Assessment of programmed death-ligand 1 expression in primary tumors and paired lymph node metastases of gastric adenocarcinoma

BACKGROUND Anti-programmed death-1/programmed death-ligand 1(PD-1/PD-L1)immuno-therapy has demonstrated promising results on gastric cancer(GC).However,PD-L1 can express differently between metastatic sites and primary tumors(PT).AIM To compare PD-L1 status in PT and matched lymph node metastases(LNM)of GC patients and to determine the correlation between the PD-L1 status and clinicopathological characteristics.METHODS We retrospectively reviewed 284 GC patients who underwent D2-gastrectomy.PD-L1 was evaluated by immunohistochemistry(clone SP142)using the com-bined positive score.All PD-L1+PT staged as pN+were also tested for PD-L1 expression in their LNM.PD-L1(-)GC with pN+served as the comparison group.RESULTS Among 284 GC patients included,45 had PD-L1+PT and 24 of them had pN+.For comparison,44 PD-L1(-)cases with pN+were included(sample loss of 4 cases).Of the PD-L1+PT,54.2%(13/24 cases)were also PD-L1+in the LNM.Regarding PD-L1(-)PT,9.1%(4/44)had PD-L1+in the LNM.The agreement between PT and LNM had a kappa value of 0.483.Larger tumor size and moderate/severe peritumoral inflammatory response were associated with PD-L1 positivity in both sites.There was no statistical difference in overall survival for PT and LNM according to the PD-L1 status(P=0.166 and P=0.837,respectively).CONCLUSION Intra-patient heterogeneity in PD-L1 expression was observed between the PT and matched LNM.This disagreement in PD-L1 status may emphasize the importance of considering different tumor sites for analyses to select patients for immunotherapy.

Risk factors for blood transfusion and its prognostic implications in curative gastrectomy for gastric cancer

BACKGROUND Gastric cancer(GC)is still a prevalent neoplasm around the world and its main treatment modality is surgical resection.The need for perioperative blood transfusions is frequent,and there is a long-lasting debate regarding its impact on survival.AIM To evaluate the factors related to the risk of receiving red blood cell(RBC)transfusion and its influence on surgical and survival outcomes of patients with GC.METHODS Patients who underwent curative resection for primary gastric adenocarcinoma at our Institute between 2009 and 2021 were retrospectively evaluated.Clinicopathological and surgical characteristics data were collected.The patients were divided into transfusion and non-transfusion groups for analysis.RESULTS A total of 718 patients were included,and 189(26.3%)patients received perioperative RBC transfusion(23 intraoperatively,133 postoperatively,and 33 in both periods).Patients in the RBC transfusions group were older(P<0.001),and had morecomorbidities(P=0.014),American Society of Anesthesiologists classification III/IV(P<0.001),and lower preoperative hemoglobin(P<0.001)and albumin levels(P<0.001).Larger tumors(P<0.001)and advanced tumor node metastasis stage(P<0.001)were also associated with the RBCtransfusion group.The rates of postoperative complications(POC)and 30-d and 90-d mortalitywere significantly higher in the RBC transfusion group than in the non-transfusion group.Lowerhemoglobin and albumin levels,total gastrectomy,open surgery,and the occurrence of POC werefactors associated with the RBC transfusion.Survival analysis demonstrated that the RBCtransfusions group had worse disease-free survival(DFS)and overall survival(OS)compared withpatients who did not receive transfusion(P<0.001 for both).In multivariate analysis,RBCtransfusion,major POC,pT3/T4 category,pN+,D1 lymphadenectomy,and total gastrectomywere independent risk factors related to worse DFS and OS.CONCLUSIONPerioperative RBC transfusion is associated with worse clinical conditions and more advancedtumors.Further,it is an independent factor related to worse survival in the curative intentgastrectomy setting.

