Comparison of the prognostic effect of pyrotinib plus trastuzumab and chemotherapy different lines therapy in HER2-positive advanced breast cancer.

This study aimed to compare the efficacy of pyrotinib, trastuzumab combined with chemotherapy with different lines therapy in human epidermal growth factor receptor 2- (HER2-) positive advanced breast cancer (ABC) and analyze the factors affecting the prognosis. A total of 84 patients with median age of 49 year-old. The mPFS of patients receiving first-line pyrotinib plus trastuzumab and chemotherapy was the longest (11 months) compared with second- and third line patients (p = 0.106). The objective response rate (ORR) and disease control rate (DCR) of the total population were 33.3% and 82.1% respectively. Subgroup analysis suggested that using pyrotinib plus trastuzumab and Albumin-bound paclitaxel was not inferior to combine with Vinorelbine in regards of PFS. Histological grade (OR: 0.233[0.069 ∼ 0.781], p = 0.018) and tumor location (OR: 0.286[0.087 ∼ 0.942], p = 0.040) were independent factors influencing the ORR. Multivariate cox analysis showed that Ki-67 was independently associated with increased risk of progression (HR: 1.843[1.044-3.254], p = 0.035). The most common adverse events were diarrhea (17.9%) and neutropenia (11.9%). In the first-, second- and third-line treatment, pyrotinib plus trastuzumab and chemotherapy is effective and safe. Pyrotinib and trastuzumab combined with Albumin-bound paclitaxel may be a potential ideal treatment plan for HER2-positive advanced breast cancer.

A Novel Liver Cancer-Selective Histone Deacetylase Inhibitor Is Effective Against Hepatocellular Carcinoma and Induces Durable Responses with Immunotherapy.

Hepatocellular cancer (HCC) progression is facilitated by gene-silencing chromatin histone hypoacetylation due to histone deacetylases (HDACs) activation. However, inhibiting HDACs - an effective treatment for lymphomas - has shown limited success in solid tumors. We report the discovery of a class of HDAC inhibitors (HDACi) that demonstrates exquisite selective cytotoxicity against human HCC cells. The lead compound STR-V-53 ( 3 ) showed favorable safety profile in mice and robustly suppressed tumor growth in orthotopic xenograft models of HCC. When combined with the anti-HCC drug sorafenib, STR-V-53 showed greater in vivo efficacy. Moreover, STR-V-53 combined with anti-PD1 therapy increased the CD8 + to regulatory T-cell (Treg) ratio and survival in an orthotopic HCC model in immunocompetent mice. This combination therapy resulted in durable responses in 40% of the mice. Collectively, our data demonstrate that the novel HDACi STR-V-53 is an effective anti-HCC agent that can induce profound responses when combined with standard immunotherapy.

Platinum-based neoadjuvant chemotherapy upregulates STING/IFN pathway expression and promotes TILs infiltration in NSCLC.

Objectives: To evaluate the effects of platinum-based neoadjuvant chemotherapy (NACT) on the STING/IFN pathway and tumor-infiltrating lymphocytes (TILs) in non-small cell lung cancer (NSCLC), as well as clinicopathological factors affecting patient survival. Materials and methods: A total of 68 patients aged 34-77 years with NSCLC who received neoadjuvant chemotherapy and surgical treatment from March 2012 to February 2019 were reviewed, and the clinical pathological data and paired tissue specimens before and after NACT were collected. Immunohistochemistry and immunofluorescence were used to detect the protein levels of STING, PD-L1 and IFN-ß, and the infiltration density of CD3+ TILs and CD8+TILs. The correlation between the expression of STING, PD-L1, IFN-ß and the infiltration density of CD3+ TILs and CD8+ TILs as well as the clinicopathological characteristics before and after NACT was analyzed. The relationship between the related indexes, clinicopathological features and prognosis was also discussed. Results: NACT increased the expression of STING, IFN-ß and PD-L1 in tumor cells, and the infiltration of CD3+ and CD8+ TILs. In addition, ypTNM stage, ypN stage, changes in CD3+ TILs and in PD-L1 were associated with DFS (disease-free survival). CD3+ TILs changes and ypN stage were associated with OS (overall survival). Notably, ypN stage and CD3+ TILs changes were independent prognostic factors for DFS and OS. Conclusion: NACT stimulates STING/IFN-ß pathway, promotes infiltration of CD3+ and CD8+ TILs, triggers innate and adaptive immunity, and also upregulates PD-L1, which complemented the rationale for neoadjuvant chemotherapy in combination with immunotherapy. In addition, DFS was longer in patients with ypTNM I, ypN0-1, and elevated CD3+TILs after NACT. Patients with ypN0 and elevated CD3+ TILs after NACT had better OS benefits.

