Patient-derived tumor-like cell clusters for personalized chemo- and immunotherapies in non-small cell lung cancer.

Many patient-derived tumor models have emerged recently. However, their potential to guide personalized drug selection remains unclear. Here, we report patient-derived tumor-like cell clusters (PTCs) for non-small cell lung cancer (NSCLC), capable of conducting 100-5,000 drug tests within 10 days. We have established 283 PTC models with an 81% success rate. PTCs contain primary tumor epithelium self-assembled with endogenous stromal and immune cells and show a high degree of similarity to the original tumors in phenotypic and genotypic features. Utilizing standardized culture and drug-response assessment protocols, PTC drug-testing assays reveal 89% overall consistency in prospectively predicting clinical outcomes, with 98.1% accuracy distinguishing complete/partial response from progressive disease. Notably, PTCs enable accurate prediction of clinical outcomes for patients undergoing anti-PD1 therapy by combining cell viability and IFN-γ value assessments. These findings suggest that PTCs could serve as a valuable preclinical model for personalized medicine and basic research in NSCLC.

A Prediction Model for Postoperative Pulmonary Complication in Pulmonary Function-Impaired Patients Following Lung Resection.

PURPOSE: Most patients with lung cancer have impaired pulmonary function. Single pulmonary function parameters have been suggested as good indices for predicting postoperative pulmonary complications (PPC). The purpose of this retrospective study was to construct a prediction model, including more than one pulmonary function parameter, for better prediction of PPC in patients with lung cancer and impaired pulmonary function. PATIENTS AND METHODS: Our database of patients who underwent lung resection for non-small cell lung cancer was reviewed and those with impaired pulmonary function were enrolled. Clinical data, including PPC, were recorded. Univariate and logistic regression analyses were applied to explore potential predictors and a prediction model constructed based on the results of logistic regression. RESULTS: Patients with impaired pulmonary function (n = 124) were enrolled. Most patients were male, current smokers, >60 years old, and had adenocarcinoma and mild ventilatory dysfunction or diffusion dysfunction. In univariate analysis, we identified six pulmonary function parameters that differed significantly between the PPC and non-PPC groups. Receiver operating characteristic curves were used to determine the best cutoff values. In logistic regression, only forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC%), peak expiratory flow (PEF%), and post predictive operation (ppo)-FEV1% remained significant. Based on these results, we constructed a prediction model for PPC including FEV1/FVC%, PEF%, and ppo-FEV1%, which had an good diagnostic performance of, with 76.7% sensitivity and 67.6% specificity. CONCLUSION: Our prediction model, including the pulmonary function parameters, FEV1/FVC%, PEF%, and ppo-FEV1%, shows excellent performance for predicting PPC in patients with lung cancer and impaired pulmonary function following resection, and has potential for wide application in clinical practice.

The Clinical Value of Pulmonary Rehabilitation in Reducing Postoperative Complications and Mortality of Lung Cancer Resection: A Systematic Review and Meta-Analysis.

Background: Pulmonary rehabilitation is one meaningful way of improving exercise tolerance and pulmonary function. Thus, it may reduce the postoperative complications and mortality of pulmonary resection. Hence, we refreshed the data and conducted this systemic analysis. Method: We searched Pubmed, Web of Science, and EMBASE using "lung OR pulmonary" AND "operation OR resection OR surgery" AND "rehabilitation or exercise." The cut-off date was September 30, 2020. The publications were filtrated, and data were extracted from all selected studies by two reviewers. Review Manger 5.1 and the fixed or random regression model were used for calculating the pooled odds ratio (OR). Result: Finally, 13 publications were enrolled in this study. Among them, five publications reported mortality, nine reported postoperative complications, and seven reported postoperative pulmonary complications. The pooled OR of mortality was 1.32 [95% confidence interval (CI): 0.54-3.23] for the pulmonary rehabilitation group, the pooled OR of postoperative complications was 0.62 (95% CI: 0.49-0.79) for the pulmonary rehabilitation group, and the pooled OR of postoperative pulmonary complications was 0.39 (95% CI: 0.27-0.56) for the pulmonary rehabilitation group. Subgroup analysis revealed the perioperative pulmonary rehabilitation was the most important part. Conclusion: Pulmonary rehabilitation may not affect the mortality of pulmonary resection patients, however, it could decrease the number of postoperative complications, especially pulmonary complications. Perioperative pulmonary rehabilitation was the most important part of the program.

