Inflammatory bowel disease(IBD), including Crohn's disease and ulcerative colitis, is a chronic intestinal inflammation of unknown etiology. The diagnosis of IBD is based on endoscopic, radiologic and histopatholo...Inflammatory bowel disease(IBD), including Crohn's disease and ulcerative colitis, is a chronic intestinal inflammation of unknown etiology. The diagnosis of IBD is based on endoscopic, radiologic and histopathologic criteria. Recently, the search for a noninvasive marker that could augment or replace part of this diagnostic process has become a focus of IBD research. In this review, antibody markers, including microbial antibodies, autoantibodies and peptide antibodies, will be described, focusing on their common features. At present, no single marker with qualities that are satisfactory for the diagnosis and treatment of IBD has been identified, although panels of some antibodies are being evaluated with keen interest. The discovery of novel IBD-specific and sensitive markers is anticipated. Such markers could minimize the use of endoscopic and radiologic examinations and could enable clinicians to implement individualized treatment plans designed to improve the long-term prognosis of patients with IBD.展开更多
AIM: To determine whether the endoscopic findings of depressed-type early gastric cancers(EGCs) could precisely predict the histological type.METHODS: Ninety depressed-type EGCs in 72 patients were macroscopically and...AIM: To determine whether the endoscopic findings of depressed-type early gastric cancers(EGCs) could precisely predict the histological type.METHODS: Ninety depressed-type EGCs in 72 patients were macroscopically and histologically identified. We evaluated the microvascular(MV) and mucosal surface(MS) patterns of depressed-type EGCs using magnifying endoscopy(ME) with narrow-band imaging(NBI)(NBI-ME) and ME enhanced by 1.5% acetic acid, respectively. First, depressed-type EGCs were classified according to MV pattern by NBI-ME. Subsequently, EGCs unclassified by MV pattern were classified according to MS pattern by enhanced ME(EME) images obtained from the same angle.RESULTS: We classified the depressed-type EGCs into the following 2 MV patterns using NBI-ME: a fine-network pattern that indicated differentiated adenocarcinoma(25/25, 100%) and a corkscrew pattern that likely indicated undifferentiated adenocarcinoma(18/23, 78.3%). However, 42 of the 90(46.7%) lesions could not be classified into MV patterns by NBI-ME. These unclassified lesions were then evaluated for MS patterns using EME, which classified 33(81.0%) lesions as MS patterns, diagnosed as differentiated adenocarcinoma. As a result, 76 of the 90(84.4%) lesions were matched with histological diagnoses using a combination of NBI-ME and EME.CONCLUSION: A combination of NBI-ME and EME was useful in predicting the histological type of depressedtype EGC.展开更多
To investigated characteristics, diagnosis, bowel-cleansing preparation, sedation, and colonoscope length and diameter in Japanese pediatric patients receiving total colonoscopy. METHODSThe present study evaluated con...To investigated characteristics, diagnosis, bowel-cleansing preparation, sedation, and colonoscope length and diameter in Japanese pediatric patients receiving total colonoscopy. METHODSThe present study evaluated consecutive patients aged ≤ 15 years who had undergone their first colonoscopy in Kurume University between January 2007 and February 2015. Data were retrospectively analyzed. We identified 110 pediatric patients who had undergone colonoscopy that had reached the cecum, allowing the observation of the total colon. RESULTSHematochezia, abdominal pain, and diarrhea were the most common symptoms. For bowel-cleansing preparation, pediatric patients aged ≤ 12 years were treated with magnesium citrate, and patients aged 13-15 years were treated with polyethylene glycol 4000. For sedation, thiamylal with pentazocine, which has an analgesic effect, was used in patients aged ≤ 6 years, and midazolam with pentazocine was used in patients aged ≥ 7 years. Regarding the choice of endoscope, short and thin endoscopes were selected for younger patients, particularly patients aged ≤ 3 years. Positive diagnoses were made in 78 patients (70.9%). Inflammatory bowel disease (n = 49, 44.5%), including ulcerative colitis (n = 37, 33.6%) and Crohn’s disease (n = 12, 10.9%), was the most common diagnosis. CONCLUSIONColonoscopy offers a high diagnostic capability for pediatric patients with gastrointestinal symptoms. The selection of appropriate management the performance of colonoscopy is important in pediatric patients.展开更多
