Gallium-68 labeled somatostatin receptor antagonist PET/CT in over 500 patients with neuroendocrine neoplasms: experience from a single center in China.

PURPOSE: Somatostatin receptor antagonists have shown promising performance for imaging neuroendocrine neoplasms. However, there is a lack of studies exploring the diagnostic performance of SSTR antagonists or comparing them with agonists in a large cohort of patients with NENs. This study aimed to retrospectively review all SSTR antagonist PET/CT scans conducted at Peking Union Medical College Hospital since November 2018 in patients with confirmed or suspected NENs. METHODS: Four types of SSTR antagonists were utilized, including [68Ga]Ga-NODAGA-LM3, [68Ga]Ga-DOTA-LM3, [68Ga]Ga-NODAGA-JR11, and [68Ga]Ga-DOTA-JR11. The reference standard was based on a combination of histopathology, clinical evaluation, imaging results, and follow-up. Patient-based sensitivity, specificity, and accuracy were evaluated. The SUVmax and tumor-to-liver ratio (TLR) of the hottest lesions was recorded and compared between antagonists and [68Ga]Ga-DOTATATE. RESULTS: A total of 622 antagonist scans from 549 patients were included in the analysis. The patient-level sensitivity, specificity, and accuracy of antagonist imaging (all tracers combined) were 91.0% (443/487), 91.9% (57/62), and 91.1% (500/549), respectively. In 181 patients with a comparative [68Ga]Ga-DOTATATE PET/CT scan, the patient-level sensitivity, specificity, and accuracy were 87.5% (147/168), 76.9% (10/13), and 86.7% (157/181), respectively. For the hottest lesions, SSTR antagonists all tracers combined demonstrated an overall comparable SUVmax to [68Ga]Ga-DOTATATE (40.1 ± 32.5 vs. 39.4 ± 23.8, p = 0.772). While [68Ga]Ga-NODAGA-LM3 showed significantly higher uptake than [68Ga]Ga-DOTATATE (57.4 ± 38.5 vs. 40.0 ± 22.8, p<0.001), [68Ga]Ga-NODAGA-JR11 (39.7 ± 26.5 vs. 34.3 ± 23.9, p = 0.108) and [68Ga]Ga-DOTA-LM3 (38.9 ± 32.1 vs. 37.2 ± 22.1, p = 0.858) showed comparable uptake to [68Ga]Ga-DOTATATE, and [68Ga]Ga-DOTA-JR11 showed lower uptake (28.9 ± 26.1 vs. 44.0 ± 25.7, p = 0.001). All antagonists exhibited significantly higher TLR than [68Ga]Ga-DOTATATE (12.1 ± 10.8 vs. 5.2 ± 4.5, p<0.001). CONCLUSION: Gallium-68 labeled SSTR antagonists could serve as alternatives to SSTR agonists for imaging of NENs. Among various antagonists, [68Ga]Ga-NODAGA-LM3 seems to have the best imaging profile.

Diagnostic efficacy of [68Ga]Ga-NY104 PET/CT to identify clear cell renal cell carcinoma.

PURPOSE: Most clear cell renal cell carcinoma (ccRCC) overexpresses carbonic anhydrase IX (CAIX). [68Ga]Ga-NY104 is a small-molecule PET agent selectively targeting CAIX. This study aims to assess the efficacy of [68Ga]Ga-NY104 PET/CT to identify ccRCC. MATERIALS AND METHODS: Participants were prospectively recruited in the study (ClinicalTrials.gov: NCT05902377). They were further divided into two groups: group 1, patients with primary renal mass who were scheduled for surgery, group 2, patients with suspected/confirmed metastatic ccRCC. All patients underwent [68Ga]Ga-NY104 PET/CT. RESULTS: A total of 47 patients (mean age, 58.8 years ± 13.5, 34 men) were recruited, including 20 patients in group 1 and 27 patients in group 2. The patient-level sensitivity, specificity, and accuracy of [68Ga]Ga-NY104 PET scan was 62%, 33%, 58% for group 1 and 95%, 100%, 96% for group 2. [68Ga]Ga-NY104 PET identified additional 26 disease regions in 67% (14/21) of patients that were previously unknown. The tumor uptake was correlated with immunohistochemical staining results. CONCLUSIONS: [68Ga]Ga-NY104 PET/CT has a high diagnostic efficacy for patients with metastatic ccRCC, while it might be of limited value in the diagnosis of primary ccRCC.

Evaluation of the safety, biodistribution, dosimetry of [18F]AlF-NOTA-LM3 and head-to-head comparison with [68Ga]Ga-DOTATATE in patients with well-differentiated neuroendocrine tumors: an interim analysis of a prospective trial.

