Complete remission in a pretreated, microsatellite-stable, KRAS-mutated colon cancer patient after treatment with sintilimab and bevacizumab and platinum-based chemotherapy: a case report and literature review.

Metastatic colon cancer remains an incurable disease, and it is difficult for existing treatments to achieve the desired clinical outcome, especially for colon cancer patients who have received first-line treatment. Although immune checkpoint inhibitors (ICIs) have demonstrated durable clinical efficacy in a variety of solid tumors, their response requires an inflammatory tumor microenvironment. However, microsatellite-stable (MSS) colon cancer, which accounts for the majority of colorectal cancers, is a cold tumor that does not respond well to ICIs. Combination regimens open the door to the utility of ICIs in cold tumors. Although combination therapies have shown their advantage even for MSS colon cancer, it remains unclear whether combination therapies show their advantage in patients with pretreated metastatic colon cancer. We report a patient who has achieved complete remission and good tolerance with sintilimab plus bevacizumab and platinum-based chemotherapy after postoperative recurrence. The patient had KRAS mutation and MSS-type colon cancer, and his PD-1+CD8+ and CD3-CD19-CD14+CD16-HLA-DR were both positive. He has achieved a progression-free survival of 43 months and is still being followed up at our center. The above results suggest that this therapeutic regimen is a promising treatment modality for the management of pretreated, MSS-type and KRAS-mutated metastatic colorectal cancer although its application to the general public still needs to be validated in clinical trials.

Photodynamic therapy may salvage chemotherapy failure in gastric cancer: A case report and a literature review.

Given the highly heterogeneous characteristics of advanced gastric cancer (GC), most patients must receive neoadjuvant therapy or conversion therapy consisting of chemotherapy to decrease tumor grade and improve the likelihood of complete resection. Drug resistance, however, always leads to an aborted conversion therapy and inevitable death. When meet drug resistance, alternative drug regimens will be applied with immunotherapy or targeted therapy, whose clinical efficacy remains limited when new drug resistance or severer liver and kidney toxicity emerge. Photodynamic therapy (PDT), a novel treatment, has demonstrated remarkable therapeutic efficacy in different stages of GC. However, no report has been reported so far on the clinical application of photodynamic therapy in conversion therapy after drug resistance. Here we report a case of middle-aged patient with advanced GC, who experienced failure of conversion therapy consisted of multi-line chemotherapy along with immunotherapy. Ultimate success was achieved through a comprehensive conversion therapy of PDT, chemotherapy, immunotherapy, and targeted therapy. Subsequently, the patient underwent robotic-assisted radical gastrectomy while the surgical specimen showed no tumor cell exists. The patient underwent 3 cycles of systemic adjuvant therapy following surgical intervention. Presently, the patient remains 17 months in a satisfactory state of health.

Good or bad: Paradox of plasminogen activator inhibitor 1 (PAI-1) in digestive system tumors.

The fibrinolytic system is involved in many physiological functions, among which the important members can interact with each other, either synergistically or antagonistically to participate in the pathogenesis of many diseases. Plasminogen activator inhibitor 1 (PAI-1) acts as a crucial element of the fibrinolytic system and functions in an anti-fibrinolytic manner in the normal coagulation process. It inhibits plasminogen activator, and affects the relationship between cells and extracellular matrix. PAI-1 not only involved in blood diseases, inflammation, obesity and metabolic syndrome but also in tumor pathology. Especially PAI-1 plays a different role in different digestive tumors as an oncogene or cancer suppressor, even a dual role for the same cancer. We term this phenomenon "PAI-1 paradox". PAI-1 is acknowledged to have both uPA-dependent and -independent effects, and its different actions can result in both beneficial and adverse consequences. Therefore, this review will elaborate on PAI-1 structure, the dual value of PAI-1 in different digestive system tumors, gene polymorphisms, the uPA-dependent and -independent mechanisms of regulatory networks, and the drugs targeted by PAI-1 to deepen the comprehensive understanding of PAI-1 in digestive system tumors.

Electrohydraulic lithotripsy through endoscopic retrograde cholangiopancreatography combined with SpyGlass in the treatment of complex pancreatic duct stones: A case report and literature review.

