AIM:To compare the reliability of gastritis staging sys-tems in ranking gastritis-associated cancer risk in a large series of consecutive patients.METHODS:Gastric mucosal atrophy is the precancer-ous condition in whic...AIM:To compare the reliability of gastritis staging sys-tems in ranking gastritis-associated cancer risk in a large series of consecutive patients.METHODS:Gastric mucosal atrophy is the precancer-ous condition in which intestinal-type gastric cancer(GC)most frequently develops.The operative link for gas-tritis assessment(OLGA)staging system ranks the GC risk according to both the topography and the severity of gastric atrophy(as assessed histologically on the ba-sis of the Sydney protocol for gastric mucosal biopsy).Both cross-sectional and long-term follow-up trials have consistently associated OLGA stages Ⅲ-Ⅳ with a higher risk of GC.A recently-proposed modification of the OLGA staging system(OLGIM)basically incorporates the OLGA frame,but replaces the atrophy score with an assessment of intestinal metaplasia(IM)alone.A series of 4552 consecutive biopsy sets(2007-2009)was re-trieved and reassessed according to both the OLGA and the OLGIM staging systems.A set of at least 5 biopsy samples was available for all the cases considered.RESULTS:In 4460 of 4552 cases(98.0%),both the high-risk stages(Ⅲ + Ⅳ)and the low-risk stages(0 +Ⅰ + Ⅱ)were assessed applying the OLGA and OL-GIM criteria.Among the 243 OLGA high-risk stages,14(5.8%)were down-staged to a low risk using OLGIM.The 67(1.5%)incidentally-found neoplastic lesions(intraepithelial or invasive)were consistently associated with high-risk stages,as assessed by both OLGA and OLGIM(P < 0.001 for both).Two of 34 intestinal-type GCs coexisting with a high-risk OLGA stage(stage Ⅲ)were associated with a low-risk OLGIM stage(stage Ⅱ).CONCLUSION:Gastritis staging systems(both OLGA and OLGIM)convey prognostically important informa-tion on the gastritis-associated cancer risk.Because of its clinical impact,the stage of gastritis should be included as a conclusive message in the gastritis histol-ogy report.Since it focuses on IM alone,OLGIM staging is less sensitive than OLGA staging in the identif ication of patients at high risk of gastric cancer.展开更多
The histo-pathologic and molecular mechanisms leading to initiation and progression of hepatocellular carcinoma(HCC)are still ill-defined;however,there is increasing evidence that the gradual accumulation of mutations...The histo-pathologic and molecular mechanisms leading to initiation and progression of hepatocellular carcinoma(HCC)are still ill-defined;however,there is increasing evidence that the gradual accumulation of mutations,genetic and epigenetic changes which occur in preneoplastic hepatocytes results in the development of dysplastic foci,nodules,and finally,overt HCC.As well as many other neoplasias,liver cancer is considered an"inflammatory cancer",arising from a context of inflammation,and characterized by inflammation-related mechanisms that favor tumor cell survival,proliferation,and invasion.Molecular mechanisms that link inflammation and neoplasia have been widely investigated,and it has been well established that inflammatory cells recruited at these sites with ongoing inflammatory activity release chemokines that enhance the production of reactive oxygen species.The latter,in turn,probably have a major pathogenic role in the continuum starting from hepatitis followed by chronic inflammation,and ultimately leading to cancer.The relationship amongst chronic liver injury,free radical production,and development of HCC is explored in the present review,particularly in the light of the complex network that involves oxidative DNA damage,cytokine synthesis,telomere dysfunction,and microRNA regulation.展开更多
Gastric cancer(GC)represents a leading cause of cancer related morbidity and mortality worldwide accounting for more than 1 million of newly diagnosed cases and thousands of deaths every year.In the last decade,the de...Gastric cancer(GC)represents a leading cause of cancer related morbidity and mortality worldwide accounting for more than 1 million of newly diagnosed cases and thousands of deaths every year.In the last decade,the development of targeted therapies and the optimization of already available chemotherapeutic drugs has expanded the available treatment options for advanced GC and granted better survival expectations to the patients.At the same time,global efforts have been undertaken to investigate in detail the genomic and epigenomic heterogeneity of this disease,resulting in the identification of new specific and sensitive predictive and prognostic biomarkers and in innovative molecular classifications based on gene expression profiling.Nonetheless,several randomized studies aimed at exploring new innovative agents,such as immune checkpoint inhibitors,failed to demonstrate clinically meaningful survival advantages.Therefore,it is essential to further improve the molecular characterization of GC subgroups in order to provide researchers and medical oncologists with new tools for patients’selection and stratification in future clinical development programs and subsequent trials.The aim of the present manuscript is to provide a global overview of the recent molecular classifications from The Cancer Genome Atlas and the Asian Cancer Research Group and to present key promising developments in the field of immunotherapy and targeted therapies in metastatic GC.展开更多
