Tumor recurrence after pathological complete response in locally advanced gastric cancer after neoadjuvant therapy:Two case reports

BACKGROUND The pathological complete response(ypCR)rate following neoadjuvant chemotherapy for advanced gastric cancer remains low and lacks a universally accepted treatment protocol.Immunotherapy has achieved breakthrough progress.CASE SUMMARY We report two female patients with gastric cancer defined as clinical stage cT4N1-2M0.Detection of mismatch repair protein showed mismatch repair function defect,and perioperative treatment with programmed death protein 1 inhibitor combined with S-1+oxaliplatin achieved ypCR.Surprisingly,the patients underwent clinical observation after surgery but developed different degrees of metastasis at~6 mo after surgery.CONCLUSION PD-1 inhibitor combined with chemotherapy provides a more strategic choice for comprehensive perioperative treatment of gastric cancer.

Combining local regional therapy and systemic therapy:Expected changes in the treatment landscape of recurrent hepatocellular carcinoma

Improvements in early screening,new diagnostic techniques,and surgical treatment have led to continuous downward trends in hepatocellular carcinoma(HCC)morbidity and mortality rates.However,high recurrence and refractory cancer after hepatectomy remain important factors affecting the long-term prognosis of HCC.The clinical characteristics and prognosis of recurrent HCC are heterogeneous,and guidelines on treatment strategies for recurrent HCC are lacking.Therapies such as surgical resection,radiofrequency ablation,and transhepatic arterial chemoembolization are effective for tumors confined to the liver,and targeted therapy is a very important treatment for unresectable recurrent HCC with systemic metastasis.With the deepening of the understanding of the immune microenvironment of HCC,blocking immune checkpoints to enhance the antitumor immune response has become a new direction for the treatment of HCC.In addition,improvements in the tumor immune microenvironment caused by local treatment may provide an opportunity to improve the therapeutic effect of HCC treatment.Ongoing and future clinical trial data of combined therapy may develop the new treatment scheme for recurrent HCC.This paper reviews the pattern of recurrent HCC and the characteristics of the immune microenvironment,demonstrates the basis for combining local treatment and systemic treatment,and reports current evidence to better understand current progress and future approaches in the treatment of recurrent HCC.

Functions and mechanisms of chemokine receptor 7 in tumors of the digestive system

Chemokine(C-X-C motif)receptor 7(CXCR7),recently termed ACKR3,belongs to the G protein-coupled cell surface receptor family,binds to stromal cellderived factor-1[SDF-1,or chemokine(C-X-C motif)ligand 12]or chemokine(CX-C motif)ligand 11,and is the most common chemokine receptor expressed in a variety of cancer cells.SDF-1 binds to its receptor chemokine(C-X-C motif)receptor 4(CXCR4)and regulates cell proliferation,survival,angiogenesis and migration.In recent years,another new receptor for SDF-1,CXCR7,has been discovered,and CXCR7 has also been found to be expressed in a variety of tumor cells and tumor-related vascular endothelial cells.Many studies have shown that CXCR7 can promote the growth and metastasis of a variety of malignant tumor cells.Unlike CXCR4,CXCR7 exhibits a slight modification in the DRYLAIV motif and does not induce intracellular Ca^2+release following ligand binding,which is essential for recruiting and activating G proteins.CXCR7 is generally thought to work in three ways:(1)Recruitingβ-arrestin 2;(2)Heterodimerizing with CXCR4;and(3)Acting as a“scavenger”of SDF-1,thus lowering the level of SDF-1 to weaken the activity of CXCR4.In the present review,the expression and role of CXCR7,as well as its prognosis in cancers of the digestive system,were investigated.

CXCR7/CXCL12 axis is involved in lymph node and liver metastasis of gastric carcinoma