AIM:To identify the characteristics of gastric tube cancer(GTC) and the complications associated with endoscopic submucosal dissection(ESD) for GTC.METHODS:Between 2007 and 2012,11 individualswith early gastric cancer...AIM:To identify the characteristics of gastric tube cancer(GTC) and the complications associated with endoscopic submucosal dissection(ESD) for GTC.METHODS:Between 2007 and 2012,11 individualswith early gastric cancer in the reconstructed gastric tube after esophagectomy who underwent ESD in this hospital were studied.The characteristics of GTC were identified,and the complications of ESD for GTC were analyzed at three phases:preoperative,intraoperative,and postoperative.RESULTS:A total of 11 consecutive patients with 11 GTCs were selected for this study.All cases underwent en bloc resections by ESD.The median procedure time was 142 min.The average GTC diameter was 26.1 mm,and the average size of the resected lesions was 45.5 mm.The histopathological diagnosis in all cases was a differentiated adenocarcinoma.In the preoperative phase,anastomotic strictures(5/11,45%) and food residues(4/11,36.4%) in the gastric tube were the main complications.In the intraoperative phase,bleeding was observed in 5 cases(45%).The postoperative complications observed were delayed bleeding in 2 cases(18.2%) and stenosis in one case(9.1%).The case with stenosis was successfully treated using endoscopic balloon dilatation.CONCLUSION:Minor complications were frequently observed.However,all GTCs underwent en bloc resection with ESD without any serious complications.ESD is considered a useful treatment for GTC.展开更多
AIM To determine the usefulness of assigning narrow-band imaging(NBI)scores for predicting tumor grade and invasion depth in colorectal tumors.METHODS A total of 161 colorectal lesions were analyzed from138 patients w...AIM To determine the usefulness of assigning narrow-band imaging(NBI)scores for predicting tumor grade and invasion depth in colorectal tumors.METHODS A total of 161 colorectal lesions were analyzed from138 patients who underwent endoscopic or surgical resection after conventional colonoscopy and magnifying endoscopy with NBI.The relationships between the surface and vascular patterns of the lesions,as visualized with NBI,and the tumor grade and depth of submucosa(SM)invasion were determined histopathologically.Scores were assigned to distinct features of the surface microstructures of tubular and papillary-type lesions.Using a multivariate analysis,a model was developed for predicting the tumor grade and depth of invasion based on NBI-finding scores.RESULTS NBI findings that correlated with a high tumor grade were associated with the"regular/irregular"(P<0.0001)surface patterns and the"avascular area"pattern(P=0.0600).The vascular patterns of"disrupted vessels"(P=0.0714)and"thick vessels"(P=0.0133)but none of the surface patterns were associated with a depth of invasion of≥1000μm.In our model,a total NBIfinding score≥1 was indicative of a high tumor grade(sensitivity:0.97;specificity:0.24),and a total NBIfinding score≥9(sensitivity:0.56;specificity:1.0)was predictive of a SM invasion depth≥1000μm.Scores less than these cutoff values signified adenomas and a SM invasion depth<1000μm,respectively.Associations were also noted between selected NBI findings and tumor tissue architecture and histopathology.CONCLUSION Our multivariate statistical model for predicting tumor grades and invasion depths from NBI-finding scores may help standardize the diagnosis of colorectal lesions and inform therapeutic strategies.展开更多
