NRS2002 score as a prognostic factor in solid tumors treated with immune checkpoint inhibitor therapy: a real-world evidence analysis.

To observe the antitumour efficacy of programmed death 1 (PD-1) inhibitors in the real world and explore the relationship between NRS2002 score or other clinical characteristics and immunotherapy efficacy, we retrospectively analyzed 341 tumor patients who received immune checkpoint inhibitor (ICI) treatment at one center. A total of 341 solid tumor patients treated with ICIs from June 2018 to December 2021 were retrospectively included in this study. Patient characteristics, ICI responses, and survival status were documented, and the relationships between clinical factors and survival were analyzed. Among all patients, the median progression-free survival (PFS) was 5.8 months, and the median overall survival (OS) was 12.5 months. The Performance Status (PS), NRS2002 score, The Naples Prognostic Score (NPS), Lymphocyte and C-reactive protein ratio (LCR), line of therapy, and nutritional support were significantly related to PFS or OS according to univariate analysis. The median PFS and OS were significantly better in the group without nutritional risk (NRS2002 0-2) than those with nutritional risk (NRS2002 ≥ 3) (PFS: HR = 1.82, 95% CI 1.30-2.54, p value < .001; OS: HR = 2.49, 95% CI 1.73-3.59, p value < .001). Cox regression analysis revealed that the NRS2002 score was an independent prognostic factor for both PFS and OS. The objective response rate (ORR) in the group at nutritional risk was lower than that in the group without nutritional risk (8.33% and 19.71%, respectively, p value = .037). Patients at nutritional risk according to the NRS2002 score at initial treatment had a poorer prognosis than those without nutritional risk. The NRS2002 could be used as a preliminary index to predict the efficacy of immune checkpoint inhibitor therapy.

A phase IV study to evaluate the safety of fruquintinib in Chinese patients in real-world clinical practice.

INTRODUCTION: Fruquintinib is approved in China for patients with metastatic colorectal cancer (CRC) who progressed after 2 lines of chemotherapy. This postmarketing study was conducted to evaluate the safety of fruquintinib in the Chinese population, including previously treated patients with advanced CRC and other solid tumors. METHODS: Patients in the first cycle of fruquintinib or expected to start fruquintinib within a week were enrolled. Fruquintinib was administrated according to the label or per physicians' discretion. Patient characteristics and safety information were collected at baseline, 1 month, and 6 months after consent (or 30 days after the last dose). RESULTS: Overall, 3005 patients enrolled between April 24, 2019 and September 27, 2022. All enrolled patients received at least one dose of fruquintinib. Most patients had metastases at baseline. The median age was 60 years. More than half (64.0%) of the patients started fruquintinib at 5 mg, and the median treatment exposure was 2.7 months. Nearly one-third (32.5%) of patients with CRC received fruquintinib with concomitant antineoplastic agents. Treatment-emergent adverse events (TEAEs) leading to dose modification were reported in 626 (20.8%) patients, and 469 (15.6%) patients experienced TEAEs leading to treatment discontinuation. The most common grade ≥ 3 TEAEs were hypertension (6.6%), palmar-plantar erythrodysesthesia syndrome (2.2%), and platelet count decreased (1.0%). Combination therapy did not lead to excessive toxicities. CONCLUSIONS: The safety profile of fruquintinib in the real world was generally consistent with that in clinical studies, and the incidence of TEAEs was numerically lower than known VEGF/VEGFR inhibitor-related AEs. Fruquintinib exhibited manageable safety and tolerability in Chinese patients in the real-world setting.

Identification and prognostic analysis of candidate biomarkers for lung metastasis in colorectal cancer.

