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Abstract

Second Cancers in Patients Treated for Gastric MALT LymphomaOne of the most dramatic discoveries in the history of modern gastroenterology was the discovery describing the association between Helicobacter pylori infection and either gastric mucosal-associated lymphoid tissue (MALT) or gastric MALT lymphomas (GML). H pylori was not only associated with MALT and GML, but in many cases its eradication resulted in their resolution. Subsequent studies of patients with more extensive disease that extended deeper into the mucosa revealed the need for more extensive therapy consisting of surgery, chemotherapy, or radiotherapy.For the majority of patients with GML, however, the disease is restricted to the superficial layers of the mucosa. H pylori eradication in these patients results in the resolution of grossly visible disease in the majority of patients. A small number of patients may continue to exhibit signs of persistent histologic features of GML.In this issue of Gastroenterology, Wündisch et al present data based on the long-term follow-up of 120 patients in Germany with stage El1 gastric mucosal lymphoma for whom H pylori was eradicated. Stage El1 represented those patients with lymphoma limited to the gastric mucosa and submucosa, and showed no evidence of lymph node involvement. For the 120 patients studied, H pylori eradication represented the only treatment received. The median follow-up of the cohort was 10 years, which consisted of regular upper endoscopies. The study was conducted to answer 2 questions. First, what is the clinical outcome of patients with histologic residual disease? Second, are patients with GML at risk for subsequent gastric cancers?Ninety-six (80%) of the original 120 study participants achieved a complete response after eradication of H pylori. Three of the 96 patients (3%) suffered a relapse and were referred for alternative treatment. Histologic residual disease was observed in 16 of the 96 patients (17%). Only 5 of these patients exhibited histologic residual disease on ≥2 consecutive examinations. Three patients alternated between complete response and histologic residual disease. Only 1 patient had evidence histologic residual disease on the last endoscopic examination. Thus, most patients with histologic residual disease attained a complete response and none showed progression of disease.With respect to the risk of gastric cancers, 7 of the 96 complete responders developed non-Hodgkin lymphoma, which reflected a Standardized Morbidity Ratio (SMR) of 18.6 compared with the general German population (Table 1). Five of the 96 complete responders developed gastric cancer, which represented a SMR of 8.6. Thus, complete responders to H pylori eradication for GML exhibited increased rates for non-Hodgkin lymphoma and gastric epithelial cancers. The results support extended surveillance for non-Hodgkin lymphoma and gastric cancers in complete responders.Table 1Standardized Morbidity Ratios (SMR) of Second Cancers in 96 Complete RespondersEntitySMR (95% CI)PAll cancers1.689 (1.050–2.717).038Non-Hodgkin lymphoma18.621 (8.365−41.448)<10−6Gastric cancer8.567 (3.566–20.582)<.001Data represent comparisons with calendar year-specific rates in the German population with the value at the end of 2006 as the final cutoff (95% confidence interval [CI]). Open table in a new tab See page 936.Risk of Esophageal and Stomach Cancers With AIDSBeginning with the emergence of AIDS in the 1980s, an association with an increase incidence of non-Hodgkin lymphoma was clear by the early 1990s. A common site where these cancers first presented was the upper gastrointestinal tract. Since those early days, the evolution of HIV and AIDS treatment has resulted in dramatically improved outcomes. Whether the incidences of other esophageal and gastric carcinomas were also similarly affected by HIV infection or AIDS was not known.In this issue of Gastroenterology, Persson et al analyzed data derived from the HIV/AIDS Cancer Match to define the risk of esophageal and gastric cancers in patients with HIV. The dataset consisted of 596,955 patients with AIDS compiled from 1980 to 2007 and was derived from 16 HIV/AIDS registries from different centers across the Unites States that were linked with their corresponding cancer registries. The period covered included the introduction of highly active antiretroviral therapy (HAART), which permitted an assessment of its effects on cancer risk in the upper gastrointestinal tract.As expected, determination of the risk of persons with AIDS to that of the general population, the standardized incidence ratio (SIR), revealed much higher rates for non-Hodgkin lymphoma. Individuals with AIDS exhibited an SIR of 261 (95% confidence interval [CI], 190–349) in