PD-1 inhibitor combined with albumin paclitaxel and apatinib as second-line treatment for patients with metastatic gastric cancer: a single-center, single-arm, phase II study.

BACKGROUND: Immune checkpoint inhibitors have been approved for first- and third-line treatment of advanced gastric cancer. However, pembrolizumab alone in the second line did not improve overall survival compared to chemotherapy in the KEYNOTE-061 study. In this study, we aimed to explore the efficacy and safety of a three-drug regimen of PD-1 inhibitor combined with albumin paclitaxel and apatinib (a VEGFR inhibitor) for the second-line treatment of patients with metastatic gastric cancer (mGC). METHODS: This was a single-center, single-arm, phase II clinical study. Patients with mGC with stable microsatellite and negative HER-2 expression who failed first-line chemotherapy were enrolled. The enrolled patients were treated with PD-1 inhibitor (selected according to patients' requirements) in combination with albumin paclitaxel (125 mg/m2, intravenously, days 1 and 8, or 250 mg/m2, intravenously, day 1) and apatinib (250 or 500 mg, orally, days 1-21) every 3 weeks. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response, and adverse events (AEs). RESULTS: From July 11, 2019, to October 13, 2022, a total of 43 patients were enrolled, of whom 10 were PD-L1 negative, 11 were PD-L1 positive, and 22 had unknown PD-L1 expression. As of the data cutoff on April 1st, 2023, nine patients had partial response, 29 had stable disease, and five experienced progressive disease, with the ORR of 20.9% and DCR of 88.3%. The median PFS was 6.2 months (95% CI, 3.9-9.3), and the median OS was 10.1 months (95% CI, 7.5-14.1). All patients suffered from alopecia and neurotoxicity. The other main AEs of grade 1 or 2 were bone marrow suppression (N = 21, 48.8%), hand-foot reaction (N = 19, 44.2%), hypertension (N = 18, 41.9%), hypothyroidism (N = 11, 25.6%), gastrointestinal bleeding (N = 3, 7.0%), and liver function damage (N = 5, 11.6%). Two patients reported grade 3-4 immune-related liver damage. CONCLUSION: Second-line PD-1 inhibitor combined with albumin paclitaxel and apatinib showed certain efficacy and safety in patients with mGC. TRIAL REGISTRATION: Clinical trials, NCT04182724. Registered 27 November 2019; retrospectively registered, https://clinicaltrials.gov/study/NCT04182724.

Prognostic value of the Lung Immune Prognostic Index for HER-2-negative metastatic gastric cancer.

Background: The aim of this study was to explore whether the Lung Immune Prognostic Index (LIPI) is associated with clinical outcomes in patients with metastatic gastric cancer (MGC) treated with anti-PD-1 and chemotherapy. Methods: Patients with MGC treated with an anti-PD-1 therapy or chemotherapy were enrolled. This study was composed of two cohorts including 266 patients in the anti-PD-1-treated group and 139 patients in the chemotherapy-treated group. Results: Patients treated with anti-PD-1 therapy that also showed a good LIPI showed a longer median progression-free survival and median overall survival in patients with an intermediate or poor LIPI. These outcomes were not observed in the chemotherapy cohort. Conclusion: Good LIPI correlated with better outcomes for patients with MGC in the anti-PD-1-treated group but not in the chemotherapy-treated group.

PD-1 inhibitors-based second-line therapy for metastatic gastric cancer.

Background: Metastatic gastric cancer (MGC) patients with progression on first-line treatment still have poor outcomes on chemotherapy. The KEYNOTE-061 study demonstrated that pembrolizumab, a PD-1inhibitor, was not better than paclitaxel as second-line therapy for MGC. Herein, we explored the efficacy and safety of PD-1inhibitor based treatment for MGC patients in the second line. Methods: In this observational, retrospective study, we enrolled MGC patients treated with anti-PD-1 based therapy as second-line in our hospital. We primarily assessed the treatment's efficacy and safety. We also evaluated the relationship between clinical features and outcomes using univariate and multivariate analyses. Results: We enrolled 129 patients with an objective response rate (ORR) of 16.3% and a disease control rate (DCR) of 79.1%. Patients treated with PD-1inhibitor combined with chemotherapy and anti-angiogenic agents had ORR of 19.6% and higher DCR of 94.1%. The median progression-free survival (PFS) was 4.10 months, and the median overall survival (OS) was 7.60 months. In univariate analysis, patients treated with PD-1inhibitor combined with chemotherapy and anti-angiogenic agents and with prior anti-PD-1 history were significantly associated with favorable PFS and OS. In the multivariate analysis, different combination therapy and prior anti-PD-1 history were independent prognosis biomarkers for PFS and OS. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 28 (21.7%) patients. Common adverse events (AEs) included fatigue, hyper/hypothyroidism, neutrophil decrease, anemia, skin reactions, proteinuria, and hypertension. We did not observe treatment-related deaths. Conclusion: Our current results indicated that PD-1-inhibitor and chemo-anti-angiogenic agents combination therapy and prior PD-1 treatment history might improve clinical activity for GC immunotherapy as second-line treatment with acceptable safety profiles. Further studies are needed to verify those outcomes for MGC in other centers.