Alectinib continuation beyond progression in ALK-positive non-small cell lung cancer with alectinib-refractory.

Background: Alectinib, a next-generation anaplastic lymphoma kinase tyrosine kinase inhibitor (ALK-TKI), has demonstrated noteworthy efficacy in the treatment of non-small cell lung cancer (NSCLC). Unfortunately, 53.3% of untreated patients receiving first-line treatment with alectinib developed resistance to alectinib. However, despite the widespread use of alectinib, studies on the efficacy and safety of continuing alectinib with other necessary therapies after progression of alectinib and possible population of benefit are still limited. Methods: This retrospective cohort study included fifteen patients with ALK-positive NSCLC from nine institutions in China who experienced disease progression after first- or second-line treatment and continued to receive alectinib treatment between 2019 and 2022. This study aimed to evaluate the median progression-free survival (mPFS), objective response rate (ORR), median overall survival (mOS), and adverse events (AEs) of continuing alectinib combined with other therapies after the emergence of drug resistance. Results: Among fifteen patients eligible for this study, all patients started continuing treatment with alectinib after oligoprogression or central nervous system (CNS) progression. The mPFS for the whole cohort receiving continuing alectinib with other necessary therapies was 8 months [95% confidence interval (CI): 4 to not applicable (NA)], with an ORR of 46.7%. The mOS was not reached. During continuing alectinib treatment, only one patient experienced grade 2 elevation of aspartate aminotransferase (AST) and serum glutamic-oxaloacetic transaminase (SGOT). Conclusions: The continuation of alectinib treatment combined with other necessary therapies demonstrates favorable response and safety in patients with ALK-positive NSCLC who experienced oligoprogression or CNS progression following alectinib in first- or second-line therapy. Instead of immediately switching to another ALK-TKI, continuing alectinib combined with other necessary therapies may offer greater survival benefits to the patients.

Reprogramming the Intrahepatic Cholangiocarcinoma Immune Microenvironment by Chemotherapy and CTLA-4 Blockade Enhances Anti-PD-1 Therapy.

Intrahepatic cholangiocarcinoma (ICC) has limited therapeutic options and a dismal prognosis. Adding blockade of the anti-programmed cell death protein (PD)-1 pathway to gemcitabine/cisplatin chemotherapy has recently shown efficacy in biliary tract cancers but with low response rates. Here, we studied the effects of anti-cytotoxic T lymphocyte antigen (CTLA)-4 when combined with anti-PD-1 and gemcitabine/cisplatin in orthotopic murine models of ICC. This combination therapy led to substantial survival benefits and reduction of morbidity in two aggressive ICC models that were resistant to immunotherapy alone. Gemcitabine/cisplatin treatment increased tumor-infiltrating lymphocytes and normalized the ICC vessels and, when combined with dual CTLA-4/PD-1 blockade, increased the number of activated CD8+Cxcr3+IFNγ+ T cells. CD8+ T cells were necessary for the therapeutic benefit because the efficacy was compromised when CD8+ T cells were depleted. Expression of Cxcr3 on CD8+ T cells is necessary and sufficient because CD8+ T cells from Cxcr3+/+ but not Cxcr3-/- mice rescued efficacy in T cell‒deficient mice. Finally, rational scheduling of anti-CTLA-4 "priming" with chemotherapy followed by anti-PD-1 therapy achieved equivalent efficacy with reduced overall drug exposure. These data suggest that this combination approach should be clinically tested to overcome resistance to current therapies in ICC patients.

Preventing NK cell activation in the damaged liver induced by cabozantinib/PD-1 blockade increases survival in hepatocellular carcinoma models.

The addition of anti-VEGF antibody treatment to immune checkpoint blockade (ICB) has increased the efficacy of immunotherapy in advanced hepatocellular carcinoma (HCC). Despite an initial promise, adding multitargeted kinase inhibitors of VEGFR with ICB has failed to increase survival in HCC. To reveal the mechanisms underlying treatment failure, we studied the effects of cabozantinib/ICB using orthotopic murine HCC models with or without liver damage. We monitored tumor growth and liver function, recorded survival outcomes, and performed immune profiling studies for intra-tumoral and surrounding liver. Cabozantinib/ICB treatment led to tumor regression and significantly improved survival in mice with normal livers. However, consistent with the clinical findings, combination therapy failed to show survival benefits despite similar tumor control when tested in the same models but in mice with liver fibrosis. Moreover, preclinical and clinical data converged, showing that activating immune responses by cabozantinib/ICB treatment induced hepatoxicity. Immune profiling revealed that combination therapy effectively reprogrammed the tumor immune microenvironment and increased NK cell infiltration and activation in the damaged liver tissue. Surprisingly, systemic depletion of NK reduced hepatotoxicity elicited by the combination therapy without compromising its anti-cancer effect, and significantly enhanced the survival benefit even in mice with HCC and underlying liver fibrosis. These findings demonstrate that preventing NK activation allowed for maintaining a favorable therapeutic ratio when combining ICB with cabozantinib in advanced HCC models.