the esophagus and 35.5 (95% CI, 31.9–39.5) in the stomach.The SIR for AIDS-associated carcinomas also revealed an increase SIR of 1.69 (95% CI, 1.37–2.07) for the esophagus and 1.44 (1.17–1.76) for the stomach. Although the results for both locations were significant, they were clearly lower than those for the lymphomas. In addition, the increase SIR for the carcinomas was only observed for patients who developed AIDS, and not for patients with HIV only.When the dataset was analyzed with respect to time, there was a significant decline in the incidence of non-Hodgkin lymphomas with the introduction of HAART, whereas the incidence of esophageal and gastric carcinomas showed no change (Figure 1).Considering the modestly increased SIR of HIV-associated carcinomas, the authors concluded that surveillance screening of all HIV patients is unlikely to be cost effective. In addition, the authors were not able to assess the impact of tobacco and alcohol on this dataset. Regardless, the dataset provided valuable insights into the effects of AIDS on the incidences of esophageal and gastric cancer, and the subsequent effects of HAART.See page 943.Similar Therapy But Different Regional Outcomes for HCV Infection!The burden of disease from hepatitis C virus (HCV) infection, as well as screening practices and access to therapy, varies considerably among countries. However, the impact of differences in access to treatment, for example, on morbidity and mortality from chronic HCV infection has not been studied. In this issue of Gastroenterology (accompanied by an editorial), Deuffic–Burban et al develop country-specific Markov models for 6 European countries—Belgium, France, Germany, Italy, Spain, and the United Kingdom—that take into account national characteristics such as epidemiologic patterns, natural history, and screening and treatment rates to predict the incidence of and mortality from HCV-related cirrhosis until 2021 for each country. The total number of patients with cirrhosis was predicted to peak in 2020 for Belgium, in 2021 for France, in 2023 for Germany (similar to that predicted in the United States), in 2030 for Spain, and in 2033 for the United Kingdom without treatment; in Italy, where the HCV epidemic wave occurred 20–30 years earlier than the other European countries, the peak was reached in 2008.From 2002 to 2011, pegylated interferon and ribavirin therapy reduced the cumulative incidence of cirrhosis by 7.1% and deaths by 3.4%, overall. Reductions in incidence of cirrhosis and deaths varied from 4% and 1.9%, respectively, in Italy to 16.3% and 9.0%, respectively, in France. The advent of protease inhibitor-based triple therapy was predicted to reduce, from 2012 to 2021, the cumulative incidence of cirrhosis by 17.7% and deaths by 9.7%, overall, assuming no change in screening or treatment practices in each country. Predicted reductions in incidence of cirrhosis and deaths varied from 10.1% and 5.4%, respectively, in Italy to 34.3% and 20.7%, respectively, in France. However, assuming that 75% of HCV-infected patients would be screened by 2015 and 50% of HCV genotype 1–infected patients would be treated with protease inhibitor-based therapy by 2015, the cumulative incidence of cirrhosis was predicted to be reduced by 27.4% and deaths by 15.0%, overall (Figure 2). Predicted reductions in incidence of cirrhosis and deaths again varied from 19.5% and 10.6%, respectively, in Italy to 36.7% and 22.5%, respectively, in France. Predictions based on the likelihood of new treatment regimens becoming available in 2017 demonstrated even greater reductions in the cumulative incidence of cirrhosis and death. These findings should help inform the development of public health policies for population-guided therapy.Figure 2Treatment impact over the period 2012–2021 for HCV genotype 1-infected patients. Reduction in cumulative incidence of HCV-related cirrhosis (A) and death (B) for each country considering either pegylated interferon bitherapy, pegylated interferon-based triple therapy alone, or pegylated interferon-based triple therapy and reinforcement of HCV screening and treatment access.View Large Image Figure ViewerDownload Hi-res image Download (PPT)See page 974; editorial on page 887.Can Activated Hepatic Stellate Cells Revert to Quiescence?In response to liver injury, hepatic stellate cells (HSCs) lose their characteristic vitamin A and lipid stores and are activated to myofibroblasts that produce the extracellular matrix scar in hepatic fibrosis. Reversal of hepatic fibrosis has been shown to be associated with a reduction in the number of myofibroblasts, mediated by enhanced apoptosis. Alternatively, activated HSCs may re-differentiate and revert to a quiescent state. In this issue of Gastroenterology (accompanied by an editorial), Troeger et