Colorectal cancer (CRC) is one of the most prevalent types of malignant tumors. It's vital to explore new biomarkers and potential therapeutic targets in CRC lung metastasis through adopting integrated bioinformatics tools. Multiple cohort datasets and databases were integrated to clarify and verify potential key candidate biomarkers and signal transduction pathways in CRC lung metastasis. DAVID, STRING, UALCAN, GEPIA, TIMER, cBioPortal, THE HUMAN PROTEIN ATLAS, GSEA 4.3.2, FUNRICH 3.1.3, and R 4.2.3 were utilized in this study. The enriched biological processes and pathways modulated by the differentially expressed genes (DEGs) were determined with Gene Ontology, Kyoto Encyclopedia of Genes and Genomes. The search tool Retrieval of Interacting Genes and Cytoscape were used to construct a protein-protein interaction network among DEGs. Four hundred fifty-nine colorectal primary cancer and lung metastatic gene expression profiles were screened from 3 gene expression profiles (GSE41258, GSE68468, and GSE41568). Forty-one upregulated genes and 8 downregulated genes were identified from these 3 gene expression profiles and verified by the transcriptional levels of hub genes in other GEO datasets and The Cancer Genome Atlas database. Two pathways (immune responses and chemokine receptors bind chemokines), 13 key DEGs, 6 hub genes (MMP3, SFTPD, ABCA3, CLU, APOE, and SPP1), and 2 biomarkers (APOE, SPP1) with significantly prognostic values were screened. Forty-nine DEGs were identified as potential candidate diagnostic biomarkers for patients with CRC lung metastasis in present study. Enrichment analysis indicated that immune responses and chemokine receptors bind chemokines may play a leading role in lung metastasis of CRC, and further studies are needed to validate these findings.

Retrospective analysis of the impact of dose delay and reduction on outcomes of colorectal cancer patients treated with FOLFIRI­based treatment.

Objectives: To determine the relationship between chemotherapy dose delay/reduction with progression-free survival (PFS) and overall survival (OS) in colorectal cancer patients treated with FOLFIRI based first-line chemotherapy in real-world retrospectively study. Methods: We identified 144 eligible patients with advanced CRC who received FOLFIRI as first-line based treatment. The study protocol was submitted to the institutional review board and was exempted. Dose delay was defined as an average delay of more than 3 days (>3 days vs. ≤3 days) from the intended date. Dose reduction (actual dose/standard dose * 100%) ≤85% was considered as chemotherapy reduction in the chemotherapy dose relative to the standard (mg/m2) regimen for all cycles. Relative dose intensity (RDI) ≤80% was described as chemotherapy reduction. OS and PFS were measured using Kaplan-Meier and Cox proportional hazard models. Results: There were 114 patients with chemotherapy dose delay (dose delay >3 days). PFS of patients without dose delay had better survival than patients with dose delay (p = 0.002). There were 28.47% patients treated with dose reduction of 5-Fu. PFS and OS were better in patients without 5-Fu dose reduction than in patients with 5-Fu dose reduction with p values of 0.024 and <0.001, respectively. Patients with high 5-FU RDI had better PFS than patients with low 5-FU RDI (p < 0.001). While, there was no statistical difference in OS between the two groups. Then we stratified the analysis by age. In <65 years cohort, both PFS and OS were better in patients with high 5-Fu RDI than in those with low 5-Fu RDI (p < 0.001, p = 0.005, respectively). But, in ≥65 years cohort, OS were better in patients with low 5-Fu RDI than in those with high 5-Fu RDI (p = 0.025). Moreover, both dose reduction and RDI of irinotecan had no statistically significant difference in both PFS and OS. Conclusion: In the advanced colorectal cancer patients who received FOLFIRI based treatment as first-line regimen, chemotherapy dose delay and reduction dose of 5-Fu were associated with worse survival, especially among patients younger than 65 years.

Case report: Circulating tumor DNA technology displays temporal and spatial heterogeneity in Waldenström macroglobulinemia during treatment with BTK inhibitors.

Background: Waldenström macroglobulinemia (WM) is a rare subtype of B-cell lymphoma. Rituximab-based combination therapy and Bruton's tyrosine kinase (BTK) inhibitors have greatly improved the prognosis of WM. Despite the high response rate and good tolerance of BTK inhibitors in treatment of WM, a proportion of patients still experience disease progression. Case presentation: We report a 55-year-old man with relapsed WM. The patient achieved partial remission after six courses of CHOP chemotherapy and multiple plasma exchanges in initial treatment. He was admitted to the hospital with abdominal distension, and was diagnosed with relapsed WM and subsequently started on zanubrutinib. Disease progression and histological transformation occurred during treatment. We performed liquid biopsies on transformed plasma, tumor tissue and ascites at the same time and found high consistency between ascites and tissues. Moreover, we detected resistance mutations of BTK inhibitors (BTK, PLCG2) in ascites that were not detected in plasma or tissue. Eventually, the patient died during the 15-month follow-up after relapse. Conclusion: We describe a rare case of WM transformation to DLCBCL treated with chemoimmunotherapy and BTK inhibition. We analyzed tumor DNA obtained at different anatomic sites and circulating tumor DNA (ctDNA) derived from plasma and ascites specimens, with apparent significant temporal and spatial heterogeneity. The case specifically highlights the clinical value of ctDNA of ascites supernatant from WM patients, which is a more convenient and relatively noninvasive method compared with traditional invasive tissue biopsy.

