Targeting the MCP-GPX4/HMGB1 Axis for Effectively Triggering Immunogenic Ferroptosis in Pancreatic Ductal Adenocarcinoma.

Induction of ferroptosis can inhibit cancer cells in vitro, however, the role of ferroptosis in treatment in vivo is controversial. The immunosuppressive cells activated by the ferroptotic tumor cells can promote the growth of residual tumor cells, hindering the application of ferroptosis stimulation in tumor treatment. In this study, a new strategy is aimed to be identified for effectively triggering immunogenic ferroptosis in pancreatic ductal adenocarcinoma (PDAC) and simultaneously stimulating antitumor immune responses. Toward this, several molecular and biochemical experiments are performed using patient-derived organoid models and a KPC mouse model (LSL-KrasG12D /+, LSL-Trp53R172H/+, Pdx-1-Cre). It is observed that the inhibition of macrophage-capping protein (MCP) suppressed the ubiquitin fold modifier (UFM)ylation of pirin (PIR), a newly identified substrate of UFM1, thereby decreasing the transcription of GPX4, a marker of ferroptosis, and promoting the cytoplasmic transportation of HMGB1, a damage-associated molecular pattern. GPX4 deficiency triggered ferroptosis, and the pre-accumulated cytosolic HMGB1 is released rapidly. This altered release pattern of HMGB1 facilitated the pro-inflammatory M1-like polarization of macrophages. Thus, therapeutic inhibition of MCP yielded dual antitumor effects by stimulating ferroptosis and activating antitumor pro-inflammatory M1-like macrophages. The nanosystem developed for specifically silencing MCP is a promising tool for treating PDAC.

A Novel Trojan Horse Nanotherapy Strategy Targeting the cPKM-STMN1/TGFB1 Axis for Effective Treatment of Intrahepatic Cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is characterized by its dense fibrotic microenvironment and highly malignant nature, which are associated with chemotherapy resistance and very poor prognosis. Although circRNAs have emerged as important regulators in cancer biology, their role in ICC remains largely unclear. Herein, a circular RNA, cPKM is identified, which is upregulated in ICC and associated with poor prognosis. Silencing cPKM in ICC cells reduces TGFB1 release and stromal fibrosis, inhibits STMN1 expression, and suppresses ICC growth and metastasis, moreover, it also leads to overcoming paclitaxel resistance. This is regulated by the interactions of cPKM with miR-199a-5p or IGF2BP2 and by the ability of cPKM to stabilize STMN1/TGFB1 mRNA. Based on these findings, a Trojan horse nanotherapy strategy with co-loading of siRNA against cPKM (si-cPKM) and paclitaxel (PTX) is developed. The siRNA/PTX co-loaded nanosystem (Trojan horse) efficiently penetrates tumor tissues, releases si-cPKM and paclitaxel (soldiers), promotes paclitaxel sensitization, and suppresses ICC proliferation and metastasis in vivo. Furthermore, it alleviates the fibrosis of ICC tumor stroma and reopens collapsed tumor vessels (opening the gates), thus enhancing the efficacy of the standard chemotherapy regimen (main force). This novel nanotherapy provides a promising new strategy for ICC treatment.

Does the number of cycles of neoadjuvant therapy affect the efficacy of neoadjuvant chemoimmunotherapy for non-small cell lung cancer in locally advanced stage? Retrospective experience based on a single center.

