutinib was associated with a significantly increased risk of bleeding (overall bleeding and major bleeding) in patients with B-cell malignancies [RR = 2.56, 95% CI 1.68–3.90, p < 0.0001 and RR = 2.08, 95% CI 1.36–3.16, p = 0.0006, respectively]. The bleeding (overall bleeding and major bleeding) risk in patients with CLL was more obvious [RR = 3.08, 95% CI 2.07–4.58, p < 0.00001 and RR = 2.46, 95% CI 1.37–4.41, p = 0.003, respectively]. There were no statistically significant differences for risk of bleeding between the subgroups based on dose and treatment setting.Conclusion: Ibrutinib was associated with a significantly higher risk of bleeding (both overall bleeding and major bleeding) in patients with B-cell malignancies, especially in CLL.