Background:While the treatment of metastatic renal cell carcinoma(mRCC)is evolving due to immune checkpoint inhibitors(ICIs),optimal strategies for later lines of therapy have yet to be defined.The combination of lenv...Background:While the treatment of metastatic renal cell carcinoma(mRCC)is evolving due to immune checkpoint inhibitors(ICIs),optimal strategies for later lines of therapy have yet to be defined.The combination of lenvatinib and everolimus represents a viable option,and the present review aimed to summarize its activity,effectiveness,and safety.Methods:A systematic review of the literature was conducted using PubMed,targeting studies published between 2018 and 2025.Eligible studies included English-language prospective and retrospective trials reporting survival outcomes in mRCC patients treated with lenvatinib and everolimus after at least one ICI-containing regimen.Results:Nine studies met the inclusion criteria,encompassing a total of 441 patients.The lenvatinib and everolimus combination was primarily used in the third and subsequent lines of therapy.Median overall survival ranged from 7.5 to 24.5 months,while median progression-free survival was more consistent,between 6.1 and 6.7 months,except for one study reporting 12.9 months.Objective response rates varied widely(14.0%–55.7%).Adverse events of grade≥3 did not exceed the expected rate,with diarrhoea and proteinuria as the most reported events.Dose reductions and treatment discontinuations due to toxicity occurred but were generally lower than in prior pivotal trials.Conclusions:Real-world evidence suggests that lenvatinib and everolimus represent an effective and safe option after ICI failure in mRCC patients.Nevertheless,the lack of randomized phase III trials and the heterogeneity of existing studies highlight the need for more robust prospective research to guide post-ICI therapeutic strategies.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
Objectives:Checkpoint inhibitors have significantly improved outcomes in a number of malignancies.To determine the most effective course of treatment for head and neck squamous cell carcinoma(HNSCC),this systematic re...Objectives:Checkpoint inhibitors have significantly improved outcomes in a number of malignancies.To determine the most effective course of treatment for head and neck squamous cell carcinoma(HNSCC),this systematic review evaluated the efficacy of several therapeutic approaches based on immune checkpoint inhibitors(ICIs).Methods:A comprehensive evaluation of the literature was conducted,looking at randomized controlled trials(RCTs)that were published in Embase,PubMed,and the Cochrane Central Register of Controlled Trials since database establishment.The risk of bias of the enrolled studies was analyzed using The Review Manager(RevMan)5.4.Using network meta-analyses(NMA),the relative treatment effects on overall survival(OS)and progression-free survival(PFS)from qualifying randomized controlled trials were synthesized and evaluated.Results:Regarding OS,compared with nivolumab plus chemotherapy,chemotherapy(Hazard ratio(HR)2.1,95%Confidence interval=(CI):1.2,3.4)showed a treatment disadvantage.Meanwhile,nivolumab plus chemotherapy may represent the most efficient(57.89%)and has a lower cost among all the treatments enrolled in this study for advanced HNSCC.Regarding PFS,compared with nivolumab plus ipilimumab,nivolumab plus chemotherapy(HR 0.4,95%CI:0.2,0.8)showed=treatment superiority.Additionally,nivolumab plus chemotherapy(77.18%)has the longest PFS among all interventions.Conclusion:Taking into account OS and PFS,the combination of nivolumab plus chemotherapy may appear to be the most effective option and is associated with a comparatively lower cost among all treatments included in this network meta-analysis,thereby recommending its use as a first-line therapy for HNSCC.Registration:INPLASY(2024070073).展开更多
BACKGROUND Hepatocellular carcinoma(HCC)remains a leading cause of cancer-related mortality worldwide.Despite improvements in surgical techniques and systemic therapies,long-term outcomes after liver resection are lim...BACKGROUND Hepatocellular carcinoma(HCC)remains a leading cause of cancer-related mortality worldwide.Despite improvements in surgical techniques and systemic therapies,long-term outcomes after liver resection are limited by high recurrence rates.While adjuvant strategies have shown limited benefit,the role of neoadjuvant immunotherapy in resectable HCC is still under investigation.AIM To assess the efficacy,feasibility,and safety of neoadjuvant immunotherapy in resectable HCC through a meta-analysis of current literature.METHODS A systematic search was conducted across PubMed,Web of Science,EMBASE,Cochrane Library,and Scopus for studies published in the past five years evaluating neoadjuvant immunotherapy in resectable HCC.Primary endpoints included major pathological response(MPR),pathological complete response(pCR),overall response rate(ORR),resection rate,and grade 3-4 treatment-related adverse events(TRAEs).A random-effects meta-analysis was conducted using log odds ratios(ORs)and pooled event rates were calculated to provide absolute estimates of clinical endpoints.RESULTS Twelve studies were included in the final analysis.The pooled ORs were 0.28(95%CI:0.19-0.41)for MPR,0.54(95%CI:0.25-1.14)for ORR,0.26(95%CI:0.11-0.66)for pCR,5.37(95%CI:2.70-10.66)for resection rate,and 0.33(95%CI:0.22-0.50)for grade 3-4 TRAEs.Corresponding pooled event rates were 19%for MPR,35%for ORR,22%for pCR,81%for resection feasibility,and 19%for severe TRAEs.CONCLUSION Neoadjuvant immunotherapy appears to be a feasible and safe approach in patients with resectable HCC,achieving moderate pathological responses and high resection rates.展开更多