PURPOSE: 18F-labelled somatostatin receptor (SSTR) analogs offer several advantages over 68Ga in terms of yield, cost, spatial resolution and detection rate. This study presents an interim analysis of a prospective trial designed to assess the safety, biodistribution and dosimetry of [18F]AlF-NOTA-LM3, and compare its diagnostic efficacy and clinical management outcomes with [68Ga]Ga-DOTATATE or [68Ga]Ga-NODAGA-LM3 in patients with well-differentiated NETs. METHODS: Twenty-one patients with histologically confirmed well-differentiated neuroendocrine tumors (G1 and G2) were prospectively recruited. The first eight patients underwent serial PET scans at 5, 15, 30, 45, 60, and 120 min after [18F]AlF-NOTA-LM3 injection to assess biodistribution and dosimetry. The remaining patients underwent whole-body PET/CT scans. [18F]AlF-NOTA-LM3 and [68Ga]Ga-DOTATATE PET/CT were done within a week, with a minimum 24-hour interval between the two scans. Focal uptake above the surrounding background activity and could not be explained by physiologic uptake was considered lesions of NETs. Lesion number, tumor uptake, and tumor-to-background ratio (TBR) were compared. In patients with discrepant findings, the size of the smallest lesions (measured on coregistered CT) detected on [68Ga]Ga-DOTATATE and [18F]AlF-NOTA-LM3 was compared. RESULTS: [18F]AlF-NOTA-LM3 was safe and well-tolerated. Physiological uptake of [18F]AlF-NOTA-LM3 was significantly lower than that of [68Ga]Ga-DOTATATE in abdominal organs and bone marrow, but higher in blood pool and lung. The mean effective dose was 0.024 ± 0.014 mSv/MBq. [18F]AlF-NOTA-LM3 detected significantly more liver lesions (457 vs. 291, P = 0.006) and lymph node lesions (30 vs. 22, P = 0.011) compared to [68Ga]Ga-DOTATATE. The tumor uptake was comparable, but TBR was significantly higher with [18F]AlF-NOTA-LM3 for lesions from all sites except for the duodenum. The size of the minimum liver lesions (0.54 ± 0.15 vs. 1.01 ± 0.49, P<0.001) and lymph node lesions (0.50 ± 0.19 vs. 1.26 ± 0.86, P = 0.024) detected on [18F]ALF-NOTA-LM3 were significantly smaller than those detected on [68Ga]Ga-DOTATATE. CONCLUSION: [18F]AlF-NOTA-LM3 shows favorable biodistribution, higher spatial resolution and superior performance than [68Ga]Ga-DOTATATE in detecting liver and lymph node metastases, with higher TBR. Notably, it is the first SSTR analog to show superiority in detecting lymph node lesions when compared to [68Ga]Ga-DOTATATE. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT06056362.

First-line nivolumab plus chemotherapy vs chemotherapy in patients with advanced gastric, gastroesophageal junction and esophageal adenocarcinoma: CheckMate 649 Chinese subgroup analysis.

First-line chemotherapy for advanced/metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric/gastroesophageal junction cancer (GC/GEJC) has poor median overall survival (OS; <1 year). We report efficacy and safety results from Chinese patients in the phase III global CheckMate 649 study of nivolumab plus chemotherapy vs chemotherapy for the first-line treatment of GC/GEJC/esophageal adenocarcinoma (EAC). Chinese patients with previously untreated advanced or metastatic GC/GEJC/EAC were randomized to receive nivolumab (360 mg Q3W or 240 mg Q2W) plus chemotherapy (XELOX [capecitabine and oxaliplatin] Q3W or FOLFOX [oxaliplatin, leucovorin and 5-fluorouracil] Q2W), nivolumab plus ipilimumab (not reported) or chemotherapy alone. OS, blinded independent central review-assessed progression-free survival (PFS), objective response rate (ORR), duration of response (DOR) and safety are reported. Of 1581 patients enrolled and randomized, 208 were Chinese. In these patients, nivolumab plus chemotherapy resulted in clinically meaningful improvement in median OS (14.3 vs 10.2 months; HR 0.61 [95% CI: 0.44-0.85]), median PFS (8.3 vs 5.6 months; HR 0.57 [95% CI: 0.40-0.80]), ORR (66% vs 45%) and median DOR (12.2 vs 5.6 months) vs chemotherapy, respectively. The safety profile was acceptable, with no new safety signals observed. Consistent with results from the global primary analysis of CheckMate 649, nivolumab plus chemotherapy demonstrated a clinically meaningful improvement in OS and PFS and higher response rate vs chemotherapy and an acceptable safety profile in Chinese patients. Nivolumab plus chemotherapy represents a new standard first-line treatment for Chinese patients with non-HER2-positive advanced GC/GEJC/EAC.

Preclinical and pilot clinical evaluation of a small-molecule carbonic anhydrase IX targeting PET tracer in clear cell renal cell carcinoma.

