Genomic temporal heterogeneity of circulating tumour DNA in unresectable metastatic colorectal cancer under first-line treatment.

OBJECTIVE: Circulating tumour DNA (ctDNA) sequencing is increasingly used in the clinical management of patients with colorectal cancer. However, the genomic heterogeneity in ctDNA during treatments and its impact on clinical outcomes remain largely unknown. DESIGN: We conducted a prospective cohort study (NCT04228614) of 171 patients with unresectable metastatic colorectal cancer (mCRC) who underwent first-line treatment and prospectively collected blood samples with or without tumour samples from patients at baseline and sequentially until disease progression or last follow-up. RESULTS: The RAS/BRAF alterations in paired baseline tissue and plasma samples from 63 patients displayed a favourable concordance (81.0%, 51/63). After a period of first-line treatment (median time between baseline and last liquid biopsy, 4.67 months), 42.6% (26/61) of RAS-mutant patients showed RAS clearance and 50.0% (5/10) of BRAF-mutant patients showed BRAF clearance, while 3.6% (3/84) and 0.7% (1/135) of patients showed new RAS or BRAF mutations in ctDNA. Patients with plasma RAS/BRAF clearance showed similar progression-free survival (PFS) and overall survival (OS) with patients who remained RAS/BRAF wild-type, while much better outcomes than those who remained RAS/BRAF mutant. Patients who gained new RAS/BRAF mutations showed similar prognosis as those who maintained RAS/BRAF mutations, and shorter PFS and OS than those who remained RAS/BRAF wild-type. CONCLUSION: This prospective, serial and large-scale ctDNA profiling study reveals the temporal heterogeneity of mCRC-related somatic variants, which should be given special attention in clinical practice, as evidenced by the finding that the shift in plasma RAS/BRAF mutational status can yield a drastic change in survival outcomes.

Performance of common genetic variants in risk prediction for colorectal cancer in Chinese: A two-stage and multicenter study.

The efficacy of susceptible variants derived from genome-wide association studies (GWAs) optimizing discriminatory accuracy of colorectal cancer (CRC) in Chinese remains unclear. In the present validation study, we assessed 75 recently identified variants from GWAs. A risk predictive model combining 19 variants using the least absolute shrinkage and selection operator (LASSO) statistics offered certain clinical advantages. This model demonstrated an area under the receiver operating characteristic (AUC) of 0.61 during training analysis and yielded robust AUCs from 0.59 to 0.61 during validation analysis in three independent centers. The individuals carrying the highest quartile of risk score revealed over 2-fold risks of CRC (ranging from 2.12 to 2.90) compared with those who presented the lowest quartile of risk score. This genetic model offered the possibility of partitioning risk within the average risk population, which might serve as a first step toward developing individualized CRC prevention strategies in China.

EPHA7 mutation as a predictive biomarker for immune checkpoint inhibitors in multiple cancers.

BACKGROUND: A critical and challenging process in immunotherapy is to identify cancer patients who could benefit from immune checkpoint inhibitors (ICIs). Exploration of predictive biomarkers could help to maximize the clinical benefits. Eph receptors have been shown to play essential roles in tumor immunity. However, the association between EPH gene mutation and ICI response is lacking. METHODS: Clinical data and whole-exome sequencing (WES) data from published studies were collected and consolidated as a discovery cohort to analyze the association between EPH gene mutation and efficacy of ICI therapy. Another independent cohort from Memorial Sloan Kettering Cancer Center (MSKCC) was adopted to validate our findings. The Cancer Genome Atlas (TCGA) cohort was used to perform anti-tumor immunity and pathway enrichment analysis. RESULTS: Among fourteen EPH genes, EPHA7-mutant (EPHA7-MUT) was enriched in patients responding to ICI therapy (FDR adjusted P < 0.05). In the discovery cohort (n = 386), significant differences were detected between EPHA7-MUT and EPHA7-wildtype (EPHA7-WT) patients regarding objective response rate (ORR, 52.6% vs 29.1%, FDR adjusted P = 0.0357) and durable clinical benefit (DCB, 70.3% vs 42.7%, FDR adjusted P = 0.0200). In the validation cohort (n = 1144), significant overall survival advantage was observed in EPHA7-MUT patients (HR = 0.62 [95% confidence interval, 0.39 to 0.97], multivariable adjusted P = 0.0367), which was independent of tumor mutational burden (TMB) and copy number alteration (CNA). Notably, EPHA7-MUT patients without ICI therapy had significantly worse overall survival in TCGA cohort (HR = 1.33 [95% confidence interval, 1.06 to 1.67], multivariable adjusted P = 0.0139). Further gene set enrichment analysis revealed enhanced anti-tumor immunity in EPHA7-MUT tumor. CONCLUSIONS: EPHA7-MUT successfully predicted better clinical outcomes in ICI-treated patients across multiple cancer types, indicating that EPHA7-MUT could serve as a potential predictive biomarker for immune checkpoint inhibitors.