Using T stage and tumor thrombosis as predictive factors for patients with resected I-IIA small cell lung cancer: a retrospective study.

BACKGROUND: Surgery is recognized as an important part of treating stage I-IIA small cell lung cancer (SCLC), but few studies have explored the predictive factors for overall survival (OS) or time to tumor progression (TTP). This paper aims to explore the predictive factors related to improved overall and relapse-free survival. METHODS: Patients with stage I-IIA SCLC were reviewed between January 1st, 2014, and December 30th, 2016, at the Shanghai Chest Hospital. Basic patient characteristics and clinical data were collected, including age, sex, tumor (T) stage, pathological characteristics, and treatment. Patient follow-ups were conducted by checking medical records or phoning the patient, with survival data and instances of recurrence and/or metastasis being collected and recorded. Univariate and multivariate analyses were used to identify the predictive factors. RESULTS: A total of 59 patients were enrolled in this study, and the median follow-up duration was 53.7 months. The 3-year disease free and 3-year OS rates were 62.5% and 75.0%, respectively. The 5-year disease free and 5-year OS rates were not reached. Univariate and multivariate analyses revealed that a higher T stage [hazard ratio (HR) 3.210, P=0.048], the presence of tumor thrombosis (HR 6.021, P=0.043), and the absence of adjuvant chemotherapy (HR 3.425, P=0.059) were more reflective of shorter TTP than other factors, with the presence of adjuvant chemotherapy also correlating with improved OS. CONCLUSIONS: A patient having a T1 stage with no tumor thrombus and receiving adjuvant chemotherapy were observed as positive factors for longer periods of TTP, and adjuvant chemotherapy was a favorable predictor for the OS of patients with resected stage I-IIA SCLC.

A circulating tumor cell-based digital assay for the detection of EGFR T790M mutation in advanced non-small cell lung cancer.

Determining the status of epidermal growth factor receptor (EGFR) T790M mutation is crucial for guiding further treatment intervention in advanced non-small cell lung cancer (NSCLC) patients who develop acquired resistance to initial EGFR tyrosine kinase inhibitor (TKI) treatment. Circulating tumor cells (CTCs) which contain plentiful copies of well-preserved RNA offer an ideal source for noninvasive detection of T790M mutation in NSCLC. We developed a CTC-based digital assay which synergistically integrates NanoVelcro Chips for enriching NSCLC CTCs and reverse-transcription droplet digital PCR (RT-ddPCR) for quantifying T790M transcripts in the enriched CTCs. We collected 46 peripheral arterial and venous blood samples from 27 advanced NSCLC patients for testing this CTC-based digital assay. The results showed that the T790M mutational status observed by the CTC-based digital assay matched with those observed by tissue-based diagnostic methods. Furthermore, higher copy numbers of T790M transcripts were observed in peripheral arterial blood than those detected in the matched peripheral venous blood. In short, our results demonstrated the potential of the NanoVelcro CTC-digital assay for noninvasive detection of the T790M mutation in NSCLC, and suggested that peripheral arterial blood sampling may offer a more abundant CTC source than peripheral venous blood in advanced NSCLC patients.

Epidermal growth factor receptor-targeted immunomagnetic liposomes for circulating tumor cell enumeration in non-small cell lung cancer treated with epidermal growth factor receptor-tyrosine kinase inhibitors.