BACKGROUND Chronic liver disease(CLD)causes approximately two million deaths each year,and its clinical diagnosis and management remain challenging.Ultrasound is currently the most widely used technique for disease de...BACKGROUND Chronic liver disease(CLD)causes approximately two million deaths each year,and its clinical diagnosis and management remain challenging.Ultrasound is currently the most widely used technique for disease detection.AIM To propose a practical cut-off value for identifying patients with hepatocellular carcinoma(HCC)among those with compensated advanced CLD or healthy individuals using the GALAD score,an algorithm based on a formula that incorporates gender,age,serum alpha-fetoprotein(AFP),AFP-L3,and des-gamma-carboxy prothrombin values.METHODS This cross-sectional analysis was conducted using prospectively collected data from five cohorts(n=1431)comprising healthy individuals,cirrhosis,and HCC patients.These subjects were enrolled from an Italian retrospective cohort,including patients from the IRCCS“Saverio de Bellis”,Department of Gastroenterology,the University of Modena and Reggio Emilia Gastroenterology Department,and the Padua University Hospital and the Department of Gastroenterology,Hepatology,Infectious diseases and Endocrinology,Hannover Medical School.RESULTS Using healthy subjects as reference,a GALAD score cut-off of-1.67 identified HCC with a sensitivity of 89.77%and specificity of 97.59%.Individuals with GALAD values>-1.67 exhibited a moderate to very high probability(over 90%)of having HCC.When cirrhotic patients were used as the reference category,a cut-off of-0.77 yielded a sensitivity of 78.17%and a specificity of 89.55%.CONCLUSION We strongly recommend incorporating this GALAD cut-off into clinical guidelines for the screening of patients with a compensated advanced CLD who are at high risk of developing HCC.Given the rapid global rise in metabolic-associated steatotic liver disease(MASLD)-related CLD,future research should prioritize larger MASLD cohorts to establish the most appropriate GALAD cut-off for diagnostic use,compared to healthy controls and to patients with other forms of CLD.展开更多
Oral squamous cell carcinoma(OSCC)is the most common manifestation of oral cancer.It has been proposed that periodontal pathogens contribute to OSCC progression,mainly by their virulence factors.However,the main perio...Oral squamous cell carcinoma(OSCC)is the most common manifestation of oral cancer.It has been proposed that periodontal pathogens contribute to OSCC progression,mainly by their virulence factors.However,the main periodontal pathogen and its mechanism to modulate OSCC cells remains not fully understood.In this study we investigate the main host-pathogen pathways in OSCC by computational proteomics and the mechanism behind cancer progression by the oral microbiome.The main hostpathogen pathways were analyzed in the secretome of biopsies from patients with OSCC and healthy controls by mass spectrometry.Then,functional assays were performed to evaluate the host-pathogen pathways highlighted in oral cancer.Host proteins associated with LPS response,cell migration/adhesion,and metabolism of amino acids were significantly upregulated in the human cancer proteome,whereas the complement cascade was downregulated in malignant samples.Then,the microbiome analysis revealed large number and variety of peptides from Fusobacterium nucleatum(F.nucleatum)in OSCC samples,from which several enzymes from the L-glutamate degradation pathway were found,indicating that L-glutamate from cancer cells is used as an energy source,and catabolized into butyrate by the bacteria.In fact,we observed that F.nucleatum modulates the cystine/glutamate antiporter in an OSCC cell line by increasing SLC7A11 expression,promoting L-glutamate efflux and favoring bacterial infection.Finally,our results showed that F.nucleatum and its metabolic derivates promote tumor spheroids growth,spheroidsderived cell detachment,epithelial-mesenchymal transition and Galectin-9 upregulation.Altogether,F.nucleatum promotes protumoral mechanism in oral cancer.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