Association between cigarette smoking and colorectal cancer sidedness: A multi-center big-data platform-based analysis.

BACKGROUND: Sidedness (right/left) of colorectal cancer (CRC) is essential for treatment. Whether carcinogenesis of tobacco varies by sidedness remains unclear. The present study aims to evaluate the sidedness tendency of cigarette smoking and to explore its impact on prognosis. METHODS: In the multi-center retrospective study, data on 46 166 Chinese CRC patients were extracted from a big-data platform. Logistic regression analyses were performed to evaluate qualitative and quantitative associations between smoking and tumor sidedness. Survival analyses were conducted in metastatic CRC. RESULTS: History of smoking was associated with left-sided CRC (LSCRC; Adjusted odds ratio, 1.25; 95% CI, 1.16 - 1.34; P < .001). The sidedness tendency towards LSCRC increased from non-smokers, to ex-smokers, and to current smokers (P for trend < .001). Longer duration (P for trend < .001) and larger total amount of cigarette smoking (P for trend < .001) were more associated with LSCRC, respectively. The association was confirmed in both left-sided colon cancer and rectal cancer, but was stronger for rectal cancer (P = .016). Alcoholism significantly enhanced the association by 7% (P = .027). Furthermore, prognostic advantage of metastatic LSCRC diminished among ever-smokers, with contrary survival impacts of smoking on either side of CRC. CONCLUSIONS: History of smoking was associated with LSCRC in a positive dose-response relationship, and presented opposite prognostic impacts on right- and left-sided tumors. Smoking potentially plays an instrumental role in the mechanism for sidedness heterogeneity in CRC.

qPhos: a database of protein phosphorylation dynamics in humans.

Temporal and spatial protein phosphorylation dynamically orchestrates a broad spectrum of biological processes and plays various physiological and pathological roles in diseases and cancers. Recent advancements in high-throughput proteomics techniques greatly promoted the profiling and quantification of phosphoproteome. However, although several comprehensive databases have reserved the phosphorylated proteins and sites, a resource for phosphorylation quantification still remains to be constructed. In this study, we developed the qPhos (http://qphos.cancerbio.info) database to integrate and host the data on phosphorylation dynamics. A total of 3 537 533 quantification events for 199 071 non-redundant phosphorylation sites on 18 402 proteins under 484 conditions were collected through exhaustive curation of published literature. The experimental details, including sample materials, conditions and methods, were recorded. Various annotations, such as protein sequence and structure properties, potential upstream kinases and their inhibitors, were systematically integrated and carefully organized to present details about the quantified phosphorylation sites. Various browse and search functions were implemented for the user-defined filtering of samples, conditions and proteins. Furthermore, the qKinAct service was developed to dissect the kinase activity profile from user-submitted quantitative phosphoproteome data through annotating the kinase activity-related phosphorylation sites. Taken together, the qPhos database provides a comprehensive resource for protein phosphorylation dynamics to facilitate related investigations.

Phase I study of high-dose ascorbic acid with mFOLFOX6 or FOLFIRI in patients with metastatic colorectal cancer or gastric cancer.

BACKGROUND: Preclinical studies suggest synergistic effectiveness of ascorbic acid (AA, vitamin C) and cytotoxic agents in gastrointestinal malignancies. This phase 1 study aimed to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of AA combined with mFOLFOX6 or FOLFIRI regimens in patients with metastatic colorectal cancer (mCRC) or gastric cancer (mGC). METHODS: In the dose-escalation phase, patients received AA (0.2-1.5 g/kg, 3-h infusion, once daily, days 1-3) with mFOLFOX6 or FOLFIRI in a 14-day cycle until the MTD was reached. In the speed-expansion phase, AA was administered at the MTD or at 1.5 g/kg if the MTD was not reached at a fixed rate of 0.6, 0.8 or 1 g/min. Pharmacokinetics and preliminary efficacy were also assessed. RESULTS: Thirty-six patients were enrolled. The MTD was not reached. The RP2D was established as AA at 1.5 g/kg/day, days 1-3, with mFOLFOX6 or FOLFIRI. No dose-limiting toxicity (DLT) was detected during dose escalation. The most common treatment-emergent adverse events (TRAEs) were sensory neuropathy (50%), nausea (38.9%), vomiting (36.1%) and neutropenia (27.8%). Grade 3-4 TRAEs were neutropenia (13.9%), sensory neuropathy (2.8%), vomiting (2.8%), diarrhea (2.8%) and leukopenia (2.8%). AA exposure was dose-proportional. The objective response rate was 58.3%, and the disease control rate was 95.8%. No difference in efficacy was found between mCRC patients with wild-type RAS/BRAF and mutant RAS or BRAF. CONCLUSIONS: The favorable safety profile and preliminary efficacy of AA plus mFOLFOX6/FOLFIRI support further evaluation of this combination in mCRC or mGC. TRIAL REGISTRATION: ClinicalTrial.gov Identifier: NCT02969681 .

