Construction and validation of a pancreatic cancer prognostic model based on genes related to the hypoxic tumor microenvironment

BACKGROUND Pancreatic cancer is one of the most lethal malignancies,characterized by poor prognosis and low survival rates.Traditional prognostic factors for pancreatic cancer offer inadequate predictive accuracy,often failing to capture the complexity of the disease.The hypoxic tumor microenvironment has been recognized as a significant factor influencing cancer progression and resistance to treatment.This study aims to develop a prognostic model based on key hypoxia-related molecules to enhance prediction accuracy for patient outcomes and to guide more effective treatment strategies in pancreatic cancer.AIM To develop and validate a prognostic model for predicting outcomes in patients with pancreatic cancer using key hypoxia-related molecules.METHODS This pancreatic cancer prognostic model was developed based on the expression levels of the hypoxia-associated genes CAPN2,PLAU,and CCNA2.The results were validated in an independent dataset.This study also examined the correlations between the model risk score and various clinical features,components of the immune microenvironment,chemotherapeutic drug sensitivity,and metabolism-related pathways.Real-time quantitative PCR verification was conducted to confirm the differential expression of the target genes in hypoxic and normal pancreatic cancer cell lines.RESULTS The prognostic model demonstrated significant predictive value,with the risk score showing a strong correlation with clinical features:It was significantly associated with tumor grade(G)(bP<0.01),moderately associated with tumor stage(T)(aP<0.05),and significantly correlated with residual tumor(R)status(bP<0.01).There was also a significant negative correlation between the risk score and the half-maximal inhibitory concentration of some chemotherapeutic drugs.Furthermore,the risk score was linked to the enrichment of metabolism-related pathways in pancreatic cancer.CONCLUSION The prognostic model based on hypoxia-related genes effectively predicts pancreatic cancer outcomes with improved accuracy over traditional factors and can guide treatment selection based on risk assessment.

Prognostic prediction models for postoperative patients with stageⅠtoⅢcolorectal cancer based on machine learning

BACKGROUND Colorectal cancer(CRC)is characterized by high heterogeneity,aggressiveness,and high morbidity and mortality rates.With machine learning(ML)algorithms,patient,tumor,and treatment features can be used to develop and validate models for predicting survival.In addition,important variables can be screened and different applications can be provided that could serve as vital references when making clinical decisions and potentially improving patient outcomes in clinical settings.AIM To construct prognostic prediction models and screen important variables for patients with stageⅠtoⅢCRC.METHODS More than 1000 postoperative CRC patients were grouped according to survival time(with cutoff values of 3 years and 5 years)and assigned to training and testing cohorts(7:3).For each 3-category survival time,predictions were made by 4 ML algorithms(all-variable and important variable-only datasets),each of which was validated via 5-fold cross-validation and bootstrap validation.Important variables were screened with multivariable regression methods.Model performance was evaluated and compared before and after variable screening with the area under the curve(AUC).SHapley Additive exPlanations(SHAP)further demonstrated the impact of important variables on model decision-making.Nomograms were constructed for practical model application.RESULTS Our ML models performed well;the model performance before and after important parameter identification was consistent,and variable screening was effective.The highest pre-and postscreening model AUCs 95%confidence intervals in the testing set were 0.87(0.81-0.92)and 0.89(0.84-0.93)for overall survival,0.75(0.69-0.82)and 0.73(0.64-0.81)for disease-free survival,0.95(0.88-1.00)and 0.88(0.75-0.97)for recurrence-free survival,and 0.76(0.47-0.95)and 0.80(0.53-0.94)for distant metastasis-free survival.Repeated cross-validation and bootstrap validation were performed in both the training and testing datasets.The SHAP values of the important variables were consistent with the clinicopathological characteristics of patients with tumors.The nomograms were created.CONCLUSION We constructed a comprehensive,high-accuracy,important variable-based ML architecture for predicting the 3-category survival times.This architecture could serve as a vital reference for managing CRC patients.