AIM To investigate the role of CXC chemokine receptor (CXCR)-7 and CXCL12 in lymph node and liver metastasis of gastric carcinoma. METHODS In 160 cases of gastric cancer, the expression of CXCR7 and CXCL12 in tumor and matched tumoradjacent non-cancer tissues, in the lymph nodes around the stomach and in the liver was detected using immunohistochemistry to analyze the relationship between CXCR7/CXCL12 expression and clinicopathological features and to determine whether CXCR7 and CXCL12 constitute a biological axis to promote lymph node and liver metastasis of gastric cancer. Furthermore, the CXCR7 gene was silenced and overexpressed in human gastric cancer SGC-7901 cells, and cell proliferation, migration and invasiveness were measured by the MTT, wound healing and Transwell assays, respectively. RESULTS CXCR7 expression was up-regulated in gastric cancer tissues (P = 0.011). CXCR7/CXCL12 expression was significantly related to high tumor stage and lymph node (r = 0.338, P = 0.000) and liver metastasis (r = 0.629, P = 0.000). The expression of CXCL12 in lymph node and liver metastasis was higher than that in primary gastric cancer tissues (chi(2) = 6.669, P = 0.010; chi(2) = 25379, P = 0.000), and the expression of CXCL12 in lymph node and liver metastasis of gastric cancer was consistent with the positive expression of CXCR7 in primary gastric cancer (r = 0.338, P = 0.000; r = 0.629, P = 0.000). Overexpression of the CXCR7 gene promoted cell proliferation, migration and invasion. Silencing of the CXCR7 gene suppressed SGC-7901 cell proliferation, migration and invasion. Human gastric cancer cell lines expressed CXCR7 and showed vigorous proliferation and migratory responses to CXCL12. CONCLUSION The CXCR7/CXCL12 axis is involved in lymph node and liver metastasis of gastric cancer. CXCR7 is considered a potential therapeutic target for the treatment of gastric cancer.

Primary hepatic angiosarcoma manifesting as hepatic sinusoidal obstruction syndrome:A case report

BACKGROUND Primary hepatic angiosarcoma(PHA)is a rare malignancy with a poor prognosis.It is difficult to diagnose PHA because of the lack of specific symptoms or tumour markers,and it rapidly progresses and has a high mortality.To our knowledge,PHA has not been reported to mimic hepatic sinusoidal obstruction syndrome.Herein,we present a case of PHA manifesting as hepatic sinusoidal obstruction syndrome,diagnosed using transjugular liver biopsy,that resulted in the death of the patient.CASE SUMMARY A 71-year-old man was admitted with the primary complaint of abdominal distension,decreased appetite,fatigue in the previous month,and loss of 10 kg of weight in the past 2 years.Both the liver and spleen were enlarged,and the liver had a medium-hard texture on percussion.Laboratory examinations were performed,and abdominal plain computed tomography(CT)and contrastenhanced CT showed hepatomegaly and splenomegaly,as well as diffuse lowdensity shadows distributed in the liver and spleen.Contrast-enhanced CT revealed diffuse,hypodense,nodular or flake shadows in the liver and heterogeneous enhancement in the spleen.A transjugular liver biopsy was performed.Based on the pathology results,the patient was diagnosed with hepatic sinusoidal obstruction syndrome secondary to PHA.The patient’s status further deteriorated and he developed serious hepatic failure.The patient was discharged,and died 3 d later.CONCLUSION PHA is rare and has a poor prognosis;however,transjugular liver biopsy can be safely performed to aid in diagnosis.

Functional mechanism on stem cells by tea(Camellia sinensis)bioactive compounds

Camellia sinensis(tea),one of the most popular commercial crops,is commonly applied in all parts of the world.The main active ingredients of tea include polyphenols,alkaloids,polysaccharides,amino acids,aroma and volatile constitutes,all of which are potentially responsible for the activities of tea.Stem cells(SCs)are the immature and undifferentiated cells by a varying capacity for proliferation,self-renewal and the capability to differentiate into one or more different derivatives with specialized function or maintain their stem cell phenotype.Herein,a thorough review is conducted of the functional mechanism on SCs by tea bioactive compounds.

Hemophagocytic lymphohistiocytosis complicated by polyserositis:A case report

BACKGROUND Hemophagocytic lymphohistiocytosis(HLH)is a rare group of disorders of immune dysregulation characterized by clinical symptoms of severe inflammation.There are basically two types of clinical scenarios:Familial HLH and sporadic HLH.It is thought that the syndrome is implicated in the development of infections,malignancies,and autoimmune diseases.HLH,whether primary or secondary,is characterized by activated macrophages in hematopoietic organs,hepatosplenomegaly,cytopenia,and fever;however,HLH complicated with polyserositis(PS)has never been reported.CASE SUMMARY We present a case of fever in a 46-year-old previously healthy Chinese woman complicated by pericardial,pleural,and abdomen effusions.She had no contact with sick individuals,recent travel,illicit drug use,or new sexual contacts.She did not consume alcohol or tobacco and lacked a family history of other diseases.Antibiotics were prescribed for suspected infection,and acute liver injury subsequently occurred.Contrast-enhanced computed tomography showed mild pericardial effusion,pleural effusion,hepatosplenomegaly,and a large amount of ascites.A full blood count revealed leukopenia and thrombocytopenia.Increased ferritin and triglyceride levels were observed.The test for Epstein-Barr(EB)virus DNA was positive.This suggests that EB virus replication and EB virus infection existed.Additional studies showed hemophagocytosis in bone marrow biopsy specimens.The patient’s condition progressed rapidly.After providing symptomatic support treatment,eliminating immune stimuli,and administering comprehensive cyclosporine and dexamethasone treatment,the patient’s condition continued to progress,and the patient’s family members decided to stop treatment;the patient subsequently died.CONCLUSION This case shows the significance of considering HLH as part of the evaluation of unexplained fever and PS of unknown origin.

