Special issue “The advance of solid tumor research in China”: Prediction of Sunitinib efficacy using computed tomography in patients with pancreatic neuroendocrine tumors

Clinically effective methods to predict the efficacy of sunitinib, for patients with metastatic or locally advanced pancreatic neuroendocrine tumors (panNET) are scarce, making precision treatment difficult. This study aimed to develop and validate a computed tomography (CT)-based method to predict the efficacy of sunitinib in patients with panNET. Pretreatment CT images of 171 lesions from 38 patients with panNET were included. CT value ratio (CT value of tumor/CT value of abdominal aorta from the same patient) and radiomics features were extracted for model development. Receiver operating curve (ROC) with area under the curve (AUC) and decision curve analysis (DCA) were used to evaluate the proposed model. Tumor shrinkage of >10% at first follow-up after sunitinib treatment was significantly associated with longer progression-free survival (PFS; P < .001) and was used as the major treatment outcome. The CT value ratio could predict tumor shrinkage with AUC of 0.759 (95% confidence interval [CI], 0.685-0.833). We then developed a radiomics signature, which showed significantly higher AUC in training (0.915; 95% CI, 0.866-0.964) and validation (0.770; 95% CI, 0.584-0.956) sets than CT value ratio. DCA also confirmed the clinical utility of the model. Subgroup analysis showed that this radiomics signature had a high accuracy in predicting tumor shrinkage both for primary and metastatic tumors, and for treatment-naive and pretreated tumors. Survival analysis showed that radiomics signature correlated with PFS (P = .020). The proposed radiomics-based model accurately predicted tumor shrinkage and PFS in patients with panNET receiving sunitinib and may help select patients suitable for sunitinib treatment.     

Special issue “The advance of solid tumor research in China”: Participants with a family history of cancer have a higher participation rate in low-dose computed tomography for lung cancer screening

We aimed to determine participation in low-dose computed tomography (LDCT) of individuals with a family history of common cancers in a population-based screening program to provide timely evidence in high-risk populations in China. The analysis was conducted using data from the Cancer Screening Program in Urban China (CanSPUC), which recruited 282 377 participants aged 40 to 74 years from eight cities in the Henan province. Using the CanSPUC risk score system, 55 428 participants were evaluated to have high risk for lung cancer and were recommended for LDCT. We calculated the overall and group-specific participation rates using family history of common cancers and compared differences in participation rates between different groups. Odds ratios (ORs) and 95% confidence intervals were derived by multivariable logistic regression. Of the 55 428 participants, 22 260 underwent LDCT (participation rate, 40.16%). Family history of lung, esophageal, stomach, liver and colorectal cancer was associated with increased participation in LDCT screening. The odds of participants with a family history of one, two, three and four or more cancer cases undergoing LDCT screening were 1.9, 2.7, 2.8 and 3.5 times, respectively, than those without a family history of cancer. Compared to those without a history of cancer, participation in LDCT gradually increased as the number of cancer cases in the family increased (P < .001). Our findings suggest that there is room for improvement in lung cancer screening given the relatively low participation rate. Lung cancer screening in populations with a family history of cancer may improve efficiency and cost-effectiveness; however, this requires further verification.     

Special issue “The advance of solid tumor research in China”: Discoidin domain receptor 2 promotes colorectal cancer metastasis by regulating epithelial mesenchymal transition via activating AKT signaling

Tumor metastasis is one of the main reasons for the high mortality rate associated with colorectal cancer (CRC). However, its underlying mechanisms have not been fully understood. Here, we reported that the expression of discoidin domain receptor 2 (DDR2) was significantly upregulated in CRC tissues compared to that in normal adjacent tissues. The expression level of DDR2 was negatively associated with prognosis of CRC patients. Therefore, DDR2 may play an oncogenic role in CRC development. Furthermore, DDR2 induced epithelial mesenchymal transition in CRC cells and regulated their invasive and metastatic capacity in vitro and in vivo. Mechanistically, increased DDR2 expression level activated the AKT/GSK-3β/Slug signaling pathway. In conclusion, these findings showed that DDR2 promoted CRC metastasis and DDR2 inhibition might represent an effective therapeutic strategy for local advanced and metastatic CRC treatment.     