al use 2 complementary approaches, single-cell quantitative polymerase chain reaction and genetic cell fate tracking, to investigate whether HSC deactivation represents an alternative mechanism for reversibility of hepatic fibrosis. Liver injury was induced with carbon tetrachloride (CCl4), thioacetamide, and bile duct ligation, standard animal models of fibrosis, in bacterial artificial chromosome-transgenic mice expressing a tamoxifen-inducible CreER driven by the endogenous promoter for vimentin, an intermediate filament predominantly expressed in HSCs, a model that allows HSCs to be identified and tracked during injury and recovery. Expression of fibrogenic genes, including collagen-α1(I) (Colla1) and -α2(I), α-smooth muscle actin, TIMP1, an inhibitor of enzymes involved in the degradation of the extracellular matrix, and lysyl oxidase, significantly increased in liver and in isolated HSCs (Figure 3) within 2 days and normalized by 15 days after CCl4 treatment.Figure 3Determination of fibrogenic expression in HSCs isolated from untreated mice or from mice treated with 4 injections of CCl4 and humanely killed either 2, 5, 12, or 30 days after the last CCl4 injection. **P < .01.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Single-cell polymerase chain reaction demonstrated that, based on Colla1 and TIMP1 gene expression, activation occurred in >90% of HSCs. Fibrogenic gene expression gradually and constantly decreased in almost all of the activated HSCs during the recovery period between day 2 and day 15 after CCl4 and thioacetamide treatment, suggesting activated HSCs that do not undergo apoptosis are HSCs undergoing deactivation. Similar findings were observed in the transgenic mice model, in which 40% of HSCs reverted to a quiescent state after CCl4-induced liver fibrosis. Furthermore, the location of HSCs changed from fibrotic septa to their characteristic perisinusoidal location during the recovery period. Of particular note, HSCs that reverted to a quiescent state after activation were more susceptible to reactivation in response to recurring fibrogenic stimuli. These novel findings are consistent with a role for both HSC apoptosis and deactivation in the reversal of liver fibrosis, although further studies are required to define the factors that determine whether an activated HSC undergoes apoptosis or reverts to a quiescent state with enhanced capacity to reactivate during repeated cycles of injury and whether these pathways can be therapeutically modified.See page 1073; editorial on page 890. Second Cancers in Patients Treated for Gastric MALT LymphomaOne of the most dramatic discoveries in the history of modern gastroenterology was the discovery describing the association between Helicobacter pylori infection and either gastric mucosal-associated lymphoid tissue (MALT) or gastric MALT lymphomas (GML). H pylori was not only associated with MALT and GML, but in many cases its eradication resulted in their resolution. Subsequent studies of patients with more extensive disease that extended deeper into the mucosa revealed the need for more extensive therapy consisting of surgery, chemotherapy, or radiotherapy.For the majority of patients with GML, however, the disease is restricted to the superficial layers of the mucosa. H pylori eradication in these patients results in the resolution of grossly visible disease in the majority of patients. A small number of patients may continue to exhibit signs of persistent histologic features of GML.In this issue of Gastroenterology, Wündisch et al present data based on the long-term follow-up of 120 patients in Germany with stage El1 gastric mucosal lymphoma for whom H pylori was eradicated. Stage El1 represented those patients with lymphoma limited to the gastric mucosa and submucosa, and showed no evidence of lymph node involvement. For the 120 patients studied, H pylori eradication represented the only treatment received. The median follow-up of the cohort was 10 years, which consisted of regular upper endoscopies. The study was conducted to answer 2 questions. First, what is the clinical outcome of patients with histologic residual disease? Second, are patients with GML at risk for subsequent gastric cancers?Ninety-six (80%) of the original 120 study participants achieved a complete response after eradication of H pylori. Three of the 96 patients (3%) suffered a relapse and were referred for alternative treatment. Histologic residual disease was observed in 16 of the 96 patients (17%). Only 5 of these patients exhibited histologic residual disease on ≥2 consecutive examinations. Three patients alternated between complete response and histologic residual disease. Only 1 patient had evidence histologic residual disease on the last endoscopic examination. Thus, most patients with histologic