IL-4/IL-4R axis signaling drives resistance to immunotherapy by inducing the upregulation of Fcγ receptor IIB in M2 macrophages.

In recent years, immunotherapy, particularly PD-1 antibodies, have significantly enhanced the outcome of gastric cancer patients. Despite these advances, some patients do not respond well to treatment, highlighting the need to understand resistance mechanisms and develop predictive markers of treatment effectiveness. This study retrospectively analyzed data from 106 patients with stage IV gastric cancer who were treated with first-line immunotherapy in combination with chemotherapy. By comparing plasma cytokine levels between patients resistant and sensitive to PD-1 antibody therapy, the researchers identified elevated IL-4 expression in the resistant patients. Mechanical investigations revealed that IL-4 induces metabolic changes in macrophages that activate the PI3K/AKT/mTOR pathway. This alteration promotes ATP production, enhances glycolysis, increases lactic acid production, and upregulates FcγRIIB expression in macrophages. Ultimately, these changes lead to CD8+ T cell dysfunction and resistance to PD-1 antibody therapy in gastric cancer. These findings highlight the role of IL-4-induced macrophage polarization and metabolic reprogramming in immune resistance and verify IL-4 as potential targets for improving treatment outcomes in gastric cancer patients.

VIC Regimen (Vemurafenib/Irinotecan/Cetuximab) Versus Bevacizumab Plus Chemotherapy as First-Line Treatment for BRAF V600E-Mutated Unresectable or Metastatic Colorectal Cancer in Asian Patients: A Prospective Cohort Study.

BACKGROUND: Colorectal cancers (CRC) with BRAF V600E mutation exhibit limited chemotherapy response and a poor prognosis. Safety and efficacy of the VIC (Vemurafenib/Irinotecan/Cetuximab) regimen in the first-line setting for patients with BRAF V600E-mutated CRC remain undetermined. METHODS: In the prospective cohort study, the untreated, BRAF V600E-mutated, unresectable or metastatic CRC patients were enrolled. The VIC regimen and bevacizumab plus chemotherapy were compared in the first-line setting. The objective response rate (ORR), disease control rate (DCR), conversion resection rate, progression-free survival (PFS), and overall survival (OS) were evaluated. RESULTS: In the intent-to-treat analysis, 38 patients received VIC regimen and 40 received bevacizumab plus chemotherapy. The ORR and DCR in the VIC group were significantly higher than in the bevacizumab-therapy group (ORR: 63.2% vs. 37.5%, P = .025; DCR: 94.7% vs. 75.0%, P = .019). The VIC regimen significantly outperformed bevacizumab plus chemotherapy in both PFS (11.9 vs. 7.7 months; hazard ratio [HR] = 0.51, 95% CI, 0.30-0.87; P = .010) and OS (25.3 vs. 14.6 months; HR = 0.43, 95% CI, 0.22-0.82; P = .011). In the VIC group, the conversion resection rate for liver metastases was 34.8% (8 of 23 patients), and for unresectable local CRC it was 54.5% (6 of 11 patients). The adverse events rates of Grade 3 to 4 were 34.2% and 32.5% for the VIC regimen and bevacizumab plus chemotherapy respectively. CONCLUSIONS: Among Asian patients with BRAF V600E-mutated CRC, the VIC regimen showed favorable outcomes compared to bevacizumab plus chemotherapy in terms of tumor response and oncological survival, with a tolerable and manageable toxicity profile in the first-line setting.

PMBC: a manually curated database for prognostic markers of breast cancer.