The incidence of pancreatic duct stones (PDS) is less than 1%. After the formation of stones, the lumen of the pancreatic duct is blocked, and the pancreatic juice cannot be discharged smoothly, resulting in the impairment of the internal and external secretions of the pancreas. Several national guidelines now recommend endoscopic retrograde cholangiopancreatography (ERCP) as the treatment for PDS. The emergence of SpyGlass makes it possible to visualize the ERCP blind area of the pancreatic system directly. Electrohydraulic lithotripsy (EHL) under SpyGlass can crush large and pressure-resistant stones into smaller fragments, significantly improving the success of the endoscopic treatment of large stones. Here, we report a patient presented with acute alcohol-associated pancreatitis, found to have PDS on imaging, who underwent ERCP combined with SpyGlass (EHL), avoiding surgery, reducing trauma, and being discharged from the hospital with a rapid recovery. Therefore, endoscopic therapy is effective and safe for PDS patients. The combination therapy of this patient is the first use of SpyGlass for PDS in our centre, which marks a new stage in the application of endoscopic therapy for pancreatic diseases.

PDT for Gastric Cancer - the view from China.

The incidence rate and mortality of gastric cancer remain elevated. Traditionally, surgical treatment (including endoscopic surgery and traditional surgery), chemotherapy, targeted therapy, and immunotherapy were used for the treatment of gastric cancer. Although the emergence of targeted therapy and immunotherapy can effectively prolong the survival of some patients with gastric cancer and improve the quality of life of patients after chemotherapy or surgery, the overall survival rate of gastric cancer has not been significantly improved. Photodynamic therapy is a local photochemical therapy with the advantages of high safety, few adverse reactions, and repeatability, although it may cause some toxic reactions. There are some differences between East and West in the treatment of gastric cancer with PDT, and most earlier studies concentrated on using PDT alone. However, some studies have indicated that PDT may enhance the efficacy of chemotherapy and other medications. This paper summarizes the study on the use of PDT and its combination therapy in gastric cancer, which is anticipated to offer novel thoughts for the treatment of gastric cancer.

Research progress of potential factors influencing photodynamic therapy for gastrointestinal cancer.

Gastrointestinal cancer is a malignant tumor of the gastrointestinal tract and its associated digestive organs, including esophageal cancer, gastric cancer, carcinoma of the ampulla, pancreas, bile duct, intestines and rectal cancer. They account for about 30% of global cancer-related incidence and about 40% of mortality. Photodynamic therapy (PDT), as a treatment mode, has been applied to the treatment of gastrointestinal cancer due to potential advantages targeting and potentially lower toxic side effects. However, In the course of clinical treatment, we have found that different patients have various responsiveness to PDT, and even the same patients may have different clinical effects after receiving treatment in different time periods. For influencing factors, traditionally, we only focus on adjusting the dose of photosensitizer and the intensity and time of irradiation,while minimizing other potential factors.Therefore, this paper looks for factors that affect PDT from the patient's own conditions, tumor characteristics and tumor microenvironment(including:tumor acidic microenvironment,tumor hypoxic microenvironment, multi-drug resistance, different tumor characteristics and the immune status of patients) and summarizes how to potentially improve the curative effect of PDT.

Coagulation- and fibrinolysis-related genes for predicting survival and immunotherapy efficacy in colorectal cancer.

Background: Colorectal cancer (CRC) is a common cancer and has a poor prognosis. The coagulation system and fibrinolysis system are closely related to the progression of malignant tumors and is also related to the immunotherapy of malignant tumors. Herein, we tried to predict survival and the immunotherapy effect for patients with CRC using a novel potential prognostic model. Methods: Through online data of TCGA and GEO, we screened significantly differentially expressed genes (DEGs) to construct a prognostic model, followed by obtaining immune-related genes (IRGs) from the ImmPort database and coagulation- and fibrinolysis-related genes (CFRGs) from the GeneCards database. The predictive power of the model is assessed by Kaplan-Meier survival curves as well as the time-dependent ROC curve. Moreover, univariate and multivariate analyses were conducted for OS using Cox regression models, and the nomogram prognostic model was built. In the end, we further studied the possibility that CXCL8 was associated with immunocyte infiltration or immunotherapy effect and identified it by immunohistochemistry and Western blot. Results: Five DEGs (CXCL8, MMP12, GDF15, SPP1, and NR3C2) were identified as being prognostic for CRC and were selected to establish the prognostic model. Expression of these genes was confirmed in CRC samples using RT-qPCR. Notably, those selected genes, both CFRGs and IRGs, can accurately predict the OS of CRC patients. Furthermore, CXCL8 is highly correlated with the tumor microenvironment and immunotherapy response in CRC. Conclusion: Overall, our established IRGPI can very accurately predict the OS of CRC patients. CXCL8 reflects the immune microenvironment and reveals the correlation with immune checkpoints among CRC patients.