A composite indicator of derived neutrophil-lymphocyte ratio and lactate dehydrogenase correlates with outcomes in pancreatic carcinoma patients treated with PD-1 inhibitors.

Background: There are currently no established biomarkers that can predict whether advanced pancreatic carcinoma (PC) patients would benefit from immune checkpoint inhibitors (ICIs). Our study investigated whether the pretreatment composite biomarker of derived neutrophil-lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH) can be used as a reliable prognostic factor for the survival of PC patients receiving PD-1 inhibitor therapy. Methods: Patients with advanced PC treated with PD-1 inhibitors at a single center from September 2015 to September 2020 were included. The high levels of dNLR (≥3) and LDH (≥250 U/L) were considered to be risk factors. Based on these two risk factors, patients in this study were categorized into two risk groups: the good dNLR-LDH group, without risk factors, and the intermediate/poor dNLR-LDH group, with one to two risk factors. Overall survival (OS) and progression-free survival (PFS) served as this study's primary and secondary endpoints. Cox regression models were used to identify independent prognostic factors for survival benefit. Results: There were 98 patients in our study. The good group included 61 (62.2%) patients and the intermediate/poor group included 37 (37.8%). The overall patients with PC who received immunotherapy had a median OS of 12.1 months, and the good dNLR-LDH group had a significantly longer OS compared with the intermediate/poor dNLR-LDH group (44.2 vs. 6.4 months; p < 0.010); median PFS was 3.7 and 2.5 months (p = 0.010). The number of metastatic sites >2 and immunotherapy as third-line or later was associated with worse PFS, and the line of immunotherapy and the dNLR-LDH indicator were independent prognostic factors for OS, according to multivariate analysis. Conclusion: The pretreatment composite biomarker of dNLR and LDH can be used as a prognostic biomarker in patients with advanced PC treated with PD-1 inhibitors.

Pretreatment platelet-to-lymphocyte ratio (PLR) as a prognosticating indicator for gastric cancer patients receiving immunotherapy.

BACKGROUND: Previous investigations suggest that systemic inflammation markers are able to provide prognostic value in several cancers. This study seeks to characterize the ability of pretreatment platelet-to-lymphocyte ratio (PLR) to prognosticate advanced or metastatic gastric cancer patients (AGC or MGC, respectively) receiving immunotherapy. METHODS: AGC and MGC patients exposed to PD-1 inhibitors from January 2016-August 2021 in the Chinese PLA General Hospital were recruited. Correlations between PLR and overall survival (OS), progression-free survival (PFS), and immunotherapy-associated tumor response rates were determined. RESULTS: 237 patients were enrolled for this retrospective investigation. The 6 month and 12 month PFS based on the area under the curve value was 0.60 and 0.65 (p < 0.05). based on a calculated PLR cut-off value of 139.41, The PLR < 139.41 group has a longer OS in contrast with the PLR ≥ 139.41 group (13.46 m vs 10.71 m, HR = 0.57, 95% CI 0.42-0.78, p = 0.004). The PLR < 139.41 group had a PFS of 7.93 m in contrast to the 4.75 m seen in those with PLR ≥ 139.41 group (HR = 0.57, 95% CI 0.43-0.76, p = 0.002). The disease control rate (DCR) and objective response rate (ORR) were 86.17% and 30.85%, respectively, in the PLR < 139.41 group, but were 82.52% and 32.17%, respectively in the PLR ≥ 139.41 group. Both groups did not show any marked differences in terms of ORR and DCR (p = 0.887, p = 0.476). PLR is an independent prognostic indicator for OS and PFS upon uni- and multivariate analyses (p < 0.05). CONCLUSIONS: Pre-treatment PLR correlated significantly with PFS and OS in AGC and MGC patients who received immunotherapy. An elevated PLR may provide guidance on subsequent treatment options.

Construction of a nomogram to predict the survival of metastatic gastric cancer patients that received immunotherapy.