AIM:To investigate the progression of hepatic histopathology in serial liver biopsies from Wilson disease(WD)patients.METHODS:We report a group of 12 WD patients treated with zinc and/or penicillamine who underwent mu...AIM:To investigate the progression of hepatic histopathology in serial liver biopsies from Wilson disease(WD)patients.METHODS:We report a group of 12 WD patients treated with zinc and/or penicillamine who underwent multiple follow-up liver biopsies.Demographic,clinical and laboratory data were gathered and all patients underwent an initial biopsy and at least one repeat biopsy.RESULTS:Time to repeat biopsy ranged from 2 to 12 years.Six patients(non-progressors)showed stable hepatic histology or improvement.In one case,we observed improvement of fibrosis from stage 2 to 0.Six patients(progressors)had worsening of fibrosis.There was no significant correlation between the histological findings and serum aminotransferases or copper me-tabolism parameters.The hepatic copper concentration reached normal levels in only two patients:one from the non-progressors and one from the progressors group.The estimated rate of progression of hepatic fibrosis in the entire group was 0 units per year in the time frame between the first and the second liver biopsy(4 years),and 0.25 between the second and the third(3 years).In the progressors group,the rate of progression of liver fibrosis was estimated at 0.11 fibrosis units per year between the first and second biopsy and,0.6 fibrosis units between the second and third biopsy.CONCLUSION:The inability of clinical tools to detect fibrosis progression in WD suggests that a liver biopsy with hepatic copper quantification every 3 years should be considered.展开更多
Western countries are seeing a constant decline in the incidence of Helicobacter pylori-associated gastritis, coupled with a rising epidemiological and clinical impact of autoimmune gastritis. This latter gastropathy ...Western countries are seeing a constant decline in the incidence of Helicobacter pylori-associated gastritis, coupled with a rising epidemiological and clinical impact of autoimmune gastritis. This latter gastropathy is due to autoimmune aggression targeting parietal cells through a complex interaction of auto-antibodies against the parietal cell proton pump and intrinsic factor, and sensitized T cells. Given the specific target of this aggression, autoimmune gastritis is typically restricted to the gastric corpus-fundus mucosa. In advanced cases, the oxyntic epithelia are replaced by atrophic(and metaplastic) mucosa, creating the phenotypic background in which both gastric neuroendocrine tumors and(intestinal-type) adenocarcinomas may develop. Despite improvements in our understanding of the phenotypic changes or cascades occurring in this autoimmune setting, no reliable biomarkers are available for identifying patients at higher risk of developing a gastric neoplasm. The standardization of autoimmune gastritis histology reports and classifications in diagnostic practice is a prerequisite for implementing definitive secondary prevention strategies based on multidisciplinary diagnostic approaches integratingendoscopy, serology, histology and molecular profiling.展开更多
In spite of the well-established understanding of the phenotypic lesions occurring in the shift from native epithelia to invasive (adeno) carcinoma, the molecular typing of the precancerous changes in the gastrointest...In spite of the well-established understanding of the phenotypic lesions occurring in the shift from native epithelia to invasive (adeno) carcinoma, the molecular typing of the precancerous changes in the gastrointestinal tract remains unreliable. In recent years, no biomarkers have aroused as much interest as the miRNAs,a class of non-coding RNA molecules that function as endogenous silencers of numerous target genes. Aberrant miRNA expression is a hallmark of human disease,including cancer. Unlike most mRNAs, miRNAs are both long-living in vivo and very stable in vitro . Such characteristics allow their testing in paraffin-embedded tissue samples, which is essential in the biological profiling of small (phenotypically characterized) preneoplastic lesions of the gastrointestinal tract (as well as in other fields of human pathology). The upcoming challenge lies in the reliable identification of disease-specific targets of dysregulated miRNAs, to enable miRNA testing in the clinical management of the secondary prevention of gastrointestinal cancer.展开更多