Establishment of a risk classifier to predict the in-hospital death risk of nosocomial fungal infections in cancer patients.

BACKGROUND: Patients with malignancy are at a higher risk of developing nosocomial infections. However, limited studies investigated the clinical features and prognostic factors of nosocomial infections due to fungi in cancer patients. Herein, this study aims to investigate the clinical characteristics of in-hospital fungal infections and develop a nomogram to predict the risk of in-hospital death during fungal infection of hospitalized cancer patients. METHODS: This retrospective observational study enrolled cancer patients who experienced in-hospital fungal infections between September 2013 and September 2021. Univariate and multivariate logistic regression analyses were performed to identify independent predictors of in-hospital mortality. Variables demonstrating significant statistical differences in the multivariate analysis were utilized to construct a nomogram for personalized prediction of in-hospital death risk associated with nosocomial fungal infections. The predictive performance of the nomogram was evaluated using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis. RESULTS: A total of 216 participants were included in the study, of which 57 experienced in-hospital death. C.albicans was identified as the most prevalent fungal species (68.0%). Respiratory infection accounted for the highest proportion of fungal infections (59.0%), followed by intra-abdominal infection (8.8%). The multivariate regression analysis revealed that Eastern Cooperative Oncology Group Performance Status (ECOG-PS) 3-4 (odds ratio [OR] = 6.08, 95% confidence interval [CI]: 2.04-18.12), pulmonary metastases (OR = 2.76, 95%CI: 1.11-6.85), thrombocytopenia (OR = 2.58, 95%CI: 1.21-5.47), hypoalbuminemia (OR = 2.44, 95%CI: 1.22-4.90), and mechanical ventilation (OR = 2.64, 95%CI: 1.03-6.73) were independent risk factors of in-hospital death. A nomogram based on the identified risk factors was developed to predict the individual probability of in-hospital mortality. The nomogram demonstrated satisfactory performance in terms of classification ability (area under the curve [AUC]: 0.759), calibration ability, and net clinical benefit. CONCLUSIONS: Fungi-related nosocomial infections are prevalent among cancer patients and are associated with poor prognosis. The constructed nomogram provides an invaluable tool for oncologists, enabling them to make timely and informed clinical decisions that offer substantial net clinical benefit to patients.

Construction and Evaluation of Clinical Prediction Model for Immunotherapy-related Adverse Events and Clinical Benefit in Cancer Patients Receiving Immune Checkpoint Inhibitors Based on Serum Cytokine Levels.

Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic landscape of cancer therapy. This study aimed to develop novel risk classifiers to predict the risk of immune-related adverse events (irAEs) and the probability of clinical benefits. Patients with cancer who received ICIs from the First Affiliated Hospital of Xi 'an Jiaotong University from November 2020 to October 2022 were recruited and followed up. Logistic regression analyses were performed to identify independent predictive factors for irAEs and clinical response. Two nomograms were developed to predict the irAEs and clinical responses of these individuals, with a receiver operating characteristic curve to assess their predictive ability. Decision curve analysis was performed to estimate the clinical utility of the nomogram. This study included 583 patients with cancer. Among them, 111 (19.0%) developed irAEs. Duration of treatment (DOT)>3 cycles, hepatic-metastases, IL2>2.225 pg/mL, and IL8>7.39 pg/mL were correlated with higher irAEs risk. A total of 347 patients were included in the final efficacy analysis, with an overall clinical benefit rate of 39.7%. DOT>3 cycles, nonhepatic-metastases, and irAEs and IL8>7.39 pg/mL were independent predictive factors of clinical benefit. Ultimately, 2 nomograms were successfully established to predict the probability of irAEs and their clinical benefits. Ultimately, 2 nomograms were successfully established to predict the probability of irAEs and clinical benefits. The receiver operating characteristic curves yielded acceptable nomogram performance. Calibration curves and decision curve analysis supported the hypothesis that nomograms could provide more significant net clinical benefits to these patients. Specific baseline plasma cytokines were closely correlated with irAEs and clinical responses in these individuals.

A novel risk classifier to predict the in-hospital death risk of nosocomial infections in elderly cancer patients.