Background: Immunotherapy has shown promising results for metastatic gastric cancer (MGC) patients. Nevertheless, not all patients can benefit from anti-PD-1 treatment. Thus, this study aimed to develop and validate a prognostic nomogram for MGC patients that received immunotherapy. Methods: Herein, MGC patients treated with anti-PD-1 between 1 October 2016 and 1 June 2022 at two separate Chinese PLA General Hospital centers were enrolled and randomly divided into training and validation sets (186 and 80 patients, respectively). The nomogram was constructed based on a multivariable Cox model using baseline variables from the training cohort. Its predictive accuracy was validated by the validation set. The consistency index (C-index) and calibration plots were used to evaluate the discriminative ability and accuracy of the nomogram. The net benefit of the nomogram was evaluated using decision curve analysis (DCA). Finally, we stratified patients by median total nomogram scores and performed Kaplan-Meier survival analyses. Results: We developed the nomogram based on the multivariate analysis of the training cohort, including four parameters: surgery history, treatment line, lung immune prognostic index (LIPI), and platelet-to-lymphocyte ratio (PLR). The C-index of the nomogram was 0.745 in the training set. The calibration curve for 1- and 2-year survival showed good agreement between nomogram predictions and actual observations. In the validation group, the calibration curves demonstrated good performance of the nomogram, with a C-index for overall survival (OS) prediction of 0.713. The OS of patients with a score greater than the median nomogram score was significantly longer than patients with a score lower or equal to the median (p < 0.001). Conclusion: We constructed a nomogram to predict the outcomes of MGC patients that received immunotherapy. This nomogram might facilitate individualized survival predictions and be helpful during clinical decision-making for MGC patients under anti-PD-1 therapy.

Fruquintinib in Combination With PD-1 Inhibitors in Patients With Refractory Non-MSI-H/pMMR Metastatic Colorectal Cancer: A Real-World Study in China.

Background: Fruquintinib, a vascular endothelial growth factor receptor inhibitor, is a new anticancer drug independently developed in China to treat refractory metastatic colorectal cancer (mCRC). In Japan, regorafenib combined with nivolumab has been demonstrated to be promising in patients with refractory mCRC. Here, in a real-world study, we were aimed to evaluate the efficacy of fruquintinib with various programmed death-1 (PD-1) inhibitors after standard treatment in Chinese non-microsatellite instability-high (MSI-H)/mismatch repair proficient mCRC patients. Methods: A total of 45 patients with refractory mCRC were involved in the study. They received fruquintinib (3 or 5 mg, orally administered once a day for 3 weeks followed by 1 week off in 4-week cycles) and a PD-1 inhibitor(200 mg pembrolizumab, 3 mg/kg nivolumab, 200 mg sintilimab or camrelizumab, intravenously administered on D1 once every 3 weeks). Progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and objective response rate (ORR) were reviewed and evaluated. Results: Among the 45 patients, the median age was 54 years (29-85). The ORR was 11.1% (5/45), DCR 62.2% (28/45), median PFS equal 3.8 months, and median OS was 14.9 months. The response duration was 3.4 months. PFS between left and right primary tumors and PFS with or without lung metastases were both not significantly different (p > 0.05), which was inconsistent with the result of REGONIVO study. The multivariate analysis indicated no association of OS benefit in the specified subgroups. No adverse-effect-related deaths were reported. Conclusions: Fruquintinib, in combination with anti-PD-1, was observed to have clinical activity in a small population of patients with heavily pretreated mCRC in our center. Further studies are needed to verify this outcome in a large population.

Analysis of a Systemic Inflammatory Biomarker in Advanced Bile Tract Carcinoma Treated with Anti-PD-1 Therapy: Prognostic and Predictive Significance of Lung Immune Prognostic Index Score.

Background: The application of immunotherapy is gradually increasing in advanced bile tract carcinoma (BTC), but only some patients could benefit from it. Validated biomarkers can screen out the beneficiaries. Therefore, the objective of this research is aimed at exploring the predictive value of lung immune prognostic index (LIPI) in advanced BTC patients receiving immunotherapy. Methods: This study was conducted on 110 BTC patients. The cut-off value of the derived neutrophil-to-lymphocyte (dNLR) ratio was obtained by the ROC curves to predict the tumor progression rate at the 6th month. The high levels of dNLR (≥the cut-off value) and lactate dehydrogenase (≥the upper limit of normal) were considered to be two risk factors for LIPI. Based on these two risk factors, patients were categorized into 3 groups based on risk factors: 0 for the good group, 1 for the intermediate group, and 2 for the poor group. Due to the limited number of patients in the poor group, it was integrated into the intermediate group to be the intermediate/poor group. Finally, the subjects were divided into two groups: LIPI-good and LIPI-intermediate/poor. Results: The results shed light on the 110 BTC patients' LIPI in advanced BTC patients receiving immunotherapy, indicating that the cut-off value of dNLR was 1.74. According to the risk stratification, 38 (34.5%) patients had a good LIPI score, whereas the LIPI score was intermediate/poor in 72 (65.5%). In addition, patients with good LIPI were related to longer progression-free survival (PFS) and overall survival (OS), compared to those with intermediate/poor LIPI (12.17 months vs. 3.17 months; 20.2 months vs. 8.7 months). According to multivariate analysis, the intermediate/poor LIPI group was independently correlated with over 2.3 times greater risk of tumor progression (HR = 2.301; 95% CI, 1.395-3.796; P = 0.001) and over 1.8 times greater risk of death (HR = 1.877; 95% CI, 1.076-3.275; P = 0.027) than the good group. Moreover, the result also revealed that there were significant differences of DCR for patients of the good group and the intermediate/poor group (86.8% vs. 65.3%; P = 0.012). Conclusion: Finally, this study verifies, for the first time, that LIPI is an independent factor affecting the survival and clinical efficacy of advanced BTC patients receiving immunotherapy. It may be difficult for patients with intermediate/poor LIPI to benefit from immunotherapy.