Special issue “The advance of solid tumor research in China”: Prognosis prediction for stage II colorectal cancer by fusing computed tomography radiomics and deep-learning features of primary lesions and peripheral lymph nodes

Currently, the prognosis assessment of stage II colorectal cancer (CRC) remains a difficult clinical problem; therefore, more accurate prognostic predictors must be developed. In our study, we developed a prognostic prediction model for stage II CRC by fusing radiomics and deep-learning (DL) features of primary lesions and peripheral lymph nodes (LNs) in computed tomography (CT) scans. First, two CT radiomics models were built using primary lesion and LN image features. Subsequently, an information fusion method was used to build a fusion radiomics model by combining the tumor and LN image features. Furthermore, a transfer learning method was applied to build a deep convolutional neural network (CNN) model. Finally, the prediction scores generated by the radiomics and CNN models were fused to improve the prognosis prediction performance. The disease-free survival (DFS) and overall survival (OS) prediction areas under the curves (AUCs) generated by the fusion model improved to 0.76 ± 0.08 and 0.91 ± 0.05, respectively. These were significantly higher than the AUCs generated by the models using the individual CT radiomics and deep image features. Applying the survival analysis method, the DFS and OS fusion models yielded concordance index (C-index) values of 0.73 and 0.9, respectively. Hence, the combined model exhibited good predictive efficacy; therefore, it could be used for the accurate assessment of the prognosis of stage II CRC patients. Moreover, it could be used to screen out high-risk patients with poor prognoses, and assist in the formulation of clinical treatment decisions in a timely manner to achieve precision medicine.     

Special issue “The advance of solid tumor research in China”: 68Ga-PSMA-11 PET/CT for evaluating primary and metastatic lesions in different histological subtypes of renal cell carcinoma

Conventional imaging examinations are not sensitive enough for the early detection of recurrent or metastatic lesions in renal cell carcinoma (RCC) patients. We aimed to explore the role of ⁶⁸Ga-prostate specific membrane antigen (PSMA)-11 positron emission tomography (PET)/computed tomography (CT) in the detection of primary and metastatic lesions in such patients. We retrospectively analyzed 50 RCC patients who underwent ⁶⁸Ga-PSMA-11 PET/CT from November 2017 to December 2020. We observed a higher median accuracy and tumor-to-background maximum standard uptake value (SUV_max) ratio (TBR) of ⁶⁸Ga-PSMA-11 PET/CT in clear cell RCC (ccRCC; 96.57% and 6.00, respectively) than in non-clear cell RCC (ncRCC; 82.05% and 2.99, respectively). The accuracies in detecting lesions in the renal region, bone, lymph nodes and lungs in ccRCC were 100.00%, 95.00%, 98.08% and 75.00%, respectively, and those in the renal region, bone and lymph nodes in ncRCC were 100.00%, 86.67% and 36.36%, respectively. The median TBRs of the lesions from the above locations were 0.38, 10.96, 6.69 and 13.71, respectively, in ccRCC and 0.13, 4.02 and 0.73, respectively, in ncRCC. The PSMA score evaluated with immunohistochemistry was correlated with the SUV_max (P = .046) in RCC. Higher PSMA scores were observed in ccRCC than in ncRCC (P = .031). ⁶⁸Ga-PSMA-11 PET/CT resulted in changes in clinical management in 12.9% (4/31) of cases because of the discovery of new metastases not detected with conventional imaging. These results indicate that ⁶⁸Ga-PSMA-11 PET/CT is a promising method for the detection of metastatic lesions in ccRCC, especially for those in the bone and lymph nodes.     

Special issue “The advance of solid tumor research in China”: Multi-omics analysis based on 1311 clear cell renal cell carcinoma samples identifies a glycolysis signature associated with prognosis and treatment response

In clear cell renal cell carcinoma (ccRCC), glycolysis is enhanced mainly because of the increased expression of key enzymes in glycolysis. Hence, the discovery of new molecular biomarkers for glycolysis may help guide and establish a precise system of diagnosis and treatment for ccRCC. Expression profiles of 1079 tumor samples of ccRCC patients (including 311 patients treated with everolimus or nivolumab) were downloaded from public databases. Proteomic profiles of 232 ccRCC samples were obtained from Fudan University Shanghai Cancer Center (FUSCC). Biological changes, tumor microenvironment and prognostic differences were explored between samples with various glycolysis characteristics. There were significant differences in CD8⁺ effector T cells, epithelial-to-mesenchymal transition and pan-fibroblast TGFb between the Low and High glyScore groups. The tumor mutation burden of the Low glyScore group was lower than that of the High glyScore group. And higher glyScore was significantly associated with worse overall survival (OS) in 768 ccRCC patients (P < .0001). External validation in FUSCC cohort also indicated that glyScore was of strong ability for predicting OS (P < .05). GlyScore may serve as a biomarker for predicting everolimus response in ccRCC patients due to its significant associations with progression-free survival (PFS). And glyScore may also predict overall survival in patients treated with nivolumab. We calculated the glyScore in ccRCC and the defined glyScore was of strong ability for predicting OS. In addition, glyScore may also serve as a biomarker for predicting PFS in patients treated with everolimus and could predict OS in patients treated with nivolumab.     