PURPOSE: Clear cell renal cell carcinoma (ccRCC) highly expresses carbonic anhydrase IX (CAIX). The purpose of this study was to evaluate 68Ga-NY104, a small-molecule CAIX-targeting PET agent, in tumor models of ccRCC and patients diagnosed with confirmed, or suspicious, ccRCC. METHODS: The in vivo and ex vivo biodistribution of 68Ga-NY104 was investigated in CAIX-positive OS-RC-2 xenograft-bearing models. The binding of the tracer was further validated using autoradiography for human ccRCC samples. In addition, three patients with confirmed or suspicious ccRCC were studied. RESULTS: NY104 can be labeled with high radiochemical yield and purity. It quickly cleared through kidney with α-half-life of 0.15 h. Discernible uptake is noted in the heart, lung, liver, stomach, and kidney. The OS-RC-2 xenograft demonstrated intense uptake 5 min after injection and gradually increased until 3 h after injection with ID%/g of 29.29 ± 6.82. Significant binding was detected using autoradiography on sections of human ccRCC tumor. In the three patients studied, 68Ga-NY104 was well-tolerated and no adverse events were reported. Substantial accumulation was observed in both primary and metastatic lesions in patient 1 and 2 with SUVmax of 42.3. Uptake in the stomach, pancreas, intestine, and choroid plexus was noted. The lesion in third patient was correctly diagnosed as non-metastatic for negative 68Ga-NY104 uptake. CONCLUSION: 68Ga-NY104 can efficiently and specifically bind to CAIX. Given the pilot nature of our study, future clinical studies are warranted to evaluate 68Ga-NY104 for detection of CAIX-positive lesions in patients with ccRCC. TRIAL REGISTRATION: The clinical evaluation part of this study was retrospectively registered at ClinicalTrial.gov (NCT05728515) as NYPILOT on 6 Feb, 2023.

A real-world analysis of trametinib in combination with hydroxychloroquine or CDK4/6 inhibitor as third- or later-line therapy in metastatic pancreatic adenocarcinoma.

BACKGROUND: There are no standard third-line treatment options for metastatic pancreatic ductal adenocarcinoma (mPDAC). Trametinib in combination with hydroxychloroquine (HCQ) or CDK4/6 inhibitors for pancreatic adenocarcinoma showed promising efficacy in preclinical studies. However, the regimens have not been well examined in patients with mPDAC. METHODS: Patients with mPDAC who received the combination of trametinib and HCQ or CDK4/6 inhibitors as third- or later-line therapy were reviewed. The efficacy and prognosis were further analyzed. RESULTS: A total of 13 mPDAC patients were enrolled, of whom 8 and 5 patients were treated with trametinib plus HCQ or a CDK4/6 inhibitor (palbociclib or abemaciclib), respectively. All enrolled patients had either KRAS G12D or G12V mutations and had received a median of 3 prior lines of therapy (range, 2-6). The median trametinib treatment duration was 1.4 months. Of the 10 patients with measurable disease, only 1 patient achieved stable disease, and the remaining patients had progressive disease. Moreover, in patients treated with trametinib plus HCQ and a CDK4/6 inhibitor, the median progression-free survival was 2.0 and 2.8 months, respectively, and the median overall survival was 4.2 and 4.7 months, respectively. Moreover, 5 (50%) patients experienced grade 3-4 adverse events in 10 patients with available safety data. CONCLUSIONS: The combination of trametinib and HCQ or CDK4/6 inhibitors may not be an effective later-line treatment for mPDAC, and the current preliminary findings need to be confirmed by other studies with larger sample sizes.

Baseline radiologic features as predictors of efficacy in patients with pancreatic neuroendocrine tumors with liver metastases receiving surufatinib.

Objective: Currently, pre-treatment prediction of patients with pancreatic neuroendocrine tumors with liver metastases (PNELM) receiving surufatinib treatment was unsatisfying. Our objective was to examine the association between radiological characteristics and efficacy/prognosis. Methods: We enrolled patients with liver metastases in the phase III, SANET-p trial (NCT02589821) and obtained contrast-enhanced computed tomography (CECT) images. Qualitative and quantitative parameters including hepatic tumor margins, lesion volumes, enhancement pattern, localization types, and enhancement ratios were evaluated. The progression-free survival (PFS) and hazard ratio (HR) were calculated using Cox's proportional hazard model. Efficacy was analyzed by logistic-regression models. Results: Among 152 patients who had baseline CECT assessments and were included in this analysis, the surufatinib group showed statistically superior efficacy in terms of median PFS compared to placebo across various qualitative and quantitative parameters. In the multivariable analysis of patients receiving surufatinib (N=100), those with higher arterial phase standardized enhancement ratio-peri-lesion (ASER-peri) exhibited longer PFS [HR=0.039; 95% confidence interval (95% CI): 0.003-0.483; P=0.012]. Furthermore, patients with a high enhancement pattern experienced an improvement in the objective response ratio [31.3% vs. 14.7%, odds ratio (OR)=3.488; 95% CI: 1.024-11.875; P=0.046], and well-defined tumor margins were associated with a higher disease control rate (DCR) (89.3% vs. 68.2%, OR=4.535; 95% CI: 1.285-16.011; P=0.019) compared to poorly-defined margins. Conclusions: These pre-treatment radiological features, namely high ASER-peri, high enhancement pattern, and well-defined tumor margins, have the potential to serve as predictive markers of efficacy in patients with PNELM receiving surufatinib.