Nine-year survival of a 60-year-old woman with locally advanced pancreatic cancer under repeated open approach radiofrequency ablation:A case report

BACKGROUND Radiofrequency ablation(RFA)is gaining popularity as an additional therapy for pancreatic ductal adenocarcinoma.RFA appears to be an attractive treatment option for patients with unresectable,locally advanced and nonmetastatic pancreatic cancer.CASE SUMMARY A 60-year-old woman with 2 mo intermittent upper abdominal pains was admitted to hospital.She had undergone radical gastrectomy(Billroth II)for gastric antral cancer.Contrast-enhanced computed tomography(CECT)and abdominal ultrasound displayed a primary tumor in the neck of the pancreas.Pathological examination showed that the lesion was a pancreatic ductal adenocarcinoma.According to the results of the imaging,open approach RFA was selected to treat the primary tumor.Eight months later,CECT follow-up revealed local recurrence of the tumor,and another open RFA was performed.Although there is evidence that RFA for recurrence of other cancers such as hepatocellular carcinoma may prolong patient survival,it remains unclear whether repeat RFA for local recurrence of pancreatic cancer is feasible.The patient continued to enjoy 9 years of life following the first RFA.CONCLUSION RFA of locally advanced,nonresectable,nonmetastatic,pancreatic tumor is characterized by feasibility-based treatment giving rise to tumor reduction based on improvement of quality of life.

Clinical Course and Outcome Patterns of Acute-on-chronic Liver Failure:A Multicenter Retrospective Cohort Study

Background and Aims:Acute-on-chronic liver failure(ACLF)is acute decompensation of liver function in the setting of chronic liver disease,and characterized by high short-term mortality.In this study,we sought to investigate the clinical course of patients at specific time points,and to propose dynamic prognostic criteria.Methods:We assessed the clinical course of 453 patients with ACLF during a 12-week follow-up period in this retrospective multicenter study.The clinical course of patients was defined as disease recovery,improvement,worsening or steady patterns based on the variation tendency in prothrombin activity(PTA)and total bilirubin(TB)at different time points.Results:Resolution of PTA was observed in 231 patients(51%)at 12 weeks after the diagnosis of ACLF.Among the remaining patients,66(14.6%)showed improvement and 156(34.4%)showed a steady or worsening course.In patients with resolved PTA,the clinical course of TB exhibited resolved pattern in 95.2%,improved in 3.9%,and steady or worse in 0.8%.Correspondingly,in patients with improved PTA,these values for TB were 28.8%,27.3%,and 43.9%,respectively.In patients with steady or worsening PTA,these values for TB were 5.7%,32.3%,and 65.6%,respectively.Dynamic prognostic criteria were developed by combining the clinical course of PTA/TB and the clinical outcomes at 4 and 12 weeks after diagnosis in ACLF patients.Conclusions:We propose the following dynamic prognostic criteria:rapid progression,slow progression,rapid recovery,slow recovery,and slow persistence,which lay the foundation for precise prediction of prognosis and the improvement of ACLF therapy.

Prognostic value of the extravascular lung water and pulmonary vascular permeability indices in severe adult respiratory distress syndrome managed with extracorporeal membrane oxygenation

Severe acute respiratory distress syndrome(ARDS)is commonly seen in intensive care units(ICUs).It is characterized by capillary endothelium and alveolar epithelium damage that results in significant increases in capillary permeability and extravascular lung water.

