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Prognosis value of heat-shock proteins in esophageal and esophagogastric cancer:A systematic review and meta-analysis

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World Journal of Gastrointestinal Oncology 2024年第4期16卷 1578-1595页

作者： Eric Toshiyuki Nakamura Amanda Park marina alessandra pereira Daniel Kikawa Francisco Tustumi Department of Gastroenterology Instituto do CâncerHospital das Clínicas da Universidade de São PauloFaculdade de MedicinaUniversidade de São PauloSão Paulo 01246000Brazil Department of Scientific Initiation Universidade Mogi das CruzesSão Paulo 08780911Brazil Department of Evidence-Based Medicine Centro Universitário LusíadaCentre for Evidence-Based MedicineCentro Universitário Lusíada(UNILUS)SantosBrazil Department of Surgery Hospital Israelita Albert EinsteinSão Paulo 05652900Brazil

BACKGROUND Heat shock proteins(HSPs)are molecular chaperones that play an important role in cellular protection against stress events and have been reported to be overex-pressed in many cancers.The prognostic significance of HSPs and their regulatory factors,such as heat shock factor 1(HSF1)and CHIP,are poorly understood.AIM To investigate the relationship between HSP expression and prognosis in esophageal and esophagogastric cancer.METHODS A systematic review was conducted in accordance with PRISMA recommend-ations(PROSPERO:CRD42022370653),on Embase,PubMed,Cochrane,and LILACS.Cohort,case-control,and cross-sectional studies of patients with eso-phagus or esophagogastric cancer were included.HSP-positive patients were compared with HSP-negative,and the endpoints analyzed were lymph node metastasis,tumor depth,distant metastasis,and overall survival(OS).HSPs were stratified according to the HSP family,and the summary risk difference(RD)was calculated using a random-effect model.RESULTS The final selection comprised 27 studies,including esophageal squamous cell carcinoma(21),esophagogastric adenocarcinoma(5),and mixed neoplasms(1).The pooled sample size was 3465 patients.HSP40 and 60 were associated with a higher 3-year OS[HSP40:RD=0.22;95%confidence interval(CI):0.09-0.35;HSP60:RD=0.33;95%CI:0.17-0.50],while HSF1 was associated with a poor 3-year OS(RD=-0.22;95%CI:-0.32 to-0.12).The other HSP families were not associated with long-term survival.HSF1 was associated with a higher probability of lymph node metastasis(RD=-0.16;95%CI:-0.29 to-0.04).HSP40 was associated with a lower probability of lymph node dissemination(RD=0.18;95%CI:0.03-0.33).The expression of other HSP families was not significantly related to tumor depth and lymph node or distant metastasis.CONCLUSION The expression levels of certain families of HSP,such as HSP40 and 60 and HSF1,are associated with long-term survival and lymph node dissemination in patients with esophageal and esophagogastric cancer.

关键词： Heat-shock proteins Heat-shock response Prognosis Esophageal neoplasms Meta-analysis

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

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World Journal of Gastrointestinal Oncology 2024年第3期16卷 883-893页

作者： Brendha Cação Coimbra marina alessandra pereira Leonardo Cardili Venancio Avancini Ferreira Alves Evandro Sobroza de Mello Ulysses Ribeiro Jr Marcus Fernando Kodama Pertille Ramos Department of Gastroenterology Instituto do CancerHospital das Clínicas da Faculdade de Medicina da Universidade de São PauloFaculdade de MedicinaUniversidade de São PauloSão Paulo 01246000Brazil Department of Pathology Instituto do CancerHospital das Clínicas da Faculdade de Medicina da Universidade de São PauloSão Paulo 01246000Brazil

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.

关键词： Gastric cancer Lymph node Programmed death ligand 1 Stomach neoplasms Immunohistochemistry Metastasis

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

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World Journal of Gastrointestinal Surgery 2023年第6期15卷 1125-1137页

作者： Daniel Jose Szor marina alessandra pereira Marcus Fernando Kodama Pertille Ramos Francisco Tustumi Andre Roncon Dias Bruno Zilberstein Ulysses Ribeiro Jr Department of Gastroenterology Instituto do CancerHospital das Clinicas HCFMUSPFaculdade de MedicinaUniversidade de Sao PauloSao Paulo 01246000Brazil

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 A

关键词： Stomach neoplasms Adenocarcinoma Albumin-bilirubin Biomarker Prognosis Survival

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

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World Journal of Gastrointestinal Surgery 2023年第4期15卷 643-654页

作者： Lucas Eiki Kawakami Pedro Barzan Bonomi marina alessandra pereira Fabrício Oliveira Carvalho Ulysses Ribeiro Jr Bruno Zilberstein Luciana Ribeiro Sampaio Luiz Augusto Carneiro-D'Albuquerque Marcus Fernando Kodama Pertille Ramos Department of Gastroenterology Instituto do CancerHospital das Clinicas HCFMUSPFaculdade de MedicinaUniversidade de Sao PauloSao Paulo 01249000Brazil Blood Transfusion Unit Instituto do CancerHospital das Clinicas HCFMUSPFaculdade de MedicinaUniversidade de Sao PauloSao Paulo 01249000Brazil

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 indep

关键词： Stomach neoplasms Blood transfusion Red blood cells Postoperative complications Survival Prognosis

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

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Chinese Journal of Cancer Research 2022年第6期34卷 612-622页

作者： marina alessandra pereira Marcus Fernando Kodama Pertille Ramos André Roncon Dias Leonardo Cardili Rafael Dyer Rodrigues de Moraes Renan Ribeiro E Ribeiro Venancio Avancini Ferreira Alves Bruno Zilberstein Evandro Sobroza de Mello Ulysses Ribeiro Jr Department of Gastroenterology Instituto do Cancer do Estado de Sao PauloHospital das ClinicasFaculdade de MedicinaUniversidade de Sao Paulo(ICESP-HCFMUSP)Sao PauloSP 01246-000Brazil Department of Pathology Instituto do Cancer do Estado de Sao PauloHospital das ClinicasFaculdade de MedicinaUniversidade de Sao Paulo(ICESP-HCFMUSP)Sao PauloSP 01246-000Brazil

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.