Background: Elderly cancer patients are more predisposed to developing nosocomial infections during anti-neoplastic treatment, and are associated with a bleaker prognosis. This study aimed to develop a novel risk classifier to predict the in-hospital death risk of nosocomial infections in this population. Methods: Retrospective clinical data were collected from a National Cancer Regional Center in Northwest China. The Least Absolute Shrinkage and Selection Operator (LASSO) algorithm was utilized to filter the optimal variables for model development and avoid model overfitting. Logistic regression analysis was performed to identify the independent predictors of the in-hospital death risk. A nomogram was then developed to predict the in-hospital death risk of each participant. The performance of the nomogram was evaluated using receiver operating characteristics (ROC) curve, calibration curve, and decision curve analysis (DCA). Results: A total of 569 elderly cancer patients were included in this study, and the estimated in-hospital mortality rate was 13.9%. The results of multivariate logistic regression analysis showed that ECOG-PS (odds ratio [OR]: 4.41, 95% confidence interval [CI]: 1.95-9.99), surgery type (OR: 0.18, 95%CI: 0.04-0.85), septic shock (OR: 5.92, 95%CI: 2.43-14.44), length of antibiotics treatment (OR: 0.21, 95%CI: 0.09-0.50), and prognostic nutritional index (PNI) (OR: 0.14, 95%CI: 0.06-0.33) were independent predictors of the in-hospital death risk of nosocomial infections in elderly cancer patients. A nomogram was then constructed to achieve personalized in-hospital death risk prediction. ROC curves yield excellent discrimination ability in the training (area under the curve [AUC]=0.882) and validation (AUC=0.825) cohorts. Additionally, the nomogram showed good calibration ability and net clinical benefit in both cohorts. Conclusion: Nosocomial infections are a common and potentially fatal complication in elderly cancer patients. Clinical characteristics and infection types can vary among different age groups. The risk classifier developed in this study could accurately predict the in-hospital death risk for these patients, providing an important tool for personalized risk assessment and clinical decision-making.

Reprogramming Intrahepatic Cholangiocarcinoma Immune Microenvironment by Chemotherapy and CTLA-4 Blockade Enhances Anti-PD1 Therapy.

Intrahepatic cholangiocarcinoma (ICC) has limited therapeutic options and a dismal prognosis. Anti-PD-L1 immunotherapy combined with gemcitabine/cisplatin chemotherapy has recently shown efficacy in biliary tract cancers, but responses are seen only in a minority of patients. Here, we studied the roles of anti-PD1 and anti-CTLA-4 immune checkpoint blockade (ICB) therapies when combined with gemcitabine/cisplatin and the mechanisms of treatment benefit in orthotopic murine ICC models. We evaluated the effects of the combined treatments on ICC vasculature and immune microenvironment using flow cytometry analysis, immunofluorescence, imaging mass cytometry, RNA-sequencing, qPCR, and in vivo T-cell depletion and CD8+ T-cell transfer using orthotopic ICC models and transgenic mice. Combining gemcitabine/cisplatin with anti-PD1 and anti-CTLA-4 antibodies led to substantial survival benefits and reduction of morbidity in two aggressive ICC models, which were ICB-resistant. Gemcitabine/cisplatin treatment increased the frequency of tumor-infiltrating lymphocytes and normalized the ICC vessels, and when combined with dual CTLA-4/PD1 blockade, increased the number of activated CD8+Cxcr3+IFN-γ+ T-cells. Depletion of CD8+ but not CD4+ T-cells compromised efficacy. Conversely, CD8+ T-cell transfer from Cxcr3-/- versus Cxcr3+/+ mice into Rag1-/- immunodeficient mice restored the anti-tumor effect of gemcitabine/cisplatin/ICB combination therapy. Finally, rational scheduling of the ICBs (anti-CTLA-4 "priming") with chemotherapy and anti-PD1 therapy achieved equivalent efficacy with continuous dosing while reducing overall drug exposure. In summary, gemcitabine/cisplatin chemotherapy normalizes vessel structure, increases activated T-cell infiltration, and enhances anti-PD1/CTLA-4 immunotherapy efficacy in aggressive murine ICC. This combination approach should be clinically tested to overcome resistance to current therapies in ICC patients.

A novel risk classifier for predicting the overall survival of patients with thymic epithelial tumors based on the eighth edition of the TNM staging system: A population-based study.

