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.

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.

Construction and Validation of a Novel Nomogram to Predict the Overall Survival of Patients With Combined Small Cell Lung Cancer: A Surveillance, Epidemiology, and End Results Population-Based Study.

INTRODUCTION: Combined small cell lung cancer (C-SCLC) represents a rare subtype of all small cell lung cancer cases, with limited studies investigated its prognostic factors. The aim of this study was to construct a novel nomogram to predict the overall survival (OS) of patients with C-SCLC. METHODS: In this retrospective study, a total of 588 C-SCLC patients were selected from the Surveillance, Epidemiology, and End Results database. The univariate and multivariate Cox analyses were performed to identify optimal prognostic variables and construct the nomogram, with concordance index (C-index), receiver operating characteristic curves, and calibration curves being used to evaluate its discrimination and calibration abilities. Furthermore, decision curve analysis (DCA), integrated discrimination improvement (IDI), and net reclassification index (NRI) were also adopted to assess its clinical utility and predictive ability compared with the classic TNM staging system. RESULTS: Seven independent predictive factors were identified to construct the nomogram, including T stage, N stage, M stage, brain metastasis, liver metastasis, surgery, and chemotherapy. We observed a higher C-index in both the training (.751) and validation cohorts (.736). The nomogram has higher area under the curve in predicting 6-, 12-, 18-, 24-, and 36-month survival probability of patients with C-SCLC. Meanwhile, the calibration curves also revealed high consistencies between the actual and predicted OS. DCA revealed that the nomogram could provide greater clinical net benefits to these patients. We found that the NRI for 6- and 12-month OS were .196 and .225, and the IDI for 6- and 12-month OS were .217 and .156 in the training group, suggesting that the nomogram can predict a more accurate survival probability. Similar results were also observed in the validation cohort. CONCLUSION: We developed and verified a novel nomogram that can help clinicians recognize high-risk patients with C-SCLC and predict their OS.

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.

Tumor Mutation Burden, Immune Cell Infiltration, and Construction of Immune-Related Genes Prognostic Model in Head and Neck Cancer.

Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide, and the prognosis of HNSCC remains bleak. Numerous studies revealed that the tumor mutation burden (TMB) could predict the survival outcomes of a variety of tumors. Objectives: This study aimed to investigate the TMB and immune cell infiltration in these patients and construct an immune-related genes (IRGs) prognostic model. Methods: The expression data of 546 HNSCC patients were obtained from The Cancer Genome Atlas (TCGA) database. All patients were divided into high- and low- TMB groups, and the relationship between TMB and clinical relevance was further analyzed. The differentially expressed genes (DEGs) were identified using the R software package, limma. Functional enrichment analyses were conducted to identify the significantly enriched pathways between two groups. CIBERSORT algorithm was adopted to calculate the abundance of 22 leukocyte subtypes. The IRGs prognostic model was constructed via the multivariate Cox regression analysis. Results: Missense mutation and single nucleotide variants (SNV) were the most predominant mutation types in HNSCC. TP53, TTN, and FAT1 were the most frequently mutated genes. Patients with high TMB were observed with worse survival outcomes. The functional analysis of TMB associated DEGs showed that the identified DEGs mainly involved in spliceosome, RNA degradation, proteasome, and RNA polymerase pathways. We observed that macrophages, T cells CD8, and T cells CD4 memory were the most commonly infiltrated subtypes of immune cells in HNSCC. Finally, an IRGs prognostic model was constructed, and the AUC of the ROC curve was 0.635. Conclusions: Our results suggest that high TMB is associated with poor prognosis in HNSCC patients. The constructed model has potential prognostic value for the prognosis of these individuals, and it needs to be further validated in large-scale and prospective studies.

Nosocomial infections due to multidrug-resistant bacteria in cancer patients: a six-year retrospective study of an oncology Center in Western China.