Phase Ia/Ib Study of the Selective MET Inhibitor, Savolitinib, in Patients with Advanced Solid Tumors: Safety, Efficacy, and Biomarkers.

BACKGROUND: Savolitinib has shown good tolerability and preliminary efficacy, but efficacy biomarkers require investigation. The main purpose of this study was to confirm in Chinese patients the recommended phase II dose (RP2D) of savolitinib and to explore overall benefit in tumors bearing c-Met aberration. METHODS: This was an open-label, multi-center, 2-part phase I study. A starting dose of 600 mg QD was initiated in the escalation phase, utilizing a 3+3 design with repeated QD and BID dosing. In the dose expansion phase, we enrolled patients with gastric cancer and non-small cell lung cancer (NSCLC) with documented c-met aberration into 5 cohorts to further explore biomarkers. c-Met overexpression and amplification were assessed by immunohistochemistry and FISH, respectively. RESULTS: The safety analysis set included 85 patients. Only one dose-limiting toxicity (grade 3 fatigue) was reported in the 600 mg BID dosing group. The most frequent treatment-related adverse events were nausea (29.4%), vomiting (27.1%), and peripheral edema (21.2%). Notably, in gastric cancer, response was only observed in patients with MET amplification (copy number 9.7-18.4), with an objective response rate of 35.7% and a disease control rate of 64.3%. For patients with NSCLC bearing a MET exon 14 skipping mutation, obvious target lesion shrinkage was observed in 2 of 4 patients, although PR was not achieved. CONCLUSION: The RP2D of savolitinib was established as 600 mg QD or 500 mg BID in Chinese patients. The promising response observed in patients with gastric cancer with c-met amplification and NSCLC with MET exon 14 skipping mutation warrants further investigation. CLINICALTRIALS.GOV IDENTIFIER: NCT0198555.

A prospective randomized, double-blind study to evaluate the diagnostic efficacy of 68Ga-NODAGA-LM3 and 68Ga-DOTA-LM3 in patients with well-differentiated neuroendocrine tumors: compared with 68Ga-DOTATATE.

PURPOSE: The purpose of this study is to evaluate the diagnostic efficacy of 68 Ga-NODAGA-LM3 and 68 Ga-DOTA-LM3 and compare them with 68 Ga-DOTATATE in patients with well-differentiated neuroendocrine tumors. METHODS: Patients were prospectively recruited and equally randomized into two arms: Arm A, patients would undergo a whole-body 68 Ga-NODAGA-LM3 PET/CT scan on the 1st day and 68 Ga-DOTATATE PET/CT scan on the 2nd day; Arm B, patients would undergo a whole-body 68 Ga-DOTA-LM3 PET/CT scan on the 1st day and 68 Ga-DOTATATE PET/CT scan on the 2nd day. Biodistribution in normal organs, lesion detection ability, and tumor uptake were compared between antagonist and agonist in each arm. RESULTS: A total of 40 patients with well-differentiated NETs, 20 in each arm, were recruited in the study. 68 Ga-NODAGA-LM3 showed a similar pattern as 68 Ga-DOTATATE, while 68 Ga-DOTA-LM3 demonstrated significantly lower uptake in almost all normal organs compared to 68 Ga-DOTATATE. Both 68 Ga-NODAGA-LM3 and 68 Ga-DOTA-LM3 showed superiority in lesion detection compared to 68 Ga-DOTATATE on lesion-based and patient-based comparison. 68 Ga-NODAGA-LM3 showed a significantly higher tumor uptake (median SUVmax 29.1 versus 21.6, P < 0.05) and tumor-to-background ratio (median tumor-to-liver ratio 5.0 versus 2.9, P < 0.05) compared to 68 Ga-DOTATATE. 68 Ga-DOTA-LM3 showed comparable uptake (median SUVmax 16.1 versus 17.8, P = 0.714) and higher tumor-to-background ratio (median tumor-to-liver ratio 5.2 versus 2.1, P < 0.05). CONCLUSION: Both 68 Ga-NODAGA-LM3 and 68 Ga-DOTA-LM3 are promising SSTR2 antagonists for neuroendocrine tumors. They demonstrated superiority in diagnostic efficacy compared to agonist 68 Ga-DOTATATE. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04318561.

A Comprehensive Prognostic Analysis of POLD1 in Hepatocellular Carcinoma.