Higher Levels of Tumour-Infiltrating Lymphocytes (TILs) are Associated with a Better Prognosis, While CDK5 Plays a Different Role Between Nonmetastatic and Metastatic Colonic Carcinoma.

OBJECTIVE: We investigated the prognostic value of cyclin-dependent kinase 5 (CDK5) in a true population-based cohort of patients with colon cancer. METHODS: 1. Immunohistochemical (IHC) staining was used to retrospectively analyse the expression of CDK5 in colon cancer tissue samples of 296 patients. The χ2 test, Kaplan-Meier method and Cox proportional regression model were used to analyse the difference between the patients with differential expression of CDK5 and with different stages (metastatic and nonmetastatic); 2. The number of tumour-infiltrating lymphocytes (TILs) in tumour sections was determined, and its relationship with prognosis was explored. RESULTS: 1. Among 296 patients stained for CDK5, 18 cases (6.09%) showed negative expression, 77 cases (26.01%) showed weak expression (+1), 124 cases (41.89%) showed medium positive expression (2+), and 77 cases (26.01%) showed strong positive expression (3+). The expression of CDK5 was neither related to mismatch repair nor TILs (p > .05). In non-metastatic patients, longer progression-free survival (PFS) and cancer-specific survival (CSS) were observed in patients with high CDK5 expression (2+ or 3+) than low CDK5 expression (- or 1+), while in metastatic disease, the opposite was true (p < .001). 2. TILs in 226 patients were detected in the study. Among them, 115 cases (50.88%) showed a low number of TILs (TILs-L), and 111 cases (49.12%) showed a high number of TILs (TILs-H). Patients with a TIL ratio greater than .2 had a significantly better CSS (p < .001) or PFS (p = .008) than patients with a lower TIL ratio. By multivariate analysis, TILs-H was a protective factor for CSS, however failed to reach a significant difference (hazard ratio: .59, 95% CI: .33∼1.06, p = .079), and so was the PFS (HR: .65, 95% CI: .29∼1.43, p = .279). CONCLUSION: High expression of CDK5 indicates a good prognosis in nonmetastatic colon cancer, while it is the opposite in metastatic colon cancer, and the expression of CDK5 is unrelated to TILs. Patients with TIL-H have a better prognosis, with a proper cut-off value of 20% for colon cancer.

Downregulation of AC092894.1 promotes oxaliplatin resistance in colorectal cancer via the USP3/AR/RASGRP3 axis.

BACKGROUND: Oxaliplatin resistance is a complex process and has been one of the most disadvantageous factors and indeed a confrontation in the procedure of colorectal cancer. Recently, long non-coding RNAs (lncRNAs) have emerged as novel molecules for the treatment of chemoresistance, but the specific molecular mechanisms mediated by them are poorly understood. METHODS: The lncRNAs associated with oxaliplatin resistance were screened by microarray. lncRNA effects on oxaliplatin chemoresistance were then verified by gain- and loss-of-function experiments. Finally, the potential mechanism of AC092894.1 was explored by RNA pull-down, RIP, and Co-IP experiments. RESULTS: AC092894.1 representation has been demonstrated to be drastically downregulated throughout oxaliplatin-induced drug-resistant CRC cells. In vivo and in vitro experiments revealed that AC092894.1 functions to reverse chemoresistance. Studies on the mechanism suggested that AC092894.1 served as a scaffold molecule that mediated the de-ubiquitination of AR through USP3, thereby increasing the transcription of RASGRP3. Finally, sustained activation of the MAPK signaling pathway induced apoptosis in CRC cells. CONCLUSIONS: In conclusion, this study identified AC092894.1 as a suppressor of CRC chemoresistance and revealed the idea that targeting the AC092894.1/USP3/AR/RASGRP3 signaling axis is a novel option for the treatment of oxaliplatin resistance.

The value of PET/CT for the diagnosis and evaluation of immunotherapy in occult primary renal cell carcinoma: a case report.