A robust microsatellite instability detection model for unpaired colorectal cancer tissue samples

Background:Microsatellite instability(MSI)is a key biomarker for cancer immunotherapy and prognosis.Integration of MSI testing into a next-generation-sequencing(NGS)panel could save tissue sample,reduce turn-around time and cost,and provide MSI status and comprehensive genomic profiling in single test.We aimed to develop an MSI calling model to detect MSI status along with the NGS panel-based profiling test using tumor-only samples.Methods:From January 2019 to December 2020,a total of 174 colorectal cancer(CRC)patients were enrolled,including 31 MSI-high(MSI-H)and 143 microsatellite stability(MSS)cases.Among them,56 paired tumor and normal samples(10 MSI-H and 46 MSS)were used for modeling,and another 118 tumor-only samples were used for validation.MSI polymerase chain reaction(MSI-PCR)was performed as the gold standard.A baseline was built for the selected microsatellite loci using the NGS data of 56 normal blood samples.An MSI detection model was constructed by analyzing the NGS data of tissue samples.The performance of the model was compared with the results of MSI-PCR.Results:We first intersected the target genomic regions of the NGS panels used in this study to select common microsatellite loci.A total of 42 loci including 23 mononucleotide repeat sites and 19 longer repeat sites were candidates for modeling.As mononucleotide repeat sites are more sensitive and specific for detecting MSI status than sites with longer length motif and the mononucleotide repeat sites performed even better than the total sites,a model containing 23 mononucleotide repeat sites was constructed and named Colorectal Cancer Microsatellite Instability test(CRC-MSI).The model achieved 100%sensitivity and 100%specificity when compared with MSI-PCR in both training and validation sets.Furthermore,the CRC-MSI model was robust with the tumor content as low as 6%.In addition,8 out of 10 MSI-H samples showed alternations in the four mismatch repair genes(MLH1,MSH2,MSH6,and PMS2).Conclusion:MSI status can be accurately determined along the targeted NGS panels using only tumor samples.The performance of mononucleotide repeat sites surpasses loci with longer repeat motif in MSI calling.

Plasma Metabolic Profile Determination in Young ST-segment Elevation Myocardial Infarction Patients with Ischemia and Reperfusion： Ultra-performance Liquid Chromatography and Mass Spectrometry for Pathway Analysis

Background： This study was to establish a disease differentiation model for ST-segment elevation myocardial infarction （STEMI） youth patients experiencing ischemia and reperfusion via ultra-performance liquid chromatography and mass spectrometry （UPLC/MS） platform, which searches for closely related characteristic metabolites and metabolic pathways to evaluate their predictive value in the prognosis after discharge. Methods： Forty-seven consecutive STEMI patients （23 patients under 45 years of age, referred to here as ＂youth,＂ and 24 elderly patients） and 48 healthy control group members （24 youth, 24 elderly） were registered prospectively. The youth patients were required to provide a second blood draw during a follow-up visit one year after morbidity （n - 22, one lost）. Characteristic metabolites and relative metabolic pathways were screened via UPLC/MS platform base on the Kyoto encyclopedia of genes and genomes （KEGG） and Human Metabolome Database. Receiver operating characteristic （ROC） curves were drawn to evaluate the predictive value of characteristic metabolites in the prognosis after discharge. Results： We successfully established an orthogonal partial least squares discriminated analysis model （R2X = 71.2%, R2Y = 79.6%, and Q2 55.9%） and screened out 24 ions; the sphingolipid metabolism pathway showed the most drastic change. The ROC curve analysis showed that ceramide [Cer（dl 8：0/16：0）, Cer（t 18：0/12：0）] and sphinganine in the sphingolipid pathway have high sensitivity and specificity on the prognosis related to major adverse cardiovascular events after youth patients were discharged. The area under curve （AUC） was 0.67 1, 0.750, and 0.711, respectively. A follow-up validation one year after morbidity showed corresponding AUC of 0.778, 0.833, and 0.806. Conclusions： By analyzing the plasma metabolism of myocardial infarction patients, we successfully established a model that can distinguish two different factors simultaneously： pathological conditions and age. Sphingolipid metabolism is the top most altered pathway in young STEMI patients and as such may represent a valuable prognostic factor and potential therapeutic target.

