We comment here on the article by Stefanolo et al entitled“Effect of Aspergillus niger prolyl endopeptidase in patients with celiac disease on a long-term gluten-free diet”,published in the World Journal of Gastroen...We comment here on the article by Stefanolo et al entitled“Effect of Aspergillus niger prolyl endopeptidase in patients with celiac disease on a long-term gluten-free diet”,published in the World Journal of Gastroenterology.Celiac disease is a well-recognized systemic autoimmune disorder.In genetically susceptible people,the most evident damage is located in the small intestine,and is caused and worsened by the ingestion of gluten.For that reason,celiac patients adopt a gluten-free diet(GFD),but it has some limitations,and it does not prevent re-exposure to gluten.Research aims to develop adjuvant therapies,and one of the most studied alternatives is supplementation with Aspergillus niger prolyl endopeptidase protease(AN-PEP),which is able to degrade gluten in the stomach,reducing its concentration in the small intestine.The study found a high adherence to the GFD,but did not address AN-PEP as a gluten immunogenic peptide reducer,as it was only tested in patients following a GFD and not in gluten-exposing conditions.This study opens up new research perspectives in this area and shows that further study is needed to clarify the points that are still in doubt.展开更多
To the Editor:Cholangiocarcinomas(CCAs)are heterogeneous group of malignancies,encompassing intrahepatic CCA(iCCA),and extrahepatic CCA(eCCA);they are also classified into common hepatic duct cholangiocarcinoma(CHDCCA...To the Editor:Cholangiocarcinomas(CCAs)are heterogeneous group of malignancies,encompassing intrahepatic CCA(iCCA),and extrahepatic CCA(eCCA);they are also classified into common hepatic duct cholangiocarcinoma(CHDCCA),choledocus extrapancreatic cholangiocarcinoma(EPCCA)and choledocus intrapancreatic cholangiocarcinoma(IPCCA)and,finally,gallbladder carcinoma(GBCCA).CCAs are relatively uncommon but.展开更多
Helicobacter pylori(H.pylori)infections may cause chronic gastritis,peptic ulcer disease,gastric cancers,and other conditions outside of the gastrointestinal tract.Hence,it is important to diagnose and treat it early....Helicobacter pylori(H.pylori)infections may cause chronic gastritis,peptic ulcer disease,gastric cancers,and other conditions outside of the gastrointestinal tract.Hence,it is important to diagnose and treat it early.H.pylori is resistant to certain drugs in traditional eradication therapy,so alternative therapy protocols are needed,such as high-dose amoxicillin dual therapy(HDADT).This article aims to comment on a recent paper by Costigan et al in the World Journal of Clinical Cases.In this study,the authors recruited 139 patients diagnosed with H.pylori,all treated with HDADT.Of these,93 were treatment-naïve and 46 had received at least one alternative treatment in the past.Four weeks after the end of the treatment,the urea breath test was administered to estimate the eradication rate.The total eradication rate was 56%(78/139),62%for the treatment-naïve arm and 43%for the previous treatment arm,thus indicating a lower success rate for the arm that had previously received a different treatment regimen.In conclusion,a therapeutic approach with first-line HDADT may potentially be a better treat-ment,but the results are not sufficient to recommend the use of this regimen in a country with high levels of dual resistance.展开更多
BACKGROUND Autopsy is a medical procedure that consists of the examination of the corpse to determine the cause of death and obtain information on pathological conditions or injuries.In recent years,there has been a r...BACKGROUND Autopsy is a medical procedure that consists of the examination of the corpse to determine the cause of death and obtain information on pathological conditions or injuries.In recent years,there has been a reduction in hospital autopsies and an increase in forensic autopsies.AIM To evaluate the utility of autopsy in the modern age and the discrepancy between clinical and autopsy diagnoses.METHODS A retrospective observational study was conducted on the reports of all 645 hospital autopsies performed at Polyclinic of Bari from 2006 to 2021.RESULTS Group A,2006-2009,174 cases were studied:58%male,58%adults,55%neonatology;pulmonary disease was the cause of death in 23%of cases;and there was a discrepancy between clinical and autopsy diagnosis in 55%of cases.Group B,2010-2013,119 cases:52%male,46%infants,48%neonatology;pulmonary disease was the cause of death in 25%of cases;and there was a discrepancy between clinical and autopsy diagnosis in 56%of cases.Group C,2014-2017,168 cases:sex equality,37%infants,25%gynecology;pulmonary disease was the cause of death in 24%of cases;and there was a discrepancy between clinical and autopsy diagnosis in 58%of cases.Group D,2018-2021,184 cases:56%male,38%adult,32%gynecology;pulmonary disease was the cause of death in 27%of cases;and there was a discrepancy between clinical and autopsy diagnosis in 58%of cases.CONCLUSION The study of hospital autopsies reveals a 56.75%discrepancy between clinical diagnosis and autopsy,highlighting the importance of autopsies,especially for fetal and neonatal diseases,which represent 59%of cases.展开更多
Enhanced osteoclastogenesis and osteoclast activity contribute to the development of osteoporosis,which is characterized by increased bone resorption and inadequate bone formation.As novel antiosteoporotic therapeutic...Enhanced osteoclastogenesis and osteoclast activity contribute to the development of osteoporosis,which is characterized by increased bone resorption and inadequate bone formation.As novel antiosteoporotic therapeutics are needed,understanding the genetic regulation of human osteoclastogenesis could help identify potential treatment targets.This study aimed to provide an overview of transcriptional reprogramming during human osteoclast differentiation.Osteoclasts were differentiated from CD14+monocytes from eight female donors.RNA sequencing during differentiation revealed 8980 differentially expressed genes grouped into eight temporal patterns conserved across donors.These patterns revealed distinct molecular functions associated with postmenopausal osteoporosis susceptibility genes based on RNA from iliac crest biopsies and bone mineral density SNPs.Network analyses revealed mutual dependencies between temporal expression patterns and provided insight into subtype-specific transcriptional networks.The donor-specific expression patterns revealed genes at the monocyte stage,such as filamin B(FLNB)and oxidized low-density lipoprotein receptor 1(OLR1,encoding LOX-1),that are predictive of the resorptive activity of mature osteoclasts.The expression of differentially expressed G-protein coupled receptors was strong during osteoclast differentiation,and these receptors are associated with bone mineral density SNPs,suggesting that they play a pivotal role in osteoclast differentiation and activity.The regulatory effects of three differentially expressed G-protein coupled receptors were exemplified by in vitro pharmacological modulation of complement 5 A receptor 1(C5AR1),somatostatin receptor 2(SSTR2),and free fatty acid receptor 4(FFAR4/GPR120).Activating C5AR1 enhanced osteoclast formation,while activating SSTR2 decreased the resorptive activity of mature osteoclasts,and activating FFAR4 decreased both the number and resorptive activity of mature osteoclasts.In conclusion,we report the occurrence of transcriptional reprogramming during human osteoclast differentiation and identified SSTR2 and FFAR4 as antiresorptive G-protein coupled receptors and FLNB and LOX-1 as potential molecular markers of osteoclast activity.These data can help future investigations identify molecular regulators of osteoclast differentiation and activity and provide the basis for novel antiosteoporotic targets.展开更多