AIM: To assess whether a correlation exists between oxidative DNA damage occurring in chronic HCV-related hepatitis and expression levels of pro-inflammatory cytokines, TGF-αand c-myc. METHODS: The series included 37...AIM: To assess whether a correlation exists between oxidative DNA damage occurring in chronic HCV-related hepatitis and expression levels of pro-inflammatory cytokines, TGF-αand c-myc. METHODS: The series included 37 patients with chronic active HCV-related hepatitis and 11 with HCV-related compensated cirrhosis. Eight-hydroxydeoxyguanosine in liver biopsies was quantified using an electrochemical detector. The mRNA expression of TIMF-α, IL-1β, TGF-αand c-myc in liver specimens was detected by semi-quantitative comparative RT-PCR. RESULTS: TNF-αlevels were significantly higher in hepatitis patients than in cirrhosis patients (P=0.05). IL-1βwas higher in cirrhosis patients (P=0.05). A significant correlation was found between TNF-αand staging (P=0.05) and between IL-1βlevels and grading (P=0.04). c-myc showed a significantly higher expression in cirrhosis patients (P=0.001). Eight-hydroxydeoxyguanosine levels were significantly higher in cirrhosis patients (P=0.05) and in HCV genotype 1 (P=0.03). Considering all patients, 8-hydroxydeoxyguanosine levels were found to be correlated with genotype (P=0.04) and grading (P=0.007). Also multiple logistic regression analysis demonstrated a significant correlation among the number of DNA adducts, TNF-αexpression and HCV genotype (P=0.02). CONCLUSION: In chronic HCV-related liver damage, oxidative DNA damage correlates with HCV genotype, grading and TNF-αlevels. As HCV-related liver damage progresses, TNF-αlevels drop while IL-1βand c-myc levels increase, which may be relevant to liver carcinogenesis.展开更多
Although the Sydney Systems (original and updated) for the classification of gastritis have contributed substantially to the uniformity of the reporting of gastric conditions, they lack immediacy in conveying to the u...Although the Sydney Systems (original and updated) for the classification of gastritis have contributed substantially to the uniformity of the reporting of gastric conditions, they lack immediacy in conveying to the user information about gastric cancer risk. In this review, we summarize the current understanding of the gastric lesions associated with an increased risk for cancer, and present the rationale for a proposal for new ways of reporting gastritis. In addition to the traditional histopathological data gathered and evaluated according to the Sydney System rules, pathologists could add an assessment expressed as grading and staging of the gastric inflammatory and atrophic lesions and integrate these findings with pertinent laboratory information on pepsinogens and gastrin levels. Such an integrated report could facilitate clinicians’ approach to the management of patients with gastric conditions.展开更多
基金Supported by An AIRC grant from the Veneto Regional Authorities,2009the"Guido Berlucchi"Foundation+1 种基金the"Morgagni"Association for Oncological Research (PadovaPD)
文摘AIM:To compare the reliability of gastritis staging sys-tems in ranking gastritis-associated cancer risk in a large series of consecutive patients.METHODS:Gastric mucosal atrophy is the precancer-ous condition in which intestinal-type gastric cancer(GC)most frequently develops.The operative link for gas-tritis assessment(OLGA)staging system ranks the GC risk according to both the topography and the severity of gastric atrophy(as assessed histologically on the ba-sis of the Sydney protocol for gastric mucosal biopsy).Both cross-sectional and long-term follow-up trials have consistently associated OLGA stages Ⅲ-Ⅳ with a higher risk of GC.A recently-proposed modification of the OLGA staging system(OLGIM)basically incorporates the OLGA frame,but replaces the atrophy score with an assessment of intestinal metaplasia(IM)alone.A series of 4552 consecutive biopsy sets(2007-2009)was re-trieved and reassessed according to both the OLGA and the OLGIM staging systems.A set of at least 5 biopsy samples was available for all the cases considered.RESULTS:In 4460 of 4552 cases(98.0%),both the high-risk stages(Ⅲ + Ⅳ)and the low-risk stages(0 +Ⅰ + Ⅱ)were assessed applying the OLGA and OL-GIM criteria.Among the 243 OLGA high-risk stages,14(5.8%)were down-staged to a low risk using OLGIM.The 67(1.5%)incidentally-found neoplastic lesions(intraepithelial or invasive)were consistently associated with high-risk stages,as assessed by both OLGA and OLGIM(P < 0.001 for both).Two of 34 intestinal-type GCs coexisting with a high-risk OLGA stage(stage Ⅲ)were associated with a low-risk OLGIM stage(stage Ⅱ).CONCLUSION:Gastritis staging systems(both OLGA and OLGIM)convey prognostically important informa-tion on the gastritis-associated cancer risk.Because of its clinical impact,the stage of gastritis should be included as a conclusive message in the gastritis histol-ogy report.Since it focuses on IM alone,OLGIM staging is less sensitive than OLGA staging in the identif ication of patients at high risk of gastric cancer.