We review 6 cases of diaphragmatic perforation, with and without herniation, treated in our institution. All patients with diaphragmatic perforation underwent radiofrequency ablation(RFA) treatments for hepatocellular...We review 6 cases of diaphragmatic perforation, with and without herniation, treated in our institution. All patients with diaphragmatic perforation underwent radiofrequency ablation(RFA) treatments for hepatocellular carcinoma(HCC) performed at Kurume University Hospital and Tobata Kyoritsu Hospital. We investigated the clinical profiles of the 6 patients between January 2003 and December 2013. We further describe the clinical presentation, diagnosis, and treatment of diaphragmatic perforation. The change in the volume of liver and the change in the Child-Pugh score from just after the RFA to the onset of perforation was evaluated using a paired t-test. At the time of perforation, 4 patients had herniation of the viscera, while the other 2 patients had no herniation. The majority of ablated tumors were located adjacent to the diaphragm, in segments 4, 6, and 8. The average interval from RFA to the onset of perforation was 12.8 mo(range, 6-21 mo). The median Child-Pugh score at the onset of perforation(8.2) was significantly higher compared to the median Child-Pugh score just after RFA(6.5)(P = 0.031). All patients underwent laparotomy and direct suture of the diaphragm defect, with uneventful post-surgical recovery. Diaphragmatic perforation after RFA is not a matter that can be ignored. Clinicians should carefully address this complication by performing RFA for HCC adjacent to diaphragm.展开更多
AIM To elucidate the role of STAT3 in hepatocarcinogenesis and biliary ductular proliferation following chronic liver injury. METHODS We investigated thioacetamide(TAA)-induced liver injury, compensatory hepatocyte pr...AIM To elucidate the role of STAT3 in hepatocarcinogenesis and biliary ductular proliferation following chronic liver injury. METHODS We investigated thioacetamide(TAA)-induced liver injury, compensatory hepatocyte proliferation, and hepatocellular carcinoma(HCC) development in hepatic STAT3-deficient mice. In addition, we evaluated TAAinduced biliary ductular proliferation and analyzed the activation of sex determining region Y-box9(SOX9) and Yes-associated protein(YAP), which regulate the transdifferentiation of hepatocytes to cholangiocytes.RESULTS Both compensatory hepatocyte proliferation and HCC formation were significantly decreased in hepatic STAT3-deficient mice as compared with control mice. STAT3 deficiency resulted in augmentation of hepatic necrosis and fibrosis. On the other hand, biliary ductular proliferation increased in hepatic STAT3-deficient livers as compared with control livers. SOX9 and YAP were upregulated in hepatic STAT3-deficient hepatocytes.CONCLUSION STAT3 may regulate hepatocyte proliferation as well as transdifferentiation into cholangiocytes and serve as a therapeutic target for HCC inhibition and biliary regeneration.展开更多
Crohn's disease and ulcerative colitis are two important categories of human inflammatory bowel disease(IBD). Because the precise mechanisms of the inflammation and immune responses in IBD have not been fully eluc...Crohn's disease and ulcerative colitis are two important categories of human inflammatory bowel disease(IBD). Because the precise mechanisms of the inflammation and immune responses in IBD have not been fully elucidated,the treatment of IBD primarily aims to inhibit the pathogenic factors of the inflammatory cascade. Inconsistencies exist regarding the response and side effects of the drugs that are currently used to treat IBD. Recent studies have suggested that the use of nanomedicine might be advantageous for the treatment of intestinal inflammation because nanosized molecules can effectively penetrate epithelial and inflammatory cells. We reviewed nanomedicine treatments,such as the use of small interfering RNAs,antisense oligonucleotides,and anti-inflammatory molecules with delivery systems in experimental colitis models and clinical trials for IBD based on a systematic search. The efficacy and usefulness of the treatments reviewed in this manuscript have been demonstrated in experimental colitis models and clinical trials using various types of nanomedicine. Nanomedicine is expected to become a new therapeutic approach to the treatment of IBD.展开更多