Preoperative albumin-bilirubin score is a prognostic factor for gastric cancer patients after curative gastrectomy

BACKGROUND Albumin-bilirubin(ALBI)score is an indicator of liver dysfunction and is useful for predicting prognosis of hepatocellular carcinomas.Currently,this liver function index has been used to predict prognosis in other neoplasms.However,the significance of ALBI score in gastric cancer(GC)after radical resection has not been elucidated.AIM To evaluate the prognostic value of the preoperative ALBI status in patients with GC who received curative treatment.METHODS Patients with GC who underwent curative intended gastrectomy were retrospectively evaluated from our prospective database.ALBI score was calculated as follows:(log10 bilirubin×0.660)+(albumin×-0.085).The receiver operating characteristic curve with area under the curve(AUC)was plotted to evaluate the ability of ALBI score in predicting recurrence or death.The optimal cutoff value was determined by maximizing Youden’s index,and patients were divided into low and high-ALBI groups.The Kaplan-Meier curve was used to analyze the survival,and the log-rank test was used for comparison between groups.RESULTS A total of 361 patients(235 males)were enrolled.The median ALBI value for the entire cohort was-2.89(IQR-3.13;-2.59).The AUC for ALBI score was 0.617(95%CI:0.556-0.673,P<0.001),and the cutoff value was-2.82.Accordingly,211(58.4%)patients were classified as low-ALBI group and 150(41.6%)as high-ALBI group.Older age(P=0.005),lower hemoglobin level(P<0.001),American Society of Anesthesiologists classification III/IV(P=0.001),and D1 lymphadenectomy P=0.003)were more frequent in the high-ALBI group.There was no difference between both groups in terms of Lauren histological type,depth of tumor invasion(pT),presence of lymph node metastasis(pN),and pathologic(pTNM)stage.Major postoperative complication,and mortality at 30 and 90 days were higher in the high-ALBI patients.In the survival analysis,the high-ALBI group had worse disease-free survival(DFS)and overall survival(OS)compared to those with low-ALBI(P<0.001).When stratified by pTNM,the difference between ALBI groups was maintained in stage I/II and stage III CG for DFS(P<0.001 and P=0.021,respectively);and for OS(P<0.001 and P=0.063,respectively).In multivariate analysis,total gastrectomy,advanced pT stage,presence of lymph node metastasis and high-ALBI were independent factors associated with worse survival.CONCLUSION The preoperative ALBI score is able to predict the outcomes of patients with GC,where high-ALBI patients have worse prognosis.Also,ALBI score allows risk stratification of patients within the same pTNM stages,and represents an independent risk factor associated with survival.

Immunohistochemical expression of thymidylate synthase and prognosis in gastric cancer patients submitted to fluoropyrimidine-based chemotherapy

Objective: Adjuvant chemotherapy with 5-fluorouracil(5-FU) has been widely used in gastric cancer(GC)patients to prevent relapse after curative resection. 5-FU acts by inhibiting thymidylate synthase(TS), and high levels of TS correlate with resistance to treatment with fluoropyrimidines. The aim of this study was to evaluate the expression of TS in GC patients, and its relation with clinicopathological characteristics and prognosis in adjuvant chemotherapy with 5-FU.Methods: We retrospectively evaluated 285 patients who underwent D2-gastrectomy with curative intent. TS expression was determined by immunohistochemistry(IHC) in tumor cells by tissue microarray(TMA). TS level was evaluated according to the intensity and percentage of cells marked by a score system. Patients were divided in three groups according to their TS-score: negative, low and high.Results: TS expression was positive in 92.3% of GC. TS-high, TS-low and TS-negative were observed in46.3%, 46.0% and 7.7% of patients, respectively. High-TS GC were associated with older age(P=0.007), high neutrophil/lymphocyte ratio(P=0.048), well/moderately differentiated histology(P=0.001), intestinal Lauren type(P<0.001) and absence of perineural invasion(P=0.003). Among 285 patients, 133 stage Ⅱ/Ⅲ patients(46.7%)received chemotherapy with 5-FU. In survival analysis, TS-high was associated with worse disease-free survival(DFS) in stage Ⅲ GC patients who received 5-FU-based chemotherapy(P=0.007). Multivariate analysis revealed that total gastrectomy, poorly differentiated tumors and high TS-score were associated with worse DFS in stage Ⅲ GC patients.Conclusions: High TS-score in stage Ⅲ GC was associated with poor DFS in patients treated with fluoropyrimidine-based chemotherapy.