Objective: Thymic epithelial tumors (TETs) are rare tumors that originated from thymic epithelial cells, with limited studies investigating their prognostic factors. This study aimed to investigate the prognostic factors of TETs and develop a new risk classifier to predict their overall survival (OS). Methods: This retrospective study consisted of 1224 TETs patients registered in the Surveillance, Epidemiology, and End Results (SEER) database, and 75 patients from the First Affiliated Hospital of Xi'an Jiaotong University. The univariate and multivariate Cox regression analyses were adopted to select the best prognostic variables. A nomogram was developed to predict the OS of these patients. The discriminative and calibrated abilities of the nomogram were assessed using the receiver operating characteristics curve (ROC) and calibration curve. Decision curve analysis (DCA), net reclassification index (NRI), and integrated discrimination improvement (IDI) were adopted to assess its net clinical benefit and reclassification ability. Results: The multivariate analysis revealed that age, sex, histologic type, TNM staging, tumor grade, surgery, radiation, and tumor size were independent prognostic factors of TETs, and a nomogram was developed to predict the OS of these patients based on these variables. The time-dependent ROC curves displayed that the nomogram yielded excellent performance in predicting the 12-, 36- and 60-month OS of these patients. Calibration curves presented satisfying consistencies between the actual and predicted OS. DCA illustrated that the nomogram will bring significant net clinical benefits to these patients compared to the classic TNM staging system. The estimated NRI and IDI showed that the nomogram could significantly increase the predictive ability of 12-, 36- and 60-month OS compared to the classic TNM staging system. Consistent findings were discovered in the internal and external validation cohorts. Conclusion: The constructed nomogram is a reliable risk classifier to achieve personalized survival probability prediction of TETs, and could bring significant net clinical benefits to these patients.

The efficacy and safety of anlotinib combined with platinum-etoposide chemotherapy as first-line treatment for extensive-stage small cell lung cancer: A Chinese multicenter real-world study.

Background: Patients with extensive-stage small-cell lung cancer (ES-SCLC) have high recurrence rates and bleak prognosis. This multicenter real-world study aimed to explore the efficacy and safety of anlotinib combined with platinum-etoposide chemotherapy as the first-line treatment of ES-SCLC. Methods: Pathologically confirmed ES-SCLC patients receiving anlotinib plus platinum-etoposide chemotherapy as the first-line treatment were enrolled in this retrospective study. The primary endpoint of this study was progression-free survival (PFS), and secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse reactions. The Cox regression analyses were employed to investigate the independent prognostic factors for OS and PFS of these individuals. Results: In total, 58 patients were included in this study. The median PFS was 6.0 months [95% confidence interval (CI): 3.5-8.5], and the median OS was 10.5 months (95%CI 8.7-12.3). Thirty-four patients achieved partial response (PR), 18 patients achieved stable disease (SD), and 6 patients achieved progressive disease (PD). The ORR and DCR were 58.6% and 89.6%. The main treatment-related adverse reactions were generally tolerated. Myelosuppression (44.8%) was the most common adverse reaction, followed by hypertension (41.4%), fatigue (34.5%), gastrointestinal reaction (32.7%), and hand-foot syndrome (24.1%). Multivariate analysis showed that post-medication hand-foot syndrome [PFS 8.5 vs. 5.5 months, Hazards Ratio (HR)=0.23, 95%CI 0.07-0.72, P =0.012] was the independent predictor of PFS, and hypertension (OS 15.9 vs. 8.3 months, HR=0.18, 95%CI 0.05-0.58, P =0.005) was the independent predictor of OS. Conclusion: Anlotinib combined with platinum-etoposide chemotherapy as the first-line treatment for ES-SCLC appears to be effective and well-tolerated in the real-world. Well-designed large-scale prospective studies are urgently needed in the future to verify our findings.

The Efficacy and Safety of Anlotinib in Extensive-Stage Small Cell Lung Cancer: A Multicenter Real-World Study.

Purpose: Anlotinib, an antiangiogenic multi-target tyrosine kinase inhibitor (TKI), has shown favorable anticancer efficacy and acceptable safety in treating extensive-stage small cell lung cancer (ES-SCLC) in some clinical studies. This research aimed to explore the real-world efficacy and safety of anlotinib in ES-SCLC. Methods: Pathologically confirmed ES-SCLC patients receiving anlotinib were enrolled for this retrospective study. The primary endpoint of this study was progression-free survival (PFS), and secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse reactions. Results: In total, 202 patients were included in this study. The median PFS of all patients was 4.8 months [95% confidence interval (CI): 3.9-5.7], and the median OS was 7.6 months (95% CI 6.5-8.7). Respectively, the overall ORR and DCR were 30.2% and 87.1%. The univariate and multivariate Cox regression analyses revealed that patients with Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤1, plus chemotherapy or immunotherapy, plus radiotherapy, and post-medication hypertension might have longer PFS and OS. The PFS and OS were significantly prolonged in combination group than that in monotherapy group [PFS 6.0 vs 3.6 months, hazards ratio (HR)=0.49, 95% CI 0.34-0.70, P < 0.001; OS 9.2 vs 4.8 months, HR = 0.48, 95% CI 0.32-0.72, P < 0.001]. The main treatment-related adverse reactions were generally tolerated. The incidence of adverse reactions in combination group was higher than that in monotherapy group (75.0% vs 52.6%, P = 0.001). The most common adverse reaction was hypertension, followed by hand-foot syndrome and fatigue, regardless of monotherapy or combination group. Conclusion: Anlotinib is effective and well tolerated in patients with ES-SCLC in the real-world. The clinical efficacy of anlotinib combined with chemotherapy or immunotherapy is better than that of monotherapy. Further investigations are needed for prospective studies with larger sample size.