文摘The histo-pathologic and molecular mechanisms leading to initiation and progression of hepatocellular carcinoma(HCC)are still ill-defined;however,there is increasing evidence that the gradual accumulation of mutations,genetic and epigenetic changes which occur in preneoplastic hepatocytes results in the development of dysplastic foci,nodules,and finally,overt HCC.As well as many other neoplasias,liver cancer is considered an"inflammatory cancer",arising from a context of inflammation,and characterized by inflammation-related mechanisms that favor tumor cell survival,proliferation,and invasion.Molecular mechanisms that link inflammation and neoplasia have been widely investigated,and it has been well established that inflammatory cells recruited at these sites with ongoing inflammatory activity release chemokines that enhance the production of reactive oxygen species.The latter,in turn,probably have a major pathogenic role in the continuum starting from hepatitis followed by chronic inflammation,and ultimately leading to cancer.The relationship amongst chronic liver injury,free radical production,and development of HCC is explored in the present review,particularly in the light of the complex network that involves oxidative DNA damage,cytokine synthesis,telomere dysfunction,and microRNA regulation.
文摘Gastric cancer(GC)represents a leading cause of cancer related morbidity and mortality worldwide accounting for more than 1 million of newly diagnosed cases and thousands of deaths every year.In the last decade,the development of targeted therapies and the optimization of already available chemotherapeutic drugs has expanded the available treatment options for advanced GC and granted better survival expectations to the patients.At the same time,global efforts have been undertaken to investigate in detail the genomic and epigenomic heterogeneity of this disease,resulting in the identification of new specific and sensitive predictive and prognostic biomarkers and in innovative molecular classifications based on gene expression profiling.Nonetheless,several randomized studies aimed at exploring new innovative agents,such as immune checkpoint inhibitors,failed to demonstrate clinically meaningful survival advantages.Therefore,it is essential to further improve the molecular characterization of GC subgroups in order to provide researchers and medical oncologists with new tools for patients’selection and stratification in future clinical development programs and subsequent trials.The aim of the present manuscript is to provide a global overview of the recent molecular classifications from The Cancer Genome Atlas and the Asian Cancer Research Group and to present key promising developments in the field of immunotherapy and targeted therapies in metastatic GC.
文摘AIM:To investigate the progression of hepatic histopathology in serial liver biopsies from Wilson disease(WD)patients.METHODS:We report a group of 12 WD patients treated with zinc and/or penicillamine who underwent multiple follow-up liver biopsies.Demographic,clinical and laboratory data were gathered and all patients underwent an initial biopsy and at least one repeat biopsy.RESULTS:Time to repeat biopsy ranged from 2 to 12 years.Six patients(non-progressors)showed stable hepatic histology or improvement.In one case,we observed improvement of fibrosis from stage 2 to 0.Six patients(progressors)had worsening of fibrosis.There was no significant correlation between the histological findings and serum aminotransferases or copper me-tabolism parameters.The hepatic copper concentration reached normal levels in only two patients:one from the non-progressors and one from the progressors group.The estimated rate of progression of hepatic fibrosis in the entire group was 0 units per year in the time frame between the first and the second liver biopsy(4 years),and 0.25 between the second and the third(3 years).In the progressors group,the rate of progression of liver fibrosis was estimated at 0.11 fibrosis units per year between the first and second biopsy and,0.6 fibrosis units between the second and third biopsy.CONCLUSION:The inability of clinical tools to detect fibrosis progression in WD suggests that a liver biopsy with hepatic copper quantification every 3 years should be considered.
