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 .

The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer, 2023.

The 2023 update of the Chinese Society of Clinical Oncology (CSCO) Clinical Guidelines for Gastric Cancer focuses on standardizing cancer diagnosis and treatment in China, reflecting the latest advancements in evidence-based medicine, healthcare resource availability, and precision medicine. These updates address the differences in epidemiological characteristics, clinicopathological features, tumor biology, treatment patterns, and drug selections between Eastern and Western gastric cancer patients. Key revisions include a structured template for imaging diagnosis reports, updated standards for molecular marker testing in pathological diagnosis, and an elevated recommendation for neoadjuvant chemotherapy in stage III gastric cancer. For advanced metastatic gastric cancer, the guidelines introduce new recommendations for immunotherapy, anti-angiogenic therapy and targeted drugs, along with updated management strategies for human epidermal growth factor receptor 2 (HER2)-positive and deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) patients. Additionally, the guidelines offer detailed screening recommendations for hereditary gastric cancer and an appendix listing drug treatment regimens for various stages of gastric cancer. The 2023 CSCO Clinical Guidelines for Gastric Cancer updates are based on both Chinese and international clinical research and expert consensus to enhance their applicability and relevance in clinical practice, particularly in the heterogeneous healthcare landscape of China, while maintaining a commitment to scientific rigor, impartiality, and timely revisions.

Comprehensive analysis reveals potential therapeutic targets and an integrated risk stratification model for solitary fibrous tumors.

Solitary fibrous tumors (SFTs) are rare mesenchymal tumors with unpredictable evolution and with a recurrence or metastasis rate of 10-40%. Current medical treatments for relapsed SFTs remain ineffective. Here, we identify potential therapeutic targets and risk factors, including IDH1 p.R132S, high PD-L1 expression, and predominant macrophage infiltration, suggesting the potential benefits of combinational immune therapy and targeted therapy for SFTs. An integrated risk model incorporating mitotic count, density of Ki-67+ cells and CD163+ cells, MTOR mutation is developed, applying a discovery cohort of 101 primary non-CNS patients with negative tumor margins (NTM) and validated in three independent cohorts of 210 SFTs with the same criteria, and in 36 primary CNS SFTs with NTM. Compared with the existing models, our model shows significantly improved efficacy in identifying high-risk primary non-CNS and CNS SFTs with NTM for tumor progression.Our findings hold promise for advancing therapeutic strategies and refining risk prediction in SFTs.

Anti-factor Xa level monitoring of low-molecular-weight heparin for prevention of venous thromboembolism in critically ill patients (AXaLPE): protocol of a randomised, open-label controlled clinical trial.

INTRODUCTION: Whether and when to monitor the amount of anti-factor Xa (aFXa) activity in critically ill patients with complex diseases to prevent venous thromboembolism (VTE) remain unclear. This study is a randomised controlled trial to investigate the effect of aFXa level monitoring on reducing VTE and to establish a new method for accurately preventing VTE in critically ill patients with low-molecular-weight heparin (LMWH). METHODS AND ANALYSIS: A randomised controlled trial is planned in two centres with a planned sample size of 858 participants. Participants will be randomly assigned to three groups receiving LMWH prophylaxis at a 1:1:1 ratio: in group A, peak aFXa levels will serve as the guide for the LMWH dose; in group B, the trough aFXa levels will serve as the guide for the LMWH dose; and in group C, participants serving as the control group will receive a fixed dose of LMWH. The peak and trough aFXa levels will be monitored after LMWH (enoxaparin, 40 mg, once daily) reaches a steady state for at least 3 days. The monitoring range for group A's aFXa peak value will be 0.3-0.5 IU/mL, between 0.1 and 0.2 IU/mL is the target range for group B's aFXa trough value. In order to reach the peak or trough aFXa levels, groups A and B will be modified in accordance with the monitoring peak and trough aFXa level. The incidence of VTE will serve as the study's primary outcome indicator. An analysis using the intention-to-treat and per-protocol criterion will serve as the main outcome measurement. ETHICS AND DISSEMINATION: The Xuanwu Hospital Ethics Committee of Capital Medical University and Peking University First Hospital Ethics Committee have approved this investigation. It will be released in all available worldwide, open-access, peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT05382481.