BACKGROUND: Bacterial infections are the most frequent complications in patients with malignancy, and the epidemiology of nosocomial infections among cancer patients has changed over time. This study aimed to evaluate the characteristics, antibiotic resistance patterns, and prognosis of nosocomial infections due to multidrug-resistant (MDR) bacteria in cancer patients. METHODS: This retrospective observational study analyzed cancer patients with nosocomial infections caused by MDR from August 2013 to May 2019. The extracted clinical data were recorded in a standardized form and compared based on the survival status of the patients after infection and during hospitalization. The data were analyzed using independent samples t-test, Chi-square test, and binary logistic regression. P-values < 0.05 were considered significant. RESULTS: One thousand eight patients developed nosocomial infections during hospitalization, with MDR strains detected in 257 patients. Urinary tract infection (38.1%), respiratory tract infection (26.8%), and bloodstream infection (BSI) (12.5%) were the most common infection types. Extended-spectrum ß-lactamase producing Enterobacteriaceae (ESBL-PE) (72.8%) members were the most frequently isolated MDR strains, followed by Acinetobacter baumannii (11.7%), and Stenotrophomonas maltophilia (6.2%). The results of multivariate regression analysis revealed that smoking history, intrapleural/abdominal infusion history within 30 days, the presence of an indwelling urinary catheter, length of hospitalization, and hemoglobin were independent factors for in-hospital mortality in the study population. The isolated MDR bacteria exhibited high rates of sensitivity to amikacin, meropenem, and imipenem. CONCLUSIONS: The burden of nosocomial infections due to MDR bacteria is considerably high in oncological patients, with ESBL-PE being the most predominant causative pathogen. Our findings suggest that amikacin and carbapenems actively against more than 89.7% of MDR isolates. The precise management of MDR bacterial infections in cancer patients may improve the prognosis of these individuals.

Epithelial-mesenchymal transition induced cancer-stem-cell-like characteristics in hepatocellular carcinoma.

Hepatocellular carcinoma in China accounts for half of the world's incidence. Both epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) are thought to be involved in tumor malignant progression. However, the relationship between EMT and CSCs is still unclear. Bioinformatics analysis was performed to evaluate the relationship between EMT and CSCs. The EMT and CSC regulatory mechanism was investigated through Transwell, wound-healing, sphere formation, colony-forming, and western blotting assays. Immunofluorescence and immunoprecipitation were used to study the interaction of hypoxia inducible factor 1α (HIF-1α) /Notch1. Immunohistochemical study was applied to investigate the expression pattern in the process of hepatocellular carcinogenesis and development. In our present study, bioinformatics results indicate that the expression of EMT-related molecules is correlated with CSCs. In vitro studies indicated that EMT activation could induce CSC characteristics. Notch1 was confirmed to mediate the process of EMT-induced CSCs through the interaction with HIF-1α directly. Our findings indicate that EMT could induce CSC-like characteristics, which is mediated by HIF-1α-upregulated Notch intracellular domain expression.

MicroRNA-760 Inhibits Doxorubicin Resistance in Hepatocellular Carcinoma through Regulating Notch1/Hes1-PTEN/Akt Signaling Pathway.

Accumulating studies have suggested that microRNA-760 (miR-760) plays an important role in chemoresistance of various cancer cells. However, whether miR-760 regulates the chemoresistance of hepatocellular carcinoma (HCC) remains unclear. In this study, we found that miR-760 was decreased in HCC cell lines, and doxorubicin (Dox) treatment significantly decreased miR-760 expression in HCC cells. Overexpression of miR-760 sensitized HCC cells to Dox-induced cytotoxicity and apoptosis, whereas miR-760 inhibition showed the opposite effects. Notch1 was predicted as a target gene of miR-760. miR-760 negatively regulated Notch1 expression and Notch1/Hes1 signaling. Overexpression of miR-760 increased PTEN expression and decreased the phosphorylation of Akt. Activation of Notch signaling significantly reversed the inhibitory effect of miR-760 on Dox-resistance and abrogated the effect of miR-760 on the PTEN/Akt signaling pathway in HCC cells. Overall, our results demonstrate that miR-760 inhibits Dox-resistance in HCC cells through inhibiting Notch1 and promoting PTEN expression.

SET7/9 inhibits oncogenic activities through regulation of Gli-1 expression in breast cancer.