Background:Antiangiogenic tyrosine kinase inhibitors(TKIs)provide one of the few therapeutic options for effective treatment of hepatocellular carcinoma(HCC).However,patients with HCC often develop resistance toward a...Background:Antiangiogenic tyrosine kinase inhibitors(TKIs)provide one of the few therapeutic options for effective treatment of hepatocellular carcinoma(HCC).However,patients with HCC often develop resistance toward antiangiogenic TKIs,and the underlying mechanisms are not understood.The aim of this study was to determine the mechanisms underlying antiangiogenic TKI resistance in HCC.Methods:We used an unbiased proteomic approach to define proteins that were responsible for the resistance to antiangiogenic TKIs in HCC patients.We evaluated the prognosis,therapeutic response,and serum insulin-like growth factor-binding protein-1(IGFBP-1)levels of 31 lenvatinib-treated HCC patients.Based on the array of results,a retrospective clinical study and preclinical experiments using mouse and human hepatoma cells were conducted.Additionally,in vivo genetic and pharmacological gain-and loss-of-function experiments were performed.Results:In the patient cohort,IGFBP-1 was identified as the signaling molecule with the highest expression that was inversely associated with overall survival.Mechanistically,antiangiogenic TKI treatment markedly elevated tumor IGFBP-1 levels via the hypoxia-hypoxia inducible factor signaling.IGFBP-1 stimulated angiogenesis through activation of the integrinα5β1-focal adhesion kinase pathway.Consequently,loss of IGFBP-1 and integrinα5β1 by genetic and pharmacological approaches re-sensitized HCC to lenvatinib treatment.Conclusions:Together,our data shed light onmechanisms underlying acquired resistance of HCC to antiangiogenic TKIs.Antiangiogenic TKIs induced an increase of tumor IGFBP-1,which promoted angiogenesis through activating the IGFBP-1-integrinα5β1 pathway.These data bolster the application of a new therapeutic concept by combining antiangiogenic TKIs with IGFBP-1 inhibitors.展开更多
Microvascular invasion(MVI)is an independent risk factor for early recurrence of hepatocellular carcinoma(HCC)after local treatment as well as poor prognosis in patients with HCC(1-3).MVI is an important factor for ma...Microvascular invasion(MVI)is an independent risk factor for early recurrence of hepatocellular carcinoma(HCC)after local treatment as well as poor prognosis in patients with HCC(1-3).MVI is an important factor for management of patients with HCC;however,MVI is based on a histopathological diagnosis using resected surgical specimens and is thus difficult to determine preoperatively.Recently,Lee et al.developed a new MVI risk score using the following 4 non-histological parameters:(I)alpha-fetoprotein(AFP);(II)protein induced by vitamin K absence-II(PIVKA-II);(III)arterial peritumoral enhancement on hepatobiliary phase of magnetic resonance imaging(MRI);(IV)peritumoral hypointensity on hepatobiliary phase of MRI(4).They also reported that,in HCC patients with MVI,the HCC recurrence rate was lower in patients treated with hepatic resection than with radiofrequency ablation(RFA)and proposed that patients with HCC who were at high risk of MVI should be treated with hepatic resection rather than RFA(4).This editorial summarizes the recent progress of the prediction method for MVI and discusses the therapeutic strategy for small HCC with MVI.展开更多
文摘Inflammatory bowel disease(IBD), including Crohn's disease and ulcerative colitis, is a chronic intestinal inflammation of unknown etiology. The diagnosis of IBD is based on endoscopic, radiologic and histopathologic criteria. Recently, the search for a noninvasive marker that could augment or replace part of this diagnostic process has become a focus of IBD research. In this review, antibody markers, including microbial antibodies, autoantibodies and peptide antibodies, will be described, focusing on their common features. At present, no single marker with qualities that are satisfactory for the diagnosis and treatment of IBD has been identified, although panels of some antibodies are being evaluated with keen interest. The discovery of novel IBD-specific and sensitive markers is anticipated. Such markers could minimize the use of endoscopic and radiologic examinations and could enable clinicians to implement individualized treatment plans designed to improve the long-term prognosis of patients with IBD.
