ALK-rearranged renal cell carcinoma: a multi-institutional study of nine cases with expanding the morphologic and molecular genetic spectrum.

ALK-rearranged renal cell carcinoma (ALK-RCC) is very rare, molecularly defined RCC subtype in the recently published 5th edition World Health Organization classification of tumors. In this study, we describe 9 ALK-RCCs from a clinicopathologic, immunohistochemical, and molecular genetic aspect, supporting and extending upon the observations by previous studies regarding this rare subgroup of RCC. There were six male and three female patients with ages ranging from 14 to 59 years (mean, 34.4 years). None of the patients had sickle cell trait. The diagnosis was based on radical or partial nephrectomy specimen for eight patients and on biopsy specimen for one. Tumor size ranged from 2.5 to 7.2 cm (mean, 2.8 cm). Follow-up was available for 6/9 patients (6 to 36 months); five had no tumor recurrence or metastasis and one developed lung metastasis at 24 months. The patient was subsequently treated with resection of the metastatic tumor followed by crizotinib targeted therapy, and he was alive without tumor 12 months later. Histologically, the tumors showed a mixed growth of multiple patterns, including papillary, solid, tubular, tubulocystic, cribriform, and corded, often set in a mucinous background. The neoplastic cells had predominantly eosinophilic cytoplasm. Focally, clear cytoplasm with polarized nuclei and subnuclear vacuoles (n=1), and pale foamy cytoplasm (n=1) were observed on the tumor cells. The biopsied tumor showed solid growth of elongated tubules merging with bland spindle cells. Other common and uncommon features included: psammomatous microcalcifications (n=5), rhabdoid cells (n=4), prominent intracytoplasmic vacuoles (n=4), prominent chronic inflammatory infiltrate (n=3), signet ring-cell morphology (n=2), and pleomorphic cells (n=2). By immunohistochemistry, all 9 tumors were diffusely positive for ALK(5A4) and 4/8 tested cases showed reactivity for TFE3 protein. By fluorescence in-situ hybridization analysis, ALK rearrangement was identified in all the 9 tumors; none of the tested tumors harbored TFE3 rearrangement (0/4) or gains of chromosomes 7 and 17 (0/3). ALK fusion partners were identified by RNA-sequencing in all 8 cases analyzed, including EML4 (n=2), STRN (n=1), TPM3 (n=1), KIF5B (n=1), HOOK1 (n=1), SLIT1(n=1), and TPM1(3'UTR) (n=1). Our study further expands the morphologic and molecular genetic spectrum of ALK-RCC.

The role of FERMT2 in the tumor microenvironment and immunotherapy in pan-cancer using comprehensive single-cell and bulk sequencing.

FERMT2 has been identified as a participant in integrin-linked kinase signaling pathways, influencing epithelial-mesenchymal transition and thereby affecting tumor initiation, progression, and invasion. While the character of FERMT2 in the tumor microenvironment (TME) as well as its implications for immunotherapy remain unclear. Thus, we conducted a comprehensive analysis to assess the prognostic significance of FERMT2 using Kaplan-Meier analysis. In addition, we employed enrichment analysis to uncover potential underlying molecular mechanisms. Using "Immunedeconv" package, we evaluated the immune characteristics of FERMT2 within TME. Furthermore, we determined the expression levels of FERMT2 in various cell types within TME, based on single-cell sequencing data. To confirm the co-expression of FERMT2 and markers of cancer-associated fibroblasts (CAFs), we performed multiplex immunofluorescence staining on tissue paraffin sections across various cancer types. Our analysis disclosed a significant correlation between elevated FERMT2 expression and unfavorable prognosis in specific cancer types. Furthermore, we identified a strong correlation between FERMT2 expression and diverse immune-related factors, including immune checkpoint molecules, immune cell infiltration, microsatellite instability (MSI), and tumor mutational burden (TMB). Additionally, there was a significant correlation between FERMT2 expression and immune-related pathways, particularly those associated with activating, migrating, and promoting the growth of fibroblasts in diverse cancer types. Interestingly, we observed consistent co-expression of FERMT2 in both malignant tumor cells and stromal cells, particularly within CAFs. Notably, our findings also indicated that FERMT2, in particular, exhibited elevated expression levels within tumor tissues and co-expressed with α-SMA in CAFs based on the multiplex immunofluorescence staining results.