Chemotherapy With or Without Anti-EGFR Agents in Left- and Right-Sided Metastatic Colorectal Cancer: An Updated Meta-Analysis.

BACKGROUND: Previous meta-analyses have suggested primary tumor location as a predictive factor for efficacy of anti-epidermal growth factor receptor (EGFR) therapies in patients with metastatic colorectal cancer (mCRC). However, the recent phase III TAILOR trial addressing this issue was not included in those analyses. This meta-analysis incorporated data from the TAILOR trial to evaluate the efficacy of chemotherapy plus anti-EGFR agents (cetuximab [Cet] or panitumumab [Pani]) versus chemotherapy alone for RAS wild-type (wt) right- and left-sided mCRC. PATIENTS AND METHODS: A PubMed-based literature search was conducted to identify randomized controlled trials (RCTs) studying the additional efficacy of Cet/Pani in combination with chemotherapy versus chemotherapy alone in RAS wt left- and right-sided mCRC. Study-level pooled analyses of hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) and odds ratios (ORs) for objective response rate (ORR) were performed. RESULTS: Three first-line RCTs (CRYSTAL, PRIME, and TAILOR) and one second-line RCT (20050181) were included. Significant OS benefits from Cet/Pani were observed in the left-sided (HR, 0.76; 95% CI, 0.66-0.86) but not right-sided subgroups (HR, 0.99; 95% CI, 0.78-1.27). However, the addition of Cet/Pani to chemotherapy significantly improved PFS and ORR in both the left-sided (HR, 0.70; 95% CI, 0.57-0.86, and OR, 3.28; 95% CI, 1.95-5.51, respectively) and right-sided subgroups (HR, 0.76; 95% CI, 0.59-0.99, and OR, 1.78; 95% CI, 1.08-2.93, respectively). CONCLUSIONS: The addition of Cet/Pani to chemotherapy significantly benefits PFS and ORR in patients with RAS wt right-sided mCRC, indicating that anti-EGFR therapies may remain an option for selected patients.

Pan-cancer genomic analyses reveal prognostic and immunogenic features of the tumor melatonergic microenvironment across 14 solid cancer types.

We performed comprehensive genomic analyses of the melatonergic system within the tumor microenvironment and their clinical relevance across a broad spectrum of solid tumors. RNA-seq data from The Cancer Genome Atlas (TCGA) of 14 solid tumors representing 6658 human samples were analyzed. The tumor melatonergic system was characterized by the rates of melatonin synthesis and metabolism using a two-gene expression model (melatonin synthesis/metabolism Index). We calculated three indexes according to different melatonin metabolism isoenzymes (Index-I [ASMT:CYP1A1], Index-II [ASMT:CYP1A2], and Index-III [ASMT:CYP1B1]). Samples of each cancer type were classified into two subgroups (high vs low) based on median values. Clinical outcomes, mutational burden, and neoepitope abundance were analyzed and compared. We found that the ability of the tumor microenvironment to synthesize and accumulate melatonin varied across cancer types and negatively correlated with tumor burden. Kaplan-Meier survival analyses and multivariable modeling showed that the three indexes played different roles across different cancers and harbored prognostic values in breast cancer (adjusted hazard ratio [AHR]Index-II  = 0.65 [0.44-0.97]; P = 0.03), cervical cancer (AHRIndex-I  = 0.62 [0.39-0.98]; P = 0.04), lung squamous cell carcinoma (AHRIndex-III  = 0.75 [0.56-0.99]; P = 0.04), melanoma (AHRIndex-I  = 0.74 [0.55-0.98]; P = 0.04), and stomach adenocarcinoma (AHRIndex-III  = 0.68 [0.41-0.94]; P = 0.02). We further investigated its clinical relevance with tumor immunogenic features (mutational burden and neoantigen abundance), which may predict immunotherapy benefits. We observed significant negative correlations with mutational burden in the majority of tumors (P < 0.05), except cervical cancer, pancreatic adenocarcinoma, and thyroid carcinoma. Our study provides a systematic overview of the oncostatic values of the melatonergic system and highlights the utilization of this simple and promising gene signature as a prognosticator and potential predictor of response to immunotherapy.