PD-1 Inhibitors Could Improve the Efficacy of Chemotherapy as First-Line Treatment in Biliary Tract Cancers: A Propensity Score Matching Based Analysis.

BACKGROUND: There are limited treatment options for advanced biliary tract cancers (BTCs), including intrahepatic cholangiocarcinoma, extrahepatic bile duct cancer, gallbladder cancer. We compared the efficacy and safety of PD-1 inhibitors plus chemotherapy and chemotherapy alone as first-line treatment in patients with advanced BTC. METHODS: We retrospectively reviewed patients with BTC treated at the oncology department of the Chinese PLA general hospital receiving PD-1 inhibitor with chemotherapy (anti-PD-1+C group) or chemotherapy alone (C group). Propensity Score Matching (PSM) (1:1) was performed to balance potential baseline confounding factors. Progression-free survival (PFS) was analyzed using Kaplan-Meier survival curves with log-rank tests. Objective response rate (ORR), disease control rate (DCR), and safety were also analyzed. RESULTS: This study included 75 patients who received PD-1 inhibitors (including Pembrolizumab, Nivolumab, Sintilimab, Toripalimab) plus chemotherapy and 59 patients who received chemotherapy alone. After matching, there were no significant differences between the two groups for baseline characteristics. Within the matched cohort, the median PFS was 5.8m in the anti-PD-1+C group, which was significantly longer than the C group, at 3.2m (HR: 0.47, 95% CI 0.29 to 0.76, P = 0.004). The ORR was 21.7% and DCR was 80.4% in the anti-PD-1+C group, while the ORR was 15.2% and DCR was 69.6% in the C group. No significant differences were found in the ORR and DCR between the two groups (P=0.423, P=0.231). Grade 3 or 4 treatment was related to adverse events (AEs) that occurred in the anti-PD-1+C group, namely hypothyroidism (n=3, 6.5%), rash (n=2, 4.2%), and hepatitis (n=1, 2.2%). There was no AE-related death. The grade 3-4 leukopenia rate was similar in the two groups (4.3% vs. 6.5%). CONCLUSIONS: Anti-PD-1 therapy plus chemotherapy prolonged the PFS compared with chemotherapy alone in advanced BTC with controllable AEs. Further clinical trials are needed to confirm this result.

Hyperprogressive Disease Caused by PD-1 Inhibitors for the Treatment of Pan-Cancer.

BACKGROUND: Nowadays, PD-1/PD-L1 inhibitors are widely used to treat various malignant tumors. However, during the immunotherapy in a few patients, a flare-up of tumor growth occurred. This new pattern of progression is called hyperprogressive disease (HPD). Patients and Methods. The retrospective study included 377 patients with various malignant tumors treated with PD-1 inhibitors (nivolumab or pembrolizumab) in the Chinese PLA General Hospital from January 2015 to January 2019. Clinicopathologic variables, tumor growth rate (TGR), and treatment outcomes were analyzed in patients with pan-cancer treated with PD-1 inhibitors. HPD was defined as the difference of TGR before and during immunotherapy exceeding 50%. RESULTS: In 38 of 377 patients (10.08%), HPD occurred after treatment with PD-1 inhibitors. Patients with HPD had lower overall survival (OS) than those without HPD (median OS, 3.6months (95% CI, 3.0-4.2) vs. 7.3 months (95% CI, 5.9-8.7); P < 0.01). Factors related to HPD include more than 2 metastatic sites, ECOG performance status ≥ 2, hepatic metastases, and lactate dehydrogenase level greater than normal upper limit. KRAS status was significantly associated with HPD in patients with colorectal cancer. In the exploratory predictors' analysis, the rapid increase of characteristic tumor markers (such as CEA in colorectal cancer, CA199 in pancreatic cancer and cholangiocarcinoma) within one month was found to be associated with the occurrence of HPD. CONCLUSIONS: HPD was developed with different rates in a variety of malignant tumor patients treated with PD-1 inhibitors and related to some clinicopathological features and poor prognosis. Tumor markers, especially CA199, might be served as early predictors of HPD.