residual disease attained a complete response and none showed progression of disease.With respect to the risk of gastric cancers, 7 of the 96 complete responders developed non-Hodgkin lymphoma, which reflected a Standardized Morbidity Ratio (SMR) of 18.6 compared with the general German population (Table 1). Five of the 96 complete responders developed gastric cancer, which represented a SMR of 8.6. Thus, complete responders to H pylori eradication for GML exhibited increased rates for non-Hodgkin lymphoma and gastric epithelial cancers. The results support extended surveillance for non-Hodgkin lymphoma and gastric cancers in complete responders.Table 1Standardized Morbidity Ratios (SMR) of Second Cancers in 96 Complete RespondersEntitySMR (95% CI)PAll cancers1.689 (1.050–2.717).038Non-Hodgkin lymphoma18.621 (8.365−41.448)<10−6Gastric cancer8.567 (3.566–20.582)<.001Data represent comparisons with calendar year-specific rates in the German population with the value at the end of 2006 as the final cutoff (95% confidence interval [CI]). Open table in a new tab See page 936. One of the most dramatic discoveries in the history of modern gastroenterology was the discovery describing the association between Helicobacter pylori infection and either gastric mucosal-associated lymphoid tissue (MALT) or gastric MALT lymphomas (GML). H pylori was not only associated with MALT and GML, but in many cases its eradication resulted in their resolution. Subsequent studies of patients with more extensive disease that extended deeper into the mucosa revealed the need for more extensive therapy consisting of surgery, chemotherapy, or radiotherapy. For the majority of patients with GML, however, the disease is restricted to the superficial layers of the mucosa. H pylori eradication in these patients results in the resolution of grossly visible disease in the majority of patients. A small number of patients may continue to exhibit signs of persistent histologic features of GML. In this issue of Gastroenterology, Wündisch et al present data based on the long-term follow-up of 120 patients in Germany with stage El1 gastric mucosal lymphoma for whom H pylori was eradicated. Stage El1 represented those patients with lymphoma limited to the gastric mucosa and submucosa, and showed no evidence of lymph node involvement. For the 120 patients studied, H pylori eradication represented the only treatment received. The median follow-up of the cohort was 10 years, which consisted of regular upper endoscopies. The study was conducted to answer 2 questions. First, what is the clinical outcome of patients with histologic residual disease? Second, are patients with GML at risk for subsequent gastric cancers? Ninety-six (80%) of the original 120 study participants achieved a complete response after eradication of H pylori. Three of the 96 patients (3%) suffered a relapse and were referred for alternative treatment. Histologic residual disease was observed in 16 of the 96 patients (17%). Only 5 of these patients exhibited histologic residual disease on ≥2 consecutive examinations. Three patients alternated between complete response and histologic residual disease. Only 1 patient had evidence histologic residual disease on the last endoscopic examination. Thus, most patients with histologic residual disease attained a complete response and none showed progression of disease. With respect to the risk of gastric cancers, 7 of the 96 complete responders developed non-Hodgkin lymphoma, which reflected a Standardized Morbidity Ratio (SMR) of 18.6 compared with the general German population (Table 1). Five of the 96 complete responders developed gastric cancer, which represented a SMR of 8.6. Thus, complete responders to H pylori eradication for GML exhibited increased rates for non-Hodgkin lymphoma and gastric epithelial cancers. The results support extended surveillance for non-Hodgkin lymphoma and gastric cancers in complete responders. Data represent comparisons with calendar year-specific rates in the German population with the value at the end of 2006 as the final cutoff (95% confidence interval [CI]). See page 936. Risk of Esophageal and Stomach Cancers With AIDSBeginning with the emergence of AIDS in the 1980s, an association with an increase incidence of non-Hodgkin lymphoma was clear by the early 1990s. A common site where these cancers first presented was the upper gastrointestinal tract. Since those early days, the evolution of HIV and AIDS treatment has resulted in dramatically improved outcomes. Whether the incidences of other esophageal and gastric carcinomas were also similarly affected by HIV infection or AIDS was not known.In this issue of Gastroenterology, Persson et al analyzed data derived from the HIV/AIDS Cancer Match to define the risk of esophageal and gastric