SET7/9 is a protein lysine methyltransferase that had been initially identified as a histone lysine methyltransferase which generates monomethylation at histone 3 lysine 4. Different functions were attributed to the protein methylation mediated by SET7/9. In this study, we found that the expression of SET7/9 declined in a majority of the human breast cancer tissues examined compared with normal tissues. Knockdown of SET7/9 promoted the proliferation, migration, and invasion of breast cancer cells. Knockdown of SET7/9 also increased the tumorigenicity of breast cancer cells in vivo. On the contrary, overexpression of SET7/9 in breast cancer cells inhibited these processes. Microarray analysis indicated that Gli-1 may play function as a downstream factor of SET7/9. Overexpression of SET7/9SET7/9 inhibits Gli-1 expression. While knockdown of SET7/9 promotes the expression of Gli-1. Gli-1 inhibited by cyclopamine blocked knockdown SET7/9-driven proliferation, migration, and invasion in breast cancer cell. Furthermore, Gli-1 expression in human breast cancer tissues is negatively correlated with SET7/9 expression. Together, these results helped to realize the antioncogene functions of SET7/9 in breast cancer cells and provided a novel direction to treat breast cancer.

Associations of components of PTEN/AKT/mTOR pathway with cancer stem cell markers and prognostic value of these biomarkers in hepatocellular carcinoma.

AIM: We aimed to investigate the associations between components of the phosphatase and tensin homolog deleted on chromosome 10/protein kinase B/mammalian target of rapamycin (PTEN/AKT/mTOR) pathway and liver cancer stem cell (LCSC) markers, including CD133, CD90, CD44, and epithelial cell adhesion molecule (EpCAM), and to further evaluate the predictive values of these biomarkers for recurrence and survival in hepatocellular carcinoma (HCC). METHOD: Protein expressions and mRNA levels of PTEN and LCSC markers were determined in 110 HCC tissues and 98 adjacent non-tumor tissues. Protein expressions of phosphorylated AKT (p-AKT) and phosphorylated mTOR (p-mTOR) were detected to evaluate the activation of the PTEN/AKT/mTOR pathway by using immunohistochemistry. Prognostic significance was analyzed by univariate and multivariate analysis. RESULTS: Loss of PTEN expression was negatively correlated with positive expression of CD133, CD90, and EpCAM (P < 0.05). Positive expression of p-AKT and p-mTOR were positively associated with positive expression for CD133, CD90, and EpCAM (P < 0.05). By univariate and multivariate analysis, a higher level of α-fetoprotein, loss of PTEN expression, and CD133-positive, p-AKT-positive, p-mTOR-positive, and EpCAM-positive signals were predictors for HCC recurrence, whereas advanced TNM stage, loss of PTEN expression, and positive expression of p-AKT, p-mTOR, and CD133 were predictors for survival. Patients with PTEN- /CD133+ or PTEN- /EpCAM+ HCC had shorter recurrence-free survival and overall survival times. CONCLUSION: The PTEN/AKT/mTOR pathway might play a crucial role in driving recurrence and influencing prognosis in HCC. There could be a potential repressive relationship between components of the PTEN/AKT/mTOR pathway and LCSCs. The combination of PTEN with CD133 or EpCAM expression may serve as a screening tool to monitor recurrence and predict prognosis.

Tripartite motif 16 inhibits epithelial-mesenchymal transition and metastasis by down-regulating sonic hedgehog pathway in non-small cell lung cancer cells.

The present study was to examine the effect of Tripartite motif 16 (TRIM16) on epithelial-mesenchymal transition (EMT) and metastasis in non-small cell lung cancer (NSCLC) cells, and its clinical significance in NSCLC. The correlation of TRIM16 expression and clinical features of NSCLC was analyzed in paraffin-embedded archived normal lung tissues and NSCLC tissues by immunohistochemical analysis. The effect of TRIM16 on EMT and metastasis was examined both in vitro and in vivo. The expression of TRIM16 was markedly decreased in NSCLC and correlated with tumor metastasis. Upregulation of TRIM16 significantly inhibited EMT and metastasis of NSCLC cells. In contrast, silencing TRIM16 expression significantly promoted the EMT and metastasis of NSCLC cells both in vitro and in vivo. Moreover, we demonstrated that downregulation of TRIM16 activated the sonic hedgehog pathway, and that inhibition of the sonic hedgehog pathway by cyclopamine abrogated the effect of TRIM16-downregulation induced EMT and metastasis on NSCLC cells. Our results suggest that TRIM16 is a potential pharmacologic target for the treatment of NSCLC and promotion TRIM16 expression might represent a novel strategy to NSCLC metastasis.