文摘AIM: To determine whether the endoscopic findings of depressed-type early gastric cancers(EGCs) could precisely predict the histological type.METHODS: Ninety depressed-type EGCs in 72 patients were macroscopically and histologically identified. We evaluated the microvascular(MV) and mucosal surface(MS) patterns of depressed-type EGCs using magnifying endoscopy(ME) with narrow-band imaging(NBI)(NBI-ME) and ME enhanced by 1.5% acetic acid, respectively. First, depressed-type EGCs were classified according to MV pattern by NBI-ME. Subsequently, EGCs unclassified by MV pattern were classified according to MS pattern by enhanced ME(EME) images obtained from the same angle.RESULTS: We classified the depressed-type EGCs into the following 2 MV patterns using NBI-ME: a fine-network pattern that indicated differentiated adenocarcinoma(25/25, 100%) and a corkscrew pattern that likely indicated undifferentiated adenocarcinoma(18/23, 78.3%). However, 42 of the 90(46.7%) lesions could not be classified into MV patterns by NBI-ME. These unclassified lesions were then evaluated for MS patterns using EME, which classified 33(81.0%) lesions as MS patterns, diagnosed as differentiated adenocarcinoma. As a result, 76 of the 90(84.4%) lesions were matched with histological diagnoses using a combination of NBI-ME and EME.CONCLUSION: A combination of NBI-ME and EME was useful in predicting the histological type of depressedtype EGC.
文摘To investigated characteristics, diagnosis, bowel-cleansing preparation, sedation, and colonoscope length and diameter in Japanese pediatric patients receiving total colonoscopy. METHODSThe present study evaluated consecutive patients aged ≤ 15 years who had undergone their first colonoscopy in Kurume University between January 2007 and February 2015. Data were retrospectively analyzed. We identified 110 pediatric patients who had undergone colonoscopy that had reached the cecum, allowing the observation of the total colon. RESULTSHematochezia, abdominal pain, and diarrhea were the most common symptoms. For bowel-cleansing preparation, pediatric patients aged ≤ 12 years were treated with magnesium citrate, and patients aged 13-15 years were treated with polyethylene glycol 4000. For sedation, thiamylal with pentazocine, which has an analgesic effect, was used in patients aged ≤ 6 years, and midazolam with pentazocine was used in patients aged ≥ 7 years. Regarding the choice of endoscope, short and thin endoscopes were selected for younger patients, particularly patients aged ≤ 3 years. Positive diagnoses were made in 78 patients (70.9%). Inflammatory bowel disease (n = 49, 44.5%), including ulcerative colitis (n = 37, 33.6%) and Crohn’s disease (n = 12, 10.9%), was the most common diagnosis. CONCLUSIONColonoscopy offers a high diagnostic capability for pediatric patients with gastrointestinal symptoms. The selection of appropriate management the performance of colonoscopy is important in pediatric patients.
文摘AIM:To identify the characteristics of gastric tube cancer(GTC) and the complications associated with endoscopic submucosal dissection(ESD) for GTC.METHODS:Between 2007 and 2012,11 individualswith early gastric cancer in the reconstructed gastric tube after esophagectomy who underwent ESD in this hospital were studied.The characteristics of GTC were identified,and the complications of ESD for GTC were analyzed at three phases:preoperative,intraoperative,and postoperative.RESULTS:A total of 11 consecutive patients with 11 GTCs were selected for this study.All cases underwent en bloc resections by ESD.The median procedure time was 142 min.The average GTC diameter was 26.1 mm,and the average size of the resected lesions was 45.5 mm.The histopathological diagnosis in all cases was a differentiated adenocarcinoma.In the preoperative phase,anastomotic strictures(5/11,45%) and food residues(4/11,36.4%) in the gastric tube were the main complications.In the intraoperative phase,bleeding was observed in 5 cases(45%).The postoperative complications observed were delayed bleeding in 2 cases(18.2%) and stenosis in one case(9.1%).The case with stenosis was successfully treated using endoscopic balloon dilatation.CONCLUSION:Minor complications were frequently observed.However,all GTCs underwent en bloc resection with ESD without any serious complications.ESD is considered a useful treatment for GTC.