The Prognostic Value of Pre-treatment Hemoglobin (Hb) in Patients With Advanced or Metastatic Gastric Cancer Treated With Immunotherapy.

BACKGROUND: Biomarkers such as prevailing PD-L1 expression and TMB have been proposed as a way of predicting the outcome of immunotherapy in patients with advanced gastric cancer (AGC) and metastatic gastric cancer (MGC). Our study aims to investigate whether there is a link between pretreatment hemoglobin (Hb) levels and survival to immunotherapy in patients with AGC and MGC. METHODS: We retrospectively reviewed patients with AGC or MGC treated at the oncology department of the Chinese PLA general hospital receiving PD-1 inhibitor. The Propensity Score Matching (PSM) (1:1) was performed to balance potential baseline confounding factors. Progression-free survival (PFS) and overall survival (OS) was analyzed among different Hb level (normal Hb group and decreased Hb group). Objective response rate (ORR), disease control rate (DCR) were also analyzed. Univariate analysis and multivariate analysis were performed further to validate the prognostic value of Hb level. RESULTS: We included 137 patients with AGC and MGC who received PD-1 inhibitors (including Pembrolizumab, Nivolumab, Sintilimab, Toripalimab) in this study. After PSM matching, there were no significant differences between the two groups for baseline characteristics. Within the matched cohort, the median PFS was 7.8 months in the normal Hb level group and 4.3 months in the decreased Hb group (HR 95% CI 0.5(0.31, 0.81), P=0.004). The OS was 14.4 months with normal Hb level as compared with 8.2 months with decreased Hb level(HR 95% CI 0.59(0.37, 0.94), P=0.024). The ORR was 40.7% and DCR was 83.0% in the normal Hb group, while the ORR was 25.5% and DCR was 85.1% in the decreased Hb group. No significant differences were found in the ORR and DCR between the two groups (P=0.127, P=0.779). Univariate analysis and multivariate analysis showed that Hb level was only independent predictor for PFS and baseline Hb level was significant prognostic factor influencing the OS. Only when patients had normal Hb level, anti-pd-1 monotherapy or combined with chemotherapy was superior to anti-pd-1 plus anti-angiogenic therapy with respect to PFS (10.3 m vs 2.8 m, HR 95% CI 0.37(0.15, 0.95), P=0.031) and OS(15 m vs 5.7 m, HR 95% CI 0.21 (0.08, 0.58), P=0.001). CONCLUSIONS: Our study have demonstrated that pretreatment Hb level was an independent prognostic biomarker in term of PFS and OS with immunotherapy for AGC and MGC patients. Correction of anemia for GC patients as immunotherapy would be a strategy to improve the survival. More data was warranted to further influence this finding.

Research on Mechanism of miR-214 Packaged with Lipidosome Nanoparticles on Prompting the Apoptosis of Intestinal Cancer Through Regulating p53 Pathway.

Our study aimed at studying mechanism of miR-214 packaged with lipidosome nanoparticles on prompting apoptosis of intestinal cancer through regulating p53 pathway. SW480 cells were divided into blank group, empty carrier group, agonist group and group with carrier and antagonist. The negative control group was set, and groups related to p53 pathway were set as agonist group, inhibitor group and group with antagonist and inhibitor. The effect of miR-214 packaged with lipidosome nanoparticles on proliferation and apoptosis of intestinal cancer cells and p53 pathway in intestinal cancer cells was observed. Expression level of miR-214 in group with carrier and antagonist was lower than in other groups. The proportion of active cells in the group with carrier and antagonist started to be reduced notably from the second day. There was no notable declining tendency active cells' proportion from other groups. The quantity of cell apoptosis in group with carrier and antagonist was higher than in the other groups. The expression level of cleaved Caspase-3 in the group with carrier and antagonist was notably higher than in the other groups. Moreover, expression of Bcl-2/Bax protein was reversed, while expression of p53 protein in the carrier and antagonist groups was notably higher than in the other groups. The antagonist of miR-214 packaged with lipidosome nanoparticles could target on p53 pathway. The activity of p53 pathway was reduced by miR-214, and expression of Bcl-2 was increased. The expressions levels of Bax and cleaved Caspase-3 were also reversed, and molecular mechanism was mainly related with restraining of p53 signal pathway.

Neutrophil-to-Lymphocyte Ratio (NLR) Predicts PD-1 Inhibitor Survival in Patients with Metastatic Gastric Cancer.