Phase II clinical trial of S-1 plus nanoparticle albumin-bound paclitaxel in untreated patients with metastatic gastric cancer.

The present study is the first phase II clinical trial aimed to evaluate the efficacy and safety of S-1 plus nanoparticle albumin-bound paclitaxel (Nab-PTX) as first-line chemotherapy for advanced gastric cancer (AGC). Previously untreated patients with metastatic gastric adenocarcinoma received S-1 in oral doses of 40 mg (BSA <1.25 m2 ), 50 mg (1.25 ≤ BSA < 1.50 m2 ) and 60 mg (BSA ≥1.50 m2 ) b.i.d. on days 1-14 in combination with Nab-PTX (120 mg/m2 , on days 1 and 8) for each 21-day cycle. Primary endpoint was progression-free survival (PFS), and secondary endpoints were overall response rate (ORR), overall survival (OS), disease control rate (DCR), and toxicity. A total of 73 gastric cancer patients with metastatic and measurable lesions were enrolled in the first-line setting. Median PFS and OS were 9.63 months and 14.60 months, respectively. Four (5.5%) patients had complete responses, 39 (53.4%) had partial responses (PRs), 21 (28.8%) had stable disease, four (5.5%) progressed and five (6.8%) were not evaluable. ORR and DCR were 58.9% and 87.7%, respectively. Most toxicities were mild, and no treatment-related deaths occurred. Grade 3 to 4 toxicities occurred in 22 patients (30.1%) as follows: leukopenia (13.7%), neutropenia (12.3%), anemia (5.5%), thrombocytopenia (1.4%), diarrhea (6.8%), vomiting (2.7%), stomatitis (1.4%), peripheral neuropathy (1.4%), and hand-foot syndrome (1.4%). Seven patients achieved good responses and underwent gastrectomy plus metastasectomy. Thirty (41.1%) patients had S-1 maintenance with a median of four cycles. S-1 plus Nab-PTX is an efficient and safe regimen as first-line treatment for patients with AGC.

Validation of the 8th Edition of the UICC/AJCC Staging System for Nasopharyngeal Carcinoma From Endemic Areas in the Intensity-Modulated Radiotherapy Era.

Background: In this study, we evaluated the 8th edition of the Union for International Cancer Control (UICC)/AJCC staging system for nasopharyngeal carcinoma (NPC) in an endemic area, with the aim of validating its applicability and providing further information for future refinements. Methods: A total of 1,790 patients with newly diagnosed, non-distant metastatic, histologically proven NPC treated with intensity-modulated radiotherapy (IMRT) were retrospectively reviewed. The performance of various staging systems was compared using the Akaike information criterion (AIC) and Harrell's concordance index (c-index). Results: For N (node) category, the survival curves of different groups according to the 8th edition were well-separated, and the prognostic model predicted outcomes fairly well. The 8th edition had higher AIC and c-index values for all end points than the 7th edition. However, probably due to the improved locoregional control provided by IMRT, the survival curves for T2 and T3 almost overlapped, without significant differences in locoregional failure-free survival (P=.606) and disease-free survival (P=.735). Due to the difficultly of differentiating T2 and T3, the AIC and c-index values were similar for the T categories of the 7th and 8th editions. Similarly, the overall survival and disease-free survival curves for stage II and III disease were not clearly separated for either the 8th or 7th editions. Conclusions: The 8th edition of the UICC/AJCC staging system for NPC enables more accurate prediction of treatment outcomes. However, several limitations need to be addressed in future editions, and it would be reasonable to further optimize the T category classification.

Nutrition support can bring survival benefit to high nutrition risk gastric cancer patients who received chemotherapy.