Doping bioactive elements into a collagen scaffold based on synchronous self-assembly/mineralization for bone tissue engineering

Pure collagen is biocompatible but lacks inherent osteoinductive,osteoimmunomodulatory and antibacterial activities.To obtain collagen with these characteristics,we developed a novel methodology of doping bioactive elements into collagen through the synchronous self-assembly/mineralization(SSM)of collagen.In the SSM model,amorphous mineral nanoparticles(AMN)(amorphous SrCO3,amorphous Ag3PO4,etc.)stabilized by the polyampholyte,carboxymethyl chitosan(CMC),and collagen molecules were the primary components under acidic conditions.As the pH gradually increased,intrafibrillar mineralization occurred via the self-adaptive interaction between the AMNs and the collagen microfibrils,which were self-assembling;the AMNs wrapped around the microfibrils became situated in the gap zones of collagen and finally transformed into crystals.Srdoped collagen scaffolds(Sr-CS)promoted in vitro cell proliferation and osteogenic differentiation of rat bone marrow mesenchymal stromal cells(rBMSCs)and synergistically improved osteogenesis of rBMSCs by altering the macrophage response.Ag-doped collagen scaffolds(Ag-CS)exhibited in vitro antibacterial effects on S.aureus,as well as cell/tissue compatibility.Moreover,Sr-CS implanted into the calvarial defect of a rat resulted in improved bone regeneration.Therefore,the SSM model is a de novo synthetic strategy for doping bioactive elements into collagen,and can be used to fabricate multifunctional collagen scaffolds to meet the clinical challenges of encouraging osteogenesis,boosting the immune response and fighting severe infection in bone defects.

Autotaxin:An Early Warning Biomarker for Acute-on-chronic Liver Failure

Background and Aims:Recent accumulating evidence indicates the biological actions of autotaxin(ATX)in liver disease.However,the relationship between ATX and liver failure has not been reported.The present study aimed to examine alterations of serum ATX in acute-on-chronic liver failure(ACLF)and evaluate whether serum ATX could be useful as an early warning biomarker of ACLF.Methods:Serum ATX was measured in 50 patients with hepatitis B-related ACLF,14 patients with alcohol-related ACLF,11 patients with hepatitis B-related pre-ACLF,11 patients with alcohol-related Child-Pugh A cirrhosis,39 patients with hepatitis B-related Child-Pugh A cirrhosis,26 patients with chronic hepatitis B,and 38 healthy volunteers by enzyme-linked immunosorbent assay.Results:Serum ATX level was significantly higher in the pre-ACLF group than in the Child-Pugh A cirrhosis and chronic hepatitis B groups but lower than in the ACLF group;furthermore,patients with pre-ACLF deteriorated to ACLF had significantly higher serum ATX levels than pre-ACLF patients that did not progress to ACLF.Serum ATX levels were significantly higher among male ACLF patients with preclinical infection,spontaneous bacterial peritonitis or pneumonia,as compared to patients with ACLF but no spontaneous bacterial peritonitis or pneumonia.Serum ATX levels were well correlated with serum biochemical parameters of liver function and model for end-stage liver disease score.Serum ATX≥584.1 ng/mL was a poor prognostic factor for ACLF(hazard ratio of 4.750,95%confidence interval of 1.106-20.392,p=0.036).Conclusions:Serum ATX level may be a useful early warning biomarker for ACLF.

Development of a Widely Applicable and Simple Prognostic Score for Patients with Acute-on-chronic Liver Failure

Background and Aims:Acute-on-chronic liver failure(ACLF)tends to progress rapidly with high short-term mortality.We aimed to create a widely applicable,simple prognostic(WASP)score for ACLF patients.Methods:A retrospective cohort of ACLF cases recruited from three centers in China were divided into training and validation sets to develop the new score.A prospective longitudinal cohort was recruited for further validation.Results:A total of 541 cases were included in the training set,and seven independent ACLF prognostic factors were screened to construct a new quantitative WASP-ACLF table.In the validation set of 671 cases,WASP-ACLF showed better predictive ability for 28-day and 90-day mortality than the currently used prognostic scores at baseline,day 3,week 1,and week 2.The predictive efficacy and clinical validity of the model improved over time.Patients were assigned to low-,intermediate-,and high-risk groups by their WASP-ACLF scores.Compared with the other two groups,intermediate-risk patients had a more uncertain prognosis,with a 90-day mortality of 44.4–50.6%.Sequential assessments at weeks 1 and 2 found the 90-day mortality of intermediate-risk groups was<20%forpatients with a≥2 point decrease in WASP-ACLF and was up to 56%for patients with a≥2 points increase.Similar results were observed in prospective data.Conclusions:The new ACLF prognostic score was simple,widely applicable,and had good predictive efficacy.Continuous assessments and trend of change in WASP-ACLF need to be considered,especially for intermediate-risk patients.