Brain parenchymal and leptomeningeal metastasis in non-small cell lung cancer.

Patients with advanced non-small cell lung cancer (NSCLC) are prone to brain metastases (BM), which essentially include brain parenchymal metastases (PM) and leptomeningeal metastases (LM). We conducted a retrospective study to comprehensively assess the clinical characteristics and risk factors of patients with advanced NSCLC who develop PM and LM. Patients with advanced NSCLC were enrolled. These patients were then divided into three groups for analysis: patients without BM (No-BM), patients with PM and patients with LM. Data on clinical characteristics of each patient at the time of diagnosis advanced NSCLC were extracted and analyzed. In addition, prediction models were developed and evaluated for PM and LM. A total of 592 patients were enrolled in the study. BM was present in 287 patients (48.5%). Among them, 185 and 102 patients had PM or LM. Patients with LM had a higher proportion of EGFR exon 21point mutations (L858R) compared to patients with No-BM and PM (p < 0.0001). The median time to the onset of PM and LM from the diagnosis of advanced NSCLC was 0 months and 8.3 months, respectively. Patients with LM had a statistically shorter over survival (OS) compared to either No-BM or PM patients (p < 0.0001). Based on independent predictive variables, two nomogram models were constructed to predict the development of PM and LM in advanced NSCLC patients, and the C-indexes were 0.656 and 0.767, respectively. Although both considered as BM, PM and LM had different clinical characteristics. And the nomogram showed good performance in predicting LM development, but not PM.

Dramatic response to neoadjuvant savolitinib in marginally resectable lung adenocarcinoma with MET exon 14 skipping mutation: A case report and literature review.

Mesenchymal-epithelial transition (MET) exon 14 skipping mutation (METex14) is a low-frequency driver mutation in metastatic non-small cell lung cancer (NSCLC) (3%-4%) and is associated with a poor prognosis. With the advent of selective MET inhibitors such as capmatinib, tepotinib, and savolitinib, the outcome for these patients was significantly improved. Here, we report a 76-year-old male patient with marginally resectable stage IIIB lung adenocarcinoma harboring METex14 who was successfully treated with savolitinib for neoadjuvant therapy. An 82% shrinkage of the primary tumor was observed, and only 5% of the tumor was viable by pathology in the following radical surgery. A dozen of studies tested the efficiency of neoadjuvant immunotherapy or immunochemotherapy, but for NSCLC with driver mutations, neoadjuvant targeted therapy might be more appropriate. We advocated the neoadjuvant MET TKI treatment for NSCLC.

A Novel Artificial Neural Network Prognostic Model Based on a Cancer-Associated Fibroblast Activation Score System in Hepatocellular Carcinoma.

Introduction: Hepatocellular carcinoma (HCC) ranks fourth as the most common cause of cancer-related death. It is vital to identify the mechanism of progression and predict the prognosis for patients with HCC. Previous studies have found that cancer-associated fibroblasts (CAFs) promote tumor proliferation and immune exclusion. However, the information about CAF-related genes is still elusive. Methods: The data were obtained from The Cancer Genome Atlas, International Cancer Genome Consortium, and Gene Expression Omnibus databases. On the basis of single-cell transcriptome and ligand-receptor interaction analysis, CAF-related genes were selected. By performing Cox regression and random forest, we filtered 12 CAF-related prognostic genes for the construction of the ANN model based on the CAF activation score (CAS). Then, functional, immune, mutational, and clinical analyses were performed. Results: We constructed a novel ANN prognostic model based on 12 CAF-related prognostic genes. Cancer-related pathways were enriched, and higher activated cell crosstalk was identified in high-CAS samples. High immune activity was observed in high-CAS samples. We detected three differentially mutated genes (NBEA, RYR2, and FRAS1) between high- and low-CAS samples. In clinical analyses, we constructed a nomogram to predict the prognosis of patients with HCC. 5-Fluorouracil had higher sensitivity in high-CAS samples than in low-CAS samples. Moreover, some small-molecule drugs and the immune response were predicted. Conclusion: We constructed a novel ANN model based on CAF-related genes. We revealed information about the ANN model through functional, mutational, immune, and clinical analyses.