Dynamic single-cell mapping unveils Epstein‒Barr virus-imprinted T-cell exhaustion and on-treatment response.

Epstein‒Barr virus (EBV)-associated gastric cancer (GC) manifests an intriguing immunotherapy response. However, the cellular basis for EBV-imprinted tumour immunity and on-treatment response remains undefined. This study aimed to finely characterize the dynamic tumour immune contexture of human EBV (+) GC treated with immunochemotherapy by longitudinal scRNA-seq and paired scTCR/BCR-seq. EBV (+) GC exhibits an inflamed-immune phenotype with increased T-cell and B-cell infiltration. Immunochemotherapy triggers clonal revival and reinvigoration of effector T cells which step to determine treatment response. Typically, an antigen-specific ISG-15+CD8+ T-cell population is highly enriched in EBV (+) GC patients, which represents a transitory exhaustion state. Importantly, baseline intratumoural ISG-15+CD8+ T cells predict immunotherapy responsiveness among GC patients. Re-emerged clonotypes of pre-existing ISG-15+CD8+ T cells could be found after treatment, which gives rise to a CXCL13-expressing effector population in responsive EBV (+) tumours. However, LAG-3 retention may render the ISG-15+CD8+ T cells into a terminal exhaustion state in non-responsive EBV (+) tumours. In accordance, anti-LAG-3 therapy could effectively reduce tumour burden in refractory EBV (+) GC patients. Our results delineate a distinct implication of EBV-imprinted on-treatment T-cell immunity in GC, which could be leveraged to optimize the rational design of precision immunotherapy.

Targeted demethylation of the CDO1 promoter based on CRISPR system inhibits the malignant potential of breast cancer cells.

BACKGROUND: Cysteine dioxygenase 1 (CDO1) is frequently methylated, and its expression is decreased in many human cancers including breast cancer (BC). However, the functional and mechanistic aspects of CDO1 inactivation in BC are poorly understood, and the diagnostic significance of serum CDO1 methylation remains unclear. METHODS: We performed bioinformatics analysis of publicly available databases and employed MassARRAY EpiTYPER methylation sequencing technology to identify differentially methylated sites in the CDO1 promoter of BC tissues compared to normal adjacent tissues (NATs). Subsequently, we developed a MethyLight assay using specific primers and probes for these CpG sites to detect the percentage of methylated reference (PMR) of the CDO1 promoter. Furthermore, both LentiCRISPR/dCas9-Tet1CD-based CDO1-targeted demethylation system and CDO1 overexpression strategy were utilized to detect the function and underlying mechanism of CDO1 in BC. Finally, the early diagnostic value of CDO1 as a methylation biomarker in BC serum was evaluated. RESULTS: CDO1 promoter was hypermethylated in BC tissues, which was related to poor prognosis (p < .05). The CRISPR/dCas9-based targeted demethylation system significantly reduced the PMR of CDO1 promotor and increased CDO1 expression in BC cells. Consequently, this leads to suppression of cell proliferation, migration and invasion. Additionally, we found that CDO1 exerted a tumour suppressor effect by inhibiting the cell cycle, promoting cell apoptosis and ferroptosis. Furthermore, we employed the MethyLight to detect CDO1 PMR in BC serum, and we discovered that serum CDO1 methylation was an effective non-invasive biomarker for early diagnosis of BC. CONCLUSIONS: CDO1 is hypermethylated and acts as a tumour suppressor gene in BC. Epigenetic editing of abnormal CDO1 methylation could have a crucial role in the clinical treatment and prognosis of BC. Additionally, serum CDO1 methylation holds promise as a valuable biomarker for the early diagnosis and management of BC.

Precise microdissection of gastric mixed adeno-neuroendocrine carcinoma dissects its genomic landscape and evolutionary clonal origins.