MEF2D facilitates liver metastasis of gastric cancer cells through directly inducing H1X under IL-13 stimulation.

Liver metastasis is the most common metastatic occurrence in gastric cancer patients, although the precise mechanism behind it remains unclear. Through a combination of proteomics and quantitative RT-PCR, our study has revealed a significant correlation between the upregulation of myocyte enhancer factor-2D (MEF2D) and both distant metastasis and poor prognosis in gastric cancer patients. In mouse models, we observed that overexpressing or knocking down MEF2D in gastric cancer cells respectively promoted or inhibited liver metastasis. Furthermore, our research has demonstrated that MEF2D regulates the transcriptional activation of H1X by binding to the H1X promoter. This regulation leads to the upregulation of H1X, which, in turn, promotes the in vivo metastasis of gastric cancer cells along with the upregulation of the downstream gene ß-CATENIN. Additionally, we found that the expression of MEF2D and H1X at both mRNA and protein levels can be induced by the inflammatory factor IL-13, and this induction exhibits a time gradient dependence. In human gastric cancer tissues, the expression of IL13RA1, the receptor for IL-13, positively correlates with the expression of MEF2D and H1X. IL13RA1 has been identified as an intermediate receptor through which IL-13 regulates MEF2D. In conclusion, our findings suggest that MEF2D plays a crucial role in promoting liver metastasis of gastric cancer by upregulating H1X and downstream target ß-CATENIN in response to IL-13 stimulation. Targeting MEF2D could therefore be a promising therapeutic strategy for the clinical management of gastric cancer. STATEMENT OF SIGNIFICANCE: MEF2D promotes its transcriptional activation in gastric cancer cells by binding to the H1X promoter and is upregulated by IL-13-IL13RA1, thereby promoting distant metastasis of gastric cancer.

Copper Nanodrugs by Atom Transfer Radical Polymerization.

In this study, some copper catalysts used for atom transfer radical polymerization (ATRP) were explored as efficient anti-tumor agents. The aqueous solution of copper-containing nanoparticles with uniform spheric morphology was in situ prepared through a copper-catalyzed activator generated by electron transfer (AGET) ATRP in water. Nanoparticles were then directly injected into tumor-bearing mice for antitumor chemotherapy. The copper nanodrugs had prolonged blood circulation time and enhanced accumulation at tumor sites, thus showing potent antitumor activity. This work provides a novel strategy for precise and large-scale preparation of copper nanodrugs with high antitumor activity.

Three years follow-up of neoadjuvant chemoimmunotherapy in resectable non-small cell lung cancer.

Neoadjuvant chemoimmunotherapy plays a crucial role in resectable non-small cell lung cancer (NSCLC). Neoadjuvant chemotherapy before sleeve lobectomy was safe and feasible, but the impact of neoadjuvant chemoimmunotherapy before sleeve lobectomy was unclear. In our retrospective study, patients diagnosed as stage IIB to IIIB resectable NSCLC between December 1, 2018 and December 1, 2020 in the Department of Thoracic Surgery, Zhejiang Cancer Hospital were collected. We analyzed the efficacy and safety of neoadjuvant chemoimmunotherapy for resectable NSCLC patients and analyzed the impact of different types of surgery on postoperative complications, surgical difficulty, and long-term survival. In total, 56 patients were included in this retrospective study. With a median follow-up of 35 months, 1-year EFS, 2-year EFS, and 3-year EFS were 87.5%, 80.4%, and 76.7%, respectively. 1-year OS, 2-year OS, and 3-year OS were 96.4%, 91.1%, and 85.6%. respectively. Both median EFS and OS were not reached. The percentage of patients with pCR was 51.8%. 48 (85.7%) patients had nodal downstaging and primary tumor downstaging. In 40 (61.4%) patients occurred neoadjuvant chemoimmunotherapy-related adverse events (AEs), most of them of Grade 1 and 2. Postoperative complications occurred in 19 (33.9%) patients. Subgroup analysis showed that sleeve lobectomy was related to better survival and had no impact on operation duration, hospital stay, intraoperative blood loss, and postoperative complications. Neoadjuvant chemoimmunotherapy led to a high pCR rate, favorable 3-year survival rate, and acceptable AEs. Sleeve lobectomy was safe and related to better survival.