BACKGROUND: The number of cycles of neoadjuvant therapy programmed cell death 1 (PD-1) inhibitor for locally advanced non-small cell lung cancer (NSCLC) remains controversial. METHODS: From October 2019 to March 2022, neoadjuvant chemoimmunotherapy followed by radical surgery for NSCLC patients with stage II-III were retrospectively reviewed in Shanghai Pulmonary Hospital. The radiologic response was assessed according to the Response Evaluation Criteria for Solid Tumors version 1.1. The major pathological response was defined as no more than 10% residual tumor. Student's t-test, chi-square test, and Mann-Whitney test were used for univariate analysis, logistic regression analysis was used for multivariate analysis. All statistical analyses were calculated by SPSS software (version 26). RESULTS: Among 108 patients, the number of patients who received 2-cycle (2-cycle group) and more than 2-cycle (>2-cycle group) neoadjuvant chemoimmunotherapy were 75 (69.4%) and 33 (30.6%), respectively. Compared with patients in the >2-cycle group, patients in the 2-cycle group had significantly smaller diagnostic radiological tumor size (37.0 mm vs. 49.6 mm, p = 0.022) and radiological tumor regression rate (36% vs. 49%, p = 0.007). However, no significant difference in pathological tumor regression rate was observed between patients in the 2-cycle group and >2-cycle group. Further logistic regression analysis demonstrated that the neoadjuvant chemoimmunotherapy cycle could independently affect the radiographic response (odds ratio [OR]: 0.173, 95% confidence interval [CI]: 0.051-0.584, p = 0.005) but not for pathological response (OR: 0.450, 95% CI: 0.161-1.257, p = 0.127). CONCLUSIONS: For patients diagnosed with stage II-III NSCLC, the number of neoadjuvant cycles administered can significantly influence the radiographic efficacy of chemoimmunotherapy.

Development and validation of nomogram prognostic model for early-stage T1-2N0M0 small cell lung cancer: A population-based analysis.

Background: Survival outcomes of early-stage T1-2N0M0 small cell lung cancer (SCLC) patients differ widely, and the existing Veterans Administration Lung Study Group (VALSG) or TNM staging system is inefficient at predicting individual prognoses. In our study, we developed and validated nomograms for individually predicting overall survival (OS) and lung cancer-specific survival (LCSS) in this special subset of patients. Methods: Data on patients diagnosed with T1-2N0M0 SCLC between 2000 and 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. All enrolled patients were split into a training cohort and a validation cohort according to the year of diagnosis. Using multivariable Cox regression, significant prognostic factors were identified and integrated to develop nomograms for 1-, 3-, and 5-year OS and LCSS prediction. The prognostic performance of our new model was measured by the concordance index (C-index) and calibration curve. We compared our latest model and the 8th AJCC staging system using decision curve analyses (DCA). Kaplan-Meier survival analyses were applied to test the application of the risk stratification system. Results: A total of 1,147 patients diagnosed from 2000 to 2011 were assigned to the training cohort, and 498 cases that were diagnosed from 2012 to 2015 comprised the validation cohort. Age, surgery, lymph node removal (LNR), and chemotherapy were independent predictors of LCSS. The variables of sex, age, surgery, LNR, and chemotherapy were identified as independent predictors of OS. The above-mentioned prognostic factors were entered into the nomogram construction of OS and LCSS. The C-index of this model in the training cohort was 0.663, 0.702, 0.733, and 0.658, 0.702, 0.733 for predicting 1-, 3-, and 5-year OS and LCSS, respectively. Additionally, in the validation cohort, there were 0.706, 0.707, 0.718 and 0.712, 0.691, 0.692. The calibration curve showed accepted prediction accuracy between nomogram-predicted survival and actual observed survival, regardless of OS or LCSS. In addition, there were significant distinctions in the survival curves of OS and LCSS between different risk groups stratified by prognostic scores. Compared with the 8th AJCC staging system, our new model also improved net benefits. Conclusions: We developed and validated novel nomograms for individual prediction of OS and LCSS, integrating the characteristics of patients and tumors. The model showed superior reliability and may help clinicians make treatment strategies and survival predictions for early-stage T1-2N0M0 SCLC patients.

The role of surgery in older patients with T1-2N0M0 small cell lung cancer: A propensity score matching analysis.