BACKGROUND: DNA polymerase delta 1 catalytic subunit (POLD1) plays a key role in DNA replication and damage repair. A defective DNA proofreading function caused by POLD1 mutation contributes to carcinogenesis, while POLD1 overexpression predicts poor prognosis in cancers. However, the effect of POLD1 in hepatocellular carcinoma (HCC) is not well-understood. METHODS: Expression patterns of POLD1 were evaluated in TCGA and the HPA databases. Kaplan-Meier curves and Cox regression were used to examine the prognostic value of POLD1. The prognostic and predictive value of POLD1 was further validated by another independent cohort from ICGC database. The influences of DNA copy number variation, methylation and miRNA on POLD1 mRNA expression were examined. The correlation between infiltrating immune cells and POLD1 expression was analyzed. GO and KEGG enrichment analyses were performed to detect biological pathways associated with POLD1 expression in HCC. RESULTS: POLD1 was overexpressed in HCC (n = 369) compared with adjacent normal liver (n = 50). POLD1 upregulation was significantly correlated with positive serum AFP and advanced TNM stage. Kaplan-Meier and multivariate analyses suggested that POLD1 overexpression predicts poor prognosis in HCC. DNA copy gain, low POLD1 methylation, and miR­139-3p downregulation were associated with POLD1 overexpression. Besides, POLD1 expression was associated with the infiltration levels of dendritic cell, macrophage, B cell, and CD4 + T cell in HCC. Functional enrichment analysis suggested "DNA replication", "mismatch repair" and "cell cycle" pathways might be involved in the effect of POLD1 on HCC pathogenesis. Additionally, POLD1 mRNA expression was significantly associated with tumor mutation burden, microsatellite instability, and prognosis in various tumors. CONCLUSIONS: POLD1 may be a potential prognostic marker and promising therapeutic target in HCC.

Evaluation of the diagnostic performance of the EFSUMB CEUS Pancreatic Applications guidelines (2017 version): a retrospective single-center analysis of 455 solid pancreatic masses.

OBJECTIVES: To explore the diagnostic performance of EFSUMB CEUS Pancreatic Applications guidelines (version 2017) before and after the addition of iso-enhancement and very fast/fast washout as supplementary diagnostic criteria for PDAC. METHODS: In this retrospective study, patients diagnosed with solid pancreatic lesions from January 2017 to December 2020 were evaluated. Pancreatic ductal adenocarcinoma (PDAC) is reported to show hypo-enhancement in all phases according to the EFSUMB guidelines. First, based on this definition, all lesions were categorized as PDAC and non-PDAC. Then, iso-enhancement and very fast/fast washout were added as supplementary diagnostic criteria, and all lesions were recategorized. The diagnostic performance was assessed in terms of the accuracy (ACC), sensitivity (SEN), specificity (SPE), positive predictive value (PPV), and negative predictive value (NPV). The reference standard consisted of histologic evaluation or composite imaging and clinical follow-up findings. RESULTS: A total of 455 nodules in 450 patients (median age, 58.37 years; 250 men) were included. The diagnostic performance using the EFSUMB CEUS guidelines for PDAC had an ACC of 69.5%, SEN of 65.4%, SPE of 84%, PPV of 93.5%, NPV of 40.6%, and ROC of 0.747. After recategorization according to the supplementary diagnostic criteria, the diagnostic performance for PDAC had an ACC of 95.8%, SEN of 99.2%, SPE of 84%, PPV of 95.7%, NPV of 96.6%, and ROC of 0.916. CONCLUSION: The EFSUMB guidelines and recommendations for pancreatic lesions can effectively identify PDAC via hypo-enhancement on CEUS. However, the diagnostic performance may be further improved by the reclassification of PDAC lesions after adding iso-enhancement and very fast/fast washout mode. KEY POINTS: • In the EFSUMB guidelines, the only diagnostic criterion for PDAC is hypo-enhancement, to which iso-enhancement and very fast/fast washout mode were added in our research. • Using hypo-enhancement/iso-enhancement with very fast/fast washout patterns as the diagnostic criteria for PDAC for solid pancreatic masses on CEUS has high diagnostic accuracy. • The blood supply pattern of PDAC can provide important information, and CEUS has unique advantages in this respect due to its real-time dynamic attenuation ability.

Synthesis and Evaluation of Bakuchiol Derivatives as Potent Anti-inflammatory Agents in Vitro and in Vivo.

Bakuchiol, a prenylated phenolic monoterpene derived from the fruit of Psoralen corylifolia L. (Buguzhi), is widely used to treat tumors, viruses, inflammation, and bacterial infections. In this study, we designed and synthesized 30 bakuchiol derivatives to identify new anti-inflammatory drugs. The anti-inflammatory activities of the derivatives were screened using lipopolysaccharide-induced RAW264.7 cells. To evaluate the anti-inflammatory activity of the compounds, we measured nitric oxide (NO), interleukin-6, and tumor necrosis factor-α production. Based on the screening results, compound 7a displayed more pronounced activity than bakuchiol and celecoxib. Furthermore, the mechanistic studies indicated that 7a inhibited pro-inflammatory cytokine release, which was correlated with activation of the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 signaling pathway and blockade of the nuclear factor-κB/mitogen-activated protein kinase signaling pathway. The in vivo anti-inflammatory activity in zebrafish indicated that 7a inhibited NO and reactive oxygen species production in a dose-dependent manner. These results indicate that 7a is a potential candidate for development as an anti-inflammatory agent.

Combination of 1,8-cineole and beta-caryophyllene synergistically reverses cardiac hypertrophy in isoprenaline-induced mice and H9c2 cells.