Immune Checkpoint Inhibitor-Associated Cardiotoxicity in Solid Tumors: Real-World Incidence, Risk Factors, and Prognostic Analysis.

Background: Immune checkpoint inhibitors (ICIs) have achieved acknowledged progress in cancer therapy. However, ICI-associated cardiotoxicity as one of the most severe adverse events is potentially life-threatening, with limited real-world studies reporting its predictive factors and prognosis. This study aimed to investigate the real-world incidence, risk factors, and prognosis of ICI-related cardiotoxicity in patients with advanced solid tumors. Methods: Electronic medical records from patients with advanced solid tumors receiving ICIs in the First Affiliated Hospital of Xi'an Jiaotong University were retrospectively reviewed. All patients were divided into the cardiotoxicity group and control group, with logistic regression analysis being implemented to identify potential risk factors of ICI-related cardiotoxicity. Furthermore, survival analysis was also performed to investigate the prognosis of patients with ICI-related cardiotoxicity. Results: A total of 1,047 participants were enrolled in this retrospective study. The incidence of ICI-related cardiotoxicity in our hospital is 7.0%, while grade 3 and above cardiotoxicity was 2.4%. The logistic regression analysis revealed that diabetes mellitus [odds ratio (OR):1.96, 95% confidence Interval (CI): 1.05-3.65, p = 0.034] was an independent risk factor, whereas baseline lymphocyte/monocyte ratio (LMR) (OR: 0.59, 95% CI: 0.36-0.97, p = 0.037) was the protective factor of ICI-related cardiotoxicity. Survival analysis indicated that severe cardiotoxicity (≥grade 3) was significantly correlated with bleak overall survival (OS) than mild cardiotoxicity (≤grade 2) (8.3 months vs. not reached, p = 0.001). Patients with ICI-related overlap syndrome had poorer overall survival than patients with mere cardiotoxicity (9.4 vs. 24.7 months, p = 0.033). However, the occurrence of ICI-related cardiotoxicity was not significantly associated with the OS of overall population with solid tumors. Subgroup analysis showed that lung cancer and PD-L1 usage were significantly correlated with a higher incidence of severe cases. Conclusion: Immune checkpoint inhibitor-related cardiotoxicity is more common in the real-world setting than the previously published studies. Diabetes mellitus and baseline LMR are the potential predictive biomarkers of ICI-related cardiotoxicity. Although ICI-related cardiotoxicity is not correlated with the prognosis of these patients in our cohort, a systematic and comprehensive baseline examination and evaluation should be performed to avoid its occurrence.

Lipid metabolism-related gene prognostic index (LMRGPI) reveals distinct prognosis and treatment patterns for patients with early-stage pulmonary adenocarcinoma.

Background: Lipid metabolism plays a pivotal role in cancer progression and metastasis. This study aimed to investigate the prognostic value of lipid metabolism-related genes (LMRGs) in early-stage lung adenocarcinoma (LUAD) and develop a lipid metabolism-related gene prognostic index (LMRGPI) to predict their overall survival (OS) and treatment response. Methods: A total of 774 early-stage LUAD patients were identified from The Cancer Genome Atlas (TCGA, 403 patients) database and Gene Expression Omnibus (GEO, 371 patients) database. The non-negative Matrix Factorization (NMF) algorithm was used to identify different population subtypes based on LMRGs. The Least Absolute Shrinkage and Selection Operator (LASSO) and multivariate Cox regression analyses were used to develop the LMRGPI, with receiver operating characteristic (ROC) curves and concordance index being used to evaluate its performance. The characteristics of mutation landscape, enriched pathways, tumor microenvironment (TME), and treatment response between different LMRGPI groups were also investigated. Results: We identified two population subtypes based on LMRGs in the TCGA-LUAD cohort, with distinct prognosis, TME, and immune status being observed. LMRGPI was developed based on the expression levels of six LMRGs, including ANGPTL4, NPAS2, SLCO1B3, ACOXL, ALOX15, and B3GALNT1. Higher LMRGPI was correlated with poor OS both in TCGA and GSE68465 cohorts. Two nomograms were established to predict the survival probability of early-stage LUAD, with higher consistencies being observed between the predicted and actual OS. Higher LMRGPI was significantly correlated with more frequent TP53 mutation, higher tumor mutation burden (TMB), and up-regulation of CD274. Besides, patients with higher LMRGPI presented unremarkable responses for gefitinib, erlotinib, cisplatin, and vinorelbine, while they tend to have a favorable response for immune checkpoint inhibitors (ICIs). The opposite results were observed in the low-LMRGPI group. Conclusions: We comprehensively investigated the prognostic value of LMRGs in early-stage LUAD. Given its good prognostic ability, LMRGPI could serve as a promising biomarker to predict the OS and treatment response of these patients.