BACKGROUND AND AIMS: Biomarkers for systemic inflammation have been introduced into clinical practice for risk-rating in cancer patients' treatment. This study is aimed at confirming the prognostic role of the neutrophil-to-lymphocyte ratio (NLR) as an effective biomarker for patients with metastatic gastric cancer (MGC) receiving anti-PD-1 agents. METHOD: Patients with MGC who received anti-PD-1 treatment at the Chinese PLA General Hospital between January 2016 and November 2020 were reviewed. The study analyzed the association of NLR and overall survival (OS) or progression-free survival (PFS) and antitumor response rate with PD-1 inhibitors. RESULTS: 137 patients were included in the final analysis. The area under the curve value of NLR for 6-month OS was 0.71. The best cut-off value for NLR was 3.23. NLR < 3.23 was associated with longer OS (HR = 0.38, 95% CI, 0.26-0.57, p < 0.001) and PFS (HR = 0.42, 95% CI, 0.29-0.62, p < 0.001) in patients with MGC. No significant difference was observed in the objective response rate (ORR) (35.8% vs. 28.6%, p = 0.377) and disease control rate (DCR) (86.4% vs. 78.6%, p = 0.229) in the NLR < 3.23 group and in the NLR ≥ 3.23 group, respectively. Univariate analysis and multivariate analysis found that NLR was an independent prognosis biomarker for PFS and OS. CONCLUSIONS: Pretreatment elevated NLR was significantly associated with inferior PFS and OS in patients with MGC who received anti-PD-1 inhibitors. Clinicians need to consider patients with elevated NLR for decisions on immunotherapy strategy.

Divergent expression of DCLK1 in gastrointestinal neuroendocrine tumors and primary hepatic, gallbladder, and pancreatic neuroendocrine tumors.

Doublecortin-like kinase 1 (DCLK1) is reported to be a negative prognostic marker in colorectal cancer and is involved in tumorigenesis and progression through several miRNA pathways. In this study, We analyzed its expression in neuroendocrine tumor (NET) and explored its relation with survival outcome. 122 patients were enrolled in the study, including 60 cases of GI-NETs, 24 cases of primary hepatic NETs (PHNETs), 16 cases of gallbladder NETs (GBNETs) and 22 cases of pancreatic NETs (pNETs). IHC was performed for DCLK1 on tumor tissue. All patients underwent a baseline visit, histologic determination, and a follow-up for survival. In the 60 cases of GI-NETs, DCLK1 showed diffuse cytoplasmic expression. The positive rates of DCLK1, Syn and CgA were 100% (60/60), 100% (60/60) and 36.7% (22/60), respectively. However, DCLK1 showed negative staining in all of the 62 cases of PHNETs, GBNETs, and pNETs. The mean score of DCLK1, Syn, and CgA were (5.77±2.012), (5.13±2.078) and (2.68±2.797), respectively. DCLK1 was correlated with primary site (P<0.001) and Syn expression (P = 0.045). Additionally, in GI-NETs, we found that DCLK1 expression was associated with worse OS (log-rank = 5.212, P = 0.022). The divergent expression of DCLK1 in NETs suggests different functional roles of DCLK1 in different locations of NET within the digestive system. However, with the limited number of tumor samples, its outcome prediciton still needs further investigation. DCLK1 expression may aid in the diagnosis and prognosis of GI-NETs.

LncRNA HEIH promotes cell proliferation, migration and invasion in cholangiocarcinoma by modulating miR-98-5p/HECTD4.

To date, a large set of long non-coding RNAs (lncRNAs) have been identified in tumorigenesis and progression. The present study focused on functions and mechanisms of HEIH in cholangiocarcinoma (CHOL). We started this study by testing the expression of HEIH in CHOL tissues by qRT-PCR technology. Next, loss-of-function experiments demonstrated the oncogenic nature of HEIH in CHOL. We also used bioinformatics tools to select miRNAs and mRNAs for support of the ceRNA network. Mechanistic experiments including RIP assay, luciferase reporter assay were carried out for further confirmation of binding situation among ceRNA molecules. At last, rescue experiments proved the ceRNA axis in CHOL. According to the results, HEIH expression was up-regulated in CHOL tissues and cells. Functionally, knockdown of HEIH attenuated cell proliferation, migration and invasion. Mechanistically, bioinformatics analysis, RIP assay and luciferase assay verified the ceRNA network among HEIH, miR-98-5p and HECTD4. Rescue experiments further demonstrated the oncogenic role of HEIH and HECTD4. The final in vivo experiments suggested that knockdown of HEIH restrained tumor growth both in weight and volume. In conclusion, HEIH promoted CHOL tumorigenesis and progression by miR-98-5p/HECTD4 axis, which opens up a new insight for CHOL therapeutics.