Gastric mixed adenoneuroendocrine carcinoma (MANEC) is a clinically aggressive and heterogeneous tumor composed of adenocarcinoma (ACA) and neuroendocrine carcinoma (NEC). The genomic properties and evolutionary clonal origins of MANEC remain unclear. We conduct whole-exome and multiregional sequencing on 101 samples from 33 patients to elucidate their evolutionary paths. We identify four significantly mutated genes, TP53, RB1, APC, and CTNNB1. MANEC resembles chromosomal instability stomach adenocarcinoma in that whole-genome doubling in MANEC is predominant and occurs earlier than most copy-number losses. All tumors are of monoclonal origin, and NEC components show more aggressive genomic properties than their ACA counterparts. The phylogenetic trees show two tumor divergence patterns, including sequential and parallel divergence. Furthermore, ACA-to-NEC rather than NEC-to-ACA transition is confirmed by immunohistochemistry on 6 biomarkers in ACA- and NEC-dominant regions. These results provide insights into the clonal origin and tumor differentiation of MANEC.

Cross-cohort analysis identified an immune checkpoint-based signature to predict the clinical outcomes of neuroblastoma.

BACKGROUND: Neuroblastoma (NB) places a substantial health burden on families worldwide. This study aimed to develop an immune checkpoint-based signature (ICS) based on the expression of immune checkpoints to better assess patient survival risk and potentially guide patient selection for immunotherapy of NB. METHODS: Immunohistochemistry integrated with digital pathology was used to determine the expression levels of 9 immune checkpoints in 212 tumor tissues used as the discovery set. The GSE85047 dataset (n=272) was used as a validation set in this study. In the discovery set, the ICS was constructed using a random forest algorithm and confirmed in the validation set to predict overall survival (OS) and event-free survival (EFS). Kaplan-Meier curves with a log-rank test were drawn to compare the survival differences. A receiver operating characteristic (ROC) curve was applied to calculate the area under the curve (AUC). RESULTS: Seven immune checkpoints, including PD-L1, B7-H3, IDO1, VISTA, T-cell immunoglobulin and mucin domain containing-3 (TIM-3), inducible costimulatory molecule (ICOS) and costimulatory molecule 40 (OX40), were identified as abnormally expressed in NB in the discovery set. OX40, B7-H3, ICOS and TIM-3 were eventually selected for the ICS model in the discovery set, and 89 patients with high risk had an inferior OS (HR 15.91, 95% CI 8.87 to 28.55, p<0.001) and EFS (HR 4.30, 95% CI 2.80 to 6.62, p<0.001). Furthermore, the prognostic value of the ICS was confirmed in the validation set (p<0.001). Multivariate Cox regression analysis demonstrated that age and the ICS were independent risk factors for OS in the discovery set (HR 6.17, 95% CI 1.78 to 21.29 and HR 1.18, 95% CI 1.12 to 1.25, respectively). Furthermore, nomogram A combining the ICS and age demonstrated significantly better prognostic value than age alone in predicting the patients' 1-year, 3-year and 5-year OS in the discovery set (1 year: AUC, 0.891 (95% CI 0.797 to 0.985) vs 0.675 (95% CI 0.592 to 0.758); 3 years: 0.875 (95% CI 0.817 to 0.933) vs 0.701 (95% CI 0.645 to 0.758); 5 years: 0.898 (95% CI 0.851 to 0.940) vs 0.724 (95% CI 0.673 to 0.775), respectively), which was confirmed in the validation set. CONCLUSIONS: We propose an ICS that significantly differentiates between low-risk and high-risk patients, which might add prognostic value to age and provide clues for immunotherapy in NB.

An immunogenic and oncogenic feature-based classification for chemotherapy plus PD-1 blockade in advanced esophageal squamous cell carcinoma.

Although chemotherapy plus PD-1 blockade (chemo+anti-PD-1) has become the standard first-line therapy for advanced esophageal squamous cell carcinoma (ESCC), reliable biomarkers for this regimen are lacking. Here we perform whole-exome sequencing on tumor samples from 486 patients of the JUPITER-06 study and develop a copy number alteration-corrected tumor mutational burden that depicts immunogenicity more precisely and predicts chemo+anti-PD-1 efficacy. We identify several other favorable immunogenic features (e.g., HLA-I/II diversity) and risk oncogenic alterations (e.g., PIK3CA and TET2 mutation) associated with chemo+anti-PD-1 efficacy. An esophageal cancer genome-based immuno-oncology classification (EGIC) scheme incorporating these immunogenic features and oncogenic alterations is established. Chemo+anti-PD-1 achieves significant survival improvements in EGIC1 (immunogenic feature-favorable and oncogenic alteration-negative) and EGIC2 (either immunogenic feature-favorable or oncogenic alteration-negative) subgroups, but not the EGIC3 subgroup (immunogenic feature-unfavorable and oncogenic alteration-positive). Thus, EGIC may guide future individualized treatment strategies and inform mechanistic biomarker research for chemo+anti-PD-1 treatment in patients with advanced ESCC.