Clinical value of the Toronto inflammatory bowel disease global endoscopic reporting score in ulcerative colitis

BACKGROUND Endoscopic evaluation in diagnosing and managing ulcerative colitis(UC)is becoming increasingly important.Several endoscopic scoring systems have been established,including the Ulcerative Colitis Endoscopic Index of Severity(UCEIS)score and Mayo Endoscopic Subscore(MES).Furthermore,the Toronto Inflammatory Bowel Disease Global Endoscopic Reporting(TIGER)score for UC has recently been proposed;however,its clinical value remains unclear.AIM To investigate the clinical value of the TIGER score in UC by comparing it with the UCEIS score and MES.METHODS This retrospective study included 166 patients with UC who underwent total colonoscopy between January 2017 and March 2023 at the Affiliated Hospital of Qingdao University(Qingdao,China).We retrospectively analysed endoscopic scores,laboratory and clinical data,treatment,and readmissions within 1 year.Spearman’s rank correlation coefficient,receiver operating characteristic curve,and univariate and multivariable logistic regression analyses were performed using IBM SPSS Statistics for Windows,version 26.0(IBM Corp.,Armonk,NY,United States)and GraphPad Prism version 9.0.0 for Windows(GraphPad Software,Boston,Massachusetts,United States).RESULTS The TIGER score significantly correlated with the UCEIS score and MES(r=0.721,0.626,both P<0.001),showed good differentiating values for clinical severity among mild,moderate,and severe UC[8(4-112.75)vs 210(109–219)vs 328(219–426),all P<0.001],and exhibited predictive value in diagnosing patients with severe UC[area under the curve(AUC)=0.897,P<0.001].Additionally,the TIGER(r=0.639,0,551,0.488,0.376,all P<0.001)and UCEIS scores(r=0.622,0,540,0.494,and 0.375,all P<0.001)showed stronger correlations with laboratory and clinical parameters,including C-reactive protein,erythrocyte sedimentation rate,length of hospitalisation,and hospitalisation costs,than MES(r=0.509,0,351,0.339,and 0.270,all P<0.001).The TIGER score showed the best predictability for patients'recent advanced treatment,including systemic corticosteroids,biologics,or immunomodulators(AUC=0.848,P<0.001)and 1-year readmission(AUC=0.700,P<0.001)compared with the UCEIS score(AUC=0.762,P<0.001;0.627,P<0.05)and MES(AUC=0.684,P<0.001;0.578,P=0.132).Furthermore,a TIGER score of≥317 was identified as an independent risk factor for advanced UC treatment(P=0.011).CONCLUSION The TIGER score may be superior to the UCIES score and MES in improving the accuracy of clinical disease severity assessment,guiding therapeutic decision-making,and predicting short-term prognosis.

Glutamine addiction and therapeutic strategies in pancreatic cancer

Pancreatic cancer remains one of the most lethal diseases worldwide owing to its late diagnosis,early metastasis,and poor prognosis.Because current therapeutic options are limited,there is an urgent need to investigate novel targeted treatment strategies.Pancreatic cancer faces significant metabolic challenges,principally hypoxia and nutrient deprivation,due to specific microenvironmental constraints,including an extensive desmoplastic stromal reaction.Pancreatic cancer cells have been shown to rewire their metabolism and energy production networks to support rapid survival and proliferation.Increased glucose uptake and glycolytic pathway activity during this process have been extensively described.However,growing evidence suggests that pancreatic cancer cells are glutamine addicted.As a nitrogen source,glutamine directly(or indirectly via glutamate conversion)contributes to many anabolic processes in pancreatic cancer,including amino acids,nucleobases,and hexosamine biosynthesis.It also plays an important role in redox homeostasis,and when converted toα-ketoglutarate,glutamine serves as an energy and anaplerotic carbon source,replenishing the tricarboxylic acid cycle intermediates.The present study aims to provide a comprehensive overview of glutamine metabolic reprogramming in pancreatic cancer,focusing on potential therapeutic approaches targeting glutamine metabolism in pancreatic cancer.

Cronkhite-Canada综合征1例

Cronkhite-Canada综合征(Cronkhite-Canada’s syndrome, CCS)是临床罕见病,病因及发病机制尚不明确,该病以胃肠道多发息肉及外胚层两大症候群为主,临床表现以腹泻为主,全消化道多发息肉,伴有皮肤色素沉着、毛发脱落、指(趾)甲萎缩脱落等.预后较差,本文报道1例CCS患者并对62篇国内文献进行回顾性分析.

Feasibility of endoscopic treatment and predictors of lymph node metastasis in early gastric cancer