Phase II study of everolimus–erlotinib in previously treated patients with advanced non-small-cell lung cancer

BackgroundPreclinical data suggest combining a mammalian target of rapamycin inhibitor with erlotinib could provide synergistic antitumor effects in advanced non-small-cell lung cancer (NSCLC).Patients and methodsIn this multicenter, open-label, phase II study, patients with advanced NSCLC that progressed after one to two previous chemotherapy regimens were randomized 1:1 to erlotinib 150 mg/day ± everolimus 5 mg/day. Primary end point was the disease control rate (DCR) at 3 months; secondary end points included progression-free survival (PFS) and safety.ResultsOne hundred thirty-three patients received everolimus–erlotinib (n = 66) or erlotinib alone (n = 67). The DCR at 3 months was 39.4% and 28.4%, respectively. The probability for the difference in disease control at 3 months to be ≥15% was estimated to be 29.8%, which was below the prespecified probability threshold of ≥40%. Median PFS was 2.9 and 2.0 months, respectively. Grade 3/4 adverse events occurred in 72.7% and 32.3% of patients, respectively. Grade 3/4 stomatitis was observed in 31.8% of combination therapy recipients.ConclusionsEverolimus 5 mg/day plus erlotinib 150 mg/day was not considered sufficiently efficacious per the predefined study criteria. The combination does not warrant further investigation based on increased toxicity and the lack of substantial improvement in disease stabilization.     

Hyperprogression under treatment with immune-checkpoint inhibitors in patients with gastrointestinal cancer: A natural process of advanced tumor progression?

Immunotherapy has shown great promise in treating various types of malignant tumors. However, some patients with gastrointestinal cancer have been known to experience rapid disease progression after treatment, a situation referred to as hyperprogressive disease (HPD). This minireview focuses on the definitions and potential mechanisms of HPD, natural disease progression in gastrointestinal malignancies, and tumor immunological microenvironment.     

Addition of cetuximab to first-line chemotherapy in patients with advanced non-small-cell lung cancer: a cost–utility analysis

BackgroundAdding cetuximab to standard chemotherapy results in a moderate increase of overall survival in patients with advanced non-small-cell lung cancer (NSCLC), but the cost-effectiveness is unknown.Materials and methodsA Markov model was constructed based on the results of the First-Line ErbituX in lung cancer randomized trial, adding cetuximab to cisplatin–vinorelbine first-line chemotherapy in patients with advanced NSCLC. The primary outcome was the incremental cost-effectiveness ratio (ICER) of adding cetuximab, expressed as cost per quality-adjusted life year (QALY) gained, and relative to a willingness-to-pay threshold of €60 000/QALY. The impact of cetuximab intermittent dosing schedules on the ICER was also evaluated.ResultsAdding cetuximab to standard chemotherapy leads to a gain of 0.07 QALYs per patient at an additional cost of €26 088. The ICER for adding cetuximab to chemotherapy was €376 205 per QALY gained. Intermittent cetuximab dosing schedules resulted in ICERs per QALY gained between €31 300 and €83 100, under the assumption of equal efficacy.ConclusionsFrom a health economic perspective, the addition of cetuximab to standard first-line chemotherapy in patients with epidermal growth factor receptor-expressing advanced NSCLC cannot be recommended to date, due to a high ICER compared with other health care interventions. Treatment schedules resulting in more favorable cost–utility ratios should be evaluated.     

ASAP3 expression in non-small cell lung cancer: association with cancer development and patients’ clinical outcome

ASAP3 belongs to Arf-specific GTPase-activating proteins which regulate Arfs by stimulating their intrinsic GTP hydrolysis. ASAP3 expression and the clinical significance in malignant tumors are largely unknown. In this study, we examined ASAP3 expression in non-small cell lung cancer (NSCLC) to find out its clinicopathological significance. Immunohistochemistry shows elevated expression of ASAP3 in cancer tissues (54.8 % (57/104)) compared to normal lung tissues (18.0 % (9/50)) (p?<?0.05). Increased ASAP3 expression was associated with poor differentiation, lymph node metastasis, and advanced TNM stages in NSCLC (p?<?0.05). Survival analysis reveals that ASAP3 expression contributes to patients’ poor clinical outcome (p?<?0.05). We also examined ASAP3 expression in several lung cancer cell lines using Western blotting. We downregulated ASAP3 expression in LTE cell which has a relative high level of ASAP3 expression using siRNA and found that reduced ASAP3 leads to significant inhibition of cancer cell invasion (p?<?0.05). These data indicate that ASAP3 is elevated in NSCLC and may contribute to cancer development and patients’ poor clinical outcome, which is possibly due to its critical roles in regulating cancer invasion.