文摘AIM To determine the usefulness of assigning narrow-band imaging(NBI)scores for predicting tumor grade and invasion depth in colorectal tumors.METHODS A total of 161 colorectal lesions were analyzed from138 patients who underwent endoscopic or surgical resection after conventional colonoscopy and magnifying endoscopy with NBI.The relationships between the surface and vascular patterns of the lesions,as visualized with NBI,and the tumor grade and depth of submucosa(SM)invasion were determined histopathologically.Scores were assigned to distinct features of the surface microstructures of tubular and papillary-type lesions.Using a multivariate analysis,a model was developed for predicting the tumor grade and depth of invasion based on NBI-finding scores.RESULTS NBI findings that correlated with a high tumor grade were associated with the"regular/irregular"(P<0.0001)surface patterns and the"avascular area"pattern(P=0.0600).The vascular patterns of"disrupted vessels"(P=0.0714)and"thick vessels"(P=0.0133)but none of the surface patterns were associated with a depth of invasion of≥1000μm.In our model,a total NBIfinding score≥1 was indicative of a high tumor grade(sensitivity:0.97;specificity:0.24),and a total NBIfinding score≥9(sensitivity:0.56;specificity:1.0)was predictive of a SM invasion depth≥1000μm.Scores less than these cutoff values signified adenomas and a SM invasion depth<1000μm,respectively.Associations were also noted between selected NBI findings and tumor tissue architecture and histopathology.CONCLUSION Our multivariate statistical model for predicting tumor grades and invasion depths from NBI-finding scores may help standardize the diagnosis of colorectal lesions and inform therapeutic strategies.
文摘We review 6 cases of diaphragmatic perforation, with and without herniation, treated in our institution. All patients with diaphragmatic perforation underwent radiofrequency ablation(RFA) treatments for hepatocellular carcinoma(HCC) performed at Kurume University Hospital and Tobata Kyoritsu Hospital. We investigated the clinical profiles of the 6 patients between January 2003 and December 2013. We further describe the clinical presentation, diagnosis, and treatment of diaphragmatic perforation. The change in the volume of liver and the change in the Child-Pugh score from just after the RFA to the onset of perforation was evaluated using a paired t-test. At the time of perforation, 4 patients had herniation of the viscera, while the other 2 patients had no herniation. The majority of ablated tumors were located adjacent to the diaphragm, in segments 4, 6, and 8. The average interval from RFA to the onset of perforation was 12.8 mo(range, 6-21 mo). The median Child-Pugh score at the onset of perforation(8.2) was significantly higher compared to the median Child-Pugh score just after RFA(6.5)(P = 0.031). All patients underwent laparotomy and direct suture of the diaphragm defect, with uneventful post-surgical recovery. Diaphragmatic perforation after RFA is not a matter that can be ignored. Clinicians should carefully address this complication by performing RFA for HCC adjacent to diaphragm.
基金Supported by JSp S Grant-in-Aid for Scientific Research(C)No.16K09385 to Torimura T
文摘AIM To elucidate the role of STAT3 in hepatocarcinogenesis and biliary ductular proliferation following chronic liver injury. METHODS We investigated thioacetamide(TAA)-induced liver injury, compensatory hepatocyte proliferation, and hepatocellular carcinoma(HCC) development in hepatic STAT3-deficient mice. In addition, we evaluated TAAinduced biliary ductular proliferation and analyzed the activation of sex determining region Y-box9(SOX9) and Yes-associated protein(YAP), which regulate the transdifferentiation of hepatocytes to cholangiocytes.RESULTS Both compensatory hepatocyte proliferation and HCC formation were significantly decreased in hepatic STAT3-deficient mice as compared with control mice. STAT3 deficiency resulted in augmentation of hepatic necrosis and fibrosis. On the other hand, biliary ductular proliferation increased in hepatic STAT3-deficient livers as compared with control livers. SOX9 and YAP were upregulated in hepatic STAT3-deficient hepatocytes.CONCLUSION STAT3 may regulate hepatocyte proliferation as well as transdifferentiation into cholangiocytes and serve as a therapeutic target for HCC inhibition and biliary regeneration.
