A Network Comparison on Safety Profiling of Immune Checkpoint Inhibitors in Advanced Lung Cancer.

Background: Immune checkpoint inhibitors (ICIs) have become one of the standard treatment options for advanced lung cancer. However, adverse events (AEs), particularly immune-related AEs (irAEs), caused by these drugs have aroused public attention. The current network meta-analysis (NMA) aimed to compare the risk of AEs across different ICI-based regimens in patients with advanced lung cancer. Methods: We systematically searched the PubMed, EMBASE, and Cochrane Library databases (from inception to 19 April 2021) for relevant randomized controlled trials (RCTs) that compared two or more treatments, with at least one ICI administered to patients with advanced lung cancer. The primary outcomes were treatment-related AEs and irAEs, including grade 1-5 and grade 3-5. The secondary outcomes were grade 1-5 and grade 3-5 irAEs in specific organs. Both pairwise and network meta-analyses were conducted for chemotherapy, ICI monotherapy, ICI monotherapy + chemotherapy, dual ICIs therapy, and dual ICIs + chemotherapy for all safety outcomes. Node-splitting analyses were performed to test inconsistencies in network. Sensitivity analyses were adopted by restricting phase III RCTs and studies that enrolled patients with non-small cell lung cancer. Results: Overall, 38 RCTs involving 22,178 patients with advanced lung cancer were enrolled. Both pooled incidence and NMA indicated that treatments containing chemotherapy increased the risk of treatment-related AEs when compared with ICI-based regimens without chemotherapy. As for grade 1-5 irAEs, dual ICIs + chemotherapy was associated with the highest risk of irAEs (probability in ranking first: 50.5%), followed by dual-ICI therapy (probability in ranking second: 47.2%), ICI monotherapy (probability in ranking third: 80.0%), ICI monotherapy + chemotherapy (probability in ranking fourth: 98.0%), and finally chemotherapy (probability in ranking fifth: 100.0%). In grade 3-5 irAEs, subtle differences were observed; when ranked from least safe to safest, the trend was dual ICIs therapy (60.4%), dual ICIs + chemotherapy (42.5%), ICI monotherapy (76.3%), ICI monotherapy + chemotherapy (95.0%), and chemotherapy (100.0%). Furthermore, detailed comparisons between ICI-based options provided irAE profiles based on specific organ/system and severity. Conclusions: In consideration of overall immune-related safety profiles, ICI monotherapy + chemotherapy might be a better choice among ICI-based treatments for advanced lung cancer. The safety profiles of ICI-based treatments are various by specific irAEs and their severity. Systematic Review Registration: https://www.crd.york.ac.uk/prospero, identifier CRD42021268650.

Modified FOLFIRINOX for unresectable locally advanced or metastatic gallbladder cancer, a comparison with GEMOX regimen.

BACKGROUND: The first-line chemotherapy regimen for advanced gallbladder cancer (GBC) is gemcitabine plus platinum (GP), despite its efficacy is limited. The current investigation is a retrospective study to compare the safety and efficacy between the modified FOLFIRINOX (mFOLFIRINOX) and gemcitabine plus oxaliplatin (GEMOX) as the first-line chemotherapy for unresectable locally advanced or metastatic GBC. METHODS: The data of patients with unresectable locally advanced or metastatic GBC, who were treated with mFOLFIRINOX or GEMOX as the first-line therapy between April 2014 and April 2018 at Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, were retrieved. This retrospective study evaluated the clinical characteristics, survival outcomes and adverse events. RESULTS: A total of 44 patients (n=25 in mFOLFIRINOX, n=19 in GEMOX) were included. There were no significant differences between groups in baseline characteristics. The median progression free survival (mPFS) was 5.0 months in the mFOLFIRINOX group and 2.5 months in the GEMOX group [P=0.021; hazard ratio (HR), 0.499; 95% CI, 0.266 to 0.937]. The median overall survival (mOS) was 9.5 months in the mFOLFIRINOX group and 7.0 months in the GEMOX group (P=0.019; HR, 0.471; 95% CI, 0.239 to 0.929). Disease control rate (DCR) was 76.0% in the mFOLFIRINOX group and 47.4% in the GEMOX group (P=0.051). The rate of grade 3-4 adverse events was 48% in the mFOLFIRINOX group and 36.8% in the GEMOX group (P=0.459). The incidence of grade 3-4 neutropenia and diarrhea were more common in the mFOLFIRINOX group, while the incidence of grade 3-4 thrombocytopenia and peripheral neuropathy were more common in the GEMOX group. CONCLUSIONS: mFOLFIRINOX might improve the poor prognosis of unresectable locally advanced or metastatic GBC, and the results need to be further verified by prospective clinical studies.