Combination drug therapy has become an effective strategy for chronic metabolic disease, especially cardiovascular disease. In the present study, possible drug combinations were screened and the mechanism of the combinations against cardiac hypertrophy was examined within 1,8-cineole, ß-caryophyllene, linalool, and ß-pinene.H9c2 cells were treatment with 1,8-cineole, ß-caryophyllene, linalool, and ß-pinene individually or in combination for 24 h after isoprenaline stimulation. Cell viability was detected by the MTT assay. Subsequently, bioinformatic analysis and network pharmacology were used to reveal the multi-targeted synergistic therapeutic effect of the combination treatment compounds on cardiac hypertrophy. Ultimately, western blot and elisa was performed to analyses the protein expression in vivo. MTT results found that 1,8-cineole and ß-caryophyllene synergistically increased cell viability with CalcuSyn software analyses. Specifically, bioinformatic and network pharmacology analysis showed PTGS2, TNF, IL-6, AKT1, NOS2, and CAT were identified as the key targets. P13K-AKT signaling pathway was involved in the reversal of cardiac hypertrophy by the combination of 1,8-cineole and ß-caryophyllene. The in vitro results indicated that the combination synergistically treated the isoprenaline-induced mice against structural and functional myocardial damage via the P13K-AKT signaling pathway. Collectively, the combined application of 1,8-cineole and ß-caryophyllene synergistically reverses cardiac hypertrophy in isoprenaline-induced H9c2 cells and mice.

Design, synthesis and biological evaluation of novel FAK inhibitors with better selectivity over IR than TAE226.

In this study, 28 novel focal adhesion kinase (FAK) inhibitors were designed and synthesized based on FAK inhibitor TAE226. Compound 18b displayed good inhibition of FAK (IC50 = 45 nM) with at least 22 fold of selectivity over insulin receptor (IR, IC50 > 1000 nM) and exhibited potent anticancer activity against Hela, HCT116 and MDA-MB-231 cell lines with IC50 values of 0.27, 0.19 and 0.26 µM respectively, compared to TAE226 (2.68, 0.64 and 4.19 µM respectively). 18b also inhibited the clone formation and migration of HCT-116 cells, tube formation of HUVECs, and stimulated cell cycle arrest in the G2/M phase, inducing apoptosis by promoting ROS production. The FAK-Src-ERK signaling pathway was inhibited by 18b in a dose-dependent manner. Moreover, 18b showed adequate oral bioavailability of 16.37% and 75.90% tumor growth inhibition in the HCT116 xenograft model was observed. These results indicate that 18b is a promising selective inhibitor of FAK.

[Advances in Treatment of Human Epidermal Growth Factor Receptor 2-Positve Gastric Cancer].

Gastric cancer ranks as the fifth most common malignant tumor worldwide and the fourth leading cause of cancer-related deaths.Human epidermal growth factor receptor 2 (HER2)-positive gastric cancer is a special type of gastric adenocarcinoma,the prognosis of which can be improved by trastuzumab plus cytotoxic chemotherapy such as cisplatin and fluorouracil.Pembrolizumab on the basis of Tmabplus chemotherapy can further improve the overall response rate,which has become the first-line standardized therapy against HER2-positive gastric cancer.However,there are still some obstacles such as the innate resistance to Tmab in specific populations.The research on HER2-targeted therapy provides clues for clinical decision-making.This review documents the current neoadjuvant and adjuvant therapies against late-stage HER2-positive gastric cancer,as well as the progress in novel HER2 pathway-targeted drugs.

A single-arm, multicenter, open-label phase 2 trial of surufatinib in patients with unresectable or metastatic biliary tract cancer.

BACKGROUND: Several clinical studies of vascular endothelial growth factor/vascular endothelial growth factor receptor (VEGF/VEGFR) therapy as a second-line treatment for biliary tract cancer (BTC) have shown modest efficacy. In this study, surufatinib was evaluated as a second-line VEGFR therapy in patients with BTC. METHODS: This was a single-arm, multicenter, open-label phase 2 study conducted in China. The study enrolled eligible patients with BTC, who had received surufatinib monotherapy as second-line treatment, at a dose of 300 mg, once daily, in 28-day cycles. Tumor assessments were performed every 8 weeks (±7 days) according to the Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: As of November 30, 2018, 39 patients with BTC, including 29 (74.4%) with intrahepatic cholangiocarcinoma, 5 (12.8%) with extrahepatic cholangiocarcinoma, and 5 (12.8%) with gallbladder cancer, were enrolled and treated with surufatinib. The 16-week progression-free survival rate was 46.33% (95% CI, 24.38-65.73), with median progression-free survival of 3.7 months and median overall survival of 6.9 months. In addition, results from subgroup and post hoc analyses revealed that patients with the proper tumor locations or appropriate levels of serum biomarkers might receive greater clinical benefits. The top 3 treatment-related adverse events with severity of grade ≥3 included blood bilirubin increased (20.5%), hypertension (17.9%), and proteinuria (12.8%). CONCLUSIONS: When applied in the treatment of patients with BTC, surufatinib monotherapy has offered moderate clinical efficacy and shown expected tolerability and safety profiles.

Association of emergence of new mutations in circulating tumuor DNA during chemotherapy with clinical outcome in metastatic colorectal cancer.