Skin and soft tissue diffusion metastasis (also known as occult cancer) is rare in renal cell carcinoma (RCC). Here, we report an extremely rare case of a 67-year-old male patient with occult primary RCC who developed metastases to the gums, skin, and diffuse soft tissue. The primary renal lesion was missed by computed tomography (CT), ultrasound, and 18F-fluorodeoxyglucose positron emission tomography (PET)/CT, and the diagnosis was confirmed by biopsy of gums and subcutaneous nodules. Subsequent enhanced CT revealed a lesion in the left kidney. The patient had progression-free survival of 16 months after treatment with axitinib and pembrolizumab. Pseudoprogression and tumor heterogeneity pose major challenges in the evaluation of immunotherapy. PET/CT is indispensable especially for cases with multiple metastases, widespread distribution of lesions, and major heterogeneity. In this case, the total lesion glycolysis was calculated by PET/CT and was used to evaluate systemic tumor load before and after immunotherapy, which was calculated as the product of the metabolic tumor volume and the mean standardized uptake value of the target lesion, which increased the accuracy of assessing diffuse lesions. Total lesion glycolysis can be used as a new method to quantitatively evaluate the efficacy of immunotherapy.

The predictive model for risk of chemotherapy-induced thrombocytopenia based on antineoplastic drugs for solid tumors in eastern China.

Chemotherapy-related thrombocytopenia (CIT) is a significant adverse event during chemotherapy, which can lead to reduced relative dose intensity, increased risk of serious bleeding and additional medical expenditure. Herein, we aimed to develop and validate a predictive nomogram model for prediction of CIT in patients with solid tumor. From Jun 1, 2018 to Sep 9, 2021, a total of 1541 patients who received 5750 cycles of chemotherapy were retrospectively enrolled. Cox regression analysis was performed to identify predictive factors to establish the nomogram model for CIT. The incidence of chemotherapy-induced thrombocytopenia was 21.03% for patient-based and 10.26% for cycles of chemotherapy. The top five solid tumors with CIT are cervix, gastric, bladder, biliary systemic, and ovarian. The incidence of chemotherapy dose delays in any cycle because of CIT was 5.39%. Multivariate analysis showed that tumor site, treatment line, AST, oxaliplatin, and capecitabine were significantly associated with CIT. Moreover, we established a nomogram model for CIT probability prediction, and the model was well calibrated (Hosme-Lemeshow P = 0.230) and the area under the receiver operating characteristic curve was 0.844 (Sensitivity was 0.625, Specificity was 0.901). We developed a predictive model for chemotherapy-induced thrombocytopenia based on readily available and easily assessable clinical characteristics. The predictive model based on clinical and laboratory indices represents a promising tool in the prediction of CIT, which might complement the clinical management of thrombocytopenia.

Adequate Number of Lymph Nodes Sampled May Determine Appropriate Surgical Modality for Early-Stage NSCLC: A Population-Based Real-World Study.

BACKGROUND: The standard surgical procedure for ≤ 2 cm non-small cell lung cancer (NSCLC), including the number of lymph nodes sampled (nLN) and surgical modality, remains controversial. This study was designed to determine the optimal cohort in which sublobectomy could be an alternative to lobectomy. MATERIALS (OR PATIENTS) AND METHODS: Patients from 1998 to 2017 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. The optimal cutoff value of nLN was identified using a restrictive cubic spline graph (RCS). Kaplan-Meier analysis was used to determine cancer-specific survival (CSS). The COX proportional hazard regression model was used to identify the influence of clinical and demographic variables on survival, and propensity score matching (PSM) was used to balance differences in baseline characteristics. Finally, we used an external cohort from a single-center medical institution to verify the conclusions drawn from the SEER database. RESULTS: A total of 6150 patients were included. The sublobectomy subgroup included segmentectomy (308, 5.0%) and wedge resection (1611, 26.2%). The cutoff value for nLN was 7. In the nLN ≥7 subgroup of the PSM cohort, the CSS of segmentectomy and wedge resection was close to that of the lobectomy subgroup (P = .12), whereas in the nLN <7 subgroup, the CSS of the lobectomy subgroup was significantly higher than that of the sublobectomy with P < .001). Surgical methods, nLN, age, sex, and differentiated grade were independent predictors of CSS. External cohort validation: A total of 1106 patients from the Affiliated Jinhua Hospital of Zhejiang University School of Medicine between 2013 and 2020 were included. The grouping criteria were consistent with the SEER database. In the nLN≥7 subgroup, sublobectomy had a survival outcome similar to that of lobectomy (P = .81). CONCLUSION: Sublobectomy and nLN < 7 were strongly associated with poorer CSS for early-stage NSCLC. On the premise of nLN ≥ 7, sublobectomy could provide similar survival outcomes to lobectomy for these patients.