Gastric partitioning for the treatment of malignant gastric outlet obstruction

BACKGROUND Gastric outlet obstruction(GOO)is one of the main complications in stage IV gastric cancer patients.This condition is usually managed by gastrojejunostomy(GJ).However,gastric partitioning(GP)has been described as an alternative to overcoming possible drawbacks of GJ,such as delayed gastric emptying and tumor bleeding.AIM To compare the outcomes of patients who underwent GP and GJ for malignant GOO.METHODS We retrospectively analyzed 60 patients who underwent palliative gastric bypass for unresectable distal gastric cancer with GOO from 2009 to 2018.Baseline clinicopathological characteristics including age,nutritional status,body mass index,and performance status were evaluated.Obstructive symptoms were graded according to GOO score(GOOS).Surgical outcomes evaluated included duration of the procedure,surgical complications,mortality,and length of hospital stay.Acceptance of oral diet after the procedure,weight gain,and overall survival were the long-term outcomes evaluated.RESULTS GP was performed in 30 patients and conventional GJ in the other 30 patients.The mean follow-up was 9.2 mo.Forty-nine(81.6%)patients died during that period.All variables were similar between groups,with the exception of worse performance status in GP patients.The mean operative time was higher in the GP group(161.2 vs 85.2 min,P<0.001).There were no differences in postoperative complications and surgical mortality between groups.The median overall survival was 7 and 8.4 mo for the GP and GJ groups,respectively(P=0.610).The oral acceptance of soft solids(GOOS 2)and low residue or full diet(GOOS 3)were reached by 28(93.3%)GP patients and 22(75.9%)GJ patients(P=0.080).Multivariate analysis demonstrated that GOOS 2 and GOOS 3 were the main prognostic factors for survival(hazard ratio:8.90,95%confidence interval:3.38-23.43,P<0.001).CONCLUSION GP is a safe and effective procedure to treat GOO.Compared to GJ,it provides similar surgical outcomes with a trend to better solid diet acceptance by patients.

Prognostic implications of tumor-infiltrating lymphocytes in association with programmed cell death ligand 1 expression in remnant gastric cancer

Objective:Remnant gastric cancer(RGC)is usually associated with a worse prognosis.As they are less common and very heterogeneous tumors,new prognostic and reliable determinants are required to predict patients’clinical course for RGC.This study aimed to investigate the tumor-infiltrating lymphocytes(TILs)and programmed cell death ligand 1(PD-L1)status as prognostic biomarkers in a cohort of patients with RGC to develop an immunerelated score.Methods:Patients with gastric cancer(GC)who underwent curative intent gastrectomy were retrospectively investigated.RGC resections with histological diagnosis of gastric adenocarcinoma were enrolled in the study.The risk score based on immune parameters was developed using binary logistic regression analysis.RGCs were divided into high-risk(HR),intermediate-risk(IR),and low-risk(LR)groups based on their immune score.The markers(CD3+,CD4+/CD8+T cells and PD-L1)were selected for their potential prognostic,therapeutic value,and evaluated by immunohistochemistry(IHC).Results:A total of 42 patients with RGC were enrolled in the study.The score based on immune parameters exhibited an accuracy of 79%[the area under the receiver operating characteristic curve(AUC)=0.79,95%confidence interval(95%CI),0.63-0.94,P=0.002],and the population was divided into 3 prognostic groups:10(23.8%)patients were classified as LR,15(35.7%)as IR,and 17(40.5%)as HR groups.There were no differences in clinicopathological and surgical characteristics between the three groups.In survival analysis,HR and IR groups had worse disease-free survival and overall survival rates compared to the LR group.In the multivariate analysis,lymph node metastasis and the immune score risk groups were independent factors related to worse survival.Conclusions:A scoring system with immune-related markers was able to distinguish prognostic groups of RGC associated with survival.Accordingly,tumor-infiltrating immune lymphocytes and PD-L1 status may serve as a potential prognostic biomarker for patients with RGC.