BACKGROUND Several cutaneous manifestations such as urticarial rash,erythematous patches and chilblain-like lesions have been described in young adults with coronavirus disease 2019(COVID-19)and are present in up to 2...BACKGROUND Several cutaneous manifestations such as urticarial rash,erythematous patches and chilblain-like lesions have been described in young adults with coronavirus disease 2019(COVID-19)and are present in up to 20%patients,but few reports exist describing histopathological and immunophenotypic characteristics of dermatological lesions in older patients.Our aim was to characterize skin lesions in elderly patients during late stages of COVID-19 from clinical,histological and immunophenotypic perspectives.CASE SUMMARY Three patients,admitted for COVID-19,and who developed cutaneous manifestations underwent skin biopsies.Immunophenotypic analysis for CD20,CD3,CD4 and CD8 was performed on skin biopsies to assess immune cell infiltrates.CD1a was used as a marker of Langerhans cells,and CD31 as a marker of endothelial cells.In the three study patients,cutaneous manifestations were evident in the late-stage of COVID-19(mean time from the first positive severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)swab to rash onset was 35 d).Skin biopsies showed a similar pattern of T lymphocyte infiltration in all patients.Indeed,a chronic dermatitis with perivascular lymphocytic infiltrate was observed with predominance of CD3+T-cell(CD3+).CONCLUSION Our study confirms previous reports.Histological and immunophenotypic patterns in our patients confirm results described in the two previous reported experiences.This pattern is similar to what is found in some lympho-proliferative disorders.Therefore,since these findings are non-specific,SARS-CoV-2 infection should be suspected.展开更多
The human intestine is a natural environment ecosystem of a complex of diversified and dynamic microorganisms,determined through a process of competition and natural selection during life.Those intestinal microorganis...The human intestine is a natural environment ecosystem of a complex of diversified and dynamic microorganisms,determined through a process of competition and natural selection during life.Those intestinal microorganisms called microbiota and are involved in a variety of mechanisms of the organism,they interact with the host and therefore are in contact with the organs of the various systems.However,they play a crucial role in maintaining host homeostasis,also influencing its behaviour.Thus,microorganisms perform a series of biological functions important for human well-being.The host provides the microorganisms with the environment and nutrients,simultaneously drawing many benefits such as their contribution to metabolic,trophic,immunological,and other functions.For these reasons it has been reported that its quantitative and qualitative composition can play a protective or harmful role on the host health.Therefore,a dysbiosis can lead to an association of unfavourable factors which lead to a dysregulation of the physiological processes of homeostasis.Thus,it has previously noted that the gut microbiota can participate in the pathogenesis of autoimmune diseases,chronic intestinal inflammation,diabetes mellitus,obesity and atherosclerosis,neurological disorders(e.g.,neurological diseases,autism,etc.)colorectal cancer,and more.展开更多
The most recent discoveries in the biochemical field are highlighting the increasingly important role of lipid droplets(LDs)in several regulatory mechanisms in living cells.LDs are dynamic organelles and therefore the...The most recent discoveries in the biochemical field are highlighting the increasingly important role of lipid droplets(LDs)in several regulatory mechanisms in living cells.LDs are dynamic organelles and therefore their complete characterization in terms of number,size,spatial positioning and relative distribution in the cell volume can shed light on the roles played by LDs.Until now,fluorescence microscopy and transmission electron microscopy are assessed as the gold standard methods for identifying LDs due to their high sensitivity and specificity.However,such methods generally only provide 2D assays and partial measurements.Furthermore,both can be destructive and with low productivity,thus limiting analysis of large cell numbers in a sample.Here we demonstrate for the first time the capability of 3D visualization and the full LD characterization in high-throughput with a tomographic phase-contrast flow-cytometer,by using ovarian cancer cells and monocyte cell lines as models.A strategy for retrieving significant parameters on spatial correlations and LD 3D positioning inside each cell volume is reported.The information gathered by this new method could allow more in depth understanding and lead to new discoveries on how LDs are correlated to cellular functions.展开更多
Background: Homocysteine is an important non-protein amino acid, very useful in all methylation reactions occurring in the body as the precursor of the sole methyl group donor S-Adenosyl-methionine (SAM). However, ele...Background: Homocysteine is an important non-protein amino acid, very useful in all methylation reactions occurring in the body as the precursor of the sole methyl group donor S-Adenosyl-methionine (SAM). However, elevated plasma homocysteine levels have been reported to contribute to epithelial damage leading to coronary artery disease and other metabolic syndromes. This study was aimed at evaluating the concentration of plasma homocysteine in diabetics and hypertensive patients in Port Harcourt, Nigeria. Methods: The study population included 60 Type II diabetes mellitus and Hypertensivesubjectsas group (I), 60 Type II diabetes mellitus and Normotensive subjects as group (II), 60 Hypertensive subjects as group (III), and 60 healthy subjects as control group within the age range of 30 - 70 years. An enzyme-linked immunosorbent assay (ELISA) method was used to quantitatively measure homocysteine in the serum sample, glycated haemoglobin were determined quantitatively using sandwich immunodetection and blood pressure was determined using mercury sphygnanometer. Statistics: The statistical analysis was done using GraphPad Prism version 9.4.1, and statistical significance was determined by a P Results: The results showed significantly higher plasma homocysteine levels in diabetics and hypertensive comorbidity patients when compared to healthy controls, P Conclusion: Our result shows an increase in plasma homocysteine levels in diabetics and hypertensives when compared to controls, and comorbidity instigates a higher increase in plasma levels when compared with the single morbidity.展开更多