The impact of age on outcomes of breast cancer in different hormone receptor and HER2 groups.

OBJECTIVE: The aim of the current study was to explore the association between age and outcomes in breast cancer. METHODS: Patients during 2010-2015 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Overall survival (OS) and breast cancer-specific death (BCSD) were taken as endpoints. The restrict cubic spline graph (RCS) was used to explore the relationship between age and outcomes in patients, and the cumulative incidence of BCSD and non-BCSD was calculated using the Gray method. Age-specific gene expression profiles were studied using RNA sequence data from the Cancer Genome Atlas (TCGA) database to explore whether there were young age-related gene or gene sets. RESULTS: A total of 142,755 patients with breast cancer were included. The hazard ratio (HR) of OS for Patients with stage I-III breast cancer was roughly stable before 53 years old and increased significantly after that, and the HR of BCSD for these patients showed a U-shaped distribution when plotted against age, with patients younger than 50 years and patients older than 70 years experiencing the worst survival. Further stratified analysis according to molecular subtype revealed that the U-shaped distribution of the HR of BCSD with was only found in the Hormone receptor-positive/HER2-negative (HoR+/HER2-) subgroup. The cumulative incidence plots showed that young age was associated with worse BCSD in the breast cancer patients with stage I-III and HoR+/HER2- subgroup. In stage IV breast cancer, there was a linearity of the relationship between poor OS and increasing age. We failed to find any differentially expressed age-specific genes between 20-40 years and 41-60 years groups in 258 patients with stage I-III and HoR+/HER2- subtype. CONCLUSION: Young age could predict worse BCSD of patient with stage I-III and HoR+/HER2- breast cancer. The escalating therapy was recommended to young age breast cancer with stage I-III and HoR+/HER2- subtype.

Resection of primary lesion with chemotherapy improves the survival of patients with metastatic colorectal neuroendocrine carcinoma.

OBJECTIVE: To evaluate the effect of resection of primary lesion and chemotherapy on survival of patients with metastatic colorectal neuroendocrine carcinoma (CRNEC). METHODS: Clinical data of 393 patients with metastatic CRNECs between January 2010 and December 2016 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database, including 171 patients who received resection of primary lesion and 221 patients who did not undergo surgery. With the propensity score matching method 172 non-operated patients were selected as controls. Kaplan-Meier method and Log-rank test were used to evaluate the survival differences, while the prognostic factors were analyzed by Cox proportional-hazards model. Metastatic CRNEC patients from January 2001 to December 2021 in Affiliated Jinhua Hospital, Zhejiang University School of Medicine were selected for validation. RESULTS: Compared with non-operated patients, patients who received resection had longer cause-specific survival ( P<0.05). Patients with resected positive lymph nodes>8 had a poorer prognosis compared to those with resected positive lymph nodes≤8 ( P<0.05). Multivariate analysis showed that gender, location of primary lesion and treatments were independent risk factors for cause-specific survival in patients with metastatic CRNEC (all P<0.05). For metastatic CRNEC patients with resection of primary lesion, rectal neuroendocrine carcinoma, positive resected lymph nodes≤8 and resection of primary lesion combined with chemotherapy were associated with better cause-specific survival (all P<0.05). CONCLUSIONS: Patients with metastatic CRNEC may benefit from resection of primary lesion, and resection of primary lesion combined with chemotherapy might be the better strategy for metastatic CRNECs. The number of positive lymph nodes resected is correlated with the prognosis of patients.

A Prediction Model for Chemotherapy-Induced Thrombocytopenia Based on Real-World Data and a Close Relationship Between AST/ALT Ratio and Platelet Count in Patients with Solid Tumors.