Breast cancer is notorious for its high mortality and heterogeneity, resulting in different therapeutic responses. Classical biomarkers have been identified and successfully commercially applied to predict the outcome of breast cancer patients. Accumulating biomarkers, including non-coding RNAs, have been reported as prognostic markers for breast cancer with the development of sequencing techniques. However, there are currently no databases dedicated to the curation and characterization of prognostic markers for breast cancer. Therefore, we constructed a curated database for prognostic markers of breast cancer (PMBC). PMBC consists of 1070 markers covering mRNAs, lncRNAs, miRNAs and circRNAs. These markers are enriched in various cancer- and epithelial-related functions including mitogen-activated protein kinases signaling. We mapped the prognostic markers into the ceRNA network from starBase. The lncRNA NEAT1 competes with 11 RNAs, including lncRNAs and mRNAs. The majority of the ceRNAs in ABAT belong to pseudogenes. The topology analysis of the ceRNA network reveals that known prognostic RNAs have higher closeness than random. Among all the biomarkers, prognostic lncRNAs have a higher degree, while prognostic mRNAs have significantly higher closeness than random RNAs. These results indicate that the lncRNAs play important roles in maintaining the interactions between lncRNAs and their ceRNAs, which might be used as a characteristic to prioritize prognostic lncRNAs based on the ceRNA network. PMBC renders a user-friendly interface and provides detailed information about individual prognostic markers, which will facilitate the precision treatment of breast cancer. PMBC is available at the following URL: http://www.pmbreastcancer.com/.

Comprehensive software suite for functional analysis and synaptic input mapping of dendritic spines imaged in vivo.

Significance: Advances in genetically encoded sensors and two-photon imaging have unlocked functional imaging at the level of single dendritic spines. Synaptic activity can be measured in real time in awake animals. However, tools are needed to facilitate the analysis of the large datasets acquired by the approach. Commonly available software suites for imaging calcium transients in cell bodies are ill-suited for spine imaging as dendritic spines have structural characteristics distinct from those of the cell bodies. We present an automated tuning analysis tool (AUTOTUNE), which provides analysis routines specifically developed for the extraction and analysis of signals from subcellular compartments, including dendritic subregions and spines. Aim: Although the acquisition of in vivo functional synaptic imaging data is increasingly accessible, a hurdle remains in the computation-heavy analyses of the acquired data. The aim of this study is to overcome this barrier by offering a comprehensive software suite with a user-friendly interface for easy access to nonprogrammers. Approach: We demonstrate the utility and effectiveness of our software with demo analyses of dendritic imaging data acquired from layer 2/3 pyramidal neurons in mouse V1 in vivo. A user manual and demo datasets are also provided. Results: AUTOTUNE provides a robust workflow for analyzing functional imaging data from neuronal dendrites. Features include source image registration, segmentation of regions-of-interest and detection of structural turnover, fluorescence transient extraction and smoothing, subtraction of signals from putative backpropagating action potentials, and stimulus and behavioral parameter response tuning analyses. Conclusions: AUTOTUNE is open-source and extendable for diverse functional synaptic imaging experiments. The ease of functional characterization of dendritic spine activity provided by our software can accelerate new functional studies that complement decades of morphological studies of dendrites, and further expand our understanding of neural circuits in health and in disease.

Clinical significance of peripheral T-cell receptor repertoire profiling and individualized nomograms in patients with gastrointestinal cancer treated with anti-programmed death 1 antibody.

Background: Immune checkpoint inhibitors (ICIs) have significant clinical benefit for a subset of patients with gastrointestinal cancers (GICs) including esophageal cancer, gastric cancer and colorectal cancer. However, it is difficult to predict which patients will respond favorably to immune checkpoint blockade therapy. Thus, this study was initiated to determine if peripheral T-cell receptor (TCR) repertoire profiling could predict the clinical efficacy of anti-programmed death 1 (PD-1) treatment. Methods: Blood samples from 31 patients with GICs were collected before anti-PD-1 antibody treatment initiation. The clinical significance of the combinatorial diversity evenness of the TCR repertoire [the diversity evenness 50 (DE50), with high values corresponding to less clonality and higher TCR diversity] from peripheral blood mononuclear cells (PBMCs) was evaluated in all the enrolled patients. A highly predictive nomogram was set up based on peripheral TCR repertoire profiling. The performance of the nomogram was assessed by receiver operating characteristic (ROC) curve, concordance index (C-index), and calibration curves, and decision curve analysis (DCA) was used to assess its clinical applicability. Results: Compared to non-responders [progression disease (PD)], the DE50 scores were significantly higher in responders [stable disease (SD) and partial response (PR)] (P=0.018). Patients with a high DE50 score showed better progression-free survival (PFS) than those with a low DE50 score (P=0.0022). The multivariable Cox regression demonstrated that high DE50 and low platelet-lymphocyte ratio (PLR) were significant independent predictors for better PFS when treated with anti-PD-1 antibody. Furthermore, a highly predictive nomogram was set up based on peripheral TCR repertoire profiling. The area under the curves (AUCs) of this system at 3-, 6- and 12-month PFS reached 0.825, 0.802, and 0.954, respectively. The nomogram had a C-index of 0.768 [95% confidence interval (CI): 0.658-0.879]. Meanwhile, the calibration curves also demonstrated the reliability and stability of the model. Conclusions: High DE50 scores were predictive of a favorable response and longer PFS to anti-PD-1 treatment in GIC patients. The nomogram based on TCR repertoire profiling was a reliable and practical tool, which could provide risk assessment and clinical decision-making for individualized treatment of patients.