Background: Surgical resection could improve the survival of patients with early-stage small cell lung cancer (SCLC). However, there is a lack of dedicated studies concentrating on surgical treatment in older patients with T1-2N0M0 SCLC. Thus, we performed this population-based study to investigate whether older patients with T1-2N0M0 SCLC could benefit from surgery. Methods: We collected the data of patients with SCLC between 2000 and 2015 from the Surveillance, Epidemiology, and End Results Program database. Older patients (≥ 65 years) with T1-2N0M0 SCLC were included, and we converted the staging information into those of the eighth edition. The propensity score matching (PSM) was used to balance the distribution of clinical characteristics between surgery and no-surgery groups. Results: Before PSM, the distribution proportions of clinical characteristics in 1,229 patients were unbalanced. The Kaplan-Meier curves of overall survival (OS) and cancer-specific survival (CSS) showed that the patients in the surgery group were better than those in the non-surgery group (all P < 0.001). After 1:2 PSM, the distribution proportions of clinical characteristics in 683 patients were balanced (all P > 0.05). The OS and CSS of patients in the surgery group were still better than that of patients in the no-surgery group (all P < 0.001), and subgroup analysis showed that the surgery was a protective factor for OS and CSS in all clinical characteristics subgroups (almost P < 0.001). The multivariate Cox analysis further confirmed this result (OS: HR, 0.33; 95% CI, 0.27-0.39; P < 0.001; CSS: HR, 0.29; 95% CI, 0.23-0.36; P < 0.001). The result of subgroup analysis based on age, T stage, and adjuvant therapy showed that surgery was related to better OS and CSS compared with non-surgery group (almost P < 0.001) and that lobectomy exhibited the longer survival than sublobectomy. Age, sex, and race were the independent prognostic factors for OS in patients undergoing surgery, whereas only the factor of age affects the CSS in patients with surgery. Conclusions: Older patients with T1-2N0M0 SCLC can benefit significantly from surgical treatment, and lobectomy provides better prognosis than sublobectomy.

Surgical Options for Resectable Lung Adenosquamous Carcinoma: A Propensity Score-Matched Analysis.

Background: Surgery is the primary treatment option for Lung adenosquamous carcinoma (ASC) patients. However, no study compares the benefits of lobectomy and sublobar resection in ASC patients. Methods: A total of 1379 patients in the Surveillance, epidemiology, and End Results (SEER) database and 466 patients in Shanghai Pulmonary Hospital (SPH) were enrolled. Survival benefits were evaluated after possible confounders were eliminated by propensity score matching (PSM). Results: After 1:3 PSM, 463 SEER database patients and 244 SPH patients were enrolled. Lobectomy was associated with better overall survival (OS) and disease-free survival (DFS) than sublobar resection for ASC patients (5-year OS of SEER: 46.9% vs. 33.3%, P =0.017; 5-year OS of SPH: 35.0% vs. 16.4%, P =0.002; 5-year DFS of SPH: 29.5% vs. 14.8%, P =0.002). Similar results were observed in stage I patients. Univariate and multivariate Cox regression analyses showed that sublobar resection was an adverse prognostic factor independently (SEER: HR: 1.40, 95%CI: 1.08-1.81, P =0.012; SPH: HR: 1.73, 95%CI: 1.11-2.70, P =0.015). Subgroup analysis showed that all of the ASC patient subtypes tended to benefit more from lobectomy than sublobar resection. Conclusions: Lobectomy remains the primary option for ASC patients compared to sublobar resection, including stage I.

Prognostic value of surgical intervention in advanced lung adenocarcinoma: a population-based study.

BACKGROUND: Surgical intervention is generally not considered as a treatment option in patients with advanced non-small cell lung cancer (NSCLC). Accumulating data suggest that surgery may have beneficial effects for these advanced patients. However, no evidence supports the significance of primary tumor resection (PTR) and metastatic tumor resection (MTR) in patients with stage IV lung adenocarcinoma (LUAD). METHODS: A total of 32,497 patients diagnosed with primary stage IV LUAD were selected through the Surveillance, Epidemiology, and End Results (SEER) database. Possible confounders were eliminated by propensity score matching (PSM). The overall survival (OS) and lung cancer-specific survival (LCSS) were estimated as the primary endpoints. Furthermore, the independent prognostic factors of patients with the surgical intervention were retrospectively analyzed. RESULTS: Patients underwent surgical intervention had better OS and LCSS than those who did not (P=0.001 for OS; P<0.001 for LCSS). Meanwhile, patients who underwent surgery combined with lymph node dissection had better survival outcomes (P<0.001 for OS and LCSS) in the K-M analysis. For different metastatic sites, PTR was beneficial to the survival of patients with isolated lung metastases (LUM) and multiple organ metastases (MOM) (LUM: P=0.041; MOM: P=0.003). As for metastatic surgery, no patients were found to benefit from resection of metastatic tumor [bone metastasis (BOM): P=0.696; brain metastasis (BRM): P=0.951; LUM: P=0.402; MOM: P=0.365]. CONCLUSIONS: Surgical intervention strategies can prolong survival to some extent, depending on different sites of metastasis and highly selected patients.