基金Supported by A grant from the Italian Association for Cancer Research(partly,AIRC Regional grant 2008 No.6421)published under the auspices of the Healthy Stomach Initiative(HIS)
文摘Western countries are seeing a constant decline in the incidence of Helicobacter pylori-associated gastritis, coupled with a rising epidemiological and clinical impact of autoimmune gastritis. This latter gastropathy is due to autoimmune aggression targeting parietal cells through a complex interaction of auto-antibodies against the parietal cell proton pump and intrinsic factor, and sensitized T cells. Given the specific target of this aggression, autoimmune gastritis is typically restricted to the gastric corpus-fundus mucosa. In advanced cases, the oxyntic epithelia are replaced by atrophic(and metaplastic) mucosa, creating the phenotypic background in which both gastric neuroendocrine tumors and(intestinal-type) adenocarcinomas may develop. Despite improvements in our understanding of the phenotypic changes or cascades occurring in this autoimmune setting, no reliable biomarkers are available for identifying patients at higher risk of developing a gastric neoplasm. The standardization of autoimmune gastritis histology reports and classifications in diagnostic practice is a prerequisite for implementing definitive secondary prevention strategies based on multidisciplinary diagnostic approaches integratingendoscopy, serology, histology and molecular profiling.
基金Supported by The AIRC grant Veneto Region 2009the "G.Berlucchi" and "G.B. Morgagni" Foundations
文摘In spite of the well-established understanding of the phenotypic lesions occurring in the shift from native epithelia to invasive (adeno) carcinoma, the molecular typing of the precancerous changes in the gastrointestinal tract remains unreliable. In recent years, no biomarkers have aroused as much interest as the miRNAs,a class of non-coding RNA molecules that function as endogenous silencers of numerous target genes. Aberrant miRNA expression is a hallmark of human disease,including cancer. Unlike most mRNAs, miRNAs are both long-living in vivo and very stable in vitro . Such characteristics allow their testing in paraffin-embedded tissue samples, which is essential in the biological profiling of small (phenotypically characterized) preneoplastic lesions of the gastrointestinal tract (as well as in other fields of human pathology). The upcoming challenge lies in the reliable identification of disease-specific targets of dysregulated miRNAs, to enable miRNA testing in the clinical management of the secondary prevention of gastrointestinal cancer.
基金Supported by PRIN grants from the Italian Ministry of Science and Technology, No. 2003063143-006
文摘AIM: To assess whether a correlation exists between oxidative DNA damage occurring in chronic HCV-related hepatitis and expression levels of pro-inflammatory cytokines, TGF-αand c-myc. METHODS: The series included 37 patients with chronic active HCV-related hepatitis and 11 with HCV-related compensated cirrhosis. Eight-hydroxydeoxyguanosine in liver biopsies was quantified using an electrochemical detector. The mRNA expression of TIMF-α, IL-1β, TGF-αand c-myc in liver specimens was detected by semi-quantitative comparative RT-PCR. RESULTS: TNF-αlevels were significantly higher in hepatitis patients than in cirrhosis patients (P=0.05). IL-1βwas higher in cirrhosis patients (P=0.05). A significant correlation was found between TNF-αand staging (P=0.05) and between IL-1βlevels and grading (P=0.04). c-myc showed a significantly higher expression in cirrhosis patients (P=0.001). Eight-hydroxydeoxyguanosine levels were significantly higher in cirrhosis patients (P=0.05) and in HCV genotype 1 (P=0.03). Considering all patients, 8-hydroxydeoxyguanosine levels were found to be correlated with genotype (P=0.04) and grading (P=0.007). Also multiple logistic regression analysis demonstrated a significant correlation among the number of DNA adducts, TNF-αexpression and HCV genotype (P=0.02). CONCLUSION: In chronic HCV-related liver damage, oxidative DNA damage correlates with HCV genotype, grading and TNF-αlevels. As HCV-related liver damage progresses, TNF-αlevels drop while IL-1βand c-myc levels increase, which may be relevant to liver carcinogenesis.
文摘Although the Sydney Systems (original and updated) for the classification of gastritis have contributed substantially to the uniformity of the reporting of gastric conditions, they lack immediacy in conveying to the user information about gastric cancer risk. In this review, we summarize the current understanding of the gastric lesions associated with an increased risk for cancer, and present the rationale for a proposal for new ways of reporting gastritis. In addition to the traditional histopathological data gathered and evaluated according to the Sydney System rules, pathologists could add an assessment expressed as grading and staging of the gastric inflammatory and atrophic lesions and integrate these findings with pertinent laboratory information on pepsinogens and gastrin levels. Such an integrated report could facilitate clinicians’ approach to the management of patients with gastric conditions.