Net Clinical Benefit of Direct Oral Anticoagulants in Patients With Cancer and Venous Thromboembolism: A Systematic Review and Trade-Off Analysis.

Background: Venous thromboembolism (VTE) is highly prevalent in cancer patients. Recent guidelines recommend considering direct oral anticoagulants (DOACs) for the treatment of cancer-associated thrombosis (CAT). However, direct head-to-head comparisons among DOACs are lacking, and almost no net clinical benefit (NCB) analysis has been performed in patients with CAT. Methods: We systematically searched PubMed, EMBASE, Cochrane Library, and ClinicalTrials.gov for randomized controlled trials (RCTs) reporting on recurrent VTE, major bleeding, or clinically relevant bleeding events in patients with CAT who received DOACs and low-molecular-weight heparins. Relative risks (RRs) and 95% confidence intervals (95% CIs) were calculated using a random-effect model. Surface under the cumulative ranking curve (SUCRA) values were calculated, and a trade-off analysis was performed to estimate the NCB. Results: Overall, four RCTs involving 2,894 patients were enrolled. DOACs were more effective than dalteparin in reducing the risk of recurrent VTE (RR: 0.62, 95% CI: 0.44-0.87), with a comparative risk of major bleeding (RR: 1.33, 95% CI: 0.84-2.11) and an increased risk of clinically relevant bleeding (RR: 1.45, 95% CI: 1.05-1.99). No significant difference was observed among individual anticoagulants in terms of recurrent VTE and major bleeding. With respect to the ranking of each anticoagulant for the primary outcome, edoxaban (SUCRA: 69.2) was more effective than dalteparin (SUCRA: 60.7), rivaroxaban (SUCRA: 60.7), and apixaban (SUCRA: 25.5) in reducing VTE recurrence. For major bleeding, apixaban (SUCRA: 76.3) had the highest cumulative ranking probability, followed by edoxaban (SUCRA: 66.4), dalteparin (SUCRA: 28.8), and rivaroxaban (SUCRA: 28.5). Similar results were observed for clinically relevant bleeding. In terms of both benefit and safety outcomes, DOACs, especially edoxaban, seemed to confer a better NCB profile than dalteparin. Conclusions: DOACs are a safe and effective alternative therapy to dalteparin in patients with CAT. Among them, edoxaban might provide a good risk-to-benefit balance. However, because of the lack of head-to-head studies, further investigations are needed to confirm our findings.

The optimal anticoagulant therapy for mechanical heart valves in a gallbladder cancer patient with hepatic metastases: A case report.

RATIONALE: Developing an optimal anticoagulant strategy poses a challenging task in patients with mechanical heart valves (MHVs) throughout their lifetime. We report an optimal anticoagulant therapy in a cancer patient with hepatic metastases after MHV replacement. PATIENT CONCERNS: A 68-year-old female with MHVs suffered from gallbladder cancer with hepatic metastases. Her international normalized ratio (INR) fluctuated owing to the declined hepatic function. DIAGNOSES: Gallbladder cancer and hepatic metastases, with a history of mechanic aortic valve replacement and mitral valve replacement. INTERVENTIONS: Warfarin was discontinued and Vitamin K1 was immediately administrated via intravenous infusion. low-molecular-weight heparin (LMWH) was regarded as a preferable option, and nadroparin at the dosage of 4100IU daily was administered. OUTCOMES: No adverse event occurred during the patient's hospitalization and two-week follow up after discharge. LESSONS: LMWH may represent a reasonable alternative regarding the inhibition of thrombus and bleeding in MHVs carriers with cancer and hepatic metastases.