PURPOSE: The aim of our study is firstly to evaluate the prevalence and prognostic value of nutrition risk in gastric cancer patients and secondly to explore whether the nutrition support can prolong the survival of advanced gastric cancer patients. METHODS: It contained two study periods. In the first period, we prospectively evaluated the nutritional risk of gastric adenocarcinoma patients from 2009 to 2011 using the method of European Nutritional Risk Screening (NRS) 2002. The Kaplan-Meier method and log-rank test were used to evaluate the prognostic value of high nutrition risk. The second period was between 2012 and 2013. We prospectively gave the nutrition support to stage IV gastric cancer patients whose NRS is ≥3. RESULTS: There were 830 patients in the first period, 50.7% patients with a NRS ≥ 3. Patients with NRS ≥ 3 presented a significantly higher percentage of stage IV diseases, elevated values of C-reactive protein, and hypoproteinemia. The median survival was significantly higher in NRS < 3 patients (31.9 vs. 25.7 months, P < 0.001). Multivariate analysis confirmed that NRS status was an independent prognostic factor. There were 347 patients in the second period. Young, male, and good response to chemotherapy were more likely to have the NRS shift to <3 after nutrition support. The median survival was 14.3 and 9.6 months for patients with and without NRS shift, respectively, P = 0.001. CONCLUSIONS: NRS ≥ 3 was an independent adverse prognostic factor in gastric cancer patients. For stage IV patients whose NRS ≥ 3, the nutrition support might be helpful to improve the prognosis.

Sinapic Acid Attenuates Chronic DSS-Induced Intestinal Fibrosis in C57BL/6J Mice by Modulating NLRP3 Inflammasome Activation and the Autophagy Pathway.

Ulcerative colitis (UC) is a chronic gastrointestinal disease that results from repeated inflammation and serious complications. Sinapic acid (SA) is a hydroxycinnamic acid present in a variety of plants that has antioxidant, anti-inflammatory, anticancer, and other protective effects. This study investigated the antifibrotic effect of SA on chronic colitis induced by dextran sulfate sodium salt (DSS) in mice. We observed that SA could significantly reduce clinical symptoms (such as improved body weight loss, increased colon length, and decreased disease activity index score) and pathological changes in mice with chronic colitis. SA supplementation has been demonstrated to repair intestinal mucosal barrier function and maintain epithelial homeostasis by inhibiting activation of the NLRP3 inflammasome and decreasing the expression of IL-6, TNF-α, IL-17A, IL-18, and IL-1ß. Furthermore, SA could induce the expression of antioxidant enzymes (Cat, Sod1, Sod2, Mgst1) by activating the Nrf2/keap1 pathway, thus improving antioxidant capacity. Additionally, SA could increase the protein expression of downstream LC3-II/LC3-I and Beclin1 and induce autophagy by regulating the AMPK-Akt/mTOR signaling pathway, thereby reducing the production of intestinal fibrosis-associated proteins Collagen-I and α-SMA. These findings suggest that SA can enhance intestinal antioxidant enzymes, reduce oxidative stress, expedite intestinal epithelial repair, and promote autophagy, thereby ameliorating DSS-induced colitis and intestinal fibrosis.

Modulator of TMB-associated immune infiltration (MOTIF) predicts immunotherapy response and guides combination therapy.

Patients with high tumor mutational burden (TMB) levels do not consistently respond to immune checkpoint inhibitors (ICIs), possibly because a high TMB level does not necessarily result in adequate infiltration of CD8+ T cells. Using bulk ribonucleic acid sequencing (RNA-seq) data from 9311 tumor samples across 30 cancer types, we developed a novel tool called the modulator of TMB-associated immune infiltration (MOTIF), which comprises genes that can determine the extent of CD8+ T cell infiltration prompted by a certain TMB level. We confirmed that MOTIF can accurately reflect the integrity and defects of the cancer-immunity cycle. By analyzing 84 human single-cell RNA-seq datasets from 32 types of solid tumors, we revealed that MOTIF can provide insights into the diverse roles of various cell types in the modulation of CD8+ T cell infiltration. Using pretreatment RNA-seq data from 13 ICI-treated cohorts, we validated the use of MOTIF in predicting CD8+ T cell infiltration and ICI efficacy. Among the components of MOTIF, we identified EMC3 as a negative regulator of CD8+ T cell infiltration, which was validated via in vivo studies. Additionally, MOTIF provided guidance for the potential combinations of programmed death 1 blockade with certain immunostimulatory drugs to facilitate CD8+ T cell infiltration and improve ICI efficacy.

Sinapic acid modulates oxidative stress and metabolic disturbances to attenuate ovarian fibrosis in letrozole-induced polycystic ovary syndrome SD rats.