Expression profiles of gastric cancer molecular subtypes in remnant tumors

BACKGROUND Remnant gastric cancer(RGC)is a carcinoma arising in the stomach remnant after previous gastric resection.It is frequently reported as a tumor with a poor prognosis and distinct biological features from primary gastric cancer(PGC).However,as it is less frequent,its profile regarding the current molecular classifications of gastric cancer has not been evaluated.AIM To evaluate a cohort of RGC according to molecular subtypes of GC using a panel of immunohistochemistry and in situ hybridization to determine whether the expression profile is different between PGC and RGC.METHODS Consecutive RGC patients who underwent gastrectomy between 2009 and 2019 were assessed using seven GC panels:Epstein-Barr virus in situ hybridization,immunohistochemistry for mismatch repair proteins(MutL homolog 1,MutS homolog 2,MutS homolog 6,and PMS1 homolog 2),p53 protein,and E-cadherin expression.Clinicopathological characteristics and survival of these patients were compared to 284 PGC patients.RESULTS A total of 40 RGC patients were enrolled in this study.Compared to PGC,older age(P<0.001),male(P<0.001),lower body mass index(P=0.010),and lower hemoglobin level(P<0.001)were associated with RGC patients.No difference was observed regarding Lauren’s type and pathologic Tumor Node Metastasis stage between the groups.Regarding the profiles evaluated,EBV-positive tumors were higher in RGC compared to PGC(P=0.039).The frequency of microsatellite instability,aberrant p53 immunostaining,and loss of E-cadherin expression were similar between RGC and PGC.Higher rates of simultaneous alterations in two or more profiles were observed in RGC compared to PGC(P<0.001).According to the molecular classification,the subtypes were defined as EBV in nine(22.5%)cases,microsatellite instability in nine(22.5%)cases,genomically stable in one(2.5%)case,and chromosomal instability in 21(52.5%)cases.There was no significant difference in survival between molecular subtypes in RGC patients.CONCLUSION RGC was associated with EBV positivity and higher rates of co-altered expression profiles compared to PGC.According to the molecular classification,there was no significant difference in survival between the subtypes of RGC.

Gastric cancer molecular classification based on immunohistochemistry and in situ hybridization:Analysis in western patients after curative-intent surgery

BACKGROUND Gastric cancer(GC)is a highly heterogeneous disease,and the identification of molecular subtyping of gastric adenocarcinoma emerged as a promising option to define therapeutic strategies and prognostic subgroups.However,the costs and technical complexity of molecular methodologies remains an obstacle to its adoption,and their clinical significance by other approaches needs further evidence.AIM To evaluate the clinicopathological characteristics and long-term survival of GC based on the subgroups of molecular classification by immunohistochemistry(IHC)and in situ hybridization(ISH).METHODS We retrospectively evaluated all patients who underwent D2-gastrectomy between 2009 and 2016 in a Western cohort of GC patients treated with curative intent.Microsatellite instability(MSI)status,E-cadherin,and p53 expression were analyzed by IHC,and Epstein-Barr virus(EBV)by ISH.Tissue microarrays were constructed for analysis.Clinicopathological characteristics and survival of GC were evaluated according to subtypes defined by The Cancer Genome Atlas(TCGA)Research Network Group and Asian Cancer Research Group(ACRG)classification systems.RESULTS A total of 287 GC patients were included.Based on IHC and ISH analysis,five profiles were defined as follows:E-cadherin aberrant(9.1%),MSI(20.9%),p53 aberrant(36.6%),EBV positivity(10.5%),and p53 normal(31%),which corresponded to tumors that showed no alteration in another profile.A flowchart according to the TCGA and ACRG classifications were used to define the subtypes,where clinical and pathological characteristics associated with GC subtypes were evidenced.Proximal location(P<0.001),total gastrectomy(P=0.001),and intense inflammatory infiltrate(P<0.001)were characteristics related to EBV subtype.MSI subtype was predominantly associated with advanced age(P=0.017)and the presence of comorbidities(P=0.011).While Laurén diffuse type(P<0.001)and advanced stage(P=0.029)were related to genomically stable(GS)subtype.GS tumors and microsatellite stable/epithelial to mesenchymal transition phenotype subtype had worse disease-free survival(DFS)and overall survival(OS)than other subtypes.Conversely,MSI subtype of GC had better survival in both classifications.Type of gastrectomy,pT and the TCGA subtypes were independent factors associated to DFS and OS.CONCLUSION The IHC/ISH analysis was able to distinguish immunophenotypic groups of GC with distinct characteristics and prognosis,resembling the subtypes of the molecular classifications.Accordingly,this method of classification may represent a viable option for use in a clinical setting.