Insulin resistance increases the risk of developing diabetes,and the degree of resistance influences the glycemic control of patients with diabetes.Numerous researchers have focused on improving insulin sensitivity in...Insulin resistance increases the risk of developing diabetes,and the degree of resistance influences the glycemic control of patients with diabetes.Numerous researchers have focused on improving insulin sensitivity in order to prevent diabetes-related complications and other chronic diseases.Several studies have also linked vitamin D levels to insulin secretion and resistance,given that both vitamin D and its receptor complex play important roles in regulating pancreaticβ-cells.It has been suggested that vitamin D supplementation improves vitamin D levels,but further research is needed to confirm this as neither insulin function nor glycemic control improves when vitamin D levels increase.Magnesium is a cofactor for many enzymes.Although the role of magnesium in the management of diabetes has long been evaluated,it has not yet been determined whether magnesium supplements improve insulin function.However,several researchers have found that patients with good glycemic control have high magnesium levels.Magnesium is closely related to vitamin D and is necessary for the transport and activation of vitamin D in humans.Combined supplementation with vitamin D and magnesium improves glycemic control in patients with diabetes.展开更多
Aim: To evaluate chronic exposure of carmoisine at ADI doses on some hepatocellular and renal parameters of male and female albino rats as well as to determine sex-dependent toxicity. Study Design: The study involves ...Aim: To evaluate chronic exposure of carmoisine at ADI doses on some hepatocellular and renal parameters of male and female albino rats as well as to determine sex-dependent toxicity. Study Design: The study involves treatment for 30, 60, and 90 days. Each phase consists of 40 rats, divided into treatment and control groups. The treated groups were orally administered with 4.0 mg/kg of carmoisine daily for the periods of 30, 60, and 90 days. Methodology: At the end of the treatment, the rats were allowed to fast for 18 hours followed by the collection of 5 ml of whole blood specimens by means of cardiac puncture into Lithium Heparin bottles and fluoride oxalate bottles (for glucose only). Plasma obtained was analyzed for glucose (GLU), AST, ALT, ALP, creatinine (CRT), and urea. Hepatic and Renal tissues collected were fixed in 10% formol saline and later examined histologically using H&E stain. Statistical data analysis was done using GraphPad Prism version 9.02. Results: Glucose indicated significant increases after 30, 60, and 90 days of chronic treatment at ADI doses. Urea, Creatinine, AST, ALT and ALP showed significantly higher values after 60 and 90 days of treatment (except creatinine in male rats and ALP in female rats after 60 and 90 days respectively). Hepatic distortions, vacuolation, compression of central vein were seen in the liver section while distortion of proximal and distal tubules, and inflammation of the glomerulus were observed in the renal tissue of the treated rats. Conclusion: The administration of camoisine over a period of 30 days at ADI dose did not indicate hepatocellullar and renal derangements as well histological distortions in liver, and kidneys. However, after 60 and 90 days, mild hepatocellular, and renal derangements were seen. No sex-dependent toxicity was observed.展开更多
Neoplasms can be considered as a group of aberrant cells that need more vascular supply to fulfill all their functions.Therefore,they promote angiogenesis through the same neovascularization pathway used physiological...Neoplasms can be considered as a group of aberrant cells that need more vascular supply to fulfill all their functions.Therefore,they promote angiogenesis through the same neovascularization pathway used physiologically.Angiogenesis is a process characterized by a heterogeneous distribution of oxygen caused by the tumor and oxidative stress;the latter being one of the most powerful stimuli of angiogenesis.As a result of altered tumor metabolism due to hypoxia,acidosis occurs.The angiogenic process and oxidative stress can be detected by measuring serum and tissue biomarkers.The study of the mechanisms underlying angiogenesis and oxidative stress could lead to the identification of new biomarkers,ameliorating the selection of patients with neoplasms and the prediction of their response to possible anti-tumor therapies.In particular,in the treatment of patients with similar clinical tumor phenotypes but different prognoses,the new biomarkers could be useful.Moreover,they may lead to a better understanding of the mechanisms underlying drug resistance.Experimental studies show that blocking the vascular supply results in antiproliferative activity in vivo in neuroendocrine tumor cells,which require a high vascular supply.展开更多
Acinar cell carcinoma(ACC)is a rare malignant epithelial neoplasm accounting for 1%-2%of all pancreatic exocrine neoplasm,affecting more frequently man with an age between 50 and 70 years.Most patients present with no...Acinar cell carcinoma(ACC)is a rare malignant epithelial neoplasm accounting for 1%-2%of all pancreatic exocrine neoplasm,affecting more frequently man with an age between 50 and 70 years.Most patients present with nonspecific symptoms,which may give rise to difficulties in clinical diagnosis[1].ACC can manifest with diarrhea,weight loss,abdominal pain and,in up to 10%-15%,with lipase hypersecretion syndrome,characterized by elevated lipase production,diffuse subcutaneous fat necrosis and polyarthralgia[1,2].Biliary obstruction and jaundice are infre-quent clinical manifestations,unlike ductal adenocarcinoma,due to pushing rather than infiltrating growth of ACC.展开更多
