Long-term survivals of immune checkpoint inhibitors as neoadjuvant and adjuvant therapy in dMMR/MSI-H colorectal and gastric cancers.

BACKGROUND: The long-term survival benefit of immune checkpoint inhibitors (ICIs) in neoadjuvant and adjuvant settings is unclear for colorectal cancers (CRC) and gastric cancers (GC) with deficiency of mismatch repair (dMMR) or microsatellite instability-high (MSI-H). METHODS: This retrospective study enrolled patients with dMMR/MSI-H CRC and GC who received at least one dose of neoadjuvant ICIs (neoadjuvant cohort, NAC) or adjuvant ICIs (adjuvant cohort, AC) at 17 centers in China. Patients with stage IV disease were also eligible if all tumor lesions were radically resectable. RESULTS: In NAC (n = 124), objective response rates were 75.7% and 55.4%, respectively, in CRC and GC, and pathological complete response rates were 73.4% and 47.7%, respectively. The 3-year disease-free survival (DFS) and overall survival (OS) rates were 96% (95%CI 90-100%) and 100% for CRC (median follow-up [mFU] 29.4 months), respectively, and were 84% (72-96%) and 93% (85-100%) for GC (mFU 33.0 months), respectively. In AC (n = 48), the 3-year DFS and OS rates were 94% (84-100%) and 100% for CRC (mFU 35.5 months), respectively, and were 92% (82-100%) and 96% (88-100%) for GC (mFU 40.4 months), respectively. Among the seven patients with distant relapse, four received dual blockade of PD1 and CTLA4 combined with or without chemo- and targeted drugs, with three partial response and one progressive disease. CONCLUSION: With a relatively long follow-up, this study demonstrated that neoadjuvant and adjuvant ICIs might be both associated with promising DFS and OS in dMMR/MSI-H CRC and GC, which should be confirmed in further randomized clinical trials.

Deep Learning Radiomics Nomogram Based on Enhanced CT to Predict the Response of Metastatic Lymph Nodes to Neoadjuvant Chemotherapy in Locally Advanced Gastric Cancer.

BACKGROUND: We aimed to construct and validate a deep learning (DL) radiomics nomogram using baseline and restage enhanced computed tomography (CT) images and clinical characteristics to predict the response of metastatic lymph nodes to neoadjuvant chemotherapy (NACT) in locally advanced gastric cancer (LAGC). METHODS: We prospectively enrolled 112 patients with LAGC who received NACT from January 2021 to August 2022. After applying the inclusion and exclusion criteria, 98 patients were randomized 7:3 to the training cohort (n = 68) and validation cohort (n = 30). We established and compared three radiomics signatures based on three phases of CT images before and after NACT, namely radiomics-baseline, radiomics-delta, and radiomics-restage. Then, we developed a clinical model, DL model, and a nomogram to predict the response of LAGC after NACT. We evaluated the predictive accuracy and clinical validity of each model using the receiver operating characteristic curve and decision curve analysis, respectively. RESULTS: The radiomics-delta signature was the best predictor among the three radiomics signatures. So, we developed and validated a DL delta radiomics nomogram (DLDRN). In the validation cohort, the DLDRN produced an area under the receiver operating curve of 0.94 (95% confidence interval, 0.82-0.96) and demonstrated adequate differentiation of good response to NACT. Furthermore, the DLDRN significantly outperformed the clinical model and DL model (p < 0.001). The clinical utility of the DLDRN was confirmed through decision curve analysis. CONCLUSIONS: In patients with LAGC, the DLDRN effectively predicted a therapeutic response in metastatic lymph nodes, which could provide valuable information for individualized treatment.

Regorafenib monotherapy or combined with an immune-checkpoint inhibitor as later-line treatment for metastatic colorectal cancer: a multicenter, real-world retrospective study in China.