Long-term impact of prophylactic central neck dissection in non-invasive classic papillary thyroid carcinoma.

BACKGROUND: The utilization of prophylactic central neck dissection (pCND) in cases of non-invasive clinical node-negative (cN0) papillary thyroid carcinoma (PTC) remains a topic of debate, with a dearth of long-term evidence. MATERIALS AND METHODS: We retrospectively reviewed 1181 cN0 PTC patients from 1997 to 2011. Of these, 641 underwent pCND (pCND + group) and 540 did not (pCND-group). Propensity score matching (PSM) was used to identify similar patients. Event-free survival and long-term complications including permanent hyperparathyroidism and permanent recurrent laryngeal nerve (RLN) paralysis were analyzed after PSM. RESULTS: The pCND + group had more aggressive characteristics. In the matched cohort after PSM, the 5-year, 10-year, and 15-year EFS rates were 98.9 %, 98.2 %, and 97.1 % for the pCND + group, and 97.7 %, 97.1 %, and 97.1 % for the pCND-group, respectively. There was no statistically significant difference in EFS rates between the two groups (Log Rank P = 0.38). There was no statistically significant difference in the incidence of permanent hyperparathyroidism (3.3 % vs. 1.5 %, P = 0.08) and permanent RLN paralysis (1.7 % vs. 0.9 %, P = 0.13) between the pCND+ and pCND- groups. CONCLUSION: Our study, with a median follow-up duration of 107 months, indicates that pCND does not lead to a significant reduction in nodal recurrence among non-invasive cN0 PTC patients.

Stem cell landscape aids in tumor microenvironment identification and selection of therapeutic agents in gastric cancer.

Gastric cancer stem cells (GCSCs) are strongly associated with the refractory characteristics of gastric cancer, including drug resistance, recurrence, and metastasis. The prognosis for advanced gastric cancer patients treated with multimodal therapy after surgery remains discouraging. GCSCs hold promise as therapeutic targets for GC patients. We obtained 26 sets of stem cell-related genes from the StemChecker database. The Consensus clustering algorithm was employed to discern three distinct stemness subtypes. Prognostic outcomes, components of the tumor microenvironment (TME), and responses to therapies were compared among these subtypes. Following this, a stemness-risk model was formulated using weighted gene correlation network analysis (WGCNA), alongside Cox regression and random survival forest analyses. The C2 subtype predominantly showed enrichment in negative prognostic CSC gene sets and demonstrated an immunosuppressive TME. This specific subtype exhibited minimal responsiveness to immunotherapies and demonstrated reduced sensitivity to drugs. Four pivotal genes were integrated into the construction of the stemness model. Gastric cancer patients with higher stemness-risk scores demonstrated poorer prognoses, a greater presence of immunosuppressive components in TME, and lower rates of treatment response. Subset analysis indicated that only the low-stemness risk subtype derives benefit from 5-fluorouracil-based adjuvant chemotherapy. The model's effectiveness in immunotherapeutic prediction was further validated in the PRJEB25780 cohort. Our study categorized gastric cancer patients into three stemness subtypes, each demonstrating distinct prognoses, components of TME infiltration, and varying sensitivity or resistance to standard chemotherapy or targeted therapy. We propose that the stemness risk model may help the development of well-grounded treatment recommendations and prognostic assessments.

EIF5A2 Promotes Doxorubicin Resistance in Bladder Cancer Cells through the TGF-ß Signaling Pathway.