Case report: PD-1 inhibitor-based treatment strategies in gastric cancer complicated by bone marrow metastasis and disseminated intravascular coagulation: A report of two cases.

Introduction: Gastric cancer (GC) complicated by bone marrow metastasis (BMM) and disseminated intravascular coagulation (DIC) represents poor prognosis and most of these patients would die in a few months. Active treatment strategies such as chemotherapy are effective in restoring coagulation function and prolonging patients' survival time. Immunotherapy including programmed death protein 1 (PD-1) or programmed death protein ligand 1 (PD-L1) inhibitors has emerged as a first-line treatment of gastric cancer. However, the efficacy of PD-1 inhibitor-based treatment strategies in these patients remains unknown. Case description: Herein, we presented two cases of advanced gastric cancer (AGC) complicated by BMM and DIC, in which two patients received chemotherapy and PD-1 inhibitor as the first-line treatment. Both of them achieved a partial response after treatment, and the coagulation function was restored. The patient who discontinued the PD-1 inhibitor after 6 months experienced DIC relapse, whereas the other patient who maintained the PD-1 inhibitor treatment cycle remained responsive after 10 months. Conclusions: We speculate that PD-1 inhibitor-based treatment strategies are effective and safe in prolonging survival against gastric cancer with BMM and DIC, and the coagulation function is well controlled by the treatment with a combination of immunotherapy and chemotherapy.

ASSOCIATION OF OCULAR PERFUSION PRESSURE AND CEREBROSPINAL FLUID PRESSURE WITH CHANGES IN DIABETIC RETINOPATHY.

PURPOSE: To investigate the association between mean ocular perfusion pressure (MOPP), estimated cerebrospinal fluid pressure (CSFP), and changes in diabetic retinopathy (DR) in a Northeastern Chinese population with Type 2 diabetes. METHODS: A total of 1,322 subjects from the Fushun Diabetic Retinopathy Cohort Study were enrolled. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and intraocular pressure (IOP) were recorded. MOPP was calculated by the following formula: MOPP = 2/3 [DBP + 1/3 (SBP - DBP)] - IOP, and CSFP was estimated according to the following formula: CSFP = 0.44 × body mass index + 0.16 × DBP - 0.18 × age - 1.91. New development, progression, and regression of DR were graded based on fundus photographs at baseline and during follow-up examinations with a mean interval of 21.2 months using the modified Early Treatment Diabetic Retinopathy Study criteria. RESULTS: Increasing MOPP was associated with the incidence of DR in the multivariate model (per 1-mmHg increase: relative risk, 1.06; 95% confidence interval, 1.02-1.10; P = 0.007) and showed a borderline negative association with DR regression (per 1-mmHg increase: relative risk, 0.98; 95% confidence interval, 0.97-1.00; P = 0.053). However, MOPP was not associated with progression of DR. Cerebrospinal fluid pressure was not associated with new development, progression, or regression of DR. CONCLUSION: The MOPP, but not the CSFP, was found to influence the development, but not the progression of DR in this Northeastern Chinese cohort.

Refractive Error in a Chinese Population with Type 2 Diabetes: A Report from the Fushun Diabetic Retinopathy Cohort Study.