BACKGROUND: The understanding of molecular changes in mCRC during treatment could be used to personalise therapeutic strategies. The aim of our study was to explore the association of circulating tumour DNA (ctDNA) with clinical outcome in metastatic colorectal cancer (mCRC). METHODS: Sequential patients with mCRC receiving standard first-line chemotherapy were included prospectively. Both plasma ctDNA and serum CEA were assessed in samples obtained before treatment and after 4 cycles of chemotherapy (C4). Computed tomography (CT) scans were carried out at baseline and post-C4 (8-10 weeks) and were assessed using Response Evaluation Criteria In Solid Tumours version 1.1 (RECIST v1.1). Target-capture deep sequencing with a panel covering 1021 genes was performed to detected somatic mutations in ctDNA. RESULTS: A total of 20 patients were prospectively included and treated with either leucovorin, fluorouracil, and oxaliplatin (FOLFOX) (15/20) or leucovorin, fluorouracil, and irinotecan (FOLFIRI) (5/20). Median follow-up was 6.9 months (range 1.6-26.6). Somatic mutations for baseline ctDNA analysis were identified in 85% (17/20) of the patients. Mutation variations of ctDNA after chemotherapy were tested in 16/20 (80.0%) of the patients. In multivariate analyses, a high baseline molecular tumour burden index (mTBI) in ctDNA was associated with a higher risk of disease progression, as well as emergence of new mutations in ctDNA during chemotherapy. Patients with newly detected mutations had shorter progression-free survival (PFS) compared to those without (median 3.0 versus 7.3 months; hazard ratio (HR), 5.97; 95% confidence interval (CI), 0.70-50.69; P = 0.0003). Fold changes in mTBI from baseline to post-C4 were obtained in 80.0% (16/20) of the patients, which were also related to PFS. Patients with fold reduction in mTBI above 0.8-fold had longer PFS compared to those below (median 9.3 versus 4.1 months; HR, 4.51; 95% CI, 1.29-15.70; P = 0.0008). CONCLUSIONS: Newly detected mutations in ctDNA during treatment might potentially be associated with clinical outcome in mCRC and may provide important clinical information.

Circulating activated immune cells as a potential blood biomarkers of non-small cell lung cancer occurrence and progression.

BACKGROUND: Treatment for non-small cell lung cancer (NSCLC) has greatly improved in recent years. However, noninvasive early screening for carcinogenesis and progression unclear. The aim of this study was to explore the predictive value of peripheral blood immune cells in untreated NSCLC patients. METHODS: We retrospectively enrolled 305 untreated NSCLC patients and 132 healthy participants from February 2016 to August 2019 in Peking Union Medical College Hospital. Immune cell levels were determined by flow cytometry and routine blood tests. RESULTS: NSCLC patients had lower levels of T lymphocytes, NK cells, CD8+ T cells, naïve CD4+/CD4+, naïve CD4+ T cells and higher levels of CD4+ T cells, memory CD4+/CD4+ T cells, memory CD4+ T cells, CD4+CD28+/CD4+ T cells, CD4+CD28+ T cells, CD8+CD28+/CD8+ T cells, CD8+HLA-DR+/CD8+ T cells, CD8+HLA-DR+ T cells T cells, CD8+CD38+/CD8+ T cells, CD8+CD38+ T cells and CD4+/CD8+ T cells than those in controls. The percentages of specific lymphocyte subtypes were significantly different in cancer patients versus healthy individuals. For instance, cancer patients had lower levels of B cells, CD4+ T cells, naïve CD4+/CD4+ T cells, naïve CD4+ T cells, CD4+CD28+ T cells, CD8+CD28+ T cells and higher levels of NK cells, white blood cells (WBC), monocytes, neutrophils, eosinophils, basophils, monocytes to lymphocyte ratio (MLR), neutrophils to lymphocyte ratio (NLR), eosinophil to lymphocyte ratio (ELR), basophil to lymphocyte ratio (BLR), and blood platelet to lymphocyte ratio (PLR). CONCLUSIONS: Abnormal T cell levels can be used as an independent predictive biomarker for noninvasive early screening in NSCLC occurrence and progression.

Surufatinib in advanced pancreatic neuroendocrine tumours (SANET-p): a randomised, double-blind, placebo-controlled, phase 3 study.