Efficacy and safety of nivolumab for metastatic biliary tract cancer.

OBJECTIVE: PD-1 inhibitors have improved efficacy in many cancers. There are currently no reports of the use of PD-1 inhibitors, such as nivolumab, for metastatic biliary tract cancer (mBTC). This study reviewed the efficacy and safety of nivolumab for mBTC with the aim of exploring ways to improve efficacy and survival. METHODS: Thirty patients with mBTC were voluntarily treated with nivolumab at the PLA General Hospital. Nivolumab 3 mg/kg was administered. Progression-free survival (PFS) and overall survival were evaluated by Kaplan-Meier and univariate and multivariate analyses were carried out for clinical characteristics. Objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (AEs) were also evaluated. RESULTS: The median treatment cycle is four cycles. One case was complete response, 5 cases partial response, 12 cases stable, and 12 cases progression. ORR was 20%, DCR was 60%, and PFS was 3.1 months (95% CI: 2.13-4.06). The AEs of nivolumab monotherapy were fatigue (three cases), fever (two cases), hypothyroidism (one case), skin reaction (one case), and liver injury (one case). Nivolumab combined with chemotherapy related grade 1-2 hematologic toxicity were leukopenia (five cases) and thrombocytopenia (two cases), and grade 3-4 were leukopenia (three cases). Non-hematologic toxicity grade 1-2 were nausea and vomiting (four cases), fatigue (four cases), fever (three cases), peripheral neurotoxicity (three cases), and hypothyroidism (one case). Univariate analysis showed that PFS of nivolumab combined with chemotherapy was statistically significant compared with that of nivolumab monotherapy (4.1 vs 2.3 months, P=0.031). Programmed death-ligand 1 (PD-L1) expression positively has no relationship with better PFS in contrast with PD-L1 negatively (3.6 vs 3.0 months P>0.05). Multivariate analysis show nivolumab combined with chemotherapy was only the independent factor for longer PFS (HR: 0.432, P<0.05). CONCLUSION: The safety of nivolumab in mBTC is controllable. Further selection of superior populations is needed to improve the efficacy of nivolumab in mBTC.

The Role of Serum CEA and CA19-9 in Efficacy Evaluations and Progression-Free Survival Predictions for Patients Treated with Cetuximab Combined with FOLFOX4 or FOLFIRI as a First-Line Treatment for Advanced Colorectal Cancer.

BACKGROUND: Previously, it was demonstrated that serum levels of tumor markers, CEA and CA19-9, correlated with chemotherapy. Consequently, it has been hypothesized that dynamic monitoring of changes in these markers may predict the shrinkage or growth of colorectal cancers. To test this hypothesis, we analyzed CEA and CA19-9 serum levels in patients with advanced colorectal cancer who received cetuximab in combination with chemotherapy. These levels were evaluated at various time points to identify their potential to serve as early efficacy predictors during treatment and early predictors of disease progression. PATIENTS AND METHODS: Measurements of tumor markers, CEA and CA 19-9, in patients with metastatic colorectal cancer (n = 73) who received cetuximab plus folinic acid, fluorouracil, and oxaliplatin or irinotecan (FOLFOX4/FOLFIRI) as a first-line treatment at our center were retrospectively analyzed. These levels were also compared with objective responses according to the World Health Organization criteria. Initially, 65 patients had elevated CEA levels (>5 ng/ml), and 59 patients had elevated levels of CA19-9 (>37 U/ml). A total of 172 cycles and 165 cycles of computed tomography/magnetic resonance imaging observations were available for review from these two patient groups. RESULTS: After completing three cycles of treatment, the best diagnosis of cetuximab resistance was achieved when CEA increased by 35% (efficacy, 83.33%; sensitivity, 75.41%) and when CA19-9 increased by 28% (efficacy, 80.00%; sensitivity, 84.31%). Next, the efficacy of cetuximab at the time of diagnosis (at the first imaging examination/after three cycles of treatment) was evaluated after the first cycle of chemotherapy. When CEA decreased by 60% from its baseline level, the best effective rate and sensitivity were observed (63.64% and 80.95%, respectively). Similarly, when CA19-9 was 45% lower than its baseline level, the best effective rate and sensitivity were observed (84.21% and 93.18%, respectively). To evaluate progression-free survival (PFS), levels of both CEA and CA19-9 were evaluated after the third cycle of chemotherapy. Increases of 35% and 28%, respectively, resulted in a shorter PFS period compared with the other patients (3.15 months vs. 9.10 months, respectively; P < 0.0001). Conversely, when the evaluation was performed after the first cycle of chemotherapy, patients exhibiting a 60% decrease in CEA and a 45% decrease in CA19-9 had a longer PFS period (11.13 months vs. 8.10 months, respectively; P = 0.0395). CONCLUSIONS: CEA and CA19-9 are useful indicators of therapeutic curative effect from cetuximab combined with first-line chemotherapy. These markers also helped assess cetuximab resistance and served as early predictors of initial treatment effectiveness. Furthermore, a simultaneous increase or decrease in the levels of both indicators was consistent with the observed differences in PFS.