The Cousa objective: a long-working distance air objective for multiphoton imaging in vivo.

Multiphoton microscopy can resolve fluorescent structures and dynamics deep in scattering tissue and has transformed neural imaging, but applying this technique in vivo can be limited by the mechanical and optical constraints of conventional objectives. Short working distance objectives can collide with compact surgical windows or other instrumentation and preclude imaging. Here we present an ultra-long working distance (20 mm) air objective called the Cousa objective. It is optimized for performance across multiphoton imaging wavelengths, offers a more than 4 mm2 field of view with submicrometer lateral resolution and is compatible with commonly used multiphoton imaging systems. A novel mechanical design, wider than typical microscope objectives, enabled this combination of specifications. We share the full optical prescription, and report performance including in vivo two-photon and three-photon imaging in an array of species and preparations, including nonhuman primates. The Cousa objective can enable a range of experiments in neuroscience and beyond.

Pulmonary lymphangitis carcinomatosis: A peculiar presentation clustering in MET-amplified gastric cancer.

BACKGROUND: The clinicopathological features of MET-amplified gastric cancer (GC) and real-world data on the efficacy of MET-targeted therapies remain unknown. Pulmonary lymphangitis carcinomatosis (PLC) is a peculiar manifestation of GC, whose management has not been thoroughly described. METHODS: This study analyzed patients diagnosed with MET-amplified GC or GC with PLC at any time point of the disease course from 2011 to 2021 in two centers. Clinicopathological features and survival outcomes of MET-amplified GC were analyzed. The clinical and molecular implications of GC with PLC were discussed. RESULTS: Fifty-eight patients with MET-amplified GC and 20 patients with GC accompanied by PLC were finally enrolled for analysis (including 13 overlapped patients). GC with PLC was more common in female patients (p = 0.010), diagnosed at a younger age (p = 0.002), presented with a higher baseline ECOG PS (p = 0.016), and was more likely to develop lung metastasis (p < 0.001), and serous effusion (p = 0.026) than GC without PLC. Patients with primary MET-amplified GC had a worse prognosis than those with secondary MET-amplified GC (p = 0.005). The application of anti-MET therapy was associated with numerically prolonged survival, but the association was not statistically significant (p = 0.07). MET amplification was concentrated in patients with PLC, in which anti-MET therapies elicited a high response rate. CONCLUSIONS: MET-targeted therapies are efficacious in real-world populations with MET-amplified GC. Patients with PLC have distinct clinical and molecular features and might benefit from MET-targeted therapies.

Stereotactic body radiotherapy combined with sintilimab in patients with recurrent or oligometastatic hepatocellular carcinoma: A phase II clinical trial.

BACKGROUND: Stereotactic body radiotherapy (SBRT) and programmed cell death 1 inhibitors have shown potential in treating hepatocellular carcinoma (HCC) in retrospective studies. AIM: To evaluate the efficacy of combining SBRT with sintilimab for patients with recurrent or oligometastatic HCC. METHODS: This trial involved patients with recurrent or oligometastatic HCC intravenously treated with SBRT plus sintilimab every 3 wk for 12 mo or until disease progression. The primary endpoint was progression-free survival (PFS). RESULTS: Twenty-five patients were enrolled from August 14, 2019, to August 23, 2021. The median treatment duration was 10.2 (range, 0.7-14.6) months. SBRT was delivered at a median dose of 54 (range, 48-60) Gy in 6 (range, 6-10) fractions. The median follow-up time was 21.9 (range, 10.3-39.7) mo, and 32 targeted lesions among 25 patients were evaluated for treatment response according to the Response Evaluation Criteria in Solid Tumors version 1.1. The median PFS was 19.7 mo [95% confidence interval (CI): 16.9-NA], with PFS rates of 68% (95%CI: 52-89) and 45.3% (95%CI: 28-73.4) at 12 and 24 mo, respectively. The median overall survival (OS) was not reached, with OS rates of 91.5% (95%CI: 80.8-100.0) and 83.2% (95%CI: 66.5-100.0) at 12 and 24 mo, respectively. The 1- and 2-year local control rate were 100% and 90.9% (95%CI: 75.4%-100.0%), respectively. The confirmed objective response rate and disease control rate was 96%, and 96%, respectively. Most adverse events were graded as 1 or 2, and grade 3 adverse events were observed in three patients. CONCLUSION: SBRT plus sintilimab is an effective, well-tolerated treatment regimen for patients with recurrent or oligometastatic HCC.