OBJECTIVE: To evaluate the efficacy and safety of regorafenib monotherapy or in combination with immune-checkpoint inhibitor while treating Chinese patients with metastatic colorectal cancer (mCRC): a real-world study. METHODS: The data of patients with metastatic colorectal cancer who received regorafenib-containing regimen as the third or later line treatment at ten Chinese hospitals from Aug 2017 to Jun 2020 were retrospectively analyzed, including dosing details, survival data as well as adverse events. Survival analysis was further performed for patients administrated with regorafenib monotherapy and combined with an immune-checkpoint inhibitor based on Kaplan-Meier and Cox regression methods. The primary endpoint was overall survival. RESULTS: A total of 537 patients were included with a median age of 61, among whom 376 received regorafenib monotherapy and 245 received regorafenib combined with immune-checkpoint inhibitors. The clinicopathological characteristics of the two groups at baseline were mainly balanced. No significant difference in progression-free survival (PFS) was observed in patients receiving regorafenib monotherapy or combination therapy (3.8 vs. 5.5 months, p = 0.170). In contrast, patients receiving combination therapy had a more prolonged overall survival (OS) than those receiving regorafenib monotherapy (13.5 vs. 10.0 months, p = 0.001). The treatment regimen and regorafenib dosage were significant prognostic factors in the multivariate analysis. Significant benefits in PFS and OS were achieved in KRAS mutant and anti-angiogenesis treatment-naïve subgroups receiving combination therapy compared to monotherapy. No apparent increase was recorded in treatment-related adverse events in patients receiving combination therapy. CONCLUSION: Regorafenib plus an immune-checkpoint inhibitor has already been a widely adopted strategy in the later-line treatment for mCRC in the real world. The combination therapy yielded a significantly prolonged overall survival than regorafenib alone, with a manageable safety profile in Chinese patients, and warrants further investigation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04835324. Registered 6th April 2021.

Activity of Anlotinib in the Second-Line Therapy of Metastatic Gastrointestinal Stromal Tumors: A Prospective, Multicenter, In Vitro Study.

BACKGROUND: Anlotinib is a multi-target tyrosine kinase inhibitor that can effectively inhibit tumor cell proliferation after receptor kinase activation caused by KIT gene mutation. METHODS: We tested the inhibitory effect of anlotinib in GIST cell lines with different gene mutations and evaluated the efficacy of anlotinib for patients with metastatic GIST after imatinib failure in a multicenter, single-arm, phase II study. RESULTS: In vitro, V654A mutation encoded by KIT exon 13 was intermediately sensitive to anlotinib. Moreover, anlotinib was able to partly suppress the activation loop mutation D820A from exon 17 while another activation loop mutation N822K, also from exon 17, was resistant to anlotinib. From September 2018 to October 2020, 64 patients from 9 Chinese medical centers were enrolled in this study. Seven patients had partial response and 39 patients had stable disease. The median PFS was 8.0 months. There was no statistical significance comparing with PFS of sunitinib second-line therapy at the same period. The most common adverse events related to anlotinib treatment were hypertension, neutropenia, and fatigue. CONCLUSION: Anlotinib showed moderate antitumor activity in drug-resistant GIST cell lines in vitro, and good PFS and better tolerance in second-line therapy study.

Investigation Driven by Network Pharmacology on Potential Components and Mechanism of DGS, a Natural Vasoprotective Combination, for the Phytotherapy of Coronary Artery Disease.

Phytotherapy offers obvious advantages in the intervention of Coronary Artery Disease (CAD), but it is difficult to clarify the working mechanisms of the medicinal materials it uses. DGS is a natural vasoprotective combination that was screened out in our previous research, yet its potential components and mechanisms are unknown. Therefore, in this study, HPLC-MS and network pharmacology were employed to identify the active components and key signaling pathways of DGS. Transgenic zebrafish and HUVECs cell assays were used to evaluate the effectiveness of DGS. A total of 37 potentially active compounds were identified that interacted with 112 potential targets of CAD. Furthermore, PI3K-Akt, MAPK, relaxin, VEGF, and other signal pathways were determined to be the most promising DGS-mediated pathways. NO kit, ELISA, and Western blot results showed that DGS significantly promoted NO and VEGFA secretion via the upregulation of VEGFR2 expression and the phosphorylation of Akt, Erk1/2, and eNOS to cause angiogenesis and vasodilation. The result of dynamics molecular docking indicated that Salvianolic acid C may be a key active component of DGS in the treatment of CAD. In conclusion, this study has shed light on the network molecular mechanism of DGS for the intervention of CAD using a network pharmacology-driven strategy for the first time to aid in the intervention of CAD.