Ultrasonography(US) and the new applications US elastography(USE) and contrast-enhanced US(CEUS) are used in the screening of thyroid nodules,for which fine-needle aspiration biopsy(FNAB) is the best single diagnostic...Ultrasonography(US) and the new applications US elastography(USE) and contrast-enhanced US(CEUS) are used in the screening of thyroid nodules,for which fine-needle aspiration biopsy(FNAB) is the best single diagnostic test.The aim of the study was to compare the sensitivity,specificity,positive predictive value(PPV),and accuracy of the four examinations in nodules with cytological and histological diagnoses.The study used data from US,FNAB,USE(elasticity(ELX 2/1) index),and CEUS(Peak index and time to peak(TTP) index) evaluated in 73 thyroid nodules in 63 consecutive patients likely to undergo surgery.Cytological-histological correlation was available for 38 nodules.No correlation emerged between nodule size and cytological results.A significant(P=0.03) positive correlation between cumulative US findings and cytological results was found.In addition,significant correlations between cumulative US findings and cytology(P=0.02) and between cumulative US findings and histology(P<0.0001) were found.US showed the best specificity and PPV,and FNAB the best sensitivity.There was no significant difference in the ELX 2/1 index,Peak index,or TTP index among nodules subdivided according to cytological scores.No significant correlation was found between ELX 2/1 index,Peak index,and TTP index,on the one hand,and nodule size,US cumulative findings,cytology,and histology on the other hand.The sensitivity of the ELX 2/1 index was high,but its specificity was very low.The accuracy and PPV of USE were lower than those of the other procedures.Only the correlation between Peak index and cumulative US findings reached a value close to significance.Our ultimate aim is to minimise unnecessary thyroidectomy.US and FNAB continue to play a central diagnostic role.The use of a US score showed high specificity and PPV.The specificity of FNAB was low in this selected series because of the numbers of indeterminate cytological responses.USE and CEUS are innovative techniques that need to be standardized.The ELX 2/1 index,Peak index,and TTP index seem to be unrelated to histology.The best statistical data on USE and CEUS concerned their sensitivity and PPV,respectively.At present,USE and CEUS are too time-consuming and of limited utility in selecting patients for surgery.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
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
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
To the Editor:Biliary tract complications remain the Achilles’heel of liver transplantation（LT）;and the transplant commu nity is exploring ways of tackling this problem.A well vascularized bile duct is a prerequisi...To the Editor:Biliary tract complications remain the Achilles’heel of liver transplantation（LT）;and the transplant commu nity is exploring ways of tackling this problem.A well vascularized bile duct is a prerequisite for successful bile duct reconstruction.Vascular assessment is usually per formed by evaluating the macroscopic aspects of both展开更多
The role of liver biopsy in the diagnosis of hepatocellular carcinoma(HCC)has been challenged over time by the ability of imaging techniques to characterize liver lesions in patients with known cirrhosis.In fact,in th...The role of liver biopsy in the diagnosis of hepatocellular carcinoma(HCC)has been challenged over time by the ability of imaging techniques to characterize liver lesions in patients with known cirrhosis.In fact,in the diagnostic algorithm for this tumor,histology is currently relegated to controversial cases.Furthermore,the risk of complications,such as tumor seeding and bleeding,as well as inadequate sampling have further limited the use of liver biopsy for HCC management.However,there is growing evidence of prognostic and therapeutic information available from microscopic and molecular analysis of HCC and,as the information content of the tissue sample increases,the advantages of liver biopsy might modify the current risk/benefit ratio.We herein review the role and potentiality of liver biopsy in the diagnosis and management of HCC.As the potentiality of precision medicine comes to the management of HCC,it will be crucial to have rapid pathways to define prognosis,and even treatment,by identifying the patients who could most benefit from target-driven therapies.All of the above reasons suggest that the current role of liver biopsy in the management of HCC needs substantial reconsideration.展开更多