cancers in patients with HIV. The dataset consisted of 596,955 patients with AIDS compiled from 1980 to 2007 and was derived from 16 HIV/AIDS registries from different centers across the Unites States that were linked with their corresponding cancer registries. The period covered included the introduction of highly active antiretroviral therapy (HAART), which permitted an assessment of its effects on cancer risk in the upper gastrointestinal tract.As expected, determination of the risk of persons with AIDS to that of the general population, the standardized incidence ratio (SIR), revealed much higher rates for non-Hodgkin lymphoma. Individuals with AIDS exhibited an SIR of 261 (95% confidence interval [CI], 190–349) in the esophagus and 35.5 (95% CI, 31.9–39.5) in the stomach.The SIR for AIDS-associated carcinomas also revealed an increase SIR of 1.69 (95% CI, 1.37–2.07) for the esophagus and 1.44 (1.17–1.76) for the stomach. Although the results for both locations were significant, they were clearly lower than those for the lymphomas. In addition, the increase SIR for the carcinomas was only observed for patients who developed AIDS, and not for patients with HIV only.When the dataset was analyzed with respect to time, there was a significant decline in the incidence of non-Hodgkin lymphomas with the introduction of HAART, whereas the incidence of esophageal and gastric carcinomas showed no change (Figure 1).Considering the modestly increased SIR of HIV-associated carcinomas, the authors concluded that surveillance screening of all HIV patients is unlikely to be cost effective. In addition, the authors were not able to assess the impact of tobacco and alcohol on this dataset. Regardless, the dataset provided valuable insights into the effects of AIDS on the incidences of esophageal and gastric cancer, and the subsequent effects of HAART.See page 943. Beginning with the emergence of AIDS in the 1980s, an association with an increase incidence of non-Hodgkin lymphoma was clear by the early 1990s. A common site where these cancers first presented was the upper gastrointestinal tract. Since those early days, the evolution of HIV and AIDS treatment has resulted in dramatically improved outcomes. Whether the incidences of other esophageal and gastric carcinomas were also similarly affected by HIV infection or AIDS was not known. In this issue of Gastroenterology, Persson et al analyzed data derived from the HIV/AIDS Cancer Match to define the risk of esophageal and gastric cancers in patients with HIV. The dataset consisted of 596,955 patients with AIDS compiled from 1980 to 2007 and was derived from 16 HIV/AIDS registries from different centers across the Unites States that were linked with their corresponding cancer registries. The period covered included the introduction of highly active antiretroviral therapy (HAART), which permitted an assessment of its effects on cancer risk in the upper gastrointestinal tract. As expected, determination of the risk of persons with AIDS to that of the general population, the standardized incidence ratio (SIR), revealed much higher rates for non-Hodgkin lymphoma. Individuals with AIDS exhibited an SIR of 261 (95% confidence interval [CI], 190–349) in the esophagus and 35.5 (95% CI, 31.9–39.5) in the stomach. The SIR for AIDS-associated carcinomas also revealed an increase SIR of 1.69 (95% CI, 1.37–2.07) for the esophagus and 1.44 (1.17–1.76) for the stomach. Although the results for both locations were significant, they were clearly lower than those for the lymphomas. In addition, the increase SIR for the carcinomas was only observed for patients who developed AIDS, and not for patients with HIV only. When the dataset was analyzed with respect to time, there was a significant decline in the incidence of non-Hodgkin lymphomas with the introduction of HAART, whereas the incidence of esophageal and gastric carcinomas showed no change (Figure 1). Considering the modestly increased SIR of HIV-associated carcinomas, the authors concluded that surveillance screening of all HIV patients is unlikely to be cost effective. In addition, the authors were not able to assess the impact of tobacco and alcohol on this dataset. Regardless, the dataset provided valuable insights into the effects of AIDS on the incidences of esophageal and gastric cancer, and the subsequent effects of HAART. See page 943. Similar Therapy But Different Regional Outcomes for HCV Infection!The burden of disease from hepatitis C virus (HCV) infection, as well as screening practices and access to therapy, varies considerably among countries. However, the impact of differences in access to treatment, for example, on morbidity and mortality from chronic HCV infection has not been studied. In this issue of Gastroenterology (accompanied by an editorial), Deuffic–Burban