Peripheral immune mapping and multi-omics analysis in Pd-1 inhibitor-induced myocarditis.

More immune-related adverse events (irAEs) have emerged along with increased immune checkpoint inhibitor (ICI) treatment. ICI-induced myocarditis is a rare type of irAE with early onset, rapid progression, and high mortality. Its specific pathophysiological mechanism is not fully understood. In total, 46 patients with tumors and 16 patients with ICI-induced myocarditis were included. We performed single-cell RNA sequencing on CD3 + T cells, flow cytometry, proteomics, and lipidomics to improve our understanding of the disease. First, we demonstrate the clinical features of patients with PD-1 inhibitor-induced myocarditis. We then identified 18 subsets of T cells using single-cell RNA sequencing and performed comparative analysis and further verification. The composition of T cells in the peripheral blood of patients has changed remarkably. Compared with non-irAE patients, effector T cells were increased in irAE patients, while naive T cells, γδ T cells, and mucosal-associated invariant T cell cluster cells were decreased. Besides, reduced γδ T cells characterized with effector functions, increased natural killer T cells with high levels of FCER1G in patients may suggest an association with disease development. Meanwhile, the peripheral inflammatory response was exacerbated in patients, accompanied by upregulation of exocytosis as well as increased levels of multiple lipids. We provide a comprehensive overview of the composition, gene profiles, and pathway signatures of CD3+ T cells driven by PD-1 inhibitor-induced myocarditis, as well as illustrate clinical features and multi-omic characteristics, providing a unique perspective on disease progression and therapy in clinical practice.

Tidal breathing lung function analysis of wheezing and non-wheezing infants with pneumonia: A retrospective observational study.

To compare lung function in wheezing and non-wheezing infants with pneumonia through tidal breathing analysis and explore the correlation between tidal breathing lung function and clinical characteristics. This retrospective observational study included infants with pneumonia hospitalized in the Affiliated Hospital of Guizhou Medical University between January 2018 and December 2018. Medical records were used to obtain the demographic characteristics, clinical characteristics, tidal breathing lung function results before and after a bronchodilator test, and positive remission rates after the bronchodilator test for each patient. Eighty-six wheezing infants (64 males, aged 6.5 [4.8, 9] months) and 27 non-wheezing infants (18 males, aged 7 [5, 12] months) were included. Non-wheezing infants were more likely to have normal airway function compared to wheezing infants (44.4% vs 23.3%, P = .033). Peak tidal expiration flow/tidal expiratory flow (TEF)25 in wheezing infants was significantly higher than that in non-wheezing infants (162.4 [141.2, 200.7] vs 143.3 [131, 178.8], P = .037). The positive remission rate of tidal inspiratory flow (TIF50)/TEF50 (53.5% vs 29.6%, P = .03) and TEF50 (58.1% vs 33.3%, P = .024) were significantly higher in the wheezing infants compared to non-wheezing infants (P = .03 and P = .024, respectively). Furthermore, respiratory rate, tidal volume, peak expiration flow, TEF25, TEF50, and TEF75 were significantly correlated to the age, height, weight, and platelet counts of infants in both the wheezing and non-wheezing infants (all P < .05). Wheezing infants with pneumonia were more likely to have worse tidal breathing lung function compared to non-wheezing infants with pneumonia. The tidal breathing lung function parameter (respiratory rate, tidal volume, peak expiration flow, TEF25, TEF50, and TEF75) were correlated to the age, height, weight, and platelet counts of both wheezing and non-wheezing infants.