AIM:To compare computed tomography enteroclysis(CTE) vs small intestine contrast ultrasonography(SICUS) for assessing small bowel lesions in Crohn's disease(CD),when using surgical pathology as gold standard.METHO...AIM:To compare computed tomography enteroclysis(CTE) vs small intestine contrast ultrasonography(SICUS) for assessing small bowel lesions in Crohn's disease(CD),when using surgical pathology as gold standard.METHODS:From January 2007 to July 2008,15 eligible patients undergoing elective resection of the distal ileum and coecum(or right colon) were prospectively enrolled.All patients were under follow-up.The study population included 6 males and 9 females,with a median age of 44 years(range:18-80 years).Inclusion criteria:(1) certain diagnosis of small bowel requiring elective ileo-colonic resection;(2) age between 18-80 years;(3) elective surgery in our Surgical Unit;and(4) written informed consent.SICUS and CTE were performed ≤ 3 mo before surgery,followed by surgical pathology.The following small bowel lesions were blindly reported by one sonologist,radiologist,surgeon and histolopathologist:disease site,extent,strictures,abscesses,fistulae,small bowel dilation.Comparison between findings at SICUS,CTE,surgical specimens and histological examination was made by assessing the specificity,sensitivity and accuracy of each technique,when using surgical findings as gold standard.RESULTS:Among the 15 patients enrolled,CTE was not feasible in 2 patients,due to urgent surgery in one patients and to low compliance in the second patient,refusing to perform CTE due to the discomfort related to the naso-jejunal tube.The analysis for comparing CTE vs SICUS findings was therefore performed in 13 out of the 15 CD patients enrolled.Differently from CTE,SICUS was feasible in all the 15 patients enrolled.No complications were observed when using SICUS or CTE.Surgical pathology findings in the tested population included:small bowel stricture in 13 patients,small bowel dilation above ileal stricture in 10 patients,abdominal abscesses in 2 patients,enteric fistulae in 5 patients,lymphnodes enlargement(> 1 cm) in 7 patients and mesenteric enlargement in 9 patients.In order to compare findings by using SICUS,CTE,histology and surgery,characteristics of the small bowel lesions observed in CD each patient were blindly reported in the same form by one gastroenterologistsonologist,radiologist,surgeon and anatomopathologist.At surgery,lesions related to CD were detected in the distal ileum in all 13 patients,also visualized by both SICUS and CTE in all 13 patients.Ileal lesions > 10 cm length were detected at surgery in all the 13 CD patients,confirmed by SICUS and CTE in the same 12 out of the 13 patients.When using surgical findings as a gold standard,SICUS and CTE showed the exactly same sensitivity,specificity and accuracy for detecting the presence of small bowel fistulae(accuracy 77% for both) and abscesses(accuracy 85% for both).In the tested CD population,SICUS and CTE were also quite comparable in terms of accuracy for detecting the presence of small bowel strictures(92% vs 100%),small bowel fistulae(77% for both) and small bowel dilation(85% vs 82%).CONCLUSION:In our study population,CTE and the non-invasive and radiation-free SICUS showed a comparable high accuracy for assessing small bowel lesions in CD.展开更多
AIM: To evaluate the protective effects on kidney tissue of frequently used intravenous anesthetics (ketamine, propofol, thiopental, and fentanyl) in rats with obstructive jaundice.
AIM:To assess the safety and effect of the supplementation of a patented blend of dietary phytoestrogens and insoluble fibers on estrogen receptor (ER)-β and biological parameters in sporadic colonic adenomas. METHOD...AIM:To assess the safety and effect of the supplementation of a patented blend of dietary phytoestrogens and insoluble fibers on estrogen receptor (ER)-β and biological parameters in sporadic colonic adenomas. METHODS:A randomized, double-blind placebo-controlled trial was performed. Patients scheduled to undergo surveillance colonoscopy for previous sporadic colonic adenomas were identified, and 60 eligible patients were randomized to placebo or active dietary intervention (ADI) twice a day, for 60 d before surveillance colonoscopy. ADI was a mixture of 175 mg milk thistle extract, 20 mg secoisolariciresinol and 750 mg oat fiber extract. ER-β and ER-α expression, apoptosis and proliferation (Ki-67 LI) were assessed in colon samples. RESULTS:No adverse event related to ADI was recorded. ADI administration showed a significant increases in ER-β protein (0.822 ± 0.08 vs 0.768 ± 0.10, P = 0.04) and a general trend to an increase in ER-β LI (39.222 ± 2.69vs 37.708 ± 5.31,P = 0.06), ER-β/ER-α LI ratio (6.564 ± 10.04 vs 2.437 ± 1.53, P = 0.06), terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (35.592 ± 14.97 vs 31.541 ± 11.54, P = 0.07) and Ki-67 (53.923 ± 20.91 vs 44.833 ± 10.38, P = 0.07) approximating statistical significance. A significant increase of ER-β protein (0.805 ± 0.13 vs 0.773 ± 0.13,P = 0.04), mRNA (2.278 ± 1.19vs 1.105 ± 1.07, P < 0.02) and LI (47.533 ± 15.47 vs 34.875 ± 16.67,P < 0.05) and a decrease of ER-α protein (0.423 ± 0.06vs 0.532 ± 0.11,P < 0.02) as well as a trend to increase of ER-β/ER-α protein in ADI vs placebo group were observed in patients without polyps (1.734 ± 0.20 vs 1.571 ± 0.42, P = 0.07). CONCLUSION:The role of ER-β on the control of apoptosis, and its amenability to dietary intervention, are supported in our study.展开更多