OBJECTIVES: To establish a circulating tumor cell (CTC) enrichment system for non-small cell lung cancer (NSCLC) patients who received first-line treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKI), using EGFR magnetic liposomes (EGFR-ML). MATERIALS AND METHODS: An inverted evaporation method was used to develop antibody modified EGFR-ML. Peripheral blood was collected from NSCLC patients who underwent first-line EGFR-TKI treatment for CTC enumeration. RESULTS: Protein electrophoresis, magnetic saturation curve, and ultraviolet absorption spectrum showed successful incorporation of the EGFR antibody on the surface of the magnetic microspheres, and the development of EGFR-ML was ascertained based on cell morphology and particle size. Using EGFR-ML, CTC were successfully enriched from blood samples and were identified in 77.3% (99/128) of the cohort. When compared to the 21L858R variant, EGFR-19del showed lower CTC counts by EGFR-ML (CTCEGFR). At one month after EGFR-TKI, a lower CTCEGFR was associated with partial response (PR) during treatment (CTCEGFR < 6 vs. ≥ 6/7.5 mL, 75% vs. 49%, P = 0.027). In addition, patients with a lower CTCEGFR at 3 months after EGFR-TKI achieved a longer progression-free survival (PFS) [CTCEGFR < 6 vs. ≥ 6/7.5 mL, 13 months vs. 10.4 months, HR = 2.4, P = 0.042]. CTCEGFR significantly increased at the time of RECIST-progressive disease (RECIST-PD). Representative cases showed that CTCEGFR might increase before and beyond RECIST-PD until no clinical benefit could be acquired from EGFR-TKI. CONCLUSION: We showed that establishing a CTC enrichment system by antibody modified EGFR-ML in NSCLC is feasible. CTC enumeration by EGFR-ML may have the potential to supplement RECIST in dynamically monitoring the response of NSCLC patients' to first-line EGFR-TKI.

Feasibility of continuing crizotinib therapy after RECIST-PD in advanced non-small cell lung cancer patients with ALK/ROS-1 mutations.

Objectives: To study whether ongoing clinical benefits of continuing anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) inhibition are achieved by crizotinib treatment post progressive disease (PD) in advanced non-small cell lung cancer (NSCLC) patients harboring ALK/ROS1 mutations. Materials and methods: Demographic and clinicopathologic parameters were collected from 38 patients who continued crizotinib therapy beyond Response Evaluation Criteria in Solid Tumors (RECIST)-defined PD and analyzed. After adjusting for potential confounding factors, factors influencing the time from RECIST-PD to crizotinib discontinuation (progress-free survival 2, PFS2) were analyzed. Results: The median time from first dose treatment to RECIST-PD (PFS1) was 9.6 months (95% CI 5.6-13.6 months). The estimated median PFS2 was 5.9 months (95% CI 0.1-11.7 months). Six- and twelve-month crizotinib treatment probabilities after initial PD were 42.1% (95% CI 25.7-58.6%) and 21.1% (95% CI 7.5-34.6%), respectively. Patients who demonstrated RECIST-PD due to new lesions had a longer median PFS2 compared to patients who were attested to enlargement of original lesions (10.0 versus 2.4 months, p = 0.009). The median PFS2 was numerically longer among patients who received local therapy compared to those who did not receive local therapy, however the difference was not significant (9.9 versus 4.2 months, p = 0.094). Multivariable Cox regression analysis showed that only the progression pattern [new lesions versus enlargement of original lesions, HR = 0.329 (95% CI 0.138-0.782), p = 0.012] remained an independent prognostic factor of PFS2. Conclusion: Continuation of crizotinib therapy after RECIST-PD in Chinese NSCLC patients with positive ALK/ROS1 mutations is feasible in clinical practice.

Krüppel-like factor 9 was down-regulated in esophageal squamous cell carcinoma and negatively regulated beta-catenin/TCF signaling.

Krüppel-like factor 9 (KLF9) has been found to play suppressive roles in several types of tumor. However, the expression pattern and biological functions of KLF9 in esophageal squamous cell carcinoma (ESCC) are still unknown. In this study, it was found that the expression of KLF9 was significantly down-regulated in ESCC compared to their adjacent normal esophageal tissues. Meanwhile, the expression of KLF9 was inversely correlated with the clinical features of ESCC patients. Moreover, in the biological function study, KLF9 was further validated to inhibit the growth, migration, and metastasis of ESCC cells in vitro and in vivo. Mechanistically, KLF9 bind with TCF4 and suppressed the beta-catenin/TCF signaling as well as the expression of its target gene Cyr61. Collectively, our study clarified the function of KLF9 in both ESCC progression and the regulation of beta-catenin/TCF signaling.