Increased coexpression of PD-L1 and TIM3/TIGIT is associated with poor overall survival of patients with esophageal squamous cell carcinoma.

BACKGROUND: Immune checkpoint (IC) blockades (ICBs) significantly improve patients' clinical outcomes with solid tumors. Because the objective response rate of single-agent ICB is limited, it is meaningful to explore the combination of ICs for immunotherapy. METHODS: RNA sequencing data of 95 newly diagnosed patients with esophageal squamous cell carcinoma (ESCC) from The Cancer Genome Atlas (TCGA) database were used to explore the prognostic significance of ICs. The results were validated by immunohistochemistry of 58 ESCC tissue samples from our clinical center. RESULTS: The results of both TCGA and validation data suggested that high expression of programmed cell death 1 ligand 1 (PD-L1), T-cell immunoglobulin and mucin-domain-containing-3 (TIM3), and T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) was associated with poor overall survival (OS) of patients with ESCC. Importantly, PD-L1/TIM3 or PD-L1/TIGIT was the optimal combination for predicting poor OS and short restricted mean survival time of patients with ESCC and was an independent prognostic factor. Moreover, a nomogram model constructed by PD-L1, TIM3, and TIGIT together with the primary tumor, regional lymph node, distant metastasis stage could provide a concise and precise prediction of 1-year and 2-year OS rates and median survival time. PD-L1/TIM3 or PD-L1/TIGIT had a positive correlation with CD8+ T cells. Notably, PD-1 and TIM3/TIGIT were primarily coexpressed on CD8+ tumor-infiltrating lymphocyte in patients with ESCC by multiplexed immunofluorescence. CONCLUSION: High expression of ICs was associated with poor OS of patients with ESCC. PD-L1/TIM3 and PD-L1/TIGIT were the optimal combinations for predicting OS, which might be potential targets for future ICBs therapy of ESCC.

The germline/somatic DNA damage repair gene mutations modulate the therapeutic response in Chinese patients with advanced pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with molecular heterogeneity, inducing differences in biological behavior, and therapeutic strategy. NGS profiles of pathogenic alterations in the Chinese PDAC population are limited. We conducted a retrospective study to investigate the predictive role of DNA damage repair (DDR) mutations in precision medicine. METHODS: The NGS profiles were performed on resected tissues from 195 Chinese PDAC patients. Baseline clinical or genetic characteristics and survival status were collected. The Kaplan-Meier survival analyses were performed by the R version 3.6.1. RESULTS: The main driver genes were KRAS, TP53, CDKN2A, and SMAD4. Advanced patients with KRAS mutation showed a worse OS than KRAS wild-type (p = 0.048). DDR pathogenic deficiency was identified in 30 (15.38%) of overall patients, mainly involving BRCA2 (n = 9, 4.62%), ATM (n = 8, 4.10%) and RAD50 genes (n = 3, 1.54%). No significance of OS between patients with or without DDR mutations (p = 0.88). But DDR mutation was an independent prognostic factor for survival analysis of advanced PDAC patients (p = 0.032). For DDR mutant patients, treatment with platinum-based chemotherapy (p = 0.0096) or olaparib (p = 0.018) respectively improved the overall survival. No statistical difference between tumor mutation burden (TMB) and DDR mutations was identified. Treatment of PD-1 blockades did not bring significantly improved OS to DDR-mutated patients than the naive DDR group (p = 0.14). CONCLUSIONS: In this retrospective study, we showed the role of germline and somatic DDR mutation in predicting the efficacy of olaparib and platinum-based chemotherapy in Chinese patients. However, the value of DDR mutation in the prediction of hypermutation status and the sensitivity to the PD-1 blockade needed further investigation.