et al develop country-specific Markov models for 6 European countries—Belgium, France, Germany, Italy, Spain, and the United Kingdom—that take into account national characteristics such as epidemiologic patterns, natural history, and screening and treatment rates to predict the incidence of and mortality from HCV-related cirrhosis until 2021 for each country. The total number of patients with cirrhosis was predicted to peak in 2020 for Belgium, in 2021 for France, in 2023 for Germany (similar to that predicted in the United States), in 2030 for Spain, and in 2033 for the United Kingdom without treatment; in Italy, where the HCV epidemic wave occurred 20–30 years earlier than the other European countries, the peak was reached in 2008.From 2002 to 2011, pegylated interferon and ribavirin therapy reduced the cumulative incidence of cirrhosis by 7.1% and deaths by 3.4%, overall. Reductions in incidence of cirrhosis and deaths varied from 4% and 1.9%, respectively, in Italy to 16.3% and 9.0%, respectively, in France. The advent of protease inhibitor-based triple therapy was predicted to reduce, from 2012 to 2021, the cumulative incidence of cirrhosis by 17.7% and deaths by 9.7%, overall, assuming no change in screening or treatment practices in each country. Predicted reductions in incidence of cirrhosis and deaths varied from 10.1% and 5.4%, respectively, in Italy to 34.3% and 20.7%, respectively, in France. However, assuming that 75% of HCV-infected patients would be screened by 2015 and 50% of HCV genotype 1–infected patients would be treated with protease inhibitor-based therapy by 2015, the cumulative incidence of cirrhosis was predicted to be reduced by 27.4% and deaths by 15.0%, overall (Figure 2). Predicted reductions in incidence of cirrhosis and deaths again varied from 19.5% and 10.6%, respectively, in Italy to 36.7% and 22.5%, respectively, in France. Predictions based on the likelihood of new treatment regimens becoming available in 2017 demonstrated even greater reductions in the cumulative incidence of cirrhosis and death. These findings should help inform the development of public health policies for population-guided therapy.See page 974; editorial on page 887. The burden of disease from hepatitis C virus (HCV) infection, as well as screening practices and access to therapy, varies considerably among countries. However, the impact of differences in access to treatment, for example, on morbidity and mortality from chronic HCV infection has not been studied. In this issue of Gastroenterology (accompanied by an editorial), Deuffic–Burban et al develop country-specific Markov models for 6 European countries—Belgium, France, Germany, Italy, Spain, and the United Kingdom—that take into account national characteristics such as epidemiologic patterns, natural history, and screening and treatment rates to predict the incidence of and mortality from HCV-related cirrhosis until 2021 for each country. The total number of patients with cirrhosis was predicted to peak in 2020 for Belgium, in 2021 for France, in 2023 for Germany (similar to that predicted in the United States), in 2030 for Spain, and in 2033 for the United Kingdom without treatment; in Italy, where the HCV epidemic wave occurred 20–30 years earlier than the other European countries, the peak was reached in 2008. From 2002 to 2011, pegylated interferon and ribavirin therapy reduced the cumulative incidence of cirrhosis by 7.1% and deaths by 3.4%, overall. Reductions in incidence of cirrhosis and deaths varied from 4% and 1.9%, respectively, in Italy to 16.3% and 9.0%, respectively, in France. The advent of protease inhibitor-based triple therapy was predicted to reduce, from 2012 to 2021, the cumulative incidence of cirrhosis by 17.7% and deaths by 9.7%, overall, assuming no change in screening or treatment practices in each country. Predicted reductions in incidence of cirrhosis and deaths varied from 10.1% and 5.4%, respectively, in Italy to 34.3% and 20.7%, respectively, in France. However, assuming that 75% of HCV-infected patients would be screened by 2015 and 50% of HCV genotype 1–infected patients would be treated with protease inhibitor-based therapy by 2015, the cumulative incidence of cirrhosis was predicted to be reduced by 27.4% and deaths by 15.0%, overall (Figure 2). Predicted reductions in incidence of cirrhosis and deaths again varied from 19.5% and 10.6%, respectively, in Italy to 36.7% and 22.5%, respectively, in France. Predictions based on the likelihood of new treatment regimens becoming available in 2017 demonstrated even greater reductions in the cumulative incidence of cirrhosis and death. These findings should help inform the development of public health policies for population-guided therapy. See page 974; editorial on page 887. Can Activated