PURPOSE: To describe the prevalence and risk factors for refractive errors in a northeastern Chinese population with type 2 diabetes. METHODS: Subjects (age ≥30 years) from a community-based study, the Fushun Diabetic Retinopathy Cohort Study, were enrolled. All subjects underwent comprehensive ocular examinations, including autorefraction. Myopia, high myopia, and hyperopia were defined as a spherical equivalent (SE) of the right eye <-0.5 diopter (D), <-5.0D, and >0.5D, respectively. Astigmatism was defined as cylinder <-0.5D in a minus cylinder prescription. Anisometropia was defined as a difference of SE >1.0D between two eyes. RESULTS: A total of 1929 participants (790 males, 41.0%) were enrolled. The age and gender standardized prevalence of myopia, high myopia, hyperopia, astigmatism, and anisometropia were 43.1% (95% confidence interval [CI]: 40.9%-45.3%), 8.5% (95% CI: 7.3%-9.8%), 21.5% (95% CI: 19.7%-23.4%), 61.0% (95% CI: 58.9%-63.2%), and 17.2% (95% CI: 15.5%-18.9%), respectively. Advancing age was associated with a higher frequency of hyperopia, astigmatism, and anisometropia, as opposed to a lower frequency of myopia. Female (adjusted odds ratio [aOR], 1.27; 95% CI, 1.02-1.57) participants, higher intraocular pressure (aOR, 1.03; 95% CI, 1.00-1.07), and lenticular opacity (aOR, 1.53; 95% CI, 1.20-1.94) were also found to be associated with myopia. Long duration of diabetes (>15 years) was found to be a significant factor for astigmatism (aOR, 1.62; 95% CI, 1.15-2.27) and anisometropia (aOR, 1.87; 95% CI, 1.29-2.71). CONCLUSION: Nearly two-thirds of participants with type 2 diabetes had a refractive error. Age is a common factor with different types of refractive errors.

Safety and Clinical Activity of SHR7390 Monotherapy or Combined With Camrelizumab for Advanced Solid Tumor: Results From Two Phase I Trials.

BACKGROUND: SHR7390 is a novel, selective MEK1/2 inhibitor. Here, we report results from two phase I trials conducted to evaluate the tolerability, safety and antitumor activity of SHR7390 monotherapy for advanced solid tumors and SHR7390 plus camrelizumab for treatment-refractory advanced or metastatic colorectal cancer (CRC). PATIENTS AND METHODS: Patients received SHR7390 alone or combined with fixed-dose camrelizumab (200 mg every 2 weeks) in an accelerated titration scheme to determine the maximum tolerated dose (MTD). A recommended dose for expansion was determined based on the safety and tolerability of the dose-escalation stage. The primary endpoints were dose limiting toxicity (DLT) and MTD. RESULTS: In the SHR7390 monotherapy trial, 16 patients were enrolled. DLTs were reported in the 1.0 mg cohort, and the MTD was 0.75 mg. Grade ≥3 treatment-related adverse events (TRAEs) were recorded in 4 patients (25.0%). No patients achieved objective response. In the SHR7390 combination trial, 22 patients with CRC were enrolled. One DLT was reported in the 0.5 mg cohort and the MTD was not reached. Grade ≥3 TRAEs were observed in 8 patients (36.4%), with the most common being rash (n=4). One grade 5 TRAE (increased intracranial pressure) occurred. Five patients (22.7%) achieved partial response, including one of 3 patients with MSS/MSI-L and BRAF mutant tumors, one of 15 patients with MSS/MSI-L and BRAF wild type tumors, and all 3 patients with MSI-H tumors. CONCLUSIONS: SHR7390 0.5 mg plus camrelizumab showed a manageable safety profile. Preliminary clinical activity was reported regardless of MSI and BRAF status.

Whole-Exome Sequencing Among Chinese Patients With Hereditary Diffuse Gastric Cancer.