Jejunostomy in the palliative treatment of gastric cancer:A clinical prognostic score

BACKGROUND Clinical stage IV gastric cancer(GC)may need palliative procedures in the presence of symptoms such as obstruction.When palliative resection is not possible,jejunostomy is one of the options.However,the limited survival of these patients raises doubts about who benefits from this procedure.AIM To create a prognostic score based on clinical variables for 90-d mortality for GC patients after palliative jejunostomy.METHODS We performed a retrospective analysis of Stage IV GC who underwent jejunostomy.Eleven preoperative clinical variables were selected to define the score categories,with 90-d mortality as the main outcome.After randomization,patients were divided equally into two groups:Development(J1)and validation(J2).The following variables were used:Age,sex,body mass index(BMI),American Society of Anesthesiologists classification(ASA),Charlson Comorbidity index(CCI),hemoglobin levels,albumin levels,neutrophil-lymphocyte ratio(NLR),tumor size,presence of ascites by computed tomography(CT),and the number of disease sites.The score performance metric was determined by the area under the receiver operating characteristic(ROC)curve(AUC)to define low and high-risk groups.RESULTS Of the 363 patients with clinical stage IVCG,80(22%)patients underwent jejunostomy.Patients were predominantly male(62.5%)with a mean age of 62.4 years old.After randomization,the binary logistic regression analysis was performed and points were assigned to the clinical variables to build the score.The high NLR had the highest value.The ROC curve derived from these pooled parameters had an AUC of 0.712(95%CI:0.537–0.887,P=0.022)to define risk groups.In the validation cohort,the diagnostic accuracy for 90-d mortality based on the score had an AUC of 0.756,(95%CI:0.598–0.915,P=0.006).According to the cutoff,in the validation cohort BMI less than 18.5 kg/m2(P<0.001),CCI≥1(P=0.001),ASA III/IV(P=0.002),high NLR(P=0.012),and the presence of ascites on CT exam(P=0.004)were significantly associated with the high-risk group.The risk groups showed a significant association with first-line(P=0.012),second-line chemotherapy(P=0.009),30-d(P=0.013),and 90-d mortality(P<0.001).CONCLUSION The scoring system developed with 11 variables related to patient’s performance status and medical condition was able to distinguish patients undergoing jejunostomy with high risk of 90 d mortality.

Remnant gastric cancer:An ordinary primary adenocarcinoma or a tumor with its own pattern?

BACKGROUND Remnant gastric cancer(RGC)is defined as a tumor that develops in the stomach after a previous gastrectomy and is generally associated with a worse prognosis.However,there little information available regarding RGCs and their prognostic factors and survival.AIM To evaluate the clinicopathological characteristics and prognosis of RGC after previous gastrectomy for benign disease.METHODS Patients who underwent curative resection for primary gastric cancer(GC)at our institute between 2009 and 2019 were retrospectively evaluated.All RGC resections with histological diagnosis of gastric adenocarcinoma were enrolled in this study.Primary proximal GC(PGC)who underwent total gastrectomy was selected as the comparison group.Clinical and pathological data were collected from a prospective medical database.RESULTS A total of 41 patients with RGC and 120 PGC were included.Older age(P=0.001),lower body mass index(P=0.006),hemoglobin level(P<0.001),and number of resected lymph nodes resected(LN)(P<0.001)were associated with the RGC group.Lauren type,pathological tumor-node-metastasis,and perioperative morbimortality were similar between RGC and PGC.There was no difference in disease-free survival(P=0.592)and overall survival(P=0.930)between groups.LN status was the only independent factor related to survival.CONCLUSION RGC had similar clinicopathological characteristics to PGC.Despite the lower number of resected LN,RGC had a similar prognosis.