Objective: Chemotherapy-induced thrombocytopenia (CIT) can lead to chemotherapy dose delay or reduction, and even serious bleeding. This study aimed to develop a CIT-predicting model based on the laboratory indices of cancer patients undergoing chemotherapy. Material and Methods: From Jun 1, 2017 to Dec 30, 2021, a total of 2043 patients who had received 7676 cycles of chemotherapy were retrospectively enrolled. A logistic regression analysis was performed to identify predictive factors, on the basis of which a nomogram model for predicting CIT was established. A bootstrapping technique was applied for internal validation. A generalized additive mixed model (GAMM) was constructed to analyze the trends in the changes of aspartate aminotransferase (AST), ratio of AST to alanine transaminase (ALT) (AST/ALT ratio), and platelet (PLT) count in patients with solid tumors. P values ≤0.05 were considered statistically significant. Results: The patient-based incidence of CIT was 20.51% and the cycle-based incidence was 10.01%. The multivariate analysis showed that AST level, AST/ALT ratio, and total bilirubin (Tbil), white blood cell (WBC), platelet (PLT), hemoglobin (Hb) levels were significantly associated with the risk of CIT. The GAMM analysis showed that PLT level was inversely associated with AST/ALT ratio and AST level, more significantly with AST/ALT ratio. And both exhibited statistically predictive abilities for CIT. The model achieved an area under the receiver operating characteristic curve (AUC) of 0.793, a sensitivity of 0.543 and a specificity of 0.930. Conclusion: The AST/ALT ratio was inversely associated with the CIT risk in cancer patients. The GAMM model based on laboratory indices presented a high accuracy in predicting the risk of CIT, and a potential to be translated into clinical management.

Nickel nanoparticles exert cytotoxic effects on trophoblast HTR-8/SVneo cells possibly via Nrf2/MAPK/caspase 3 pathway.

Nickel nanoparticles are widely used in the industry and may affect the reproductive system. The potential molecular mechanism of exposing the first-trimester trophoblast cell line (HTR-8/SVneo) to nickel nanoparticles remains unclear. Hence, the aim of this study was to investigate the in vitro cytotoxicity of Ni NPs on HTR-8/SVneo cells. HTR-8/SVneo cells were subjected to various concentrations (0, 2.5, 5, 7.5, 10, and 12.5 µg/cm2) of Ni NPs. The toxicity of the Ni NPs was evaluated in HTR-8/SVneo cells by measuring cell viability. The underlying mechanism of nickel nanoparticles toxicity to HTR-8/SVneo cells was determined by measuring the content of intracellular reactive oxygen species, mitochondrial membrane potential, and the rate of cell apoptosis and cell cycle, by measuring adenosine triphosphate levels, intracellular lipid peroxidation malondialdehyde, total superoxide dismutase, and CuZn/Mn-SOD activities, and by determining proteins related to Nrf2, MAPK, and Cytochrome c. Our results showed that the nickel nanoparticles treatment reduced the viability of HTR-8/SVneo cells, while it increased their oxidative stress and lowered their mitochondrial respiratory capacity. Additionally, the nickel nanoparticles treatment induced cell S-phase arrest and apoptosis. These molecular events may be linked to the oxidative stress-Nrf2 pathway/MAPK/Caspase 3 cascade. Thus, nickel nanoparticles exert cytotoxic effects on HTR-8/SVneo cells, which could affect the function of the placenta in human.

Inhibition of MAT2A-Related Methionine Metabolism Enhances The Efficacy of Cisplatin on Cisplatin-Resistant Cells in Lung Cancer.

Objective: Tumor drug resistance is a vital obstacle to chemotherapy in lung cancer. Methionine adenosyltransferase 2A has been considered as a potential target for lung cancer treatment because targeting it can disrupt the tumorigenicity of lung tumor-initiating cells. In this study, we primarily observed the role of methionine metabolism in cisplatin-resistant lung cancer cells and the functional mechanism of MAT2A related to cisplatin resistance. Materials and Methods: In this experimental study, we assessed the half maximal inhibitory concentration (IC50) of cisplatin in different cell lines and cell viability via Cell Counting Kit-8. Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) was used to determine the expression of relative proteins and genes. Crystal violet staining was used to investigate cell proliferation. Additionally, we explored the transcriptional changes in lung cancer cells via RNA-seq. Results: We found H460/DDP and PC-9 cells were more resistant to cisplatin than H460, and MAT2A was overexpressed in cisplatin-resistant cells. Interestingly, methionine deficiency enhanced the inhibitory effect of cisplatin on cell activity and the pro-apoptotic effect. Targeting MAT2A not only restrained cell viability and proliferation, but also contributed to sensitivity of H460/DDP to cisplatin. Furthermore, 4283 up-regulated and 5841 down-regulated genes were detected in H460/DDP compared with H460, and 71 signal pathways were significantly enriched. After treating H460/DDP cells with PF9366, 326 genes were up-regulated, 1093 genes were down-regulated, and 13 signaling pathways were significantly enriched. In TNF signaling pathway, CAS7 and CAS8 were decreased in H460/DDP cells, which increased by PF9366 treatment. Finally, the global histone methylation (H3K4me3, H3K9me2, H3K27me3, H3K36me3) was reduced under methionine deficiency conditions, while H3K9me2 and H3K36me3 were decreased specially via PF9366. Conclusion: Methionine deficiency or MAT2A inhibition may modulate genes expression associated with apoptosis, DNA repair and TNF signaling pathways by regulating histone methylation, thus promoting the sensitivity of lung cancer cells to cisplatin.