BACKGROUND Endoscopic submucosal dissection (ESD) has been routinely performed in applicable early gastric cancer (EGC) patients as an alternative to conventional surgical operations that involve lymph node dissection. The indications for ESD have been recently expanded to include larger, ulcerated, and undifferentiated mucosal lesions, and differentiated lesions with slight submucosal invasion. The risk of lymph node metastasis (LNM) is the most important consideration when deciding on a treatment strategy for EGC. Despite the advantages over surgical procedures, lymph nodes cannot be removed by ESD. In addition, whether patients who meet the expanded indications for ESD can be managed safely remains controversial. AIM To determine whether the ESD indications are applicable to Chinese patients and to investigate the predictors of LNM in EGC. METHODS We retrospectively analyzed 12552 patients who underwent surgery for gastric cancer between June 2007 and December 2018 at the Affiliated Hospital of Qingdao University. A total of 1262 (10.1%) EGC patients were eligible for inclusion in this study. Data on the patients’ clinical, endoscopic, and histopathological characteristics were collected. The absolute and expanded indications for ESD were validated by regrouping the enrolled patients and determining the positive LNM results in each subgroup. Predictors of LNM in patients were evaluated by univariate and multivariate analyses. RESULTS LNM was observed in 182 (14.4%) patients. No LNM was detected in the patients who met the absolute indications (0/90). LNM occurred in 4/311 (1.3%) patients who met the expanded indications. According to univariate analysis, LNM was significantly associated with positive tumor marker status, medium (20-30 mm) and large (>30 mm) lesion sizes, excavated macroscopic-type tumors, ulcer presence, submucosal invasion (SM1 and SM2), poor differentiation, lymphovascular invasion (LVI), perineural invasion, and diffuse and mixed Lauren’s types. Multivariate analysis demonstrated SM1 invasion (odds ration [OR]= 2.285, P = 0.03), SM2 invasion (OR = 3.230, P < 0.001), LVI (OR = 15.702, P < 0.001), mucinous adenocarcinoma (OR = 2.823, P = 0.015), and large lesion size (OR = 1.900, P = 0.006) to be independent risk factors. CONCLUSION The absolute indications for ESD are reasonable, and the feasibility of expanding the indications for ESD requires further investigation. The predictors of LNM include invasion depth, LVI, mucinous adenocarcinoma, and lesion size.

Expression of gastrointestinal nesfatin-1 and gastric emptying in ventromedial hypothalamic nucleus- and ventrolateral hypothalamic nucleus-lesioned rats

AIM: To determine the expression levels of gastrointestinal nesfatin-1 in ventromedial hypothalamic nucleus (VMH)-lesioned (obese) and ventrolateral hypothalamic nucleus (VLH)-lesioned (lean) rats that exhibit an imbalance in their energy metabolism and gastric mobility.

Endoscopic stenting and concurrent chemoradiotherapy for advanced esophageal cancer:A case-control study

AIM:To evaluate the role of endoscopic stenting with or without concurrent 3-dimensional conformal chemoradiotherapy (3D-CRT) in patients with inoperable esophageal cancer.METHODS:Advanced esophageal cancer patients indicated for esophagectomy received esophageal stents.A part of patients completed 3D-CRT after stenting.Efficacy was assessed by endoscopy and computed tomographic scan before and 4 wk after completion of the treatment.The median survival,3D-CRT toxicity and complications were compared between 3D-CRT and control groups.RESULTS:From 1999 to 2008,99 consecutive patients with T3/T4 disease and unsuitable for esophagectomy were placed with esophageal stents.Sixty-seven patients received 3D-CRT,while 36 patients treated withendoscopic stents alone were recruited as controls.After 3D-CRT treatment,the median tumor volume of 3D-CRT patients were reduced significantly from 43.7 ± 10.2 cm 3 to 28.8 ± 8.5 cm 3 (P < 0.05).The complete and partial response rate was 85.1%,and no response was 14.9%.After 3D-CRT,the incidence rate of T2 and T3 disease evident on CT scan increased to 78.4% while T4 decreased from 66.7% to 21.6% (P < 0.05).3DCRT Karnofsky Performance Status improved in 3D-CRT patients compared with the control group (P=0.031).3D-CRT patients had a longer survival than the control group (251.7 d vs 91.1 d,P < 0.05).And the median half-year survival rate in 3D-CRT group (91%) was higher than in the control group (50%,P < 0.05).The most common toxicity was leukocytopenia in the 3D-CRT group (46.7% vs 18.8%,P=0.008).The control group had a higher rate of restenosis than the 3D-CRT group (81.3% vs 9.0%,P < 0.05).The rate of nephrotoxicity was increased in 3D-CRT as compared with the control group (31.3% vs 15.6%,P < 0.05).CONCLUSION:3D-CRT can improve dysphagia in patients with inoperable esophageal carcinoma.3D-CRT combined with stenting results in better survival as compared with endoscopic stents used alone.