Correlated high expression of FXR and Sp1 in cancer cells confers a poor prognosis for pancreatic cancer: A study based on TCGA and tissue microarray.

Bile acids (BAs) was critical in the initiation and progression of various tumors. However, their prognostic significance in pancreatic cancer was still illusive. In the present study, the expression and biological significance of FXR, a major receptor of BAs, in the lethal disease were evaluated in mRNA and protein levels. We found that FXR protein was elevated in the cancerous tissues, which was significantly higher than the adjacent tissues (p < 0.05). Meanwhile, our data showed that FXR was positively correlated with primary tumor location (p = 0.04) and poor survival (p = 0.002). Finally, COX regression model indicated that FXR protein was an independent prognostic factor (p = 0.01; HR = 2.15; 95% CI 1.27-3.63). Consistently, we also found a significant difference of FXR expression between the high and low groups in mRNA level (p < 0.001), and that high FXR expression confers a poor prognosis (p < 0.001). More importantly, the correlation assay showed that FXR was positively correlated Sp1 in both protein (r = 0.351, p = 0.008) and mRNA levels (r = 0.263, p < 0.01), with the simultaneously high expression indicated the worst prognosis on protein (p < 0.001) and mRNA levels (p < 0.001). Additionally, we also showed that FXR was elevated in the pancreatic cancer cells responsible for proliferation and migration. Overall, the data suggested co-high expression of the two factors was an independent prognostic factor (p < 0.001; HR = 3.27; 95% CI 1.86-5.76). Based on these data, we proposed a model to link FXR to Sp1, which included triggered FXR, p38/MAPK and/or PI3K/AKT signaling and phosphorylated Sp1, to illustrate the potential crosstalk between the two factors.

The critical role and potential target of the autotaxin/lysophosphatidate axis in pancreatic cancer.

Autotaxin, an ecto-lysophospholipase D encoded by the human ENNP2 gene, is expressed in multiple tissues, and participates in numerous critical physiologic and pathologic processes including inflammation, pain, obesity, embryo development, and cancer via the generation of the bioactive lipid lysophosphatidate. Overwhelming evidences indicate that the autotaxin/lysophosphatidate signaling axis serves key roles in the numerous processes central to tumorigenesis and progression, including proliferation, survival, migration, invasion, metastasis, cancer stem cell, tumor microenvironment, and treatment resistance by interacting with a series of at least six G-protein-coupled receptors (LPAR1-6). This review provides an overview of the autotaxin/lysophosphatidate axis and collates current knowledge regarding its specific role in pancreatic cancer. With a deeper understanding of the critical role of the autotaxin/lysophosphatidate axis in pancreatic cancer, targeting autotaxin or lysophosphatidate receptor may be a potential and promising strategy for cancer therapy.

Expression profile and prognostic value of SAV1 in patients with pancreatic ductal adenocarcinoma.

SAV1 is a human homolog of salvador that contains two protein-protein interaction modules known as WW domains and acts as a scaffolding protein for Hpo and Warts. SAV1 is known to be a tumor suppressor, but its clinical and prognostic implications remain elusive. This study aimed at evaluating the prognostic significance and associated expression of SAV1 in pancreatic ductal adenocarcinoma (PDAC) patients. The expression of SAV1 in tissue specimens of PDAC patients were assayed with immunohistochemistry on a tissue microarray. The correlations between SAV1 expression and clinicopathological characteristics were analyzed by Pearson's chi-square test, Fisher's exact test, and Spearman's rank. The prognostic factors for overall survival were analyzed by univariate and multivariate Cox regression. The percentage of SAV1 expression in PDAC (50.6 %) was significantly lower than those in paratumor tissues (69.9 %) (P = 0.017). Expression of SAV1 was only significantly correlated with histological differentiation (P = 0.025) and N classification (P = 0.009). On multivariate analysis, elevated expression of SAV1 and N0 was a significant favorable prognostic factor of OS. Our study demonstrated for the first time that lower expression of SAV1 might be involved in the progression of PDAC, suggesting that SAV1 may be a potential prognostic marker and target for PDAC therapy.