Establishment and validation of prognostic nomograms to predict the overall and cancer-specific survival in patients with hepatic malignant vascular tumors.

OBJECTIVE: To characterize the clinicopathologic features and to investigate the prognostic nomograms for overall survival (OS) and cancer-specific survival (CSS) in patients with Hepatic malignant vascular tumors (HMVT). METHOD: Patients diagnosed with HMVT between 1973 and 2015 were screened from the Surveillance, Epidemiology, and End Results (SEER) database. The Kaplan-Meier (KM) was used for survival analysis. The univariate and multivariate Cox analyses were performed to identify independent predictors. Furthermore, the prognostic nomograms were established and evaluated. RESULTS: A total of 510 HMVT patients were collected, and randomly divided into HMVT-training (N=308) and validation cohort (N=202) groups. The 3- and 5-year OS for overall HMVT were 21.3% and 19.8%, and the corresponding CSS was 29.8% and 27.7% respectively. Age at diagnosis, grade, tumor size, and histological type were identified as prognostic factors for OS and CSS in patients with HMVT. However, sex was just for predicting CSS, and T stage was only an indicator of OS. These factors were further utilized to construct the nomograms for OS and CSS in the HMVT-training cohort showing credible performance with the C-index of 0.763 and 0.762, respectively. Moreover, the AUC value for 1-, 3-, 5-year OS was 0.873, 0.905 and 0.898, and the corresponding value for CSS was 0.808, 0.794 and 0.788 respectively. Additionally, the calibration curves demonstrated a favorable agreement between the predicted and actual 1-, 3- and 5-year survival rates both in the training and validated cohorts. CONCLUSION: This was the largest population-based study to describe the clinicopathologic characteristics in patients with HMVT. Moreover, we established and validated prognostic nomograms that indicated an accurate prediction for 1-, 3- and 5-year of OS and CSS.

Increased CD8+ T-cell Infiltration and Efficacy for Multikinase Inhibitors After PD-1 Blockade in Hepatocellular Carcinoma.

Immune checkpoint blockade combined with antiangiogenic therapy induces vascular normalization and antitumor immunity and is efficacious in hepatocellular carcinoma (HCC); but whether and how initial immunotherapy affects the efficacy of subsequent antiangiogenic therapy are unknown. We evaluated a cohort of HCC patients (n = 25) who received the pan-vascular endothelial growth factor receptor multikinase inhibitor sorafenib after initial therapy with an antiprogrammed cell death protein (PD)-1 antibody and found superior outcomes in these patients (12% overall response rate to sorafenib and a median overall survival of 12.1 months). To prove this potential benefit, we examined the impact of an anti-PD-1 antibody on response to subsequent sorafenib treatment in orthotopic models of murine HCC. Prior anti-PD-1 antibody treatment amplified HCC response to sorafenib therapy and increased survival (n = 8-9 mice per group, hazard ratio = 0.28, 95% confidence interval = 0.09 to 0.91; 2-sided P = .04). Anti-PD-1 therapy showed angioprotective effects on HCC vessels to subsequent sorafenib treatment, which enhanced the benefit of this therapy sequence in a CD8+ T-cell-dependent manner. This priming approach using immunotherapy provides an immediately translatable strategy for effective HCC treatment while reducing drug exposure.

Combining p53 mRNA nanotherapy with immune checkpoint blockade reprograms the immune microenvironment for effective cancer therapy.

Immunotherapy with immune checkpoint blockade (ICB) has shown limited benefits in hepatocellular carcinoma (HCC) and other cancers, mediated in part by the immunosuppressive tumor microenvironment (TME). As p53 loss of function may play a role in immunosuppression, we herein examine the effects of restoring p53 expression on the immune TME and ICB efficacy. We develop and optimize a CXCR4-targeted mRNA nanoparticle platform to effectively induce p53 expression in HCC models. Using p53-null orthotopic and ectopic models of murine HCC, we find that combining CXCR4-targeted p53 mRNA nanoparticles with anti-PD-1 therapy effectively induces global reprogramming of cellular and molecular components of the immune TME. This effect results in improved anti-tumor effects compared to anti-PD-1 therapy or therapeutic p53 expression alone. Thus, our findings demonstrate the reversal of immunosuppression in HCC by a p53 mRNA nanomedicine when combined with ICB and support the implementation of this strategy for cancer treatment.