AIM:To investigate the progression of hepatic histopathology in serial liver biopsies from Wilson disease(WD)patients.METHODS:We report a group of 12 WD patients treated with zinc and/or penicillamine who underwent mu...AIM:To investigate the progression of hepatic histopathology in serial liver biopsies from Wilson disease(WD)patients.METHODS:We report a group of 12 WD patients treated with zinc and/or penicillamine who underwent multiple follow-up liver biopsies.Demographic,clinical and laboratory data were gathered and all patients underwent an initial biopsy and at least one repeat biopsy.RESULTS:Time to repeat biopsy ranged from 2 to 12 years.Six patients(non-progressors)showed stable hepatic histology or improvement.In one case,we observed improvement of fibrosis from stage 2 to 0.Six patients(progressors)had worsening of fibrosis.There was no significant correlation between the histological findings and serum aminotransferases or copper me-tabolism parameters.The hepatic copper concentration reached normal levels in only two patients:one from the non-progressors and one from the progressors group.The estimated rate of progression of hepatic fibrosis in the entire group was 0 units per year in the time frame between the first and the second liver biopsy(4 years),and 0.25 between the second and the third(3 years).In the progressors group,the rate of progression of liver fibrosis was estimated at 0.11 fibrosis units per year between the first and second biopsy and,0.6 fibrosis units between the second and third biopsy.CONCLUSION:The inability of clinical tools to detect fibrosis progression in WD suggests that a liver biopsy with hepatic copper quantification every 3 years should be considered.展开更多
文摘Background:While the treatment of metastatic renal cell carcinoma(mRCC)is evolving due to immune checkpoint inhibitors(ICIs),optimal strategies for later lines of therapy have yet to be defined.The combination of lenvatinib and everolimus represents a viable option,and the present review aimed to summarize its activity,effectiveness,and safety.Methods:A systematic review of the literature was conducted using PubMed,targeting studies published between 2018 and 2025.Eligible studies included English-language prospective and retrospective trials reporting survival outcomes in mRCC patients treated with lenvatinib and everolimus after at least one ICI-containing regimen.Results:Nine studies met the inclusion criteria,encompassing a total of 441 patients.The lenvatinib and everolimus combination was primarily used in the third and subsequent lines of therapy.Median overall survival ranged from 7.5 to 24.5 months,while median progression-free survival was more consistent,between 6.1 and 6.7 months,except for one study reporting 12.9 months.Objective response rates varied widely(14.0%–55.7%).Adverse events of grade≥3 did not exceed the expected rate,with diarrhoea and proteinuria as the most reported events.Dose reductions and treatment discontinuations due to toxicity occurred but were generally lower than in prior pivotal trials.Conclusions:Real-world evidence suggests that lenvatinib and everolimus represent an effective and safe option after ICI failure in mRCC patients.Nevertheless,the lack of randomized phase III trials and the heterogeneity of existing studies highlight the need for more robust prospective research to guide post-ICI therapeutic strategies.
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Objectives:Checkpoint inhibitors have significantly improved outcomes in a number of malignancies.To determine the most effective course of treatment for head and neck squamous cell carcinoma(HNSCC),this systematic review evaluated the efficacy of several therapeutic approaches based on immune checkpoint inhibitors(ICIs).Methods:A comprehensive evaluation of the literature was conducted,looking at randomized controlled trials(RCTs)that were published in Embase,PubMed,and the Cochrane Central Register of Controlled Trials since database establishment.The risk of bias of the enrolled studies was analyzed using The Review Manager(RevMan)5.4.Using network meta-analyses(NMA),the relative treatment effects on overall survival(OS)and progression-free survival(PFS)from qualifying randomized controlled trials were synthesized and evaluated.Results:Regarding OS,compared with nivolumab plus chemotherapy,chemotherapy(Hazard ratio(HR)2.1,95%Confidence interval=(CI):1.2,3.4)showed a treatment disadvantage.Meanwhile,nivolumab plus chemotherapy may represent the most efficient(57.89%)and has a lower cost among all the treatments enrolled in this study for advanced HNSCC.Regarding PFS,compared with nivolumab plus ipilimumab,nivolumab plus chemotherapy(HR 0.4,95%CI:0.2,0.8)showed=treatment superiority.Additionally,nivolumab plus chemotherapy(77.18%)has the longest PFS among all interventions.Conclusion:Taking into account OS and PFS,the combination of nivolumab plus chemotherapy may appear to be the most effective option and is associated with a comparatively lower cost among all treatments included in this network meta-analysis,thereby recommending its use as a first-line therapy for HNSCC.Registration:INPLASY(2024070073).