MiR-21 upregulation induced by promoter zone histone acetylation is associated with chemoresistance to gemcitabine and enhanced malignancy of pancreatic cancer cells.

BACKGROUND AND AIMS: MicroRNA-21 (miR-21) is reported to be overexpressed and to contribute to proliferation, apoptosis and gemcitabine resistance in pancreatic ductal adenocarcinomas (PDACs). The aims of this study were to explore regulation of miR-21 expression by epigenetic change and its impact on chemoresistance and malignant properties of of pancreatic cancer. MATERIALS AND METHODS: We retrospectively collected 41 cases of advanced pancreatic cancer patients who were sensitive or resistant to gemcitabine and assessed levels of serum circulating miR-21 for correlation with cytotoxic activity. Histone acetylation in the miR-21 promoter was also studied in gemcitabine-sensitive and gemcitabine-resistant PDAC cells. Gemcitabine-resistant HPAC and PANC-1 cells were transfected with pre-miR-21 precursors (pre-miR-21) and antisense oligonucleotides (anti-miR-21), and were treated with TSA. Finally, invasion and metastasis assays were performed and alteration in mir-21, PTEN, AKT and pAKT level was evaluated in these cells. RESULTS: Serum miR-21 levels were increased in gemcitabine- resistant PDAC patients compared with gemcitabine-sensitive subjects. The miR-21 levels were increased in 6 PDAC cells treated with gemcitabine significantly, associated with 50% inhibitory concentrations (IC50s). Histone acetylation levels at miR-21 promoter were increased in PDAC cells after treatment with gemcitabine. Enhanced invasion and metastasis, increased miR-21 expression, decreased PTEN, elevated pAKT level were demonstrated in gemcitabine-resistant HPAC and PANC-1 cells. Pre-miR-21 transfection or TSA treatment further increased invasion and metastasis ability, decreased PTEN, and elevated pAKT levels in these two lines. In contrast, anti-miR-21 transfection could reverse invasion and metastasis, and PTEN and pAKT expressions induced by gemcitabine. CONCLUSIONS: MiR-21 upregulation induced by histone acetylation in the promoter zone is associated with chemoresistance to gemcitabine and enhanced malignant potential in pancreatic cancer cells.

Inhibition of tumor growth in vitro by a combination of extracts from Rosa roxburghii Tratt and Fagopyrum cymosum.

OBJECTIVE: Traditional Chinese herbal medicines have a very long history. Rosa roxburghii Tratt and Fagopyrum cymosum are two examples of plants which are reputed to have benefits in improving immune responses, enhancing digestive ability and demonstrating anti-aging effects. Some evidence indicates that herbal medicine soups containing extracts from the two in combination have efficacy in treating malignant tumors. However, the underlying mechanisms are far from well understood. The present study was therefore undertaken to evaluate anticancer effects and explore molecular mechanisms in vitro. METHODS: Proliferation and apoptosis were assessed with three carcinoma cell lines (human esophageal squamous carcinoma CaEs-17, human gastric carcinoma SGC-7901 and pulmonary carcinoma A549) by MTT assay and flow cytometry, respectively, after exposure to extract from Rosa roxburghii Tratt (CL) and extract from Fagopyrum cymosum (FR). IC30 of CL and FR were obtained by MTT assay. Tumor cells were divided into four groups: control with no exposure to CL or FR; CL with IC30 CL; FR with IC30 FR; CL+FR group with 1/2 (IC30 CL+IC30 FR). RT-PCR and Western blot analysis were used to detect the expression of Ki-67, Bax and Bcl-2 at mRNA and protein levels. RESULTS: Compared with the CL or FR groups, the combination of CL+FR showed significant inhibition of cell growth and increase in apoptosis; the mRNA and protein expression levels of Ki-67 and Bcl-2 in CL+FR group were all greatly decreased, while the expression of Bax was markedly increased. CONCLUSIONS: These results indicate that the synergistic antitumor effects of combination of CL and FR are related to inhibition of proliferation and induction of apoptosis.