Hepatic Stellate Cells Revert to Quiescence?In response to liver injury, hepatic stellate cells (HSCs) lose their characteristic vitamin A and lipid stores and are activated to myofibroblasts that produce the extracellular matrix scar in hepatic fibrosis. Reversal of hepatic fibrosis has been shown to be associated with a reduction in the number of myofibroblasts, mediated by enhanced apoptosis. Alternatively, activated HSCs may re-differentiate and revert to a quiescent state. In this issue of Gastroenterology (accompanied by an editorial), Troeger et al use 2 complementary approaches, single-cell quantitative polymerase chain reaction and genetic cell fate tracking, to investigate whether HSC deactivation represents an alternative mechanism for reversibility of hepatic fibrosis. Liver injury was induced with carbon tetrachloride (CCl4), thioacetamide, and bile duct ligation, standard animal models of fibrosis, in bacterial artificial chromosome-transgenic mice expressing a tamoxifen-inducible CreER driven by the endogenous promoter for vimentin, an intermediate filament predominantly expressed in HSCs, a model that allows HSCs to be identified and tracked during injury and recovery. Expression of fibrogenic genes, including collagen-α1(I) (Colla1) and -α2(I), α-smooth muscle actin, TIMP1, an inhibitor of enzymes involved in the degradation of the extracellular matrix, and lysyl oxidase, significantly increased in liver and in isolated HSCs (Figure 3) within 2 days and normalized by 15 days after CCl4 treatment.Single-cell polymerase chain reaction demonstrated that, based on Colla1 and TIMP1 gene expression, activation occurred in >90% of HSCs. Fibrogenic gene expression gradually and constantly decreased in almost all of the activated HSCs during the recovery period between day 2 and day 15 after CCl4 and thioacetamide treatment, suggesting activated HSCs that do not undergo apoptosis are HSCs undergoing deactivation. Similar findings were observed in the transgenic mice model, in which 40% of HSCs reverted to a quiescent state after CCl4-induced liver fibrosis. Furthermore, the location of HSCs changed from fibrotic septa to their characteristic perisinusoidal location during the recovery period. Of particular note, HSCs that reverted to a quiescent state after activation were more susceptible to reactivation in response to recurring fibrogenic stimuli. These novel findings are consistent with a role for both HSC apoptosis and deactivation in the reversal of liver fibrosis, although further studies are required to define the factors that determine whether an activated HSC undergoes apoptosis or reverts to a quiescent state with enhanced capacity to reactivate during repeated cycles of injury and whether these pathways can be therapeutically modified.See page 1073; editorial on page 890. In response to liver injury, hepatic stellate cells (HSCs) lose their characteristic vitamin A and lipid stores and are activated to myofibroblasts that produce the extracellular matrix scar in hepatic fibrosis. Reversal of hepatic fibrosis has been shown to be associated with a reduction in the number of myofibroblasts, mediated by enhanced apoptosis. Alternatively, activated HSCs may re-differentiate and revert to a quiescent state. In this issue of Gastroenterology (accompanied by an editorial), Troeger et al use 2 complementary approaches, single-cell quantitative polymerase chain reaction and genetic cell fate tracking, to investigate whether HSC deactivation represents an alternative mechanism for reversibility of hepatic fibrosis. Liver injury was induced with carbon tetrachloride (CCl4), thioacetamide, and bile duct ligation, standard animal models of fibrosis, in bacterial artificial chromosome-transgenic mice expressing a tamoxifen-inducible CreER driven by the endogenous promoter for vimentin, an intermediate filament predominantly expressed in HSCs, a model that allows HSCs to be identified and tracked during injury and recovery. Expression of fibrogenic genes, including collagen-α1(I) (Colla1) and -α2(I), α-smooth muscle actin, TIMP1, an inhibitor of enzymes involved in the degradation of the extracellular matrix, and lysyl oxidase, significantly increased in liver and in isolated HSCs (Figure 3) within 2 days and normalized by 15 days after CCl4 treatment. Single-cell polymerase chain reaction demonstrated that, based on Colla1 and TIMP1 gene expression, activation occurred in >90% of HSCs. Fibrogenic gene expression gradually and constantly decreased in almost all of the activated HSCs during the recovery period between day 2 and day 15 after CCl4 and thioacetamide treatment, suggesting activated HSCs that do not undergo apoptosis are HSCs undergoing deactivation. Similar findings were observed in the transgenic mice model, in which 40% of HSCs