A nomogram for predicting late radiation-induced xerostomia among locoregionally advanced nasopharyngeal carcinoma in intensity modulated radiation therapy era.

BACKGROUND: Dry mouth sensation cannot be improved completely even though parotids are spared correctly. Our purpose is to develop a nomogram to predict the moderate-to-severe late radiation xerostomia for patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) in intensity modulated radiation therapy (IMRT) / volumetric modulated arc radiotherapy (VMAT) era. METHODS: A dataset of 311 patients was retrospectively collected between January 2010 and February 2013. The binary logistic regression was to estimate each factor's prognostic value for development of moderate-to-severe patient-reported xerostomia at least 2 years (Xer2y) after completion of radiotherapy. Therefore, we can develop a nomogram according to binary logistic regression coefficients. This novel model was validated by bootstrapping analyses. RESULTS: Contralateral Parotid mean dose (coMD<24.4Gy), VMAT (yes), and platinum-based concurrent chemoradiotherapy (no) were significantly related to patient-reported xerostomia at least 2 years (Xer2y) (all p < 0.001), and were included in the nomogram. Receiver operating characteristic (ROC) analysis revealed AUC (area under the ROC curve) with the value of 0.811 (0.710-0.912) of the nomogram, which was significantly higher than coMD 0.698 (0.560-0.840) from QUANTEC2010 (p<0.001). Calibration plots illustrated that the predicted Xer2y was close to the actual observation, and decision curve analyses (DCA) indicated valid positive net benefits. CONCLUSION: We developed a feasible nomogram to predict patient-rated Xer2y based on comprehensive individual data in patients with LA-NPC in the real world. The proposed model is able to facilitate the development of treatment plan and quality of life improvement.

Inferior outcome of bone metastasis in non-small-cell-lung-cancer patients treated with epidermal growth factor receptor inhibitors.

BACKGROUND: Targeted therapy has been established as the standard-of-care for patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Among patients with advanced lung cancer, 30-40% have bone metastases (BoM) at first diagnosis. However, little is known on the clinical characteristics and prognostic factors of BoM in patients with NSCLC harboring EGFR mutations. METHODS: Treatment-naive patients with advanced NSCLC harboring EGFR mutations who were prescribed tyrosine kinase inhibitors (TKIs) were screened and enrolled between June 2009 and April 2019 from West China Hospital. Patients were dichotomized according to whether they had BoM. The demographic characteristics, gene mutation status and therapeutic efficacy, including objective response rate (ORR), progression-free survival (PFS) and overall survival (OS), were collected. RESULTS: A cohort of 604 patients were enrolled. The BoM group had worse PFS (11.7 vs. 14.0 months, HR = 0.73, p = 0.00013) and OS (32.8 vs. 46.1 months, HR = 0.54, p < 0.0001) compared with the non-BoM group. No significant differences were observed in disease control rate (p = 0.407) or ORR (p = 0.537) between the two groups. The metastatic sites in the two groups exhibited obvious differences. In multivariate analysis, BoM was found to be an independent factor of worse prognosis. CONCLUSION: BoM was identified as an independent inferior prognostic factor for EGFR-TKI treatment, and may have complex biological implications.

The efficacy of aprepitant in salvage treatment of chemotherapy-induced nausea and vomiting associated with moderately emetogenic chemotherapy for patients with gastrointestinal cancer.