Does resection after neoadjuvant chemotherapy of docetaxel, oxaliplatin, and S-1 (DOS regimen) benefit for gastric cancer patients with single non-curable factor? a multicenter, prospective cohort study (Neo-REGATTA).

BACKGROUND: The Neo-REGATTA study evaluated the effectiveness and safety of Docetaxel, oxaliplatin, and S-1 (DOS regimen) followed by radical resection vs. chemotherapy in advanced gastric adenocarcinoma patients with single non-curable factor. METHODS: This cohort study prospectively enrolled advanced gastric adenocarcinoma patients with single non-curable factor between November 2017 and June 2021. Patients without progression after four cycles of DOS were divided into resection group and chemotherapy group. The outcomes included overall survival (OS), progression-free survival (PFS) and safety. Effectiveness analysis was also performed by propensity score matching (PSM). RESULTS: A total of 73 patients were enrolled and 13 patients were withdrawn due to disease progression after 4 cycles of DOS. Afterwards, 35 and 25 participants were in the resection and chemotherapy groups, respectively. After a median follow-up time of 30.0 months, the median PFS and OS were 9.0 months, and 18.0 months for the chemotherapy group, but not reached in the resection group. After PSM, 19 matched participants were in each group, and the median PFS and OS were longer in resection group than that in chemotherapy group. The most common grade 3 or 4 adverse events both in the resection group and chemotherapy groups were neutropenia (5.7%, 8.0%) and leukopenia (5.7%, 8.0%). CONCLUSIONS: Radical resection might provide survival benefit compared with continuous chemotherapy alone in advanced gastric adenocarcinoma patients who had a disease control after DOS, with a good safety profile. TRIAL REGISTRATION: The study protocol was registered on ClinicalTrial.gov (NCT03001726, 23/12/2016).

Synovial mesenchymal stem cell-derived exosomal microRNA-320c facilitates cartilage damage repair by targeting ADAM19-dependent Wnt signalling in osteoarthritis rats.

OBJECTIVE: Our previous study revealed that synovial mesenchymal stem cell (SMSC)-derived exosomal microRNA-302c enhanced chondrogenesis by targeting a disintegrin and metalloproteinase 19 (ADAM19) in vitro. This study aimed to validate the potential of SMSC-derived exosomal microRNA-302c for the treatment of osteoarthritis in vivo. METHODS: After 4 weeks of destabilization of the medial meniscus surgery (DMM) to establish an osteoarthritis model, the rats received weekly articular cavity injection of SMSCs with or without GW4869 treatment (exosome inhibitor) or exosomes from SMSCs with or without microRNA-320c overexpression for another 4 weeks. RESULTS: SMSCs and SMSC-derived exosomes reduced the Osteoarthritis Research Society International (OARSI) score, improved cartilage damage repair, suppressed cartilage inflammation, suppressed extracellular matrix (ECM) degradation, and inhibited chondrocyte apoptosis in DMM rats. However, these effects were largely hampered in rats that were injected with GW4869-treated SMSCs. Moreover, exosomes from microRNA-320c-overexpressing SMSCs exerted a better effect than exosomes from negative control SMSCs on decreasing the OARSI score, enhancing cartilage damage repair, suppressing cartilage inflammation, and inhibiting ECM degradation and chondrocyte apoptosis. Mechanistically, exosomes from microRNA-320c-overexpressing SMSCs reduced the levels of ADAM19, as well as ß-catenin and MYC, which are two critical proteins in Wnt signalling. CONCLUSION: SMSC-derived exosomal microRNA-320c suppresses ECM degradation and chondrocyte apoptosis to facilitate cartilage damage repair in osteoarthritis rats by targeting ADAM19-dependent Wnt signalling.

Asparaginyl endopeptidase contributes to cetuximab resistance via MEK/ERK signaling in RAS wide-type metastatic colorectal cancer.