AIM： To evaluate the diagnostic accuracy of endoscopic ultrasound-guided fine-needle aspiration （EUS-FNA） for pancreatic solid tumors larger or smaller than 3 cm, and cystic lesions.METHODS： From January/1997 to D...AIM： To evaluate the diagnostic accuracy of endoscopic ultrasound-guided fine-needle aspiration （EUS-FNA） for pancreatic solid tumors larger or smaller than 3 cm, and cystic lesions.METHODS： From January/1997 to December/2006, 611 patients with pancreatic tumors were subjected to EUSFNA. The final diagnosis was obtained either by surgery （356 cases） or after a mean clinical follow-up of 11.8 mo in the remaining patients.RESULTS： There were 405 solid tumors, 189 cystic lesions and 17 mixed. Pancreatic specimens for cytological assessment were successfully obtained by EUS-FNA in 595 （97.4%） cases. There were 352 （57.6%） malignancies and 259 （42.4%） benign tumors. Among the malignancies, pancreatic adenocarcinomas accounted for 67% of the lesions. Overall, the sensitivity, specificity, positive and negative predictive values, and accuracy of EUS-FNA were, respectively, 78.4%, 99.2%, 99.3%, 77.2% and 87.2%. Specifically for solid tumors, the same parameters for neoplasms larger and smaller than 3 cm were, respectively, 78.8% ys 82.4%, 100% ys 98.4%, 100% vs 99%, 54.8% vs 74.1% and 83.1% vs 87.8%. For cystic lesions, the values were, respectively, 72.2%, 99.3%, 97.5%, 91% and 92.2%.CONCLUSION： EUS-FNA can be used to sample pancreatic tumors in most patients. Even though the negative predictive value is inadequate for large solid tumors, the results are rather good for small solid tumors, especially concerning the sensitivity, negative predictive value and diagnostic accuracy. Among all pancreatic lesions, EUS-FNA for cystic lesions can reveal the best negative predictive value and diagnostic accuracy, both higher than 90%.展开更多
Ulcerative colitis(UC), a chronic, relapsing, remitting disease of the colon and rectum, is characterized by inflammatory ulceration of the mucosa. Current UC therapy relies on controlling acute episodes and preventin...Ulcerative colitis(UC), a chronic, relapsing, remitting disease of the colon and rectum, is characterized by inflammatory ulceration of the mucosa. Current UC therapy relies on controlling acute episodes and preventing relapse. To predict modifications in the natural course of UC, mucosal healing(MH) has emerged as a major treatment goal. Endoscopic evaluation is considered the gold standard for assessing MH, which can be achieved by conventional drugs and biologics in many, but not all, patients. Consequently, interest is focusing on the development of new substances for UC therapy, and new oral agents are in the pipeline. This review will focus on the ability of newly developed oral drugs to induce and maintain MH in UC patients.展开更多
HER2 is overexpressed in approximately 10%-20% of gastric and gastroesophageal junction carcinomas. In these types of cancer, accurate assessment of HER2 status is mandatory, for selecting patients who may benefit fro...HER2 is overexpressed in approximately 10%-20% of gastric and gastroesophageal junction carcinomas. In these types of cancer, accurate assessment of HER2 status is mandatory, for selecting patients who may benefit from targeted therapies with anti-HER2 drugs such as Trastuzumab. This manuscript focuses on HER2 in gastric carcinogenesis, on optimal evaluation of HER2 and on the possible causes which may contribute to inaccurate HER2 evaluation. Similarly to breast cancer HER2 evaluation, standardization of HER2 testing in gastric cancer is necessary in diagnostic practice. The three principle aspects which require consideration are:(1) the choice of sample with regards to cancer morphology- intestinal vs diffuse areas;(2) the choice of scoring criteria- use of HER2 scoring criteria specific for gastric cancer; and(3) the choice of HER2 evaluation methods- use of an algorithm in which both immunohistochemistry and in situ hybridization play a role. Problematic issues include:(1) pre-analytic variables with particular emphasis on fixation;(2) recommended methodology for HER2 assessment(immunohistochemistry vs in situ hybridization);(3) HER2 heterogeneity both within the primary tumor and between primary tumor and metastases;(4) reliability of biopsies in HER 2 evaluation; and(5) quantity of sample(FFPE blocks from surgical specimens or endoscopic biopsies) necessary for an adequate assessment.展开更多
Objective： To investigate the role of apparent diffusion coefficient （ADC） from diffusion-weighted magnetic resonance imaging （DW-MRI） when applied to the 7th TNM classification in the staging and prognosis of ga...Objective： To investigate the role of apparent diffusion coefficient （ADC） from diffusion-weighted magnetic resonance imaging （DW-MRI） when applied to the 7th TNM classification in the staging and prognosis of gastric cancer （GC）. Methods： Between October 2009 and May 2014, a total of 89 patients with non-metastatic, biopsy proven GC underwent 1.5T DW-MRI, and then treated with radical surgery. Tumor ADC was measured retrospectively and compared with final histology following the 7th TNM staging （local invasion, nodal involvement and according to the different groups -- stage Ⅰ, Ⅱ and Ⅲ）. Kaplan-Meier curves were also generated. The follow-up period is updated to May 2016. Results： Median follow-up period was 33 months and 45/89 （51%） deaths from GC were observed. ADC was significantly different both for local invasion and nodal involvement （P〈0.001）. Considering final histology as the reference standard, a preoperative ADC cut-offof 1.80×10-3 mm^2/s could distinguish between stages I and Ⅱ and an ADC value of ≤1.36-10-3 mm^2/s was associated with stage Ⅲ（P〈0.001）. Kaplan-Meier curves demonstrated that the survival rates for the three prognostic groups were significantly different according to final histology and ADC cut-offs （P〈0.001）. Conclusions： ADC is different according to local invasion, nodal involvement and the 7th TNM stage groups for GC, representing a potential, additional prognostic biomarker. The addition of DW-MRI could aid in the staging and risk stratification of GC.展开更多
The biosynthesis of prostaglandins and thromboxanes has been a focus of interest in the management of many liver diseases.Cyclooxygenases are the enzymes involved in the first step of the biosynthesis of these lipid m...The biosynthesis of prostaglandins and thromboxanes has been a focus of interest in the management of many liver diseases.Cyclooxygenases are the enzymes involved in the first step of the biosynthesis of these lipid mediators and selective inhibitors for these isoenzymes as well as pharmacological analogues of prostaglandins have been developed and are currently applied therapeutically.Here we discuss the implications of these enzymes in the onset of metabolic and lipid disorders in the liver and their potential role in the progression of the diseases towards fibrosis and hepatocellular carcinogenesis.展开更多
Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. To date, most patients with HCC are diagnosed at an advanced tumor stage, excluding them from potentially curative therapies (i.e., re...Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. To date, most patients with HCC are diagnosed at an advanced tumor stage, excluding them from potentially curative therapies (i.e., resection, liver transplantation, percutaneous ablation). Treatments with palliative intent include chemoembolization and systemic therapy. Among systemic treatments, the small-molecule multikinase inhibitor sorafenib has been the only systemic treatment available for advanced HCC over 10 years. More recently, other smallmolecule multikinase inhibitors (e.g., regorafenib, lenvatinib, cabozantinib) have been approved for HCC treatment. The promising immune checkpoint inhibitors (e.g., nivolumab, pembrolizumab) are still under investigation in Europe while in the US nivolumab has already been approved by FDA in sorafenib refractory or resistant patients. Other molecules, such as the selective CDK4/6inhibitors (e.g., palbociclib, ribociclib), are in earlier stages of clinical development, and the c- MET inhibitor tivantinib did not show positive results in a phase III study. However, even if the introduction of targeted agents has led to great advances in patient response and survival with an acceptable toxicity profile, a remarkable inter-individual heterogeneity in therapy outcome persists and constitutes a significant problem in disease management. Thus, the identification of biomarkers that predict which patients will benefit from a specific intervention could significantly affect decision-making and therapy planning. Germ-line variants have been suggested to play an important role in determining outcomes of HCC systemic therapy in terms of both toxicity and treatment efficacy. Particularly, a number of studies have focused on the role of genetic polymorphisms impacting the drug metabolic pathway and membrane translocation as well as the drug mechanism of action as predictive/prognostic markers of HCC treatment. The aim of this review is to summarize and critically discuss the pharmacogenetic literature evidences, with particular attention to sorafenib and regorafenib, which have been used longer than the others in HCC treatment.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
文摘We comment here on the article by Stefanolo et al entitled“Effect of Aspergillus niger prolyl endopeptidase in patients with celiac disease on a long-term gluten-free diet”,published in the World Journal of Gastroenterology.Celiac disease is a well-recognized systemic autoimmune disorder.In genetically susceptible people,the most evident damage is located in the small intestine,and is caused and worsened by the ingestion of gluten.For that reason,celiac patients adopt a gluten-free diet(GFD),but it has some limitations,and it does not prevent re-exposure to gluten.Research aims to develop adjuvant therapies,and one of the most studied alternatives is supplementation with Aspergillus niger prolyl endopeptidase protease(AN-PEP),which is able to degrade gluten in the stomach,reducing its concentration in the small intestine.The study found a high adherence to the GFD,but did not address AN-PEP as a gluten immunogenic peptide reducer,as it was only tested in patients following a GFD and not in gluten-exposing conditions.This study opens up new research perspectives in this area and shows that further study is needed to clarify the points that are still in doubt.
基金This study was supported by a grant from the Italian Ministry of Health,Ricerca Corrente Program 2016-2018 to Paola Parente.
文摘To the Editor:Cholangiocarcinomas(CCAs)are heterogeneous group of malignancies,encompassing intrahepatic CCA(iCCA),and extrahepatic CCA(eCCA);they are also classified into common hepatic duct cholangiocarcinoma(CHDCCA),choledocus extrapancreatic cholangiocarcinoma(EPCCA)and choledocus intrapancreatic cholangiocarcinoma(IPCCA)and,finally,gallbladder carcinoma(GBCCA).CCAs are relatively uncommon but.
文摘Helicobacter pylori(H.pylori)infections may cause chronic gastritis,peptic ulcer disease,gastric cancers,and other conditions outside of the gastrointestinal tract.Hence,it is important to diagnose and treat it early.H.pylori is resistant to certain drugs in traditional eradication therapy,so alternative therapy protocols are needed,such as high-dose amoxicillin dual therapy(HDADT).This article aims to comment on a recent paper by Costigan et al in the World Journal of Clinical Cases.In this study,the authors recruited 139 patients diagnosed with H.pylori,all treated with HDADT.Of these,93 were treatment-naïve and 46 had received at least one alternative treatment in the past.Four weeks after the end of the treatment,the urea breath test was administered to estimate the eradication rate.The total eradication rate was 56%(78/139),62%for the treatment-naïve arm and 43%for the previous treatment arm,thus indicating a lower success rate for the arm that had previously received a different treatment regimen.In conclusion,a therapeutic approach with first-line HDADT may potentially be a better treat-ment,but the results are not sufficient to recommend the use of this regimen in a country with high levels of dual resistance.
文摘BACKGROUND Autopsy is a medical procedure that consists of the examination of the corpse to determine the cause of death and obtain information on pathological conditions or injuries.In recent years,there has been a reduction in hospital autopsies and an increase in forensic autopsies.AIM To evaluate the utility of autopsy in the modern age and the discrepancy between clinical and autopsy diagnoses.METHODS A retrospective observational study was conducted on the reports of all 645 hospital autopsies performed at Polyclinic of Bari from 2006 to 2021.RESULTS Group A,2006-2009,174 cases were studied:58%male,58%adults,55%neonatology;pulmonary disease was the cause of death in 23%of cases;and there was a discrepancy between clinical and autopsy diagnosis in 55%of cases.Group B,2010-2013,119 cases:52%male,46%infants,48%neonatology;pulmonary disease was the cause of death in 25%of cases;and there was a discrepancy between clinical and autopsy diagnosis in 56%of cases.Group C,2014-2017,168 cases:sex equality,37%infants,25%gynecology;pulmonary disease was the cause of death in 24%of cases;and there was a discrepancy between clinical and autopsy diagnosis in 58%of cases.Group D,2018-2021,184 cases:56%male,38%adult,32%gynecology;pulmonary disease was the cause of death in 27%of cases;and there was a discrepancy between clinical and autopsy diagnosis in 58%of cases.CONCLUSION The study of hospital autopsies reveals a 56.75%discrepancy between clinical diagnosis and autopsy,highlighting the importance of autopsies,especially for fetal and neonatal diseases,which represent 59%of cases.
基金funded by grants from the Novo Nordisk Foundation (NNF18OC0052699) (M.S.H.) and NNF18OC0055047 (M.F.)the Region of Southern Denmark (ref: 18/17553 (M.S.H.))+3 种基金Odense University Hospital (ref: A3147) (M.F.)a faculty fellowship from the University of Southern Denmark (K.M.), the Lundbeck Foundation (ref: R335-2019-2195) (K.M.and A.R.)an Academy of Medical Sciences Springboard Award supported by the British Heart Foundation, Diabetes UK, the Global Challenges Research Fund, the Government Department of Business, Energy and Industrial Strategy and the Wellcome Trust (ref: SBF004 | 1034, C.M.G)a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 224155/Z/21/Z to C.M.G.).