文摘BACKGROUND Hepatocellular carcinoma(HCC)remains a leading cause of cancer-related mortality worldwide.Despite improvements in surgical techniques and systemic therapies,long-term outcomes after liver resection are limited by high recurrence rates.While adjuvant strategies have shown limited benefit,the role of neoadjuvant immunotherapy in resectable HCC is still under investigation.AIM To assess the efficacy,feasibility,and safety of neoadjuvant immunotherapy in resectable HCC through a meta-analysis of current literature.METHODS A systematic search was conducted across PubMed,Web of Science,EMBASE,Cochrane Library,and Scopus for studies published in the past five years evaluating neoadjuvant immunotherapy in resectable HCC.Primary endpoints included major pathological response(MPR),pathological complete response(pCR),overall response rate(ORR),resection rate,and grade 3-4 treatment-related adverse events(TRAEs).A random-effects meta-analysis was conducted using log odds ratios(ORs)and pooled event rates were calculated to provide absolute estimates of clinical endpoints.RESULTS Twelve studies were included in the final analysis.The pooled ORs were 0.28(95%CI:0.19-0.41)for MPR,0.54(95%CI:0.25-1.14)for ORR,0.26(95%CI:0.11-0.66)for pCR,5.37(95%CI:2.70-10.66)for resection rate,and 0.33(95%CI:0.22-0.50)for grade 3-4 TRAEs.Corresponding pooled event rates were 19%for MPR,35%for ORR,22%for pCR,81%for resection feasibility,and 19%for severe TRAEs.CONCLUSION Neoadjuvant immunotherapy appears to be a feasible and safe approach in patients with resectable HCC,achieving moderate pathological responses and high resection rates.
文摘BACKGROUND Chronic liver disease(CLD)causes approximately two million deaths each year,and its clinical diagnosis and management remain challenging.Ultrasound is currently the most widely used technique for disease detection.AIM To propose a practical cut-off value for identifying patients with hepatocellular carcinoma(HCC)among those with compensated advanced CLD or healthy individuals using the GALAD score,an algorithm based on a formula that incorporates gender,age,serum alpha-fetoprotein(AFP),AFP-L3,and des-gamma-carboxy prothrombin values.METHODS This cross-sectional analysis was conducted using prospectively collected data from five cohorts(n=1431)comprising healthy individuals,cirrhosis,and HCC patients.These subjects were enrolled from an Italian retrospective cohort,including patients from the IRCCS“Saverio de Bellis”,Department of Gastroenterology,the University of Modena and Reggio Emilia Gastroenterology Department,and the Padua University Hospital and the Department of Gastroenterology,Hepatology,Infectious diseases and Endocrinology,Hannover Medical School.RESULTS Using healthy subjects as reference,a GALAD score cut-off of-1.67 identified HCC with a sensitivity of 89.77%and specificity of 97.59%.Individuals with GALAD values>-1.67 exhibited a moderate to very high probability(over 90%)of having HCC.When cirrhotic patients were used as the reference category,a cut-off of-0.77 yielded a sensitivity of 78.17%and a specificity of 89.55%.CONCLUSION We strongly recommend incorporating this GALAD cut-off into clinical guidelines for the screening of patients with a compensated advanced CLD who are at high risk of developing HCC.Given the rapid global rise in metabolic-associated steatotic liver disease(MASLD)-related CLD,future research should prioritize larger MASLD cohorts to establish the most appropriate GALAD cut-off for diagnostic use,compared to healthy controls and to patients with other forms of CLD.
基金supported by Agencia Nacional de Investigación y Desarrollo(ANID),Chilean Government Fondecyt Regular 1211480supported by a Master ANID Scholarship+1 种基金funded by ANID/Fondecyt Regular 1211480funded by EQM150061(FONDEQUIP-ANID)。
文摘Oral squamous cell carcinoma(OSCC)is the most common manifestation of oral cancer.It has been proposed that periodontal pathogens contribute to OSCC progression,mainly by their virulence factors.However,the main periodontal pathogen and its mechanism to modulate OSCC cells remains not fully understood.In this study we investigate the main host-pathogen pathways in OSCC by computational proteomics and the mechanism behind cancer progression by the oral microbiome.The main hostpathogen pathways were analyzed in the secretome of biopsies from patients with OSCC and healthy controls by mass spectrometry.Then,functional assays were performed to evaluate the host-pathogen pathways highlighted in oral cancer.Host proteins associated with LPS response,cell migration/adhesion,and metabolism of amino acids were significantly upregulated in the human cancer proteome,whereas the complement cascade was downregulated in malignant samples.Then,the microbiome analysis revealed large number and variety of peptides from Fusobacterium nucleatum(F.nucleatum)in OSCC samples,from which several enzymes from the L-glutamate degradation pathway were found,indicating that L-glutamate from cancer cells is used as an energy source,and catabolized into butyrate by the bacteria.In fact,we observed that F.nucleatum modulates the cystine/glutamate antiporter in an OSCC cell line by increasing SLC7A11 expression,promoting L-glutamate efflux and favoring bacterial infection.Finally,our results showed that F.nucleatum and its metabolic derivates promote tumor spheroids growth,spheroidsderived cell detachment,epithelial-mesenchymal transition and Galectin-9 upregulation.Altogether,F.nucleatum promotes protumoral mechanism in oral cancer.