PURPOSE: To evaluate the efficacy of aprepitant and its effect on the quality of life when added to standard antiemetic therapy as salvage therapy. PATIENTS AND METHODS: This is an open-label, noncomparative prospective phase II clinical trial. A total of 224 patients receiving initial moderately emetogenic chemotherapy (MEC) were enrolled. Patients received standard antiemetic treatment (5-hydroxytryptamine (5-HT3) antagonists + dexamethasone) in the first cycle. Patients failing to achieve a complete response (CR) during cycle 1 entered cycle 2 with the addition of aprepitant as salvage treatment. RESULTS: Of the 224 patients eligible for cycle 1, 159 (71.0%, 95% CI 65.0-77.0) had a CR, and 65 patients with a noncomplete response (NCR) proceeded to cycle 2 to receive aprepitant-based salvage therapy. Then, 49 (75.4%, 95% CI 64.6-84.1) of these patients achieved a CR. The Functional Living Index-Emesis (FLIE) questionnaire showed that NCR patients in cycle 1 had an improved quality of life after receiving aprepitant-based salvage therapy in cycle 2 (cycle 1 and 2: 80.3 vs 114.0, P < 0.001). Failing to achieve a CR had a significant impact on the quality of life in both cycle 1 (FLIE score of NCR and CR patients: 80.3 vs 119.7, P < 0.001) and cycle 2 (FLIE score of NCR and CR patients: 88.3 vs 122.4, P < 0.001). CONCLUSION: The addition of aprepitant as salvage therapy for patients with gastrointestinal cancer is effective and has a positive effect on quality of life.

Nomograms for predicting survival outcomes in intensity-modulated radiotherapy era of nasopharyngeal carcinoma: A study based on Epstein-Barr virus DNA biological responses.

BACKGROUND: Treatment of nasopharyngeal carcinoma (NPC) is evolving toward Intensity-modulated radiotherapy (IMRT) era, which requires patient-specific reestimation of survival outcomes in modern health care. METHODS: A total of 488 detectable pre-treatment Epstein-Barr virus (EBV) DNA patients (stage II-IVa) treated with induction chemotherapy (IC) and IMRT were examined (training set, n = 325; validation set, n = 163). RESULTS: Concurrent chemotherapy (CC) was still an independent prognosticator for overall survival (OS) and progression-free survival (PFS). Both nomograms included age, T classification, N classification, post-IC EBV DNA, and CC. Predictions correlated well with observed 3-/5-year OS and PFS. The concordance index was 0.776 (95% confidence interval (CI) 0.69-0.86) for OS and 0.742 (95% CI 0.65-0.83) for PFS in the validation cohort. The nomograms can successfully classify patients into low- and high-risk groups. CONCLUSION: The validated nomograms provided useful prediction of OS and PFS for detectable pre-treatment EBV DNA patients with NPC in IMRT era.

A multidimensional nomogram combining overall stage, dose volume histogram parameters and radiomics to predict progression-free survival in patients with locoregionally advanced nasopharyngeal carcinoma.

OBJECTIVES: To develop a multidimensional nomogram for predicting the progression-free survival (PFS) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) (stage III-IVa). MATERIALS AND METHODS: A total of 224 patients with locoregionally advanced NPC (training cohort, n = 149; validation cohort, n = 75) were retrospectively included. We extracted 260 radiomic features from the primary tumor and lymph nodes on the axial contrast-enhanced T1 weighted and T2 weighted MRI. Radiomic signatures of the gross tumor volume (RSnx) and lymph node (RSnd), Dose Volume Histogram (DVH) signature reflecting planning score (PS), and clinical characteristics were included as potential predictors of PFS. The least absolute shrinkage and selection operator (LASSO) regression were applied for feature selection and data dimension reduction. A nomogram was developed by incorporating the selected predictors. The C-index and calibration curve were used to assess discrimination and calibration power of the nomogram, respectively. RESULTS: RSnd, PS, and tumor-node-metastasis (TNM) stage were the independent predictors for PFS (all p < 0.05). The nomogram integrating the three factors achieved a C-index of 0.811 (95% CI: 0.74-0.882) in the validation cohort for predicting PFS, which outperformed than that of the TNM stage alone (C-index, 0.613, 95% CI: 0.532-0.694). Subgroup analysis showed Epstein-Barr virus (EBV) DNA status improved the predictive accuracy of the nomogram (C-index, 0.86, 95% CI: 0.787-0.933). CONCLUSIONS: The multidimensional nomogram incorporating RSnd, PS, and TNM stage showed high performance for predicting PFS in patients with locoregionally advanced NPC.