BACKGROUND: Doxorubicin (DOX) is a commonly used chemotherapeutic agent, but bladder cancer (BC) patients often develop resistance that limits therapeutic efficacy. Recent research has demonstrated a link between medication resistance and the expression of eukaryotic translation initiation factor 5A2 (EIF5A2) in tumors. This study aimed to investigate whether EIF5A2 affects the resistance of BC cells to doxorubicin through the transforming growth factor (TGF)-ß signaling pathway. METHODS: Doxorubicin-resistant cells in BC (T24/DOX and 5637/DOX) were constructed, then cell viability was detected by cell counting kit-8 (CCK-8); EIF5A2 mRNA expression was detected using quantitative real-time PCR (qRT-PCR); cell proliferation was detected using clone formation; apoptosis was detected by flow cytometry; and finally, proteins related to the TGF-ß signaling pathway (EIF5A2, TGF-ß1, p-small mothers against decapentaplegic 2 (Smad2)/Smad2, p-Smad3/Smad3) were detected using western blot. RESULTS: EIF5A2 was up-regulated in DOX-resistant BC cells, and DOX intervention promoted proliferation and inhibited apoptosis in DOX-resistant BC cells. si-EIF5A2 reversed the above effects. EIF5A2 resulted in DOX resistance by activating the TGF-ß pathway, and the TGF-ß activator SRI-011381 reversed the inhibitory effect of si-EIF5A2 on DOX resistance. CONCLUSIONS: EIF5A2 promotes DOX resistance in BC cells through the TGF-ß signaling pathway, and EIF5A2 may be a potential counter-resistance therapeutic strategy in BC chemotherapy.

The Memorial Sloan Kettering Prognostic Score: Correlation with survival in patients with advanced gastric cancer.

BACKGROUND: Notwithstanding that the past decade has witnessed unprecedented medical progress, gastric cancer (GC) remains a leading cause of cancer death, highlighting the need for effective prognostic markers. The Memorial Sloan Kettering Prognostic Score (MPS) has been validated as a valuable prognostic tool for patients with metastatic pancreatic adenocarcinoma (mPDAC). This study aimed to assess the prognostic value of the MPS in advanced GC. METHODS: Data from 367 patients were analyzed in the present study. The MPS for each patient was calculated based on the sum of scores based on the neutrophil-to-lymphocyte ratio and serum albumin levels. Multivariate analyses were performed to identify the independent clinicopathological parameters associated with overall survival (OS). Further subgroup analyses based on clinicopathological features were conducted. RESULTS: Patients with MPS 0 (n = 161), MPS 1 (n = 158), and MPS 2 (n = 48) exhibited significantly different OS, with a median survival duration of 20.7 (95%CI: 12.2-29.2), 14.9 (95%CI: 12.5-17.3), and 12.7 (95%CI: 9.3-16.0) months, respectively (p < 0.001). Significant differences in survival were observed among different groups of patients receiving chemotherapy (18.5 months vs. 14.7 months vs. 11.0 months, p = 0.03) or the subgroup receiving chemotherapy plus immunotherapy as first-line treatment (32.6 months vs. 17.7 months vs. 12.7 months, p = 0.02). The MPS was identified as an independent prognostic factor in multivariate analysis. During subgroup analyses, MPS-low (MPS 0) was consistently associated with a better prognosis than MPS-high (MPS 1 or 2). CONCLUSIONS: MPS is a practical, simple, and useful prognostic tool for patients with advanced GC. Further studies are warranted to validate its prognostic value in advanced GC.

Anti-PD-1/Her2 Bispecific Antibody IBI315 Enhances the Treatment Effect of Her2-Positive Gastric Cancer through Gasdermin B-Cleavage Induced Pyroptosis.

The majority of patients with human epidermal growth factor receptor 2 (Her2)-positive gastric cancer develop refractory to Her2-targeted therapy, where upregulation of immune checkpoints plays an essential role. Herein, a recombinant fully human IgG1 bispecific antibody IBI315 targeting both PD-1 and Her2 is developed  and its antitumor efficacy as well as the underlying mechanism is investigated. IBI315 crosslinks the physical interaction between Her2-positive tumor cells and PD-1-positive T cells, resulting in significantly enhanced antitumor effects compared to each parent antibody or their combination, both in vitro and in vivo mouse tumor models reconstituted with human immune cells using patient-derived xenografts and organoids. Moreover, IBI315 treatment also induces the recruitment and activation of immune cells in tumors. Mechanistically, IBI315 triggers gasdermin B (GSDMB)-mediated pyroptosis in tumor cells, leading to the activation and recruiments of T cells. The activated T cells secret IFNγ, enhancing GSDMB expression and establishing a positive feedback loop of T cell activation and tumor cell killing. Notably, GSDMB is found to be elevated in Her2-positive gastric cancer cells, providing a rationale for IBI315's efficacy. IBI315 is supported here as a promising bispecific antibody-based immunotherapy approach for Her2-positive gastric cancer in preclinical studies, broadening the therapeutic landscape of this patient population.