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Ultrasonography(US) and the new applications US elastography(USE) and contrast-enhanced US(CEUS) are used in the screening of thyroid nodules,for which fine-needle aspiration biopsy(FNAB) is the best single diagnostic test.The aim of the study was to compare the sensitivity,specificity,positive predictive value(PPV),and accuracy of the four examinations in nodules with cytological and histological diagnoses.The study used data from US,FNAB,USE(elasticity(ELX 2/1) index),and CEUS(Peak index and time to peak(TTP) index) evaluated in 73 thyroid nodules in 63 consecutive patients likely to undergo surgery.Cytological-histological correlation was available for 38 nodules.No correlation emerged between nodule size and cytological results.A significant(P=0.03) positive correlation between cumulative US findings and cytological results was found.In addition,significant correlations between cumulative US findings and cytology(P=0.02) and between cumulative US findings and histology(P<0.0001) were found.US showed the best specificity and PPV,and FNAB the best sensitivity.There was no significant difference in the ELX 2/1 index,Peak index,or TTP index among nodules subdivided according to cytological scores.No significant correlation was found between ELX 2/1 index,Peak index,and TTP index,on the one hand,and nodule size,US cumulative findings,cytology,and histology on the other hand.The sensitivity of the ELX 2/1 index was high,but its specificity was very low.The accuracy and PPV of USE were lower than those of the other procedures.Only the correlation between Peak index and cumulative US findings reached a value close to significance.Our ultimate aim is to minimise unnecessary thyroidectomy.US and FNAB continue to play a central diagnostic role.The use of a US score showed high specificity and PPV.The specificity of FNAB was low in this selected series because of the numbers of indeterminate cytological responses.USE and CEUS are innovative techniques that need to be standardized.The ELX 2/1 index,Peak index,and TTP index seem to be unrelated to histology.The best statistical data on USE and CEUS concerned their sensitivity and PPV,respectively.At present,USE and CEUS are too time-consuming and of limited utility in selecting patients for surgery.
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Supported by A grant from the Italian Association for Cancer Research(partly,AIRC Regional grant 2008 No.6421)published under the auspices of the Healthy Stomach Initiative(HIS)
文摘Western countries are seeing a constant decline in the incidence of Helicobacter pylori-associated gastritis, coupled with a rising epidemiological and clinical impact of autoimmune gastritis. This latter gastropathy is due to autoimmune aggression targeting parietal cells through a complex interaction of auto-antibodies against the parietal cell proton pump and intrinsic factor, and sensitized T cells. Given the specific target of this aggression, autoimmune gastritis is typically restricted to the gastric corpus-fundus mucosa. In advanced cases, the oxyntic epithelia are replaced by atrophic(and metaplastic) mucosa, creating the phenotypic background in which both gastric neuroendocrine tumors and(intestinal-type) adenocarcinomas may develop. Despite improvements in our understanding of the phenotypic changes or cascades occurring in this autoimmune setting, no reliable biomarkers are available for identifying patients at higher risk of developing a gastric neoplasm. The standardization of autoimmune gastritis histology reports and classifications in diagnostic practice is a prerequisite for implementing definitive secondary prevention strategies based on multidisciplinary diagnostic approaches integratingendoscopy, serology, histology and molecular profiling.
基金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.
文摘To the Editor:Biliary tract complications remain the Achilles’heel of liver transplantation（LT）;and the transplant commu nity is exploring ways of tackling this problem.A well vascularized bile duct is a prerequisite for successful bile duct reconstruction.Vascular assessment is usually per formed by evaluating the macroscopic aspects of both
文摘The role of liver biopsy in the diagnosis of hepatocellular carcinoma(HCC)has been challenged over time by the ability of imaging techniques to characterize liver lesions in patients with known cirrhosis.In fact,in the diagnostic algorithm for this tumor,histology is currently relegated to controversial cases.Furthermore,the risk of complications,such as tumor seeding and bleeding,as well as inadequate sampling have further limited the use of liver biopsy for HCC management.However,there is growing evidence of prognostic and therapeutic information available from microscopic and molecular analysis of HCC and,as the information content of the tissue sample increases,the advantages of liver biopsy might modify the current risk/benefit ratio.We herein review the role and potentiality of liver biopsy in the diagnosis and management of HCC.As the potentiality of precision medicine comes to the management of HCC,it will be crucial to have rapid pathways to define prognosis,and even treatment,by identifying the patients who could most benefit from target-driven therapies.All of the above reasons suggest that the current role of liver biopsy in the management of HCC needs substantial reconsideration.