BACKGROUND: Cetuximab, a monoclonal antibody targeting epidermal growth factor receptor (EGFR), is effective for RAS wild-type metastatic colorectal cancer (mCRC) patients. However, cetuximab resistance often occur and the mechanism has not been fully elucidated. The purpose of this study was to investigate the role of asparaginyl endopeptidase (AEP) in cetuximab resistance. METHODS: Differentially expressed genes between cetuximab responders and non-responders were identified by analyzing the gene expression profile GSE5851, retrieved from Gene Expression Omnibus (GEO). The potential genes were further validated in cetuximab-resistant CRC cell lines. The expression of AEP in the peripheral blood and tumor tissues of mCRC patients in our hospital were detected by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry, respectively. The survival analysis was carried out by Kaplan-Meier method. The function and associated pathways of AEP were further investigated by lentivirus transfection, CCK8 assay, colony formation assay, real-time polymerase chain reaction (qPCR) and western blot. RESULTS: Through bioinformatics analysis, we found that the expression of AEP gene was related to progress free survival (PFS) of mCRC patients treated with cetuximab alone (P = 0.00133). The expression of AEP was significantly higher in the cetuximab-resistant CRC cell lines, as well as in mCRC patients with shorter PFS treated with cetuximab-containing therapy. Furthermore, AEP could decrease the sensitivity of CRC cells to cetuximab in vitro. And the phosphorylation level of MEK and ERK1/2 was increased in AEP overexpression cells. The downregulation of AEP using specific inhibitors could partially restore the sensitivity of CRC cells to cetuximab. CONCLUSION: The higher expression of AEP could contribute to the shorter PFS of cetuximab treatment in mCRC. The reason might be that AEP could promote the phosphorylation of MEK/ERK protein in the downstream signal pathway of EGFR.

Phase I study of adjuvant chemotherapy with nab-paclitaxel and S-1 for stage III Lauren's diffuse-type gastric cancer after D2 resection (NORDICA study).

PURPOSE: The prognosis of diffuse-type gastric cancer (DGC) is poorer than that of intestinal type, but S-1 is a potential treatment option in DGC. This study explored the maximal tolerated dose (MTD) and the recommended dose for phase II study (RP2D) of nab-paclitaxel combined with S-1 (AS regimen) as adjuvant chemotherapy in stage III DGC. METHODS: Patients with stage III DGC were recruited into this phase I dose-escalation study between July 2019 and June 2020 in Zhongshan Hospital. Nab-paclitaxel and S-1 (80-120 mg/day, d1-14, q3w) were administrated for 6 cycles, and then 8 cycles of S-1 monotherapy were applied. The patients received nab-paclitaxel at 180, 220, or 260 mg/m2 according to the 3 + 3 design based on dose-limiting toxicity (DLT). The primary endpoint was RP2D. Secondary endpoints were the 1-year disease-free survival (DFS) rate and adverse events (AEs). RESULTS: One case experienced DLT in 180-mg/m2 dose group, subsequently three additional subjects were enrolled. DLT was not observed in the 220- and 260-mg/m2 dose groups (both n = 3). Therefore, the MTD has not reached, and the RP2D of nab-paclitaxel would be 260 mg/m2 . Five participants showed progressive disease, with three and two participants in the 180- and 220-mg/m2 dose groups, respectively. The 6-, 12-, and 18-month DFS rates were 100%, 63.6%, and 50.9%, respectively. The most frequently observed AEs were neutropenia (83.3%) and leukopenia (66.7%). CONCLUSION: The RP2D of nab-paclitaxel as adjuvant chemotherapy in DGC was 260 mg/m2 . The AS regimen had a tolerable AE profile in stage III DGC.

Interaction between glycolysis‒cholesterol synthesis axis and tumor microenvironment reveal that gamma-glutamyl hydrolase suppresses glycolysis in colon cancer.