Case Report: Anlotinib combined with PD-1 inhibitor and sequential GA regimen or FOLFIRINOX Chemotherapy in treatment of KRAS G12V mutated pancreatic ductal adenocarcinoma with liver metastasis: A case and literature review.

There is a high mortality rate associated with pancreatic cancer, and the incidence has been rising globally in recent decades. When patients are diagnosed, there is little chance that surgery will be beneficial. Systemic chemotherapy is the currently accepted treatment option for patients with metastatic advanced pancreatic cancer. However, a very limited survival improvement is possible with chemotherapy for advanced pancreatic cancer, and chemotherapy resistance plays a significant role in poor prognosis. Despite the fact that targeting growth factor receptor inhibitors such as anti-vascular endothelial growth factor (VEGFR) antibodies significantly improves survival in pancreatic cancer, only a very small number of patients benefit from the treatment. As emerging drugs, immune checkpoint inhibitors (ICIs) have demonstrated significant therapeutic effects in several tumor types, but monotherapy is not effective in pancreatic cancer. In the first-line treatment of solid tumors, combination therapy may result in remarkable outcomes. Here in, we have reported a younger patient with pancreatic ductal adenocarcinoma with liver metastasis (PDACLM) who had a long-term partial response and good tolerance to the combination of anlotinib and programmed cell death protein 1 (PD-1) inhibitor and chemotherapy. Gene analysis suggested only one mutation in the Kirsten rat sarcoma viral oncogene (KRAS) G12V gene. Consequently, there is some hope for patients with pancreatic cancer, especially for KRAS G12V gene mutated patients. Upon reviewing the literature, this patient's combination therapy is the first to have been reported.

Construction and validation of a novel coagulation-related 7-gene prognostic signature for gastric cancer.

Background: Gastric cancer (GC) is the most common malignant tumor. Due to the lack of practical molecular markers, the prognosis of patients with advanced gastric cancer is still poor. A number of studies have confirmed that the coagulation system is closely related to tumor progression. Therefore, the purpose of this study was to construct a coagulation-related gene signature and prognostic model for GC by bioinformatics methods. Methods: We downloaded the gene expression and clinical data of GC patients from the TCGA and GEO databases. In total, 216 coagulation-related genes (CRGs) were obtained from AmiGO 2. Weighted gene co-expression network analysis (WGCNA) was used to identify coagulation-related genes associated with the clinical features of GC. Last absolute shrinkage and selection operator (LASSO) Cox regression was utilized to shrink the relevant predictors of the coagulation system, and a Coag-Score prognostic model was constructed based on the coefficients. According to this risk model, GC patients were divided into high-risk and low-risk groups, and overall survival (OS) curves and receiver operating characteristic (ROC) curves were drawn in the training and validation sets, respectively. We also constructed nomograms for predicting 1-, 2-, and 3-year survival in GC patients. Single-sample gene set enrichment analysis (ssGSEA) was exploited to explore immune cells' underlying mechanisms and correlations. The expression levels of coagulation-related genes were verified by real-time quantitative polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). Results: We identified seven CRGs employed to construct a Coag-Score risk model using WGCNA combined with LASSO regression. In both training and validation sets, GC patients in the high-risk group had worse OS than those in the low-risk group, and Coag-Score was identified as an independent predictor of OS, and the nomogram provided a quantitative method to predict the 1-, 2-, and 3-year survival rates of GC patients. Functional analysis showed that Coag-Score was mainly related to the MAPK signaling pathway, complement and coagulation cascades, angiogenesis, epithelial-mesenchymal transition (EMT), and KRAS signaling pathway. In addition, the high-risk group had a significantly higher infiltration enrichment score and was positively associated with immune checkpoint gene expression. Conclusion: Coagulation-related gene models provide new insights and targets for the diagnosis, prognosis prediction, and treatment management of GC patients.