Efficacy and safety of apatinib in patients with previously treated metastatic colorectal cancer: a real-world retrospective study.

No definitive treatment strategy has been established for patients with metastatic colorectal cancer (mCRC) who experienced progression after three or more lines of chemotherapy. A total of 36 mCRC patients were enrolled in this retrospective study who received apatinib therapy under non-clinical trial setting after progression in People's liberation army general Hospital from March 2015 and August 2017. Progression free survival (PFS), overall survival (OS), disease control rate (DCR), objective response rate (ORR) and treatment-related adverse events (AEs) were reviewed and evaluated. Five patients achieved partial response (PR), and 25 achieved stable disease (SD), and 6 achieved progression disease (PD), illustrating a DCR of 83.3% and an ORR of 13.9%. Median PFS was 3.82 m and median OS was not reached. The toxicities associated with apatinib were generally acceptable with a total grade 3/4 adverse event incidence of 27.8%. The most common grade 3/4 adverse events were hypertension (n = 4, 11.1%), liver function damage (n = 3, 8.3%) and hand-foot syndrome (n = 2, 5.6%). No drug-related death occurred. Apatinib therapy provides a reasonable option with an acceptable safety profile for Chinese mCRC patients failed to prior chemotherapy.

Efficacy and safety of apatinib as second-line therapy for advanced gastric cancer: a single-center observational study.

Apatinib has been proven to be effective and safe among patients in the third-line treatment of advanced gastric cancer in phase II and III trials. We aimed to evaluate its efficacy and safety in second-line practice, and to explore the factors associated with efficacy. Between April 2015 and May 2017, a total of 23 patients with advanced gastric adenocarcinoma or adenocarcinoma of gastroesophageal junction were enrolled and followed up retrospectively after failing the first line of systemic therapy. The median progression-free survival was 4.43 months (95% confidence interval: 1.63-7.22) and the median overall survival was 9.11 months (95% confidence interval: 8.22-9.99). Two patients achieved a partial response and 14 patients achieved stable disease. The disease control rate was 69.6% and the objective response rate was 8.7%. The most common adverse events over grade 3 were hypertension (8.7%) and thrombocytopenia (8.7%). No treatment-related death was documented during the drug administration. Apatinib is an effective regimen for the second-line treatment of advanced gastric and gastroesophageal cancer with manageable toxicity.

CD19loCD27hi Plasmablasts Suppress Harmful Th17 Inflammation Through Interleukin 10 Pathway in Colorectal Cancer.

The enrichment of CD20+ and CD138+ immune cells were previously associated with improved survival in colorectal cancer (CRC). We previously discovered that the resected tumors in CRC patients were highly enriched with interleukin (IL)-10-producing CD19loCD27hi plasmablasts with potential suppressor functions. It is still unknown what roles the CD19loCD27hi plasmablasts play in CRC patients. In this study, we first demonstrated that B cells from peripheral blood mononuclear cells (PBMCs) could be stimulated to resemble tumor-infiltrating plasmablasts using a coculture containing Caco-2 and heat-killed bacteria. The PBMC-derived CD19loCD27hi plasmablasts and tumor-infiltrating plasmablasts contained comparable frequencies of IL-10-expressing cells and secreted similar levels of IL-10. We later found that these CD19loCD27hi plasmablasts significantly suppressed the mRNA and cytokine expression of IL-17A in PBMCs, as well as the expression of RAR-related orphan receptor gamma t (RORγt) in CD4+ T cells. This suppressive effect did not involve the induction of Foxp3+ regulatory T cells, since no upregulation of Foxp3 level was observed. Through IL-10/IL-10R blocking and exogenous IL-10 experiments, we found that these CD19loCD27hi plasmablasts primarily mediated IL-17A suppression through IL-10 production. Other B cell-related mechanisms might also contribute to this inhibitory effect. In our cohort of patients, patients with high frequency of tumor-infiltrating IL-10+ CD19loCD27hi plasmablasts presented low IL-17A+ CD4+ T cell frequency and better survival. Altogether, these results suggested that CD19loCD27hi plasmablasts with Breg functions were associated with better prognosis in CRC, possibly by suppressing harmful Th17 inflammation.