Sinapic acid (SA) is renowned for its many pharmacological activities as a polyphenolic compound. The cause of polycystic ovary syndrome (PCOS), a commonly encountered array of metabolic and hormonal abnormalities in females, has yet to be determined. The present experiment was performed to evaluate the antifibrotic properties of SA in rats with letrozole-induced PCOS-related ovarian fibrosis. SA treatment successfully mitigated the changes induced by letrozole in body weight (BW) (p < .01) and relative ovary weight (p < .05). Histological observation revealed that SA reduced the number of atretic and cystic follicles (AFs) and (CFs) (p < .01), as well as ovarian fibrosis, in PCOS rats. Additionally, SA treatment impacted the serum levels of sex hormones in PCOS rats. Luteinizing hormone (LH) and testosterone (T) levels were decreased (p < .01, p < .05), and follicle-stimulating hormone (FSH) levels were increased (p < .05). SA administration also decreased triglyceride (TG) (p < .01) and total cholesterol (TC) levels (p < .05) and increased high-density lipoprotein cholesterol (HDL-C) levels (p < .01), thereby alleviating letrozole-induced metabolic dysfunction in PCOS rats. Furthermore, SA treatment targeted insulin resistance (IR) and increased the messenger RNA (mRNA) levels of antioxidant enzymes in the ovaries of PCOS rats. Finally, SA treatment enhanced the activity of peroxisome proliferator-activated receptor-γ (PPAR-γ), reduced the activation of transforming growth factor-ß1 (TGF-ß1)/Smads, and decreased collagen I, α-smooth muscle actin (α-SMA), and connective tissue growth factor (CTGF) levels in the ovaries of PCOS rats. These observations suggest that SA significantly ameliorates metabolic dysfunction and oxidative stress and ultimately reduces ovarian fibrosis in rats with letrozole-induced PCOS.

First-line serplulimab in metastatic colorectal cancer: Phase 2 results of a randomized, double-blind, phase 2/3 trial.

BACKGROUND: Whether or not the addition of immunotherapy to current standard-of-care treatments can improve efficacy in proficient mismatch repair (pMMR)/microsatellite-stable (MSS) metastatic colorectal cancer (mCRC), the predominant type of mCRC, is unclear. METHODS: This randomized, double-blind, phase 2 part of a phase 2/3 trial was conducted at 23 hospitals across China (ClinicalTrials.gov: NCT04547166). Patients with unresectable metastatic/recurrent colorectal adenocarcinoma and no prior systemic therapy were randomly assigned 1:1 to receive every-3-weeks intravenous serplulimab (300 mg) plus HLX04 (7.5 mg/kg) and XELOX (serplulimab group) or placebo (300 mg) plus bevacizumab (7.5 mg/kg) and XELOX (placebo group). The primary endpoint was independent radiology review committee (IRRC)-assessed progression-free survival (PFS). Secondary endpoints included other efficacy endpoints and safety. FINDINGS: Between July 16, 2021, and January 20, 2022, 114 patients were enrolled and randomly assigned to the serplulimab (n = 57) or placebo (n = 57) group. All patients had stage IV CRC, and 95.7% of the patients with available microsatellite instability (MSI) status were MSS. With a median follow-up duration of 17.7 months, median PFS was prolonged in the serplulimab group (17.2 vs. 10.7 months; hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.31-1.14). Although the median overall survival (OS) was not reached for either group, a trend of an OS benefit was observed for the serplulimab group (HR, 0.77; 95% CI, 0.41-1.45). 36 (65.5%) and 32 (56.1%) patients in the serplulimab and placebo groups had grade ≥3 treatment-related adverse events, respectively. CONCLUSIONS: Serplulimab plus HLX04 and XELOX exhibits promising efficacy and is safe and tolerable in patients with treatment-naive mCRC. FUNDING: This work was funded by Shanghai Henlius Biotech, Inc.

Combined anti-PD-1, HDAC inhibitor and anti-VEGF for MSS/pMMR colorectal cancer: a randomized phase 2 trial.