Application of intraoperative photodynamic therapy in patients suspected of recurrence post radical surgery: A single center experience.

BACKGROUND: Difficult to resect tumors may be treated with a combination of radical surgery and photodynamic therapy to try to reduce recurrence. The aim of this single center study is to present results from a combined application of radical surgery with intraoperative PDT for patients with various cancers suspected of high risk for post-operative local recurrence. METHODS: Radical surgery combined with intraoperative PDT was performed in each and every patient under study at different time points from June 2020 to July 2021, and the PDT irradiation time ranged from 10, 20, 25 and 30 min. Hematoporphyrin, as a photo synthesizer, was administered intravenously 48 h before surgery and during the operative period respectively, at a 3 mg/kg dose. In addition, the mean and median survival times for each of these patients were also evaluated. Patient's overall disease-Free Survival (DFS) and survival (OS) were immensely evaluated. RESULTS: 12 patients (33.3% female and 66.7 % male) underwent radical surgery and PDT simultaneously. No photosensitivity events were reported in the included patients, except for one case with a moderate to severe erythema. Intraoperative PDT was tolerated in all included patients without serious liver and kidney damages. As from the time these patients underwent radical surgery and PDT, three mortalities were recorded and the remaining 9 patients had some remarkable outcomes with less or no recurrences. CONCLUSIONS: Intraoperative PDT is a potentially safe therapeutic strategy for various tumor patients who undergo operation. Intraoperative PDT combined with surgery may improve local tumor control but this needs to be tested in a larger patient population.

The N6-methyladenosine:mechanisms, diagnostic value, immunotherapy prospec-ts and challenges in gastric cancer.

The N6-methyladenosine (m6A) RNA modification is important in post-transcriptional regulation of RNA and are regulated reversibly by methyltransferases (writers), demethylases (erasers) and m6A recognition proteins (readers). Changes in the structure and function of key RNAs contribute to the development of diseases, particularly tumors. Many abnormal expressions of molecules related to m6A RNA methylation modification are discovered in gastric cancer (GC), which changes the methylation level and stability of target genes after transcription, and then regulates related metabolic pathways, affecting the occurrence and progression of GC. Therefore, an in-depth study of m6A RNA modification in GC is conducive to the development of new tumor therapies and the achieve of individualized treatment. At present, both basic and clinical studies indicate that m6A plays a complex and contentious role in GC. In this paper, we not only review the roles and mechanisms of m6A modified related proteins, but also discuss the value of m6A modulators in the clinical applications and current challenges of GC, aiming to provide research clues for the early diagnosis and explore the feasibility of m6A related proteins as specific targets for GC immunotherapy.

The "Light Knife" for Gastric Cancer: Photodynamic Therapy.

Photodynamic therapy (PDT) has been used clinically to treat cancer for more than 40 years. Some solid tumors, including esophageal cancer, lung cancer, head and neck cancer, cholangiocarcinoma, and bladder cancer, have been approved for and managed with PDT in many countries globally. Notably, PDT for gastric cancer (GC) has been reported less and is not currently included in the clinical diagnosis and treatment guidelines. However, PDT is a potential new therapeutic modality used for the management of GC, and its outcomes and realization are more and more encouraging. PDT has a pernicious effect on tumors at the irradiation site and can play a role in rapid tumor shrinkage when GC is combined with cardiac and pyloric obstruction. Furthermore, because of its ability to activate the immune system, it still has a specific effect on systemic metastatic lesions, and the adverse reactions are mild. In this Review, we provide an overview of the current application progress of PDT for GC; systematically elaborate on its principle, mechanism, and the application of a new photosensitizer in GC; and focus on the efficacy of PDT in GC and the prospect of combined use with other therapeutic methods to provide a theoretical basis for clinical application.