基金Supported by The Fondazione Umberto Di Mario,Largo Marchiafava,1,Roma,Italya Grant Research from PRIN 2008,No. 2008X8NRH4,Italy
文摘AIM:To compare computed tomography enteroclysis(CTE) vs small intestine contrast ultrasonography(SICUS) for assessing small bowel lesions in Crohn's disease(CD),when using surgical pathology as gold standard.METHODS:From January 2007 to July 2008,15 eligible patients undergoing elective resection of the distal ileum and coecum(or right colon) were prospectively enrolled.All patients were under follow-up.The study population included 6 males and 9 females,with a median age of 44 years(range:18-80 years).Inclusion criteria:(1) certain diagnosis of small bowel requiring elective ileo-colonic resection;(2) age between 18-80 years;(3) elective surgery in our Surgical Unit;and(4) written informed consent.SICUS and CTE were performed ≤ 3 mo before surgery,followed by surgical pathology.The following small bowel lesions were blindly reported by one sonologist,radiologist,surgeon and histolopathologist:disease site,extent,strictures,abscesses,fistulae,small bowel dilation.Comparison between findings at SICUS,CTE,surgical specimens and histological examination was made by assessing the specificity,sensitivity and accuracy of each technique,when using surgical findings as gold standard.RESULTS:Among the 15 patients enrolled,CTE was not feasible in 2 patients,due to urgent surgery in one patients and to low compliance in the second patient,refusing to perform CTE due to the discomfort related to the naso-jejunal tube.The analysis for comparing CTE vs SICUS findings was therefore performed in 13 out of the 15 CD patients enrolled.Differently from CTE,SICUS was feasible in all the 15 patients enrolled.No complications were observed when using SICUS or CTE.Surgical pathology findings in the tested population included:small bowel stricture in 13 patients,small bowel dilation above ileal stricture in 10 patients,abdominal abscesses in 2 patients,enteric fistulae in 5 patients,lymphnodes enlargement(> 1 cm) in 7 patients and mesenteric enlargement in 9 patients.In order to compare findings by using SICUS,CTE,histology and surgery,characteristics of the small bowel lesions observed in CD each patient were blindly reported in the same form by one gastroenterologistsonologist,radiologist,surgeon and anatomopathologist.At surgery,lesions related to CD were detected in the distal ileum in all 13 patients,also visualized by both SICUS and CTE in all 13 patients.Ileal lesions > 10 cm length were detected at surgery in all the 13 CD patients,confirmed by SICUS and CTE in the same 12 out of the 13 patients.When using surgical findings as a gold standard,SICUS and CTE showed the exactly same sensitivity,specificity and accuracy for detecting the presence of small bowel fistulae(accuracy 77% for both) and abscesses(accuracy 85% for both).In the tested CD population,SICUS and CTE were also quite comparable in terms of accuracy for detecting the presence of small bowel strictures(92% vs 100%),small bowel fistulae(77% for both) and small bowel dilation(85% vs 82%).CONCLUSION:In our study population,CTE and the non-invasive and radiation-free SICUS showed a comparable high accuracy for assessing small bowel lesions in CD.
文摘AIM: To evaluate the protective effects on kidney tissue of frequently used intravenous anesthetics (ketamine, propofol, thiopental, and fentanyl) in rats with obstructive jaundice.
基金Supported by Wholly granted from R and D, CMD Pharma Limited, United Kingdom
文摘AIM:To assess the safety and effect of the supplementation of a patented blend of dietary phytoestrogens and insoluble fibers on estrogen receptor (ER)-β and biological parameters in sporadic colonic adenomas. METHODS:A randomized, double-blind placebo-controlled trial was performed. Patients scheduled to undergo surveillance colonoscopy for previous sporadic colonic adenomas were identified, and 60 eligible patients were randomized to placebo or active dietary intervention (ADI) twice a day, for 60 d before surveillance colonoscopy. ADI was a mixture of 175 mg milk thistle extract, 20 mg secoisolariciresinol and 750 mg oat fiber extract. ER-β and ER-α expression, apoptosis and proliferation (Ki-67 LI) were assessed in colon samples. RESULTS:No adverse event related to ADI