BACKGROUND: Surufatinib showed superior efficacy in extrapancreatic neuroendocrine tumours (NETs) in the phase 3 SANET-ep study. In SANET-p, we aimed to assess the efficacy and safety of surufatinib in patients with advanced pancreatic NETs. METHODS: SANET-p was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study, done in 21 hospitals across China. Eligible patients were adults (aged 18 years or older) with progressive, advanced, well differentiated pancreatic NETs, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and progression on up to two kinds of previous systemic regimens for advanced disease. Patients were randomly assigned (2:1) via an interactive web response system to receive 300 mg of surufatinib or placebo, taken orally once per day in consecutive 4-week treatment cycles until disease progression, intolerable toxicity, withdrawal of consent, poor compliance, use of other antitumour medication, pregnancy, loss to follow-up, or if the investigator deemed discontinuation in the patient's best interest. Randomisation was done centrally using stratified block randomisation (block size three), stratified by pathological grade, previous systemic antitumour treatment, and ECOG performance status score. Patients, investigators, research staff, and the sponsor study team were masked to treatment allocation. Crossover to surufatinib was permitted for patients in the placebo group with disease progression. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, which included all patients in randomisation. A pre-planned interim analysis was done at 70% of the predicted progression-free survival events. This study is registered at ClinicalTrials.gov, NCT02589821. FINDINGS: Between Feb 18, 2016, and Nov 11, 2019, of 264 patients who were screened, 172 (65%) patients were randomly assigned to receive surufatinib (n=113) or placebo (n=59). The median follow-up was 19·3 months (95% CI 9·3-19·4) in the surufatinib group and 11·1 months (5·7-35·9) in the placebo group. The median investigator-assessed progression-free survival was 10·9 months (7·5-13·8) for surufatinib versus 3·7 months (2·8-5·6) for placebo (hazard ratio 0·49, 95% CI 0·32-0·76; p=0·0011). The trial met the early stopping criteria at the interim analysis and was terminated on recommendation from the independent data monitoring committee. The most common grade 3 or worse treatment-related adverse events were hypertension (43 [38%] of 113 with surufatinib vs four [7%] of 59 with placebo), proteinuria (11 [10%] vs one [2%]), and hypertriglyceridaemia (eight [7%] vs none). Treatment-related serious adverse events were reported in 25 (22%) patients in the surufatinib group and four (7%) patients in the placebo group. There were three on-treatment deaths in the surufatinib group, including two deaths due to adverse events (gastrointestinal haemorrhage [possibly treatment-related] and cerebral haemorrhage [unlikely to be treatment-related]), and one death attributed to disease progression. One on-treatment death in the placebo group was attributed to disease progression. INTERPRETATION: Surufatinib significantly improves progression-free survival and has an acceptable safety profile in patients with progressive, advanced pancreatic NETs, and could be a potential treatment option in this patient population. FUNDING: Hutchison MediPharma.

Surufatinib in advanced extrapancreatic neuroendocrine tumours (SANET-ep): a randomised, double-blind, placebo-controlled, phase 3 study.

BACKGROUND: Therapeutic options for advanced neuroendocrine tumours (NETs) are limited. We investigated the efficacy and safety of surufatinib (HMPL-012, sulfatinib) in patients with extrapancreatic NETs. METHODS: SANET-ep was a randomised, double-blind, placebo-controlled, phase 3 trial undertaken at 24 hospitals across China. Patients (aged 18 years or older) with unresectable or metastatic, well differentiated, extrapancreatic NETs, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and progression on no more than two types of previous systemic regimens were enrolled. Patients were centrally randomly assigned (2:1) using stratified block randomisation (block size 3) via an interactive web response system to receive oral surufatinib at 300 mg per day or matching placebo. Randomisation was stratified by tumour origin, pathological grade, and previous treatment. Patients, investigators, research staff and the sponsor study team were masked to treatment allocation. Crossover to the surufatinib group was allowed for patients in the placebo group at disease progression. The primary endpoint was investigator-assessed progression-free survival, which was analysed in the intention-to-treat population. A preplanned interim analysis was done at 70% of predicted progression-free survival events. This study was registered with ClinicalTrials.gov, NCT02588170. Follow-up is ongoing. FINDINGS: Between Dec 9, 2015, and March 31, 2019, 198 patients were randomly assigned to surufatinib (n=129) or placebo (n=69). Median follow-up was 13·8 months (95% CI 11·1-16·7) in the surufatinib group and 16·6 months (9·2-not calculable) in the placebo group. Investigator-assessed median progression-free survival was 9·2 months (95% CI 7·4-11·1) in the surufatinib group versus 3·8 months (3·7-5·7) in the placebo group (hazard ratio 0·33; 95% CI 0·22-0·50; p<0·0001). As the trial met the predefined criteria for early discontinuation of the study at the interim analysis, the study was terminated early, as recommended by the independent data monitoring committee. The most common treatment-related adverse events of grade 3 or worse were hypertension (47 [36%] of 129 patients in the surufatinib group vs nine [13%] of 68 patients in the placebo group) and proteinuria (25 [19%] vs zero). Treatment-related serious adverse events were reported in 32 (25%) of 129 patients in the surufatinib group and nine (13%) of 68 patients in the placebo group. Treatment-related deaths occurred in three patients in the surufatinib group (disseminated intravascular coagulation and hepatic encephalopathy, liver injury, and death with unknown reason) and one patient in the placebo group (cachexia and respiratory failure). INTERPRETATION: Progression-free survival was significantly longer in patients given surufatinib compared with patients given placebo, and surufatinib has a favourable benefit-to-risk profile in patients with progressive, advanced, well differentiated extrapancreatic NETs. Our results suggest that surufatinib might be a new treatment option for this population. FUNDING: Hutchison MediPharma.