BRAFV600E restructures cellular lactylation to promote anaplastic thyroid cancer proliferation.

Anaplastic thyroid cancer (ATC) is a rare but fatal cancer with BRAF mutation ranging from 30 to 50%. Histone lysine lactylation represents a novel epigenetic mark that translates cellular metabolic signals into transcriptional regulation. It is not clear whether the Warburg effect can promote the proliferation of ATC with BRAFV600E mutation via metabolite-mediated histone lactylation. Our study aimed at illustrating how BRAFV600E restructures the cellular protein lactylation landscape to boost ATC proliferation, and determining whether blockade of protein lactylation can sensitize mutant ATC to BRAFV600E inhibitors. Western blotting was used to evaluate lactylation status. Aerobic glycolysis was intervened by adding cell-permeable ethyl lactate or using metabolic inhibitors. Chromatin immunoprecipitation and RT-qPCR were applied to analyze the expression of growth-related genes. Different chemical inhibitors were used to inhibit BRAFV600E and other enzymes. ATC cell line-derived xenograft model was employed to examine the efficacy of mono and combinatorial therapies. The results showed that aerobic glycolysis in ATC increased global protein lactylation via improving cellular lactate availability. In particular, lactylation on Histone 4 Lysine 12 residue (H4K12La) activated the expression of multiple genes essential for ATC proliferation. Furthermore, oncogenic BRAFV600E boosted glycolytic flux to restructure the cellular lactylation landscape, leading to H4K12La-driven gene transcription and cell cycle deregulation. Accordingly, the blockade of cellular lactylation machinery synergized with BRAFV600E inhibitor to impair ATC progression both in vitro and in vivo. Our results demonstrated an extra beneficial effect of aerobic glycolysis on ATC, revealing a novel metabolism-epigenetics axis suitable for combinatorial therapy with BRAFV600E inhibition.

Proteomic profiling of gastric cancer with peritoneal metastasis identifies a protein signature associated with immune microenvironment and patient outcome.

BACKGROUND: Peritoneal metastasis (PM) frequently occurs in patients with gastric cancer (GC) and is a major cause of mortality. Risk stratification for PM can optimize decision making in GC treatment. METHODS: A total of 25 GC patients (13 with synchronous, 6 with metachronous PM and 6 PM-free) were included in this study. Quantitative proteomics by high-depth tandem mass tags labeling and whole-exome sequencing were conducted in primary GC and PM samples. Proteomic signature and prognostic model were established by machine learning algorithms in PM and PM-free GC, then validated in two external cohorts. Tumor-infiltrating immune cells in GC were analyzed by CIBERSORT. RESULTS: Heterogeneity between paired primary and PM samples was observed at both genomic and proteomic levels. Compared to primary GC, proteome of PM samples was enriched in RNA binding and extracellular exosomes. 641 differently expressed proteins (DEPs) between primary GC of PM group and PM-free group were screened, which were enriched in extracellular exosome and cell adhesion pathways. Subsequently, a ten-protein signature was derived based on DEPs by machine learning. This signature was significantly associated with patient prognosis in internal cohort and two external proteomic datasets of diffuse and mixed type GC. Tumor-infiltrating immune cell analysis showed that the signature was associated with immune microenvironment of GC. CONCLUSIONS: We characterized proteomic features that were informative for PM progression of GC. A protein signature associated with immune microenvironment and patient outcome was derived, and it could guide risk stratification and individualized treatment.

Combined fine-needle aspiration and selective intraoperative frozen section to optimize prediction of malignant thyroid nodules: A retrospective cohort study of more than 3000 patients.