Establishment and validation of a nomogram to predict the in-hospital death risk of nosocomial infections in cancer patients.

BACKGROUND: Attributed to the immunosuppression caused by malignancy itself and its treatments, cancer patients are vulnerable to developing nosocomial infections. This study aimed to develop a nomogram to predict the in-hospital death risk of these patients. METHODS: This retrospective study was conducted at a medical center in Northwestern China. The univariate and multivariate logistic regression analyses were adopted to identify predictive factors for in-hospital mortality of nosocomial infections in cancer patients. A nomogram was developed to predict the in-hospital mortality of each patient, with receiver operating characteristic curves and calibration curves being generated to assess its predictive ability. Furthermore, decision curve analysis (DCA) was also performed to estimate the clinical utility of the nomogram. RESULTS: A total of 1,008 nosocomial infection episodes were recognized from 14,695 cancer patients. Extended-spectrum ß-lactamase (ESBL)-producing Escherichia coli (15.5%) was the most predominant causative pathogen. Besides, multidrug-resistant strains were discovered in 25.5% of cases. The multivariate analysis indicated that Eastern Cooperative Oncology Group Performance Status 3-4, mechanical ventilation, septic shock, hypoproteinemia, and length of antimicrobial treatment < 7 days were correlated with higher in-hospital mortality. Patients who received curative surgery were correlated with favorable survival outcomes. Ultimately, a nomogram was constructed to predict the in-hospital mortality of nosocomial infections in cancer patients. The area under the curve values of the nomogram were 0.811 and 0.795 in the training and validation cohorts. The calibration curve showed high consistency between the actual and predicted in-hospital mortality. DCA indicated that the nomogram was of good clinical utility and more credible net clinical benefits in predicting in-hospital mortality. CONCLUSIONS: Nosocomial infections stay conjoint in cancer patients, with gram-negative bacteria being the most frequent causative pathogens. We developed and verified a nomogram that could effectively predict the in-hospital death risk of nosocomial infections among these patients. Precise management of high-risk patients, early recognition of septic shock, rapid and adequate antimicrobial treatment, and dynamic monitoring of serum albumin levels may improve the prognosis of these individuals.

Assessment of the Clinical Utility of Circulating Tumor Cells at Different Time Points in Predicting Prognosis of Patients With Small Cell Lung Cancer: A Meta-Analysis.

OBJECTIVES: Numerous studies have elucidated that circulating tumor cells (CTCs) have significant prognostic value in various solid tumors. However, the prognostic value of CTCs in small cell lung cancer (SCLC) remains controversial. The current study was performed to investigate the prognostic significance of different time points of CTCs in SCLC. METHODS: PubMed, EMBASE, Web of Science, and Cochrane Library databases were retrieved for eligible studies. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to investigate the association between CTCs level and overall survival (OS) and progression-free survival (PFS) in SCLC. Furthermore, subgroup analyses, sensitivity analysis, Begg's and Egger's tests were also conducted. RESULTS: Sixteen cohort studies with 1103 participants were eligible for this meta-analysis. Our results revealed that higher pretreatment CTCs level was significantly correlated with worse OS in SCLC no matter CellSearch (HR, 2.95; 95%CI, 1.56-5.58; P = .001) or other methods (HR, 2.37; 95%CI, 1.13-4.99; P = .023) was used to detect CTCs. Higher pretreatment CTCs status detected by CellSearch was associated with shorter PFS (HR, 3.75; 95%CI, 2.52-5.57; P < .001), while there was no significant association when other methods were adopted to CTC detection (HR, 2.04; 95%CI, .73-5.68; P = .172). Likewise, we observed that higher post-therapy CTCs level detected by both CellSearch (HR, 2.99; 95%CI, 1.51-5.93; P = .002) and other methods (HR, 4.79; 95%CI, 2.03-11.32; P < .001) was significantly correlated with decreased OS in SCLC. However, higher post-therapy CTCs count detected by CellSearch was not correlated with worse PFS (HR, 1.80; 95%CI, .83-3.90; P = .135). Sensitivity analysis demonstrated that the pooled data were still stable after eliminating studies one by one. However, significant publication bias was observed between pretreatment CTCs level detected by CellSearch and OS of SCLC. CONCLUSION: Dynamic monitoring of CTCs level could be a non-invasive and effective tool to predict the disease progression and prognosis in patients with SCLC.