文摘Enhanced osteoclastogenesis and osteoclast activity contribute to the development of osteoporosis,which is characterized by increased bone resorption and inadequate bone formation.As novel antiosteoporotic therapeutics are needed,understanding the genetic regulation of human osteoclastogenesis could help identify potential treatment targets.This study aimed to provide an overview of transcriptional reprogramming during human osteoclast differentiation.Osteoclasts were differentiated from CD14+monocytes from eight female donors.RNA sequencing during differentiation revealed 8980 differentially expressed genes grouped into eight temporal patterns conserved across donors.These patterns revealed distinct molecular functions associated with postmenopausal osteoporosis susceptibility genes based on RNA from iliac crest biopsies and bone mineral density SNPs.Network analyses revealed mutual dependencies between temporal expression patterns and provided insight into subtype-specific transcriptional networks.The donor-specific expression patterns revealed genes at the monocyte stage,such as filamin B(FLNB)and oxidized low-density lipoprotein receptor 1(OLR1,encoding LOX-1),that are predictive of the resorptive activity of mature osteoclasts.The expression of differentially expressed G-protein coupled receptors was strong during osteoclast differentiation,and these receptors are associated with bone mineral density SNPs,suggesting that they play a pivotal role in osteoclast differentiation and activity.The regulatory effects of three differentially expressed G-protein coupled receptors were exemplified by in vitro pharmacological modulation of complement 5 A receptor 1(C5AR1),somatostatin receptor 2(SSTR2),and free fatty acid receptor 4(FFAR4/GPR120).Activating C5AR1 enhanced osteoclast formation,while activating SSTR2 decreased the resorptive activity of mature osteoclasts,and activating FFAR4 decreased both the number and resorptive activity of mature osteoclasts.In conclusion,we report the occurrence of transcriptional reprogramming during human osteoclast differentiation and identified SSTR2 and FFAR4 as antiresorptive G-protein coupled receptors and FLNB and LOX-1 as potential molecular markers of osteoclast activity.These data can help future investigations identify molecular regulators of osteoclast differentiation and activity and provide the basis for novel antiosteoporotic targets.
文摘BACKGROUND Several cutaneous manifestations such as urticarial rash,erythematous patches and chilblain-like lesions have been described in young adults with coronavirus disease 2019(COVID-19)and are present in up to 20%patients,but few reports exist describing histopathological and immunophenotypic characteristics of dermatological lesions in older patients.Our aim was to characterize skin lesions in elderly patients during late stages of COVID-19 from clinical,histological and immunophenotypic perspectives.CASE SUMMARY Three patients,admitted for COVID-19,and who developed cutaneous manifestations underwent skin biopsies.Immunophenotypic analysis for CD20,CD3,CD4 and CD8 was performed on skin biopsies to assess immune cell infiltrates.CD1a was used as a marker of Langerhans cells,and CD31 as a marker of endothelial cells.In the three study patients,cutaneous manifestations were evident in the late-stage of COVID-19(mean time from the first positive severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)swab to rash onset was 35 d).Skin biopsies showed a similar pattern of T lymphocyte infiltration in all patients.Indeed,a chronic dermatitis with perivascular lymphocytic infiltrate was observed with predominance of CD3+T-cell(CD3+).CONCLUSION Our study confirms previous reports.Histological and immunophenotypic patterns in our patients confirm results described in the two previous reported experiences.This pattern is similar to what is found in some lympho-proliferative disorders.Therefore,since these findings are non-specific,SARS-CoV-2 infection should be suspected.
文摘The human intestine is a natural environment ecosystem of a complex of diversified and dynamic microorganisms,determined through a process of competition and natural selection during life.Those intestinal microorganisms called microbiota and are involved in a variety of mechanisms of the organism,they interact with the host and therefore are in contact with the organs of the various systems.However,they play a crucial role in maintaining host homeostasis,also influencing its behaviour.Thus,microorganisms perform a series of biological functions important for human well-being.The host provides the microorganisms with the environment and nutrients,simultaneously drawing many benefits such as their contribution to metabolic,trophic,immunological,and other functions.For these reasons it has been reported that its quantitative and qualitative composition can play a protective or harmful role on the host health.Therefore,a dysbiosis can lead to an association of unfavourable factors which lead to a dysregulation of the physiological processes of homeostasis.Thus,it has previously noted that the gut microbiota can participate in the pathogenesis of autoimmune diseases,chronic intestinal inflammation,diabetes mellitus,obesity and atherosclerosis,neurological disorders(e.g.,neurological diseases,autism,etc.)colorectal cancer,and more.
基金funded by the Italian Ministry of University and Research(PRIN 2017-Prot.2017N7R2CJ)Fondazione Cassa di Risparmio in Bologna(Italy)for the financial support to I.K.finalized to the acquisition of EVOS M5000。
文摘The most recent discoveries in the biochemical field are highlighting the increasingly important role of lipid droplets(LDs)in several regulatory mechanisms in living cells.LDs are dynamic organelles and therefore their complete characterization in terms of number,size,spatial positioning and relative distribution in the cell volume can shed light on the roles played by LDs.Until now,fluorescence microscopy and transmission electron microscopy are assessed as the gold standard methods for identifying LDs due to their high sensitivity and specificity.However,such methods generally only provide 2D assays and partial measurements.Furthermore,both can be destructive and with low productivity,thus limiting analysis of large cell numbers in a sample.Here we demonstrate for the first time the capability of 3D visualization and the full LD characterization in high-throughput with a tomographic phase-contrast flow-cytometer,by using ovarian cancer cells and monocyte cell lines as models.A strategy for retrieving significant parameters on spatial correlations and LD 3D positioning inside each cell volume is reported.The information gathered by this new method could allow more in depth understanding and lead to new discoveries on how LDs are correlated to cellular functions.
文摘Background: Homocysteine is an important non-protein amino acid, very useful in all methylation reactions occurring in the body as the precursor of the sole methyl group donor S-Adenosyl-methionine (SAM). However, elevated plasma homocysteine levels have been reported to contribute to epithelial damage leading to coronary artery disease and other metabolic syndromes. This study was aimed at evaluating the concentration of plasma homocysteine in diabetics and hypertensive patients in Port Harcourt, Nigeria. Methods: The study population included 60 Type II diabetes mellitus and Hypertensivesubjectsas group (I), 60 Type II diabetes mellitus and Normotensive subjects as group (II), 60 Hypertensive subjects as group (III), and 60 healthy subjects as control group within the age range of 30 - 70 years. An enzyme-linked immunosorbent assay (ELISA) method was used to quantitatively measure homocysteine in the serum sample, glycated haemoglobin were determined quantitatively using sandwich immunodetection and blood pressure was determined using mercury sphygnanometer. Statistics: The statistical analysis was done using GraphPad Prism version 9.4.1, and statistical significance was determined by a P Results: The results showed significantly higher plasma homocysteine levels in diabetics and hypertensive comorbidity patients when compared to healthy controls, P Conclusion: Our result shows an increase in plasma homocysteine levels in diabetics and hypertensives when compared to controls, and comorbidity instigates a higher increase in plasma levels when compared with the single morbidity.