Background: Preoperative fine-needle aspiration (FNA) is widely used to differentiate malignant from benign thyroid nodules, while intraoperative frozen sections (FS) are suggested as a systematic supplement for intraoperative decision-making, but limitations still remain for both procedures. Methods: Medical records of 3807 patients with thyroid nodules who underwent both pathological diagnoses (FS and FNA) at our hospital were reviewed. The diagnostic accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of FNA and FS were also evaluated. We further designed an optimal integration scheme (FNA+selective FS) to predict thyroid nodule malignancy. Finally, the efficiency of the proposed integrated diagnostic model was validated using an independent external cohort. Results: For distinguishing malignant nodules, FNA had an accuracy of 90.3%, sensitivity of 90.7%, specificity of 85.2%, PPV of 98.8% and NPV of 40.4%. In contrast, the FS represented higher discriminative power (Accuracy, 94.5%; Sensitivity, 94.1%; Specificity, 100%; PPV, 100%; and NPV, 55.6%). we proposed the selective usage of FS (removed nodules with Bethesda category VI from routine FS, ~1/3 of total). The integrated new diagnostic model of FNA plus selective FS (FNA+sFS) achieved accuracy of 96.9%, sensitivity of 97.3%, specificity of 92%, PPV of 99.4%, and NPV of 71.6% (NRI=0.135, 95% CI 0.103-0.167, P <0.001) and was successfully applied to an external cohort (N=554). Conclusion: Compared with the FNA diagnostic system, FS has an increased ability to distinguish benign and malignant thyroid nodules. The newly proposed integrated diagnostic model of FNA + selective FS can optimize the accuracy of diagnosis.

MAPK4 silencing in gastric cancer drives liver metastasis by positive feedback between cancer cells and macrophages.

Liver metastasis is a major cause of death in gastric cancer patients, but the underlying mechanisms are poorly understood. Through a combination of in vivo screening and transcriptome profiling followed by quantitative RT-PCR and tissue array analyses, we found that mitogen-activated protein kinase 4 (MAPK4) downregulation in gastric cancer tissues from patients is significantly associated with liver metastasis and poor prognosis. The knockdown of MAPK4 in gastric cancer cells promotes liver metastasis in orthotopic mouse models. MAPK4 depletion in gastric cancer cells induces the secretion of macrophage migration inhibitory factor (MIF) to polarize tumor-associated macrophages (TAMs) in orthotopic xenograft tumors. Moreover, TAMs activate epithelial-mesenchymal transition of gastric cancer cells to suppress MAPK4 expression, which further increases MIF secretion to polarize TAMs. Taken together, our results suggest a previously undescribed positive feedback loop between cancer cells and macrophages mediated by MAPK4 silencing that facilitates gastric cancer liver metastasis.

Patient-derived xenograft models for gastrointestinal tumors: A single-center retrospective study.

Background: Patient-derived xenograft (PDX) models have shown a great efficiency in preclinical and translational applications. Gastrointestinal (GI) tumors have a strong heterogeneity, and the engraftment rate of PDX models remarkably vary. However, the clinicopathological and molecular characteristics affecting the engraftment rate still remain elusive. Methods: A total of 312 fresh tumor tissue samples from patients with GI cancer were implanted into immunodeficient mice. The median follow-up time of patients was 37 months. Patients' characteristics were compared in terms of PDX growth and overall survival. PDX models of 3-6 generations were used for drug evaluation. Results: In total, 171 (54.8%, 171/312) PDX models were established, including 85 PDX models of colorectal cancer, 21 PDX models of esophageal cancer, and 65 PDX models of gastric cancer. Other than tumor site, histology, differentiation degree, and serum alpha-fetoprotein (AFP) level, no significant differences were found between transplantation of xenografts and patients' characteristics. For patients who had undergone neoadjuvant therapy, the incidence of tumor formation was higher in those with progressive disease (PD) or stable disease (SD). In gastric cancer, the results showed a higher transplantation rate in deficient mismatch repair (dMMR) tumors, and Ki-67 could be an important factor affecting the engraftment rate. The gene mutation status of RAS and BRAF, two important molecular markers in colorectal cancer, showed a high degree of consistency between patients' tumors and PDXs. However, no significant effects of these two mutations on PDX engraftment rate were observed. More importantly, in this study although KRAS mutations were detected in two clinical cases, evident tumor inhibition was still observed after cetuximab treatment in both PDX models and patients. Conclusion: A large-scale PDX model including 171 cases was successfully established for GI tumors in our center. The relationship between clinicopathological and molecular features and engraftment rates were clarified. Furthermore, this resource provides us with profound insights into tumor heterogeneity, making these models valuable for PDX-guided treatment decisions, and offering the PDX model as a great tool for personalized treatment and translation research.