Concordance Between Watson for Oncology and a Multidisciplinary Clinical Decision-Making Team for Gastric Cancer and the Prognostic Implications: Retrospective Study.

BACKGROUND: With the increasing number of cancer treatments, the emergence of multidisciplinary teams (MDTs) provides patients with personalized treatment options. In recent years, artificial intelligence (AI) has developed rapidly in the medical field. There has been a gradual tendency to replace traditional diagnosis and treatment with AI. IBM Watson for Oncology (WFO) has been proven to be useful for decision-making in breast cancer and lung cancer, but to date, research on gastric cancer is limited. OBJECTIVE: This study compared the concordance of WFO with MDT and investigated the impact on patient prognosis. METHODS: This study retrospectively analyzed eligible patients (N=235) with gastric cancer who were evaluated by an MDT, received corresponding recommended treatment, and underwent follow-up. Thereafter, physicians inputted the information of all patients into WFO manually, and the results were compared with the treatment programs recommended by the MDT. If the MDT treatment program was classified as "recommended" or "considered" by WFO, we considered the results concordant. All patients were divided into a concordant group and a nonconcordant group according to whether the WFO and MDT treatment programs were concordant. The prognoses of the two groups were analyzed. RESULTS: The overall concordance of WFO and the MDT was 54.5% (128/235) in this study. The subgroup analysis found that concordance was less likely in patients with human epidermal growth factor receptor 2 (HER2)-positive tumors than in patients with HER2-negative tumors (P=.02). Age, Eastern Cooperative Oncology Group performance status, differentiation type, and clinical stage were not found to affect concordance. Among all patients, the survival time was significantly better in concordant patients than in nonconcordant patients (P<.001). Multivariate analysis revealed that concordance was an independent prognostic factor of overall survival in patients with gastric cancer (hazard ratio 0.312 [95% CI 0.187-0.521]). CONCLUSIONS: The treatment recommendations made by WFO and the MDT were mostly concordant in gastric cancer patients. If the WFO options are updated to include local treatment programs, the concordance will greatly improve. The HER2 status of patients with gastric cancer had a strong effect on the likelihood of concordance. Generally, survival was better in concordant patients than in nonconcordant patients.

A multi-center survey on dietary knowledge and behavior among inpatients in oncology department.

OBJECTIVE: To investigate the current associated factors of dietary knowledge and behavior, the intake and nutritional status in malignancy Chinese inpatients, and the malnutrition causes involved in dietary nutrition knowledge level and behavior, providing recommendations to patients for nutrition education and intervention. METHOD: Five hundred and thirty-five participants from 18 hospitals were investigated by a questionnaire related to dietary knowledge and behavior. Physicians asked and recorded the level of dietary intake and appetite scoring of the participants. The nutritional risk screening with the Nutritional Risk Screening 2002 (NRS-2002) and the dietary survey by 24 h dietary recalls were completed by a dietitian. Besides, the target energy intake and the target protein intake were calculated by the "rule of thumb" recommended by ESPEN guideline, comparing the difference between the actual intake and target intake. RESULTS: According to the questionnaire, 95.2% of participants thought it was important to have a good dietetic habit, and nearly half of them have searched for guides on how to diet; 70% of the patients had no clear idea of what was a scientific diet; 82% of patients had contradictory dietary knowledge; 64.2% of patients would listen to the opinion of the attending physician when a contradiction happened. The main three ways of learning about healthy diet were attending physician, network, and TV, respectively, with the values 26.0, 18.5, and 16.1%. Importantly, 99.6% of patients have made mistakes about dietary knowledge, for example, crab, chicken, lamb, fish, and prawns should not be eaten in their concept. In addition, more than 90% of participants have taken Ganoderma lucidum spore powder, sea cucumber, ginseng, Cordyceps sinensis, and so on. Ninety-three percent of the patients never reached a qualified nutrition education. Besides, 15.6% of the participants had nutritional risk (NRS-2002 ≥ 3). The actual daily energy intake was 1169.20 ± 465.97 kcal, which was significantly less than target energy intake (P < 0.01), amounting to 65.3% of the target requirements. The actual daily protein intake was 46.55 ± 21.40 g, which was significantly less than target protein intake (P < 0.01), amounting to 74.44%. On the other hand, 69% of the participants were "Not too bad, Ok, Good, or Very good" according to the records of physicians, while 34% of them did not reach 60%of the target requirements through dietary survey. CONCLUSION: The survey indicated that cancer patients had poor understanding of the scientific dietary nutrition and were in low level of normative nutritional education among Chinese malignancy inpatients. Dietary intake of most cancer patients decreased, and the actual intake cannot be revealed by NRS-2002 score or the physicians' inquiry. It is necessary to enhance the cooperation between dietitians and physicians and develop nutrition education to improve the level of dietary knowledge.