文摘Insulin resistance increases the risk of developing diabetes,and the degree of resistance influences the glycemic control of patients with diabetes.Numerous researchers have focused on improving insulin sensitivity in order to prevent diabetes-related complications and other chronic diseases.Several studies have also linked vitamin D levels to insulin secretion and resistance,given that both vitamin D and its receptor complex play important roles in regulating pancreaticβ-cells.It has been suggested that vitamin D supplementation improves vitamin D levels,but further research is needed to confirm this as neither insulin function nor glycemic control improves when vitamin D levels increase.Magnesium is a cofactor for many enzymes.Although the role of magnesium in the management of diabetes has long been evaluated,it has not yet been determined whether magnesium supplements improve insulin function.However,several researchers have found that patients with good glycemic control have high magnesium levels.Magnesium is closely related to vitamin D and is necessary for the transport and activation of vitamin D in humans.Combined supplementation with vitamin D and magnesium improves glycemic control in patients with diabetes.
文摘Aim: To evaluate chronic exposure of carmoisine at ADI doses on some hepatocellular and renal parameters of male and female albino rats as well as to determine sex-dependent toxicity. Study Design: The study involves treatment for 30, 60, and 90 days. Each phase consists of 40 rats, divided into treatment and control groups. The treated groups were orally administered with 4.0 mg/kg of carmoisine daily for the periods of 30, 60, and 90 days. Methodology: At the end of the treatment, the rats were allowed to fast for 18 hours followed by the collection of 5 ml of whole blood specimens by means of cardiac puncture into Lithium Heparin bottles and fluoride oxalate bottles (for glucose only). Plasma obtained was analyzed for glucose (GLU), AST, ALT, ALP, creatinine (CRT), and urea. Hepatic and Renal tissues collected were fixed in 10% formol saline and later examined histologically using H&E stain. Statistical data analysis was done using GraphPad Prism version 9.02. Results: Glucose indicated significant increases after 30, 60, and 90 days of chronic treatment at ADI doses. Urea, Creatinine, AST, ALT and ALP showed significantly higher values after 60 and 90 days of treatment (except creatinine in male rats and ALP in female rats after 60 and 90 days respectively). Hepatic distortions, vacuolation, compression of central vein were seen in the liver section while distortion of proximal and distal tubules, and inflammation of the glomerulus were observed in the renal tissue of the treated rats. Conclusion: The administration of camoisine over a period of 30 days at ADI dose did not indicate hepatocellullar and renal derangements as well histological distortions in liver, and kidneys. However, after 60 and 90 days, mild hepatocellular, and renal derangements were seen. No sex-dependent toxicity was observed.
文摘Neoplasms can be considered as a group of aberrant cells that need more vascular supply to fulfill all their functions.Therefore,they promote angiogenesis through the same neovascularization pathway used physiologically.Angiogenesis is a process characterized by a heterogeneous distribution of oxygen caused by the tumor and oxidative stress;the latter being one of the most powerful stimuli of angiogenesis.As a result of altered tumor metabolism due to hypoxia,acidosis occurs.The angiogenic process and oxidative stress can be detected by measuring serum and tissue biomarkers.The study of the mechanisms underlying angiogenesis and oxidative stress could lead to the identification of new biomarkers,ameliorating the selection of patients with neoplasms and the prediction of their response to possible anti-tumor therapies.In particular,in the treatment of patients with similar clinical tumor phenotypes but different prognoses,the new biomarkers could be useful.Moreover,they may lead to a better understanding of the mechanisms underlying drug resistance.Experimental studies show that blocking the vascular supply results in antiproliferative activity in vivo in neuroendocrine tumor cells,which require a high vascular supply.
文摘Acinar cell carcinoma(ACC)is a rare malignant epithelial neoplasm accounting for 1%-2%of all pancreatic exocrine neoplasm,affecting more frequently man with an age between 50 and 70 years.Most patients present with nonspecific symptoms,which may give rise to difficulties in clinical diagnosis[1].ACC can manifest with diarrhea,weight loss,abdominal pain and,in up to 10%-15%,with lipase hypersecretion syndrome,characterized by elevated lipase production,diffuse subcutaneous fat necrosis and polyarthralgia[1,2].Biliary obstruction and jaundice are infre-quent clinical manifestations,unlike ductal adenocarcinoma,due to pushing rather than infiltrating growth of ACC.
文摘AIM： To evaluate the diagnostic accuracy of endoscopic ultrasound-guided fine-needle aspiration （EUS-FNA） for pancreatic solid tumors larger or smaller than 3 cm, and cystic lesions.METHODS： From January/1997 to December/2006, 611 patients with pancreatic tumors were subjected to EUSFNA. The final diagnosis was obtained either by surgery （356 cases） or after a mean clinical follow-up of 11.8 mo in the remaining patients.RESULTS： There were 405 solid tumors, 189 cystic lesions and 17 mixed. Pancreatic specimens for cytological assessment were successfully obtained by EUS-FNA in 595 （97.4%） cases. There were 352 （57.6%） malignancies and 259 （42.4%） benign tumors. Among the malignancies, pancreatic adenocarcinomas accounted for 67% of the lesions. Overall, the sensitivity, specificity, positive and negative predictive values, and accuracy of EUS-FNA were, respectively, 78.4%, 99.2%, 99.3%, 77.2% and 87.2%. Specifically for solid tumors, the same parameters for neoplasms larger and smaller than 3 cm were, respectively, 78.8% ys 82.4%, 100% ys 98.4%, 100% vs 99%, 54.8% vs 74.1% and 83.1% vs 87.8%. For cystic lesions, the values were, respectively, 72.2%, 99.3%, 97.5%, 91% and 92.2%.CONCLUSION： EUS-FNA can be used to sample pancreatic tumors in most patients. Even though the negative predictive value is inadequate for large solid tumors, the results are rather good for small solid tumors, especially concerning the sensitivity, negative predictive value and diagnostic accuracy. Among all pancreatic lesions, EUS-FNA for cystic lesions can reveal the best negative predictive value and diagnostic accuracy, both higher than 90%.