PD-L1: Biological mechanism, function, and immunotherapy in gastric cancer.

Gastric cancer (GC) is one of the main causes of cancer incidence rate and mortality worldwide. As the main breakthrough direction, the application of immune checkpoint inhibitors makes patients with GC have better prognosis, where PD-L1/PD-1 inhibitors in immunotherapy have good anti-tumor immune efficacy. Further understanding of the regulatory mechanism of PD-L1 in GC may bring substantial progress to the immunotherapy. In this review, we provide information on the endogenous and exogenous regulatory mechanisms of PD-L1 and its biological functions combined with current clinical trials of PD-L1/PD-1 inhibitors in GC. The malignant biological phenotypes caused by PD-L1 and the corresponding clinical combined treatment scheme have been reported. Identifying the biomarkers of the potential efficacy of immunotherapy and specifying the clinical immunotherapy scheme in combination with molecular characteristics of patients may maximize clinical benefits and better prognosis.

Association of inflammatory markers with survival in patients with advanced gastric cancer treated with immune checkpoint inhibitors combined with chemotherapy as first line treatment.

Background: The emergence of immune checkpoint inhibitors has changed the landscape of first-line treatment of patients with advanced gastric cancer. Currently, the prognostic significance of inflammatory markers in first-line immunotherapy combined with chemotherapy for gastric cancer is currently unclear. This study aimed to identify inflammatory markers with potential to predict treatment outcome in advanced gastric cancer patients receiving immunotherapy combined with chemotherapy. Methods: This retrospective study enrolled untreated advanced or metastatic gastric or gastro-esophageal junction cancer patients from 5 clinical trials (the clinical trial cohort) and the real world (the real-word cohort). Inflammatory markers included in the analysis included neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), systemic inflammation index (SII), and derived neutrophil-to-lymphocyte ratio (dNLR). Receiver operating characteristic (ROC) curves were constructed to identify optimal cut-off values. The prognostic potential of the markers was determined using Kaplan-Meier analysis, univariate and multivariate Cox-regression analyses in the clinical trial cohort and the findings were validated in the real-world cohort. Results: In the clinical trial cohort (n=45), MLR, PLR and SII were associated with PFS but not OS (All P<0.05), while dNLR was not correlated with PFS or OS. Only NLR was associated with PFS and OS and identified as an independent prognostic predictor in the univariate and multivariate analyses. The prognostic value of NLR was validated in the real-world cohort (n=55). Conclusions: NLR was a strong predictor of PFS and OS in patients with advanced gastric cancer receiving immune checkpoint inhibitors combined with chemotherapy. Further prospective studies are required to validate our results.

PN3b as an independent risk factor for poor prognosis and peritoneal recurrence in Borrmann type IV gastric cancer: A retrospective cohort study.

Background: The clinicopathological features and surgical treatment strategies of Borrmann type IV gastric cancer (GC) remain controversial. Peritoneal metastasis is the most common recurrence pattern in patients with Borrmann type IV GC. Methods: Among 2026 gastric cancer between January 2009 and August 2019, 159 cases of Borrmann type IV GC were included in this study (7.8%). We retrospectively analyzed the clinicopathological characteristics and prognosis of these patients. Univariate and multivariate Cox proportional hazards were applied to identify independent prognostic factors. Predictors related to peritoneal metastasis of type IV GC were analyzed by multivariate Cox regression analysis. Results: Borrmann type IV gastric cancer was associated with more advanced clinicopathological features at diagnosis than the other Borrmann type GC. Of the 159 patients with Borrmann type IV GC, the median OS was 23 months. The number of patients with peritoneal metastasis was 43, accounted for 27.0% of all the patients and 87.8% of the patients with distant metastasis. Multivariate analyses revealed lymph node metastasis to be independent prognostic factor for survival in Borrmann type IV GC patients. pN3b and tumor size > 50 mm showed to be risk factors for peritoneal metastasis. Conclusions: Borrmann type IV GC is an important independent prognostic factor. pN3b is an independent prognostic factor and a predictor of peritoneal metastasis in patients with Borrmann type IV GC.