Comparison of GP and TPF induction chemotherapy for locally advanced nasopharyngeal carcinoma.

OBJECTIVES: This study aims to compare two induction chemotherapy regimens, TPF and GP, for patients with locally advanced nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: We analyzed patients with newly diagnosed stage III-IVA NPC (excluding T3/T4N0, AJCC) between December 2010 and May 2015 who were treated with TPF or GP induction chemotherapy (IC) followed with concurrent chemoradiotherapy (CCRT) and those treated with CCRT alone. Treatment compliance, survival outcomes and grade 3-4 side effects were compared among these three groups. RESULTS: A total of 189 patients were eligible for this study, with 87 (46.0%), 71 (37.6%) and 31 (16.4%) in the TPF, GP and CCRT alone groups. All patients were followed for 3 years. There was no difference in the 3-year survival rate between GP- and TPF-treated patients. Disease-free survival (DFS) and overall survival (OS) were significantly improved in both IC groups compared with those in the CCRT alone group. Multivariable analysis suggested that patients with N3 had a higher risk of distant metastasis than those with N1-2. GP is not inferior to TPF regardless of different N categories. There were significant more grade 3-4 treatment-related toxicity in TPF group than in GP group. CONCLUSION: Our study found that in locally advanced NPC, the GP induction chemotherapy regimen is equivalent to TPF in treatment outcomes, but with significant less grade 3-4 acute toxicity. Further studies are needed to validate our findings.

Prognostic factors and treatment outcomes in patients with non-ampullary small bowel adenocarcinoma: Long-term analysis.

Small bowel adenocarcinoma (SBA) is a relatively rare malignancy in gastrointestinal tumors. In addition, the difficulty of early diagnosis, its poor prognosis compared to large bowel adenocarcinoma, and inadequate treatment experiences due to lack of prospective randomized trials make it necessary to explore the characteristics of the disease for early diagnosis and treatment.Patients diagnosed with primary malignant tumor of small intestine in West China Hospital of Sichuan University between January 2001 and 2013 were reviewed retrospectively. A total of 208 patients with SBA were selected and 160 patients with duodenal periampullary tumor were excluded. Forty-two cases of patients were finally enrolled for statistical analysis as 6 patients were lost of follow-up. The clinical characteristics, the response to treatment and their overall survival (OS) time were reviewed and analyzed.Of the 42 patients, 11 (26.2%) primary tumors were originated from duodenum, 29 (69.0%) from jejunum, and 2 (4.8%) from ileum. All patients (64.3% male; median age, 54.7 years) included in this study underwent primary resection of the tumor to confirm final diagnosis. Three-year survival rate is 21% and 5-year survival rate is 9%. Median OS were 24.2 months (95% CI: 4.0-72.0). The univariate predictors for prognosis of SBA were as follows: age (P = .021), severe intestinal symptoms at first diagnosis (P < .001), T4 of tumor stage (P = .011), tumor size (P = .004), relatively late clinical stage (P < .001), peritoneal metastasis (P < .001), and no chemotherapy (P = .011). The multivariate predictors for poor prognosis were age of more than 60 years old (P = .035), intestinal obstruction or perforation at first diagnosis (P = .026), relatively late clinical stage (P = .000), and no chemotherapy (P = .027).SBA was a relatively rare malignancy that was difficult for early diagnosis and treatment. Intestinal obstruction was the common clinical manifestation at first diagnosis, with a tendency of early peritoneal metastasis. Precaution of the disease in early phase, radical resection of the primary tumor while resectable, followed with in-time chemotherapy might improve prognosis and survival of patients with SBA.