Background: Metabolic reprogramming is a feature of cancer. However, colon cancer subtypes based on the glycolysis‒cholesterol synthesis axis have not been identified, and little is known about connections between metabolic features and the tumor microenvironment. Methods: Data for 430 colon cancer cases were extracted from The Cancer Genome Atlas, including transcriptome data, clinical information, and survival outcomes. Glycolysis and cholesterol synthesis-related gene sets were obtained from the Molecular Signatures Database for a gene set variation analysis. The relationship between the genomic landscape and immune landscape were investigated among four metabolic subtypes. Hub genes were determined. The clinical significance of candidate hub gene was evaluated in 264 clinical samples and potential functions were validated in vitro and in vivo. Results: Colon cancer cases were clustered into four metabolic subtypes: quiescent, glycolytic, cholesterogenic, and mixed. The metabolic subtypes differed with respect to the immune score, stromal score, and estimate score using the ESTIMATE algorithm, cancer-immunity cycle, immunomodulator signatures, and signatures of immunotherapy responses. Patients in the cholesterogenic group had better survival outcomes than those for other subtypes, especially glycolytic. The glycolytic subtype was related to unfavorable clinical characteristics, including high mutation rates in TTN, APC, and TP53, high mutation burden, vascular invasion, right colon cancer, and low-frequency microsatellite instability. GGH, CACNG4, MME, SLC30A2, CKMT2, SYN3, and SLC22A31 were identified as differentially expressed both in glycolytic-cholesterogenic subgroups as well as between colon cancers and healthy samples, and were involved in glycolysis‒cholesterol synthesis. GGH was upregulated in colon cancer; its high expression was correlated with CD4+ T cell infiltration and longer overall survival and it was identified as a favorable independent prognostic factor. The overexpression of GGH in colon cancer-derived cell lines (SW48 and SW480) inhibited PKM, GLUT1, and LDHA expression and decreased the extracellular lactate content and intracellular ATP level. The opposite effects were obtained by GGH silencing. The phenotype associated with GGH was also validated in a xenograft nude mouse model. Conclusions: Our results provide insight into the connection between metabolism and the tumor microenvironment in colon cancer and provides preliminary evidence for the role of GGH, providing a basis for subsequent studies.

The Neo-PLANET phase II trial of neoadjuvant camrelizumab plus concurrent chemoradiotherapy in locally advanced adenocarcinoma of stomach or gastroesophageal junction.

The synergistic effect of neoadjuvant immunotherapy and chemoradiotherapy in gastric adenocarcinoma is unclear. This phase II trial (NCT03631615) investigated this neoadjuvant combination in locally advanced adenocarcinoma of stomach or gastroesophageal junction. Thirty-six patients received capecitabine 850 mg/m2 twice daily and simultaneous radiotherapy for 5 weeks, sandwiched by a 21-day cycle of oxaliplatin 130 mg/m2 (day 1) plus capecitabine 1000 mg/m2 twice daily (days 1-14), respectively, followed by surgery. Camrelizumab 200 mg (day 1) was given for 5 cycles since initiating chemotherapy. Primary endpoint was pathological complete response (pCR, ypT0) rate. Secondary endpoints included total pCR (tpCR, ypT0N0) rate, major pathological response (MPR, < 10% residual tumor cells) rate, margin-free (R0) resection rate, downstaging, progression-free survival (PFS), overall survival (OS), and safety. The pCR rate was 33.3% (95% CI, 18.6-51.0), meeting pre-specified endpoint. TpCR, MPR, and R0 resection rates were 33.3%, 44.4%, and 91.7%, respectively. Twenty-eight (77.8%) patients reached ypN0. Two-year PFS and OS rates were 66.9% and 76.1%, respectively. The most common grade 3-4 adverse event was decreased lymphocyte count (27 [75.0%]). Neoadjuvant camrelizumab plus concurrent chemoradiotherapy exhibits promising pathological response in patients with locally advanced gastric adenocarcinoma, with an acceptable safety profile.

Heparanase modulates the prognosis and development of BRAF V600E-mutant colorectal cancer by regulating AKT/p27Kip1/Cyclin E2 pathway.

BRAF V600E-mutant colorectal cancer (CRC) is a rare subtype of colorectal cancer with poor prognosis. Compelling evidence indicates that the heparanase (HPSE) gene has multiple functions in cancer, however, its role in BRAF V600E-mutant CRC remains elusive. Differentially expressed genes between BRAF V600E-mutant and wild-type patients were explored by analyzing public data from The Cancer Genome Atlas and the Gene Expression Omnibus. Clinical samples of 172 patients with BRAF V600E-mutant CRC diagnosed at Zhongshan Hospital Fudan University were collected. Overall survival was analyzed using Kaplan-Meier curves and Cox regression models. Cell models and xenografts were utilized to investigate the effect of HPSE on tumor proliferation. HPSE was significantly highly expressed in the BRAF V600E-mutant group. High HPSE expression level was independently associated with inferior survival in the BRAF V600E-mutant cohort. HPSE knockdown impeded tumor proliferation of BRAF V600E-mutant CRC cells in vitro and in vivo. Mechanistically, HPSE silencing arrested cell cycle in G0/G1 phase by downregulating Cyclin E2 expression via the AKT/p27Kip1 pathway. These findings support a role for HPSE in promoting BRAF V600E-mutant CRC progression, which suggests it holds great promise as a prognostic biomarker and a potential therapeutic target for the aggressive CRC subtype.