Participation of microbiota in the development of gastric cancer

There are a large number of bacteria inhabiting the human body,which provide benefits for the health.Alterations of microbiota participate in the pathogenesis of diseases.The gastric microbiota consists of bacteria from seven to eleven phyla,predominantly Proteobacteria,Firmicutes,Bacteroidetes,Actinobacteria and Fusobacteria.Intrusion by Helicobacter pylori(H.pylori)does not remarkably interrupt the composition and structure of the gastric microbiota.Absence of bacterial commensal from the stomach delays the onset of H.pylori-induced gastric cancer,while presence of artificial microbiota accelerates the carcinogenesis.Altered gastric microbiota may increase the production of N-nitroso compounds,promoting the development of gastric cancer.Further investigation of the carcinogenic mechanisms of microbiota would benefit for the prevention and management of gastric cancer.

Gastric adenocarcinoma of fundic gland type after Helicobacter pylori eradication:A case report

BACKGROUND Gastric adenocarcinoma of fundic gland type (GA-FG) has recently been proposed as a novel histological type of gastric cancer. CASE SUMMARY We report a case of GA-FG in a 77-year-old Chinese woman with epigastric distention who was referred to endoscopy for the management of an incidentally found submucosal tumor-like elevated lesion in the lower part of the gastric body. The tumor occurred after Helicobacter pylori (H. pylori) eradication therapy without long-term use of proton pump inhibitors. Complete and curable removal of the tumor was performed by endoscopic submucosal dissection. Histopathological findings showed numerous cells with basophilic cytoplasm and mildly atypical nuclei-like chief cells of the fundic gland. The tumor was observed to have the so-called “endless glands” pattern of the well-differentiated mixed phenotype. A safe resection margin without lymphatic and venous invasion was observed. As the tumor occurred after H. pylori eradication therapy, it is unknown whether there was a relationship with H. pylori eradication. The patient will be followed up by periodic gastroscopic observation. CONCLUSION In conclusion, we report a case of GA-FG after H. pylori eradication therapy without long-term proton pump inhibitors use. Further analysis of similar cases will reveal the clinical behavior of GA-FG.

Gastrointestinal amyloidosis in a patient with smoldering multiple myeloma:A case report

BACKGROUND Smoldering multiple myeloma(SMM)is an asymptomatic plasma cell proliferative disorder that can progress to multiple myeloma(MM).Amyloidosis(light chain)(AL)is the most common form of systemic amyloidosis.There are few reports of SMM coexisting with AL involving the digestive tract.CASE SUMMARY A 63-year-old woman presented with lower limb edema,abdominal distension,abdominal pain,and hematochezia.Gastroscopy showed gastric retention,gastric angler mucosal coarseness,hyperemia,and mild oozing of blood.Colonoscopy showed hyperemic and edematous mucosa of the distal ascending colon and sigmoid colon with the presence of multiple round and irregular ulcers,submucosal ecchymosis,and hematoma.Gastric and colonic tissue biopsy confirmed the diagnosis of AL by positive Congo red staining.MM was confirmed by bone marrow biopsy and immunohistochemistry.The patient had no hypercalcemia,renal dysfunction,anemia,bone lesions or biomarkers of malignancy defined as plasma cells>60%in bone marrow.Additionally,no elevated serum free light chain ratio,or presence of bone marrow lesions by magnetic resonance imaging(SLiM criteria)were detected.The patient was finally diagnosed with SMM coexisting with AL.She received chemotherapy and was discharged when the symptoms were relieved.She is doing well at nearly five years of follow up.CONCLUSION This case highlights that high index of suspicion is required to diagnose gastrointestinal AL.It should be suspected in elderly patients with endoscopic findings of granular-appearing mucosa,ecchymosis,and submucosal hematoma.Timely diagnosis and appropriate therapy can help to improve the prognosis of these patients.

Early colon cancer with enteropathy-associated T-cell lymphoma involving the whole gastrointestinal tract:A case report

BACKGROUND Enteropathy-associated T-cell lymphoma(EATL)is a rare invasive lymphoma derived from gastrointestinal epithelial T lymphocytes.EATL involving the whole gastrointestinal tract accompanied with early colon cancer is extremely rare.CASE SUMMARY We present the case of a 67-year-old man with diarrhea for more than 5 mo whose colonoscopy in another hospital showed multiple colonic polyps,which indicated moderate to severe dysplasia and focal early cancer.Therefore,he was referred to our hospital for further endoscopic treatment.Colonoscopy after admission showed that the mucosa of the terminal ileum and the entire colon were slightly swollen and finely granular.Endoscopic mucosal resection was performed for colonic polyps located in the liver flexure of the colon and descending colon,respectively.Histopathological findings revealed diffuse infiltration of mediumsized lymphoid cells in the colonic mucosa and visible lymphoepithelial lesions.The histopathology of the polyp in the descending colon indicated moderately differentiated adenocarcinoma limited to the mucosa with negative resection margins.Additionally,immunohistochemical analysis showed positive staining for CD7 and CD8.Therefore,we arrived at a diagnosis of EATL with early colon cancer.Subsequently,the patient was transferred to the hematology department for chemotherapy.The patient’s diarrhea was not significantly relieved after receiving chemotherapy,and he ultimately died of severe myelosuppression.CONCLUSION EATL should be considered in unexplained chronic diarrhea.EATL progresses rapidly with a poor prognosis,especially when accompanied with early colon cancer.