Importance: The E-cadherin gene, CDH1, and the α-E-catenin gene, CTNNA1, were previously identified as hereditary diffuse gastric cancer (HDGC) susceptibility genes, explaining 25% to 50% of HDGC cases. The genetic basis underlying disease susceptibility in the remaining 50% to 75% of patients with HDGC is still unknown. Objective: To assess the incidence rate of CDH1 germline alterations in HDGC, identify new susceptibility genes that can be used for screening of HDGC, and provide a genetic landscape for HDGC. Design, Setting, and Participants: This cohort study conducted retrospective whole-exome and targeted sequencing of 284 leukocyte samples and 186 paired tumor samples from Chinese patients with HDGC over a long follow-up period (median, 21.7 [range, 0.6-185.9] months). Among 10 431 patients diagnosed with gastric cancer between January 1, 2002, and August 31, 2018, 284 patients who met the criteria for HDGC were included. Data were analyzed from August 1 to 30, 2020. Main Outcomes and Measures: Incidence rate of CDH1 germline alterations, identification of new HDGC susceptibility genes, and genetic landscape of HDGC. Results: Among 284 Chinese patients, 161 (56.7%) were female, and the median age was 35 (range, 20-75) years. The frequency of CDH1 germline alterations was 2.8%, whereas the frequency of CDH1 somatic alterations was 25.3%. The genes with the highest incidence (>10%) of private germline alterations (including insertions and deletions) in the HDGC cohort were MUC4, ABCA13, ZNF469, FCGBP, IGFN1, RNF213, and SSPO, whereas previously reported germline alterations of CTNNA1, BRCA2, STK11, PRSS1, ATM, MSR1, PALB2, BRCA1, and RAD51C were observed at low frequencies (median, 4 [range, 1-12] cases). Furthermore, enrichment of the somatic variant signature of exposure to aflatoxin suggested potential interaction between genetics and environment in HDGC. Double-hit events in genes such as CACNA1D were observed, which suggested that these events might serve as important mechanisms for HDGC tumorigenesis. In addition, germline variants of FSIP2, HSPG2, and NCKAP5 and somatic alterations of FGFR3, ASPSCR1, CIC, DGCR8, and LZTR1 were associated with poor overall survival among patients with HDGC. Conclusions and Relevance: This study provided a genetic landscape for HDGC. The study's findings challenged the previously reported high germline alteration rate of CDH1 in HDGC and identified new potential susceptibility genes. Analyses of variant signatures and double-hit events revealed potentially important mechanisms for HDGC tumorigenesis. Findings from the present study may provide helpful information for further investigations of HDGC.

First-in-human phase Ia study of the PI3Kα inhibitor CYH33 in patients with solid tumors.

PIK3CA mutations are highly prevalent in solid tumors. Targeting phosphatidylinositol 3-kinase α is therefore an attractive strategy for treating cancers harboring PIK3CA mutations. Here, we report the results from a phase Ia, open label, dose-escalation and -expansion study (NCT03544905) of CYH33, a highly selective PI3Kα inhibitor, in advanced solid tumors. The primary outcomes were the safety, tolerability, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of CYH33. The secondary outcomes included evaluation of pharmacokinetics, preliminary efficacy and changes in pharmacodynamic biomarkers in response to CYH33 treatment. The exploratory outcome was the relationship between the efficacy of CYH33 treatment and tumor biomarker status, including PIK3CA mutations. A total of 51 patients (19 in the dose escalation stage and 32 in the dose expansion stage) including 36 (70.6%) patients (4 in the dose escalation stage and 32 in the dose expansion stage) with PIK3CA mutations received CYH33 1-60 mg. The MTD of CYH33 was 40 mg once daily, which was also selected as the RP2D. The most common grade 3/4 treatment-related adverse events were hyperglycemia, rash, platelet count decreased, peripheral edema, and fatigue. Forty-two out of 51 patients were evaluable for response, the confirmed objective response rate was 11.9% (5/42). Among 36 patients harboring PIK3CA mutations, 28 patients were evaluable for response, the confirmed objective response rate was 14.3% (4/28). In conclusion, CYH33 exhibits a manageable safety profile and preliminary anti-tumor efficacy in solid tumors harboring PIK3CA mutations.

PD-1-mAb Plus Regimen in the First and Second Lines of Advanced and Unresectable Biliary Tract Carcinoma: A Real-World, Multicenter Retrospective Analysis.