Epigenetic modifications of chromatin, including histone acetylation, and tumor angiogenesis play pivotal roles in creating an immunosuppressive tumor microenvironment. In the randomized phase 2 CAPability-01 trial, we investigated the potential efficacy of combining the programmed cell death protein-1 (PD-1) monoclonal antibody sintilimab with the histone deacetylase inhibitor (HDACi) chidamide with or without the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab in patients with unresectable chemotherapy-refractory locally advanced or metastatic microsatellite stable/proficient mismatch repair (MSS/pMMR) colorectal cancer. Forty-eight patients were randomly assigned to either the doublet arm (sintilimab and chidamide, n = 23) or the triplet arm (sintilimab, chidamide and bevacizumab, n = 25). The primary endpoint of progression-free survival (PFS) rate at 18 weeks (18wPFS rate) was met with a rate of 43.8% (21 of 48) for the entire study population. Secondary endpoint results include a median PFS of 3.7 months, an overall response rate of 29.2% (14 of 48), a disease control rate of 56.3% (27 of 48) and a median duration of response of 12.0 months. The secondary endpoint of median overall survival time was not mature. The triplet arm exhibited significantly improved outcomes compared to the doublet arm, with a greater 18wPFS rate (64.0% versus 21.7%, P = 0.003), higher overall response rate (44.0% versus 13.0%, P = 0.027) and longer median PFS rate (7.3 months versus 1.5 months, P = 0.006). The most common treatment-emergent adverse events observed in both the triplet and doublet arms included proteinuria, thrombocytopenia, neutropenia, anemia, leukopenia and diarrhea. There were two treatment-related fatalities (hepatic failure and pneumonitis). Analysis of bulk RNA sequencing data from the patients suggested that the triplet combination enhanced CD8+ T cell infiltration, resulting in a more immunologically active tumor microenvironment. Our study suggests that the combination of a PD-1 antibody, an HDACi, and a VEGF antibody could be a promising treatment regimen for patients with MSS/pMMR advanced colorectal cancer. ClinicalTrials.gov registration: NCT04724239 .

Perioperative toripalimab and chemotherapy in locally advanced gastric or gastro-esophageal junction cancer: a randomized phase 2 trial.

Perioperative chemotherapy is the standard treatment for locally advanced gastric or gastro-esophageal junction cancer, and the addition of programmed cell death 1 (PD-1) inhibitor is under investigation. In this randomized, open-label, phase 2 study (NEOSUMMIT-01), patients with resectable gastric or gastro-esophageal junction cancer clinically staged as cT3-4aN + M0 were randomized (1:1) to receive either three preoperative and five postoperative 3-week cycles of SOX/XELOX (chemotherapy group, n = 54) or PD-1 inhibitor toripalimab plus SOX/XELOX, followed by toripalimab monotherapy for up to 6 months (toripalimab plus chemotherapy group, n = 54). The primary endpoint was pathological complete response or near-complete response rate (tumor regression grade (TRG) 0/1). The results showed that patients in the toripalimab plus chemotherapy group achieved a higher proportion of TRG 0/1 than those in the chemotherapy group (44.4% (24 of 54, 95% confidence interval (CI): 30.9%-58.6%) versus 20.4% (11 of 54, 95% CI: 10.6%-33.5%)), and the risk difference of TRG 0/1 between toripalimab plus chemotherapy group and chemotherapy group was 22.7% (95% CI: 5.8%-39.6%; P = 0.009), meeting a prespecified endpoint. In addition, a higher pathological complete response rate (ypT0N0) was observed in the toripalimab plus chemotherapy group (22.2% (12 of 54, 95% CI: 12.0%-35.6%) versus 7.4% (4 of 54, 95% CI: 2.1%-17.9%); P = 0.030), and surgical morbidity (11.8% in the toripalimab plus chemotherapy group versus 13.5% in the chemotherapy group) and mortality (1.9% versus 0%), and treatment-related grade 3-4 adverse events (35.2% versus 29.6%) were comparable between the treatment groups. In conclusion, the addition of toripalimab to chemotherapy significantly increased the proportion of patients achieving TRG 0/1 compared to chemotherapy alone and showed a manageable safety profile. ClinicalTrials.gov registration: NCT04250948 .

Clinical Benefit of First-Line Programmed Death-1 Antibody Plus Chemotherapy in Low Programmed Cell Death Ligand 1-Expressing Esophageal Squamous Cell Carcinoma: A Post Hoc Analysis of JUPITER-06 and Meta-Analysis.