Comparing the clinical application values of the Degree of Ulcerative Colitis Burden of Luminal Inflammation(DUBLIN)score and Ulcerative Colitis Endoscopic Index of Severity(UCEIS)in patients with ulcerative colitis

Background:The significance of endoscopic evaluation in the diagnosis and management of ulcerative colitis(UC)has been widely recognized.Over the years,scholars have established several endoscopic scores.Herein,we assessed the clinical application value of the Mayo Endoscopic Subscore(Mayo ES),the Degree of Ulcerative Colitis Burden of Luminal Inflammation(DUBLIN)score,and the Ulcerative Colitis Endoscopic Index of Severity(UCEIS)score in UC patients,by comparing their correlation with disease activity and their predictive potential for treatment response and clinical outcomes.Methods:UC patients hospitalized from September 2015 to September 2019 were retrospectively analysed.We employed Spearman’s rank correlation coefficient to assess the linear association of the assessed endoscopic scores with the clinical parameters.The receiver-operating characteristic curve was applied to evaluate the predictive capabilities of the endoscopic scores for treatment escalation and 1-year readmission.Results:A total of 178 patients were enrolled;most of them(82%)suffered moderate or severe colitis.Among them,48(27%)patients received treatment escalation and 59(33%)were readmitted within 1 year.The DUBLIN and UCEIS scores demonstrated higher correlations with clinical parameters than the Mayo ES.The DUBLIN scores significantly differed between patients with mild,moderate,and severe colitis(all P<0.001).The UCEIS scores demonstrated the best predictabilities for treatment escalation and 1-year readmission with an area under the curve of 0.88 and 0.75,respectively.Compared to the UCEIS and DUBLIN scores,the predictive capabilities of the Mayo ES for treatment escalation(both P<0.001)and 1-year readmission(P<0.001 and P紏0.002,respectively)were lower.The UCEIS scores exhibited a significant difference between the steroid-responsive group and the steroid-dependent or steroid-refractory group(both P<0.001),while no significant differences in the Mayo ES and DUBLIN scores were found among the three groups(both P>0.05).Conclusion:This study demonstrates that both the DUBLIN and UCEIS scores outperform the Mayo ES in assessing disease severity and predicting treatment response and clinical outcomes in UC patients.

Beta2-glycoprotein I cooperate with hepatitisB surface antigen promotes hepatocellular carcinogenesis via the nuclear factor kappa B signalpathway were enhanced by the lipopolysaccharide

Aim: We aimed to elucidate whether beta2-glycoprotein I (β2GPI) cooperation with hepatitis B surface antigen (HBsAg) promoted hepatocellular carcinogenesis enhanced by the lipopolysaccharide (LPS) via activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and expression of tumor necrosis factor-α(TNF-α), interleukin-1β (IL-1β), and alpha fetal protein (AFP) in liver cancer cells. Methods: Liver cancer cells (SMMC-7721) were transiently transfected with β2GPI and/or HBsAg and were subjected to LPS treatment. TNF-α, IL-1β, and AFP expression were measured in all groups by ELISA. NF-κB activation was assessed by non-radioactive electrophoretic mobility shift assay (EMSA) and was quantified in all groups. Results: Cells transfected with β2GPI and/or HBsAg induced activation of NF-κB, with the highest activation seen in the doubly β2GPI- and HBsAg-transfected cells treated with LPS. Non-transfected cells treated with LPS exhibited lower activation compared to either β2GPI- or HBsAg-transfected cells with LPS treatment. In addition, cells transfected with β2GPI and/or HBsAg induced significantly increased expression of TNF-α, IL-1β and AFP, with the highest levels again seen in the doubly β2GPI- and HBsAg-transfected cells treated with LPS. Conclusion: These observations suggest that the activity of NF-κB induced by β2GPI and HBsAg was enhanced by LPS. Expression of TNF-α, IL-1β and AFP increased in β2GPI and HBsAg cotransfected liver cancer cells.