GATA6 is overexpressed in breast cancer and promotes breast cancer cell epithelial-mesenchymal transition by upregulating slug expression.

Metastasis is the leading cause of death in breast cancer (BC) patients. However, until now, the mechanisms of BC metastasis remain elusive. GATA6 is a member of the GATA transcription factor family that plays critical regulatory roles in tissue development, which has been proposed as an oncogene in many types of tumors; however, its role and underlying mechanisms in BC remain unclear. Here we show that GATA6 is elevated in BC and its expression level is positively correlated with metastasis. In addition Kaplan-Meier survival analysis showed that high expression of GATA6 was associated with decreased overall survival of BC patients. Overexpression of GATA6 in BC cells increased epithelial-mesenchymal transition. In contrast, silencing GATA6 in aggressive BC cells inhibited this process. Mechanistically, we found GATA6 exerts its function through active slug transcription. Slug knockdown blocked the GATA6-driven EMT. Furthermore, slug expression in human BC is positively correlated with GATA6 expression. Our results, for the first time, portray a pivotal role of GATA6 in regulating metastatic behaviors of BC cells, suggesting GATA6 is a potential therapeutic target in metastatic BCs.

The role of cytoplasmic p57 in invasion of hepatocellular carcinoma.

BACKGROUND: Our previous research suggested that p57 downregulation could accelerate the growth and invasion of hepatocellular carcinoma in vitro and in vivo. AIM: To evaluate the role of cytoplasmic p57 and its regulatory mechanism during hepatocellular carcinoma invasion. METHODS: We examined the subcellular localization of p57 by immunohistochemistry in 45 pairs of cancerous tissues and adjacent non-cancerous tissues. Moreover, we generated stable p57 knockdown hepatoma cell lines to investigate the mechanism of cytoplasmic p57-mediated regulation of invasion by immunoprecipitation, confocal immunofluorescence microscopy and western blot of nuclear and cytoplasmic extracts. RESULTS: Our results showed that cytoplasmic expression of p57 was reduced in specimens from patients with capsular invasion and metastasis (P < 0.05). Moreover, the level of p-cofilin was decreased in the group lacking cytoplasmic p57 expression (P < 0.05). Co-expression of p57 and p-cofilin was reduced in specimens from patients with tumors at later stages (III + IV), tumors showing capsular invasion and metastatic tumors. We further observed that p57 downregulation decreased the assembly of p57 and LIM domain kinase 1 and its kinase activity, subsequently reducing the level of p-cofilin in the cytoplasm. CONCLUSIONS: Cytoplasmic p57 might be a key regulator in hepatocellular carcinoma invasion via the LIM domain kinase 1/p-cofilin pathway.

[Retracted] Tripartite motif 16 suppresses breast cancer stem cell properties through regulation of Gli­1 degradation via the ubiquitin­proteasome pathway.

Following the publication of the above paper, it was drawn to the Editors' attention by a concerned reader that the data obtained from sphere­forming assay experiments shown in Figs. 4C­F and 8B and C, and western blotting data in Figs. 4A and 8A, were strikingly similar to data appearing in different form in other articles by different authors from different research institutes that had already been published, one of which has been retracted. Moreover, a pair of data panels comparing between Fig. 4E and 8C were partly overlapping, such that these data appear to have been derived from the same original source. Owing to the fact that the contentious data in the above article had already been published elsewhere prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 35: 1204­1212, 2016; DOI: 10.3892/or.2015.4437].

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.

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.

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.

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.