Introduction: Advanced biliary tract carcinoma (BTC) has a poor prognosis and few treatment options. We compared the efficacy of the PD-1 monoclonal antibody (PD-1-mAb) combined regimens with the standard chemotherapy in the first-line and second-line treatment of advanced BTC. Methods: We retrospectively assessed the patients with advanced BTC, who received treatment at the First Affiliated Hospital of Sun Yat-Sen University and the Sun Yat-Sen University Cancer Center. The patients were treated with PD-1-mAb combined regimens or standard chemotherapy at the first line or treated with PD-1-mAb combined regimens or systematic therapy at the second line. Further subgroup analyses were assessed to identify superior regimens. Results: This study included 210 patients. The first-line PD-1-mAb combination group (n = 83) achieved longer median PFS (mPFS) (7.3 vs 5.3 months, p=0.001) and median OS (mOS) (15.6 vs 11.4 months, p=0.002) than the first-line standard chemotherapy group (n=76). Similarly, the second-line PD-1-mAb combination group (n=50) yielded longer mPFS (6.1 vs 2.6 months, p<0.001) and mOS (11.7 vs 7.2 months, p=0.008) than the second-line systematic therapy group (n=51). Subgroup analyses showed that the PD-1-mAb combined with TKI group achieved better mPFS than the chemotherapy group whether in the first-line (HR = 0.468, p=0.005) or the second-line setting (HR = 0.45, p=0.009), but did not achieve superiority in mOS (both p>0.05). Compared with the chemotherapy group, the PD-1-mAb combined with chemotherapy group achieved longer mOS (HR = 0.53, p=0.023) in the first-line setting and longer mPFS in the second-line setting (HR = 0.54, p=0.044). Conclusion: The PD-1-mAb combination therapy is superior to the standard chemotherapy in advanced or unresectable BTC, whether as a first-line or second-line treatment. Among the combination therapy, both the PD-1-mAb combined with TKI and combined with standard chemotherapy were promising options for advanced BTC patients.

Monitoring tumour resistance to the BRAF inhibitor combination regimen in colorectal cancer patients via circulating tumour DNA.

AIMS: This study aimed to identify mechanisms of drug resistance to the combination of vemurafenib, irinotecan, and cetuximab (VIC) in BRAFV600E metastatic colorectal cancer (mCRC). METHODS: Forty-one patients with BRAFV600E mCRC from July 2018 and June 2020 were evaluated, with tissue and/or plasma samples collected. We profiled tissue and plasma samples using whole-exome sequencing and targeted sequencing of 425 cancer-relevant genes. Clinical cohort analysis from published studies was performed to consolidate our findings. RESULTS: BRAF mutant in baseline plasma and its dynamics are significantly associated with VIC-related response, and concurrent RNF43 mutation significantly sensitises tumour to VIC treatment. VIC resistance frequently involves genes in PI3K, MAPK pathway, and several novel resistance mechanisms such as TGFBR2 and SMAD4 mutations, and copy-number gains in PTK2, MYC, and GATA6 have been identified. We also firstly describe acquired altered genes in DNA damaging repair pathway, occurring in 33 % of patients after VIC treatment, and particularly, patients with this pre-treatment resistance subclones developed inferior responses, along with higher tumour mutation burden both at baseline and progression plasma. CONCLUSION: Analysis of ctDNA can provide novel insights into molecular resistance mechanisms to VIC in BRAFV600E mCRC patients, allowing accurate guidance for clinicians in personalised treatment strategies.

Comparison of response evaluation criteria in solid tumors and tumor regression grade in evaluating the effect of preoperative systemic therapy of gastric cancer.

BACKGROUND: Both Response Evaluation Criteria in Solid Tumors (RECIST) and tumor regression grade (TRG) play key roles in evaluating tumor response. We analyzed the consistency of TRG and RECIST 1.1 for gastric cancer (GC) patients and compared their prognostic values. METHODS: Patients with GC who received preoperative chemotherapy or chemoimmunotherapy and had records of TRG from December 2013 to October 2021 were enrolled retrospectively. TRG 0-1 and 2-3 are considered as corresponding to complete response (CR)/partial response (PR) and stable disease (SD)/progress disease (PD) in RECIST 1.1, respectively. The primary endpoints were disease-free survival (DFS) and overall survival (OS). The consistency of RECIST and TRG was examined by kappa statistics. Survival analysis was performed using the Kaplan Meier method. RESULT: One hundred fifty seven GC patients were enrolled, including 125 with preoperative chemotherapy and 32 with chemoimmunotherapy. Among them, 56 patients had measurable lesions. Only 19.6% (11/56) of the patients had consistent results between RECIST 1.1 and TRG. TRG was correlated with both OS and DFS (P = 0.02 and 0.03, respectively) while response according to RECIST1.1 was not (P = 0.86 and 0.23, respectively). The median DFS had not reached in the TRG 0-1 group and was 16.13 months in TRG 2-3 group. TRG 2-3 was associated with young age and peritoneal or liver metastasis. Besides, preoperative chemoimmunotherapy had a significantly higher pCR rate than chemotherapy alone (34.4% vs 8.0%, P < 0.001). CONCLUSION: TRG was in poor agreement with RECIST 1.1. TRG was better than RECIST 1.1 in predicting DFS and OS for GC patients who received preoperative therapy.