Identification of stage-specific biomarkers in lung adenocarcinoma based on RNA-seq data.

Tumorigenesis is a multistep process that attributes to the sequential accumulation of abnormal expression in key oncogenes or tumor suppressors. We aimed to identify stage-specific biomarkers to distinguish lung adenocarcinoma (LAC) stages in cancer progression. RNA-sequencing data of LAC and matched adjacent non-cancer tissues were downloaded from the Cancer Genome Atlas, including 29 pairs of samples from LAC at stage I, 14 from LAC at stage II, 13 from LAC at stage III, and 1 from LAC at stage IV. Differentially expressed genes (DEGs) were analyzed for each case at different stages of LAC. DEGs were further annotated based on transcription factor data information, tumor-associated gene database, and protein-protein interaction database. Functional annotation was performed for genes in PPI network by DAVID online tool. Our analysis identified 11 high-frequency DEGs in the stage I, 29 in the stage II, and 90 in the stage III of LAC. Among them, eight genes were significantly correlated with LAC stages and identified as biomarkers in LAC progression. ANGPTL5, C7orf16, EDN3, LOC150622, HOXA11AS, IL1F5, and USH1G significantly distinguished stage III from stages I and II. GJB6 was significantly enriched in the gap junction trafficking pathway, while C7orf16 and EDN3 were enriched in Wnt signaling pathway, cell cycle, and G protein-coupled receptor (GPCR) signaling. Up-regulated GJB6 especially in LAC stage II and down-regulated C7orf16 and EDN3 specifically in stage III were identified as biomarkers for distinguishing cancer stage in tumor progression through dysregulating gap junction, Wnt signaling, and GPCR signaling pathways.

Identification of dysfunctional biological pathways and their synergistic mechanism in hepatocellular carcinoma process.

BACKGROUND: Hepatocellular carcinoma (HCC) is a lethal and prevalent cancer worldwide. This study was conducted to investigate dysfunctional pathways and their synergistic mechanism in the HCC process. METHODS: We downloaded transcriptome profiling data (GSE25097) from the Gene Expression Omnibus (GEO) database, including 6 healthy liver samples, 40 cirrhosis samples, 243 adjacent non-tumor samples, and 268 HCC samples. Robust Multi-Array (RMA) in R software was employed to preprocess the downloaded dataset, and Student's t-test (FDR less than 0.001) was performed to identify the differentially expressed genes (DEGs) between 4 sample groups. Then, pathway enrichment analysis (FDR less than 0.05) based on iSubpathwayMiner was performed. Furthermore, we performed collaborative analysis on these pathways through calculating the Jaccard index, and crosstalk networks were constructed and visualized by Cytoscape. RESULTS: Totally, 4617, 9517, and 12,479 DEGs were identified between healthy liver and cirrhosis samples, cirrhosis and adjacent non-tumor samples, and adjacent non-tumor and HCC samples, respectively. Furthermore, a total of 26 crosstalks involving 13 pathways, 78 crosstalks involving 54 pathways, and 86 crosstalks involving 52 pathways were identified through the DEGs between healthy liver and cirrhosis samples, cirrhosis and adjacent non-tumor samples, and adjacent non-tumor and HCC samples, respectively. Moreover, 5 dysfunctional pathways were found to co-exist in the three processes of HCC. Among them, 3 dysfunctional pathways have collaborative relationship, including Staphylococcus aureus infection, leishmaniasis, and Chagas disease. CONCLUSIONS: In this study, dysfunctional pathways in the HCC process and crosstalks between these pathways were investigated for the first time, providing new insight into the potential mechanisms of HCC.