Efficacy of AS versus SOX regimen as first-line chemotherapy for gastric cancer patients with peritoneal metastasis: a real-world study.

BACKGROUND: To compare the prognosis of first-line systemic chemotherapy of AS (Albumin-bound paclitaxel and S-1) versus SOX (S-1 and oxaliplatin) regimen in Chinese gastric cancer patients with peritoneal metastasis. METHODS: This was a real-world study of gastric cancer patients with peritoneal metastasis who have been treated with AS or SOX regimen as first-line chemotherapy. Patients were matched by the method of propensity score matching (PSM). The primary and secondary endpoints were overall survival (OS) and progress-free survival (PFS). RESULTS: A total of 108 gastric cancer patients with peritoneal metastasis were enrolled after PSM analysis. There was no significant difference between AS and SOX regimen based on gender, age, ascites, treatment cycles, gastric cancer resection, received checkpoint inhibitors, and HER-2 expression after PSM analysis. The median OS (14.13 vs. 11.17 months, p = 0.0356) and median PFS (10.30 vs. 6.70 months, p = 0.0003) of patients who received AS regimen were longer than those treated by SOX regimen as first-line systemic chemotherapy. In sub-group analysis, the median OS and median PFS were longer for patients in AS regimen than SOX regimen in Lauren diffuse type. The occurrence of toxicity between the two groups was shown no significant difference. CONCLUSIONS: The results verified that AS regimen was more effective than SOX chemotherapy in gastric cancer patients with peritoneal metastasis, especially in Lauren diffuse type.

Toripalimab in advanced biliary tract cancer.

Gemcitabine combined with platinum/fluorouracil drugs is the standard first-line treatment for advanced biliary tract cancers (BTCs). We explored the safety and efficacy of toripalimab plus gemcitabine and S-1 (GS) as the first-line treatment for advanced BTCs. At a one-sided significance level of 0.025, a total of 50 patients could provide 80% power to show the efficacy at targeted progression-free survival (PFS) rate at 6 months of 70% versus 40% for the combined treatment. This single-arm, phase II study enrolled 50 patients with advanced BTCs who previously received no systemic treatment. The regimen was as follows: toripalimab (240 mg, i.v., d1), gemcitabine (1,000 mg/m2, i.v., d1 and d8), and S-1 (40-60 mg bid p.o., d1-14, Q21d). The primary endpoint was progression-free survival. The secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR), and safety. The associations between response with PD-L1 expression, tumor mutational burden (TMB), and genetic variations were explored. Patients were enrolled from January 2019 to August 2020, with a median follow-up time of 24.0 months (IQR: 4.3-31.0 months). The 6-month PFS rate was 62%. The median PFS was 7.0 months (95% CI: 5.0-8.9 months), and median OS was 15.0 months (95% CI: 11.6-18.4 months). Forty-nine patients completed the evaluation for tumor response. The ORR was 30.6% (95% CI: 17.2%-44.0%), and the disease control rate was 87.8% (95% CI: 78.2%-97.3%). The most common treatment-related adverse events (TRAEs) were leukopenia (98.0%), neutropenia (92%), and anemia (86.0%). Grade III/IV TRAEs included leukopenia (38.0%), neutropenia (32%), skin rash (6%), anemia (2.0%), mucositis (2%), and immune-related colitis (2%). Among them, the grade III/IV immune-related adverse events (irAEs) were skin rash and colitis. In addition, biomarker analysis showed that negative PD-L1 expression and SMARCA4 mutation were significantly associated with worse survival outcomes, while no significant associations were observed for TP53, KRAS, or CDKN 2 A mutation as well as TMB. In conclusion, our data suggest that a regimen of toripalimab plus GS could improve PFS and OS with a good safety profile as a first-line treatment option for advanced BTC and warrants further verification.