PURPOSE: Pembrolizumab or nivolumab plus chemotherapy was approved as a first-line treatment for high programmed cell death ligand 1 (PD-L1)-expressing esophageal squamous cell carcinoma (ESCC) by the European Medicines Agency, whereas the US Food and Drug Administration approved this regimen regardless of PD-L1 expression. The superiority of programmed death-1 (PD-1) antibody plus chemotherapy over chemotherapy alone in patients with low PD-L1-expressing ESCC remains debatable. METHODS: Post hoc analysis of the Chinese JUPITER-06 study focusing on efficacy stratified by PD-L1 tumor proportion score (TPS; using JS311 antibody) was conducted. Electronic databases were searched to identify eligible randomized controlled trials for meta-analysis. Study-level pooled analyses of hazard ratios (HRs) for overall survival and progression-free survival and odds ratios for objective response rate according to PD-L1 expression were performed. RESULTS: The post hoc analysis of JUPITER-06 showed more prominent clinical benefit with PD-1 antibody plus chemotherapy than with chemotherapy alone in both the high and low PD-L1-expressing subgroups. Five randomized controlled trials were included in the meta-analysis, and two PD-L1 expression scoring criteria, TPS (≥ 1%/< 1%) and combined positive score (CPS, ≥ 10/< 10), were analyzed. Significant overall survival benefit by adding PD-1 antibody to chemotherapy was observed in both the TPS < 1% (HR, 0.74; 95% CI, 0.56 to 0.97) and CPS < 10 (HR, 0.77; 95% CI, 0.66 to 0.89) subgroups. Similarly, significantly prolonged progression-free survival was observed in both the TPS < 1% (HR, 0.66; 95% CI, 0.50 to 0.86) and CPS < 10 (HR, 0.63; 95% CI, 0.47 to 0.84) subgroups. In addition, the objective response rate of the TPS < 1% subgroup was significantly improved (odds ratio, 1.71; 95% CI, 1.27 to 2.29). In all high PD-L1-expressing subgroups, the pooled benefit of PD-1 antibody plus chemotherapy was significantly better than that of chemotherapy. CONCLUSION: This study provided novel evidence supporting the superiority of PD-1 antibody plus chemotherapy to chemotherapy alone in patients with advanced ESCC with low PD-L1 expression. Further studies of predictive biomarkers are warranted.

Irpex lacteus polysaccharide exhibits therapeutic potential for ovarian fibrosis in PCOS rats via the TGF-ß1/smad pathway.

Polycystic ovarian syndrome (PCOS) is one of the commonest endocrinopathies in childbearing women. The research was conducted to assess the impact of Irpex lacteus polysaccharide (ILP, 1000 mg/kg) on the letrozole (1 mg/kg)-induced PCOS model in female rats. Metformin (Met, 265 mg/kg) as the positive control. The study suggested that ILP restored the estrous cycle in rats with PCOS as well as lowered relative ovarian weight and body weight, in comparison to normal. Rats with PCOS showed improvement in ovarian structure and fibrosis when given ILP. ILP decreased the testosterone (T), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), total cholesterol (TC), luteinizing hormone (LH), homeostasis model assessment-insulin resistance (HOMA-IR), fasting blood glucose (FBG), and insulin (INS) levels and elevated the follicle-stimulating hormone (FSH) and estrogen (E2) levels in PCOS rats. In addition, ILP increased the content of superoxide dismutase (SOD) in serum and the antioxidant enzymes (Prdx3, Sod1, Gsr, Gsta4, Mgst1, Gpx3, Sod2 and Cat) expression levels in the ovaries and decreased the serum expression of malondialdehyde (MDA). In addition, ILP treatment slowed down the process of the fibrosis-associated TGF-ß1/Smad pathway and downregulated α-smooth muscle actin (α-SMA) and connective tissue growth factor (CTGF) levels in PCOS rats ovaries. According to these findings, ILP may be able to treat letrozole-induced PCOS in rats by ameliorating metabolic disturbances, sex hormone levels, oxidative stress, and ovarian fibrosis.

Comprehensive genomic characterization of sporadic synchronous colorectal cancer: Implications for treatment optimization and clinical outcome.

Sporadic synchronous colorectal cancer (SCRC) refers to multiple primary CRC tumors detected simultaneously in an individual without predisposing hereditary conditions, which accounts for the majority of multiple CRCs while lacking a profound understanding of the genomic landscape and evolutionary dynamics to optimize its treatment. In this study, 103 primary tumor samples from 51 patients with SCRC undergo whole-exome sequencing. The germline and somatic mutations and evolutionary and clinical features are comprehensively investigated. Somatic genetic events are largely inconsistent between paired tumors. Compared with solitary CRC, SCRCs have higher prevalence of tumor mutation burden high (TMB-H; 33.3%) and microsatellite-instability high (MSI-H; 29.4%) and different mutation frequencies in oncogenic signaling pathways. Moreover, neutrally evolving SCRC tumors are associated with higher intratumoral heterogeneity and better prognosis. These findings unveil special molecular features, carcinogenesis, and prognosis of sporadic SCRC. Strategies for targeted therapy and immunotherapy should be optimized accordingly.