reverted to a quiescent state after CCl4-induced liver fibrosis. Furthermore, the location of HSCs changed from fibrotic septa to their characteristic perisinusoidal location during the recovery period. Of particular note, HSCs that reverted to a quiescent state after activation were more susceptible to reactivation in response to recurring fibrogenic stimuli. These novel findings are consistent with a role for both HSC apoptosis and deactivation in the reversal of liver fibrosis, although further studies are required to define the factors that determine whether an activated HSC undergoes apoptosis or reverts to a quiescent state with enhanced capacity to reactivate during repeated cycles of injury and whether these pathways can be therapeutically modified. See page 1073; editorial on page 890. Data to Guide the “Test and Treat Era” of Hepatitis CGastroenterologyVol. 143Issue 4PreviewHealth leaders around the world are facing critical questions regarding how to combat a rising tide of hepatitis C virus (HCV)-associated liver disease. Worldwide, an estimated 130–170 million persons are living with chronic HCV infection, and HCV causes 1 in 4 cases of cirrhosis and 170,000 deaths per year.1 Persons living with HCV are often unaware they are infected, reflecting the relatively asymptomatic nature of HCV infection until late in the course of disease and the often decades-long latency between acquisition of HCV and the development of end-stage liver disease and death. Full-Text PDF Standing Down the Guard: Stellate Cells Leave QuietlyGastroenterologyVol. 143Issue 4PreviewFibrosis of the liver, and its end stage, cirrhosis, represents a huge healthcare burden worldwide, and is increasing in incidence globally. The main causes of this rising tide of liver disease include viral hepatitis (hepatitis B and C), nonalcoholic steatohepatitis, and alcohol. Currently, our therapeutic repertoire for the treatment of liver fibrosis is severely limited and liver transplantation is the only effective treatment for end-stage fibrotic liver disease. However, liver transplantation has several disadvantages, including limited donor liver availability, comorbidities in potential recipients, high cost; in the global context, this procedure can only be offered to a small fraction of the patients suffering from the complications of liver fibrosis. Full-Text PDF RETRACTED: Increased Risk of Stomach and Esophageal Malignancies in People With AIDSGastroenterologyVol. 143Issue 4PreviewThis article has been retracted: please see Elsevier Policy on Article Withdrawal ( http://www.elsevier.com/locate/withdrawalpolicy ). This article has been retracted at the request of the Editor-in-Chief and Authors. The authors recently discovered two programming errors that affected the results in their article on the epidemiology of esophageal and stomach cancers in human immunodeficiency virus infected people. As a result of these errors, the standardized incidence ratios (SIRs) were too high. The corrected SIRs are all lower than the authors reported, and the corrected SIR for stomach cancer is no longer significantly elevated. Full-Text PDF Predicted Effects of Treatment for HCV Infection Vary Among European CountriesGastroenterologyVol. 143Issue 4PreviewThe dynamics of hepatitis C virus (HCV) infection, as well as screening practices and access to therapy, vary among European countries. It is important to determine the magnitude of the effects of such differences on incidence and mortality of infection. We compared the dynamics of infection and screening and treatment practices among Belgium, France, Germany, Italy, Spain, and the United Kingdom. We also assessed the effects of treatment with pegylated interferon and additional effects of triple therapy with protease inhibitors. Full-Text PDF Deactivation of Hepatic Stellate Cells During Liver Fibrosis Resolution in MiceGastroenterologyVol. 143Issue 4PreviewActivated hepatic stellate cells (HSCs), the main fibrogenic cell type in the liver, undergo apoptosis after cessation of liver injury, which contributes to resolution of fibrosis. In this study, we investigated whether HSC deactivation constitutes an additional mechanism of liver fibrosis resolution. Full-Text PDF Second Cancers and Residual Disease in Patients Treated for Gastric Mucosa-Associated Lymphoid Tissue Lymphoma by Helicobacter pylori Eradication and Followed for 10 YearsGastroenterologyVol. 143Issue 4PreviewCure of Helicobacter pylori infection induces remission in most patients with gastric mucosa-associated lymphoid tissue lymphoma (GML) that is associated with these bacteria. We determined the long-term outcomes of these patients in a prospective multicenter trial and investigated whether they developed second cancers or had histologic residual disease. Full-Text PDF