基金Supported by the Japanese Society for the Promotion of Science,KAKENHI Grant No.25460963
文摘Crohn's disease and ulcerative colitis are two important categories of human inflammatory bowel disease(IBD). Because the precise mechanisms of the inflammation and immune responses in IBD have not been fully elucidated,the treatment of IBD primarily aims to inhibit the pathogenic factors of the inflammatory cascade. Inconsistencies exist regarding the response and side effects of the drugs that are currently used to treat IBD. Recent studies have suggested that the use of nanomedicine might be advantageous for the treatment of intestinal inflammation because nanosized molecules can effectively penetrate epithelial and inflammatory cells. We reviewed nanomedicine treatments,such as the use of small interfering RNAs,antisense oligonucleotides,and anti-inflammatory molecules with delivery systems in experimental colitis models and clinical trials for IBD based on a systematic search. The efficacy and usefulness of the treatments reviewed in this manuscript have been demonstrated in experimental colitis models and clinical trials using various types of nanomedicine. Nanomedicine is expected to become a new therapeutic approach to the treatment of IBD.
基金Ishibashi Foundation for the Promotion of ScienceTakeda Science Foundation+3 种基金Shinnihon Foundation of Advanced Medical Treatment Researchthe Kurume University Branding Projectthe Yasuda Medical Foundationthe JSPS KAKENHI grant。
文摘Background:Antiangiogenic tyrosine kinase inhibitors(TKIs)provide one of the few therapeutic options for effective treatment of hepatocellular carcinoma(HCC).However,patients with HCC often develop resistance toward antiangiogenic TKIs,and the underlying mechanisms are not understood.The aim of this study was to determine the mechanisms underlying antiangiogenic TKI resistance in HCC.Methods:We used an unbiased proteomic approach to define proteins that were responsible for the resistance to antiangiogenic TKIs in HCC patients.We evaluated the prognosis,therapeutic response,and serum insulin-like growth factor-binding protein-1(IGFBP-1)levels of 31 lenvatinib-treated HCC patients.Based on the array of results,a retrospective clinical study and preclinical experiments using mouse and human hepatoma cells were conducted.Additionally,in vivo genetic and pharmacological gain-and loss-of-function experiments were performed.Results:In the patient cohort,IGFBP-1 was identified as the signaling molecule with the highest expression that was inversely associated with overall survival.Mechanistically,antiangiogenic TKI treatment markedly elevated tumor IGFBP-1 levels via the hypoxia-hypoxia inducible factor signaling.IGFBP-1 stimulated angiogenesis through activation of the integrinα5β1-focal adhesion kinase pathway.Consequently,loss of IGFBP-1 and integrinα5β1 by genetic and pharmacological approaches re-sensitized HCC to lenvatinib treatment.Conclusions:Together,our data shed light onmechanisms underlying acquired resistance of HCC to antiangiogenic TKIs.Antiangiogenic TKIs induced an increase of tumor IGFBP-1,which promoted angiogenesis through activating the IGFBP-1-integrinα5β1 pathway.These data bolster the application of a new therapeutic concept by combining antiangiogenic TKIs with IGFBP-1 inhibitors.
基金supported by AMED under Grant Number JP19fk0210040.
文摘Microvascular invasion(MVI)is an independent risk factor for early recurrence of hepatocellular carcinoma(HCC)after local treatment as well as poor prognosis in patients with HCC(1-3).MVI is an important factor for management of patients with HCC;however,MVI is based on a histopathological diagnosis using resected surgical specimens and is thus difficult to determine preoperatively.Recently,Lee et al.developed a new MVI risk score using the following 4 non-histological parameters:(I)alpha-fetoprotein(AFP);(II)protein induced by vitamin K absence-II(PIVKA-II);(III)arterial peritumoral enhancement on hepatobiliary phase of magnetic resonance imaging(MRI);(IV)peritumoral hypointensity on hepatobiliary phase of MRI(4).They also reported that,in HCC patients with MVI,the HCC recurrence rate was lower in patients treated with hepatic resection than with radiofrequency ablation(RFA)and proposed that patients with HCC who were at high risk of MVI should be treated with hepatic resection rather than RFA(4).This editorial summarizes the recent progress of the prediction method for MVI and discusses the therapeutic strategy for small HCC with MVI.