文摘Ulcerative colitis(UC), a chronic, relapsing, remitting disease of the colon and rectum, is characterized by inflammatory ulceration of the mucosa. Current UC therapy relies on controlling acute episodes and preventing relapse. To predict modifications in the natural course of UC, mucosal healing(MH) has emerged as a major treatment goal. Endoscopic evaluation is considered the gold standard for assessing MH, which can be achieved by conventional drugs and biologics in many, but not all, patients. Consequently, interest is focusing on the development of new substances for UC therapy, and new oral agents are in the pipeline. This review will focus on the ability of newly developed oral drugs to induce and maintain MH in UC patients.
文摘HER2 is overexpressed in approximately 10%-20% of gastric and gastroesophageal junction carcinomas. In these types of cancer, accurate assessment of HER2 status is mandatory, for selecting patients who may benefit from targeted therapies with anti-HER2 drugs such as Trastuzumab. This manuscript focuses on HER2 in gastric carcinogenesis, on optimal evaluation of HER2 and on the possible causes which may contribute to inaccurate HER2 evaluation. Similarly to breast cancer HER2 evaluation, standardization of HER2 testing in gastric cancer is necessary in diagnostic practice. The three principle aspects which require consideration are:(1) the choice of sample with regards to cancer morphology- intestinal vs diffuse areas;(2) the choice of scoring criteria- use of HER2 scoring criteria specific for gastric cancer; and(3) the choice of HER2 evaluation methods- use of an algorithm in which both immunohistochemistry and in situ hybridization play a role. Problematic issues include:(1) pre-analytic variables with particular emphasis on fixation;(2) recommended methodology for HER2 assessment(immunohistochemistry vs in situ hybridization);(3) HER2 heterogeneity both within the primary tumor and between primary tumor and metastases;(4) reliability of biopsies in HER 2 evaluation; and(5) quantity of sample(FFPE blocks from surgical specimens or endoscopic biopsies) necessary for an adequate assessment.
文摘Objective： To investigate the role of apparent diffusion coefficient （ADC） from diffusion-weighted magnetic resonance imaging （DW-MRI） when applied to the 7th TNM classification in the staging and prognosis of gastric cancer （GC）. Methods： Between October 2009 and May 2014, a total of 89 patients with non-metastatic, biopsy proven GC underwent 1.5T DW-MRI, and then treated with radical surgery. Tumor ADC was measured retrospectively and compared with final histology following the 7th TNM staging （local invasion, nodal involvement and according to the different groups -- stage Ⅰ, Ⅱ and Ⅲ）. Kaplan-Meier curves were also generated. The follow-up period is updated to May 2016. Results： Median follow-up period was 33 months and 45/89 （51%） deaths from GC were observed. ADC was significantly different both for local invasion and nodal involvement （P〈0.001）. Considering final histology as the reference standard, a preoperative ADC cut-offof 1.80×10-3 mm^2/s could distinguish between stages I and Ⅱ and an ADC value of ≤1.36-10-3 mm^2/s was associated with stage Ⅲ（P〈0.001）. Kaplan-Meier curves demonstrated that the survival rates for the three prognostic groups were significantly different according to final histology and ADC cut-offs （P〈0.001）. Conclusions： ADC is different according to local invasion, nodal involvement and the 7th TNM stage groups for GC, representing a potential, additional prognostic biomarker. The addition of DW-MRI could aid in the staging and risk stratification of GC.
基金MINECO,Spain,No.SAF2014-52492RCOOPB20213(CSIC)+2 种基金No.SAF2013-43713R and No.SAF2016-75004RISCIII,Spain,CIBERcv and CIBERehdFEDER for financial support
文摘The biosynthesis of prostaglandins and thromboxanes has been a focus of interest in the management of many liver diseases.Cyclooxygenases are the enzymes involved in the first step of the biosynthesis of these lipid mediators and selective inhibitors for these isoenzymes as well as pharmacological analogues of prostaglandins have been developed and are currently applied therapeutically.Here we discuss the implications of these enzymes in the onset of metabolic and lipid disorders in the liver and their potential role in the progression of the diseases towards fibrosis and hepatocellular carcinogenesis.
基金the European Union’s Horizon 2020 Research and Innovation Programme,No.668353
文摘Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. To date, most patients with HCC are diagnosed at an advanced tumor stage, excluding them from potentially curative therapies (i.e., resection, liver transplantation, percutaneous ablation). Treatments with palliative intent include chemoembolization and systemic therapy. Among systemic treatments, the small-molecule multikinase inhibitor sorafenib has been the only systemic treatment available for advanced HCC over 10 years. More recently, other smallmolecule multikinase inhibitors (e.g., regorafenib, lenvatinib, cabozantinib) have been approved for HCC treatment. The promising immune checkpoint inhibitors (e.g., nivolumab, pembrolizumab) are still under investigation in Europe while in the US nivolumab has already been approved by FDA in sorafenib refractory or resistant patients. Other molecules, such as the selective CDK4/6inhibitors (e.g., palbociclib, ribociclib), are in earlier stages of clinical development, and the c- MET inhibitor tivantinib did not show positive results in a phase III study. However, even if the introduction of targeted agents has led to great advances in patient response and survival with an acceptable toxicity profile, a remarkable inter-individual heterogeneity in therapy outcome persists and constitutes a significant problem in disease management. Thus, the identification of biomarkers that predict which patients will benefit from a specific intervention could significantly affect decision-making and therapy planning. Germ-line variants have been suggested to play an important role in determining outcomes of HCC systemic therapy in terms of both toxicity and treatment efficacy. Particularly, a number of studies have focused on the role of genetic polymorphisms impacting the drug metabolic pathway and membrane translocation as well as the drug mechanism of action as predictive/prognostic markers of HCC treatment. The aim of this review is to summarize and critically discuss the pharmacogenetic literature evidences, with particular attention to sorafenib and regorafenib, which have been used longer than the others in HCC treatment.
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.