关键词： Stomach neoplasms gastric remnant tumor-infiltrating lymphocytes immune microenvironment

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Gastric cancer with concurrent pancreatic schwannoma: A casereport

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World Journal of Gastrointestinal Pathophysiology 2022年第3期13卷 107-113页

作者： Mateus Barradas Ribeiro Emerson Shigueaki Abe AndréKondo Adriana Vaz Safatle-Ribeiro marina alessandra pereira Bruno Zilberstein Ulysses Ribeiro Jr Department of Gastroenterology Instituto do CancerHospital das Clínicas da Faculdade de Medicina da Universidade de São PauloSao Paulo 01249000Brazil

BACKGROUND The differential diagnosis of abdominal masses is somewhat troublesome,especially when there is a malignancy to be evaluated.We report herein a unique case of gastric adenocarcinoma concurrent with a pancreatic schwannoma.Correct assessment of intraoperative findings is essential for adequate tumor staging and to decide the proper management of a concurrent pancreatic lesion.CASE SUMMARY Computed tomography scan performed for gastric cancer staging revealed a solid and cystic pancreatic mass that had no signs of local invasiveness.Surgical resection of the pancreas was decided preoperatively since a radical approach of the gastric tumor could be performed.There were no signs of distant metastases,and the large pancreatic mass was in contact with the posterior gastric wall.Histopathological study revealed a pancreatic schwannoma,which is an uncommon neoplasm that arises from Schwann cells around peripheral nerves.CONCLUSION Therefore,pancreatic masses deserve special attention regarding the differential diagnosis in patients with gastric cancer.The presence of a large pancreatic mass should not preclude the potentially curative intent of the gastric cancer treatment.

关键词： Stomach neoplasms Gastric adenocarcinoma Schwannoma Pancreas Case report

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Expression profiles of gastric cancer molecular subtypes in remnant tumors

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World Journal of Gastrointestinal Oncology 2021年第4期13卷 265-278页

作者： Marcus Fernando Kodama Pertille Ramos marina alessandra pereira Leonardo Cardili Evandro Sobroza de Mello Ulysses Ribeiro Jr Bruno Zilberstein Ivan Cecconello Department of Gastroenterology Instituto do CancerHospital das ClinicasHCFMUSPFaculdade de MedicinaUniversidade de São PauloSão Paulo 01249000São PauloBrazil Department of Pathology Instituto do CancerHospital das Clinicas HCFMUSPFaculdade de MedicinaUniversidade de São PauloSão Paulo 01249000São PauloBrazil

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 rat

关键词： Stomach neoplasms Gastric remnant Gastric remnant cancer Adenocarcinoma Immunohistochemistry

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Gastric partitioning for the treatment of malignant gastric outlet obstruction

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World Journal of Gastrointestinal Oncology 2019年第12期11卷 1161-1171页

作者： Marcus Fernando Kodama Pertille Ramos Leandro Cardoso Barchi Rodrigo Jose de Oliveira marina alessandra pereira Donato Roberto Mucerino Ulysses Ribeiro Jr Bruno Zilberstein Ivan Cecconello Department of Gastroenterology Hospital das Clinicas HCFMUSPFaculdade de MedicinaUniversidade de Sao Paulo

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.

关键词： Stomach neoplasms Gastric outlet obstruction Palliative surgery Gastrojejunostomy Gastric cancer

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

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World Journal of Gastrointestinal Surgery 2021年第4期13卷 366-378页

作者： Marcus Fernando Kodama Pertille Ramos marina alessandra pereira Andre Roncon Dias Anna Carolina Batista Dantas Daniel Jose Szor Ulysses Ribeiro Jr Bruno Zilberstein Ivan Cecconello Department of Gastroenterology Instituto do CancerHospital das Clínicas da Faculdade de Medicina da Universidade de São PauloSão PauloSão Paulo 01249000Brazil

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.

关键词： Stomach neoplasms Gastric remnant Gastric cancer Remnant gastric cancer Peptic ulcer Gastric stump

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

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Chinese Journal of Cancer Research 2018年第5期30卷 526-536页

作者： marina alessandra pereira Marcus Fernando Kodama Pertille Ramos ANDre Roncon Dias Sheila Friedrich Faraj Cinthya dos Santos Cirqueira EvANDro Sobroza de Mello Bruno Zilberstein Venancio Avancini Ferreira Alves Ulysses Ribeiro Jr Department of Gastroenterology Cancer InstituteUniversity of Sao Paulo Medical School Department of Pathology Cancer InstituteUniversity of Sao Paulo Medical School Department of Pathology Instituto Adolfo Lutz

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 fluoropyfimidines. 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 in 46.3%, 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 IUIII 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.

关键词： Gastric cancer adjuvant therapy thymidylate synthase 5-fluorouracil-based chemotherapy

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