Phosphoserine phosphatase as an indicator for survival through potentially influencing the infiltration levels of immune cells in neuroblastoma.

Introduction: Metabolic deregulation, a hallmark of cancer, fuels cancer cell growth and metastasis. Phosphoserine phosphatase (PSPH), an enzyme of the serine metabolism pathway, has been shown to affect patients' prognosis in many cancers but its significance in neuroblastoma remains unknown. Here, we show that the functional role and potential mechanism of PSPH and it is correlated with survival of neuroblastoma patients. Patients and Methods: The TARGET dataset (n = 151) and our hospital-based cases (n = 55) were used for assessing the expression level of PSPH associated with survival in neuroblastoma patients, respectively. Then, in vitro experiments were performed to define the role of PSPH in neuroblastoma. The ESTIMATE and TIMER algorithms were utilized to examine the correlation between PSPH expression level and abundance of immune cells. Further, Kaplan-Meier survival analysis was performed to evaluate the effect of both PSPH and immune cells on patients' prognosis. Results: High expression of PSPH was significantly associated with unfavorable overall survival (OS) and event-free survival (EFS) in both the TARGET dataset and our hospital-based cases, and was an independent predictor of OS (hazard ratio, 2.00; 95% confidence intervals, 1.21-3.30, p = 0.0067). In vitro experiments showed that high expression of PSPH significantly promoted cell growth and metastasis. Further, the ESTIMATE result suggested that high expression level of PSPH was negatively associated with low stromal and ESTIMATE score. Specifically, high PSPH expression was found to be negatively associated with CD8+ T cell, macrophages and neutrophils, which negatively affected survival of neuroblastoma patients (p < 0.0001, p = 0.0005, and p = 0.0004, respectively). Conclusion: These findings suggested that PSPH expression could be a promising indicator for prognosis and immunotherapy in neuroblastoma patients by potentially influencing infiltration levels of immune cells.

A Randomized, Open-Label, Multicenter, Phase 3 Study of High-Dose Vitamin C Plus FOLFOX ± Bevacizumab versus FOLFOX ± Bevacizumab in Unresectable Untreated Metastatic Colorectal Cancer (VITALITY Study).

PURPOSE: To compare the efficacy and safety of high-dose vitamin C plus FOLFOX ± bevacizumab versus FOLFOX ± bevacizumab as first-line treatment in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Between 2017 and 2019, histologically confirmed patients with mCRC (n = 442) with normal glucose-6-phosphate dehydrogenase status and no prior treatment for metastatic disease were randomized (1:1) into a control (FOLFOX ± bevacizumab) and an experimental [high-dose vitamin C (1.5 g/kg/d, intravenously for 3 hours from D1 to D3) plus FOLFOX ± bevacizumab] group. Randomization was based on the primary tumor location and bevacizumab prescription. RESULTS: The progression-free survival (PFS) of the experimental group was not superior to the control group [median PFS, 8.6 vs. 8.3 months; HR, 0.86; 95% confidence interval (CI), 0.70-1.05; P = 0.1]. The objective response rate (ORR) and overall survival (OS) of the experimental and control groups were similar (ORR, 44.3% vs. 42.1%; P = 0.9; median OS, 20.7 vs. 19.7 months; P = 0.7). Grade 3 or higher treatment-related adverse events occurred in 33.5% and 30.3% of patients in the experimental and control groups, respectively. In prespecified subgroup analyses, patients with RAS mutation had significantly longer PFS (median PFS, 9.2 vs. 7.8 months; HR, 0.67; 95% CI, 0.50-0.91; P = 0.01) with vitamin C added to chemotherapy than with chemotherapy only. CONCLUSIONS: High-dose vitamin C plus chemotherapy failed to show superior PFS compared with chemotherapy in patients with mCRC as first-line treatment but may be beneficial in patients with mCRC harboring RAS mutation.