Development and validation of a radiomics-based nomogram for the preoperative prediction of microsatellite instability in colorectal cancer.

BACKGROUND: Preoperative prediction of microsatellite instability (MSI) status in colorectal cancer (CRC) patients is of great significance for clinicians to perform further treatment strategies and prognostic evaluation. Our aims were to develop and validate a non-invasive, cost-effective reproducible and individualized clinic-radiomics nomogram method for preoperative MSI status prediction based on contrast-enhanced CT (CECT)images. METHODS: A total of 76 MSI CRC patients and 200 microsatellite stability (MSS) CRC patients with pathologically confirmed (194 in the training set and 82 in the validation set) were identified and enrolled in our retrospective study. We included six significant clinical risk factors and four qualitative imaging data extracted from CECT images to build the clinics model. We applied the intra-and inter-class correlation coefficient (ICC), minimal-redundancy-maximal-relevance (mRMR) and the least absolute shrinkage and selection operator (LASSO) for feature reduction and selection. The selected independent prediction clinical risk factors, qualitative imaging data and radiomics features were performed to develop a predictive nomogram model for MSI status on the basis of multivariable logistic regression by tenfold cross-validation. The area under the receiver operating characteristic (ROC) curve (AUC), calibration plots and Hosmer-Lemeshow test were performed to assess the nomogram model. Finally, decision curve analysis (DCA) was performed to determine the clinical utility of the nomogram model by quantifying the net benefits of threshold probabilities. RESULTS: Twelve top-ranked radiomics features, three clinical risk factors (location, WBC and histological grade) and CT-reported IFS were finally selected to construct the radiomics, clinics and combined clinic-radiomics nomogram model. The clinic-radiomics nomogram model with the highest AUC value of 0.87 (95% CI, 0.81-0.93) and 0.90 (95% CI, 0.83-0.96), as well as good calibration and clinical utility observed using the calibration plots and DCA in the training and validation sets respectively, was regarded as the candidate model for identification of MSI status in CRC patients. CONCLUSION: The proposed clinic-radiomics nomogram model with a combination of clinical risk factors, qualitative imaging data and radiomics features can potentially be effective in the individualized preoperative prediction of MSI status in CRC patients and may help performing further treatment strategies.

Specific metabolic response of patient-derived organoids to curcumin of colorectal cancer.

Organoid is a burgeoning model that have emerged in the past decade. Tumor organoids can simulate specific aspects of the 3D structure, cell type composition and function of real tumors to make up for the deficiencies of cell models and animal models. Curcumin has been found to be effective in suppressing various phases of colorectal cancer development. Nevertheless, there is no clear evidence that the results obtained on cultured cells or animal models can be translated in humans. Therefore, we constructed patient-derived organoids of colorectal cancer to show the curcumin responses of these organoids. Then, a MS-based non-targeted metabolomic strategy was to gain a system-level understanding of the mechanism of curcumin on colorectal cancer patient-derived organoids. Then non-targeted metabonomic analysis found that curcumin mainly regulated the phenylalanine, tyrosine and tryptophan biosynthesis, nicotinate and nicotinamide metabolism, purine metabolism in the organoids of colorectal cancer. Our research provided a reference for further revealing the role of curcumin in human-derived colorectal cancer-like solid tumors.

Metabolomics studies on cachexia in patients with cancer: a scoping review protocol.

INTRODUCTION: Cancer seriously threatens human health worldwide. Cancer cachexia is one of the life-threatening consequences that occurs commonly in patients with cancer, and severely worsens patient survival, prognosis and quality of life. Previous studies have demonstrated that cancer cachexia is closely related to differential metabolites and metabolic pathways based on metabolomics analysis. This scoping review protocol, therefore, aims to provide the strategy for a formal scoping review that will summarise the differential metabolites and related metabolic pathways of cachexia in patients with cancer. METHODS AND ANALYSIS: The proposed scoping review will follow the Arksey and O'Malley's methodological framework, Levac et al's recommendations for applying this framework, and Peters' enhancements of the framework. The key information from the selected studies will be extracted, including author, year of publication, cachexia definition, country/origin, study design, setting, population and sample size, biological specimens, independent variables, independent variables' measure and statistical analysis. A summary of metabolites will be divided into several sections depending on the biological specimen. Differential metabolites will be compared between paired groups, and the number and names of related metabolic pathways will be counted and described. The reporting of this scoping review will be in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews checklist. This is a scoping review protocol and describes the planned review process and provides data examples extracted from a pilot study to confirm the feasibility of further investigation of the subject. ETHICS AND DISSEMINATION: An ethical approval is not required for this scoping review protocol, nor for the scoping review. The results of this scoping review will be disseminated through publication in a peer-reviewed journal, or presentation at a national or international conference.

Estrogen receptor-negative/progesterone receptor-positive and her-2-negative breast cancer might no longer be classified as hormone receptor-positive breast cancer.

BACKGROUND: The single progesterone receptor (PR)-positive phenotype (estrogen receptor (ER)-/PR + , sPR positive) is an infrequent and independent biological entity. However, the prognosis of patients with sPR-positive and her-2-negative phenotype is still controversial, and it is not always easy to decide treatment strategies for them. METHODS: Patients during 2010-2014 were identified from Surveillance, Epidemiology, and End Results (SEER) database. The Kaplan-Meier method was used to evaluate cancer-specific survival (CSS). The propensity score matching (PSM) method was used to balance differences of characteristics in groups. The Life-Table method was used to calculate 5-year CSS rates and the annual hazard rate of death (HRD). RESULTS: A total of 97,527 patients were included, and only 745 (0.76%) patients were sPR-positive phenotype. The majority of sPR-positive breast cancer were basal-like subtype. Survival analysis showed that the sPR-positive breast cancer had similar prognosis comparing to double hormonal receptor-negative (ER-/PR-, dHoR-negative) breast cancer, and had the highest HRD during the initial 1-2 years of follow-up, then maintained the HRD of almost zero during the late years of follow-up. CONCLUSIONS: The patients with sPR-positive and her-2-negative breast cancer, similar to dHoR-negative breast cancer, had a worse survival, and could benefit from chemotherapy significantly. However, the escalating endocrine therapy was not recommended for sPR-positive patients. The patients with sPR positive should be excluded from future clinical trials concerning endocrine therapy.

Efficacy and safety of pyrotinib in advanced lung adenocarcinoma with HER2 mutations: a multicenter, single-arm, phase II trial.

BACKGROUND: There is currently a lack of effective treatments for non-small cell lung cancer (NSCLC) patients harboring HER2 mutations. We examined the efficacy and safety of, and potential resistance mechanism to, pyrotinib, a pan-HER inhibitor, in advanced NSCLC carrying HER2 mutations. METHODS: In this multicenter, single-arm, phase II trial, stage IIIB-IV NSCLC patients harboring HER2 mutations, as determined using next-generation sequencing, were enrolled and treated with pyrotinib at a dose of 400 mg/day. The primary endpoint was 6-month progression-free survival (PFS) rate, and secondary endpoints were objective response rate (ORR), PFS, overall survival (OS), disease control rate (DCR), and safety. The impact of different HER2 mutation types on sensitivity to pyrotinib and the potential of utilizing mutational profile derived from circulating tumor DNA (ctDNA) to predict disease progression were also explored. RESULTS: Seventy-eight patients were enrolled for efficacy and safety analysis. The 6-month PFS rate was 49.5% (95% confidence interval [CI], 39.2-60.8). Pyrotinib produced an ORR of 19.2% (95% CI, 11.2-30.0), with median PFS of 5.6 months (95% CI, 2.8-8.4), and median OS of 10.5 months (95% CI, 8.7-12.3). The median duration of response was 9.9 months (95% CI, 6.2-13.6). All treatment-related adverse events (TRAEs) were grade 1-3 (all, 91.0%; grade 3, 20.5%), and the most common TRAE was diarrhea (all, 85.9%; grade 3, 16.7%). Patients with exon 20 and non-exon 20 HER2 mutations had ORRs of 17.7% and 25.0%, respectively. Brain metastases at baseline and prior exposure to afatinib were not associated with ORR, PFS, or OS. Loss of HER2 mutations and appearance of amplification in HER2 and EGFR were detected upon disease progression. CONCLUSIONS: Pyrotinib exhibited promising efficacy and acceptable safety in NSCLC patients carrying exon 20 and non-exon 20 HER2 mutations and is worth further investigation. TRIAL REGISTRATION: Chinese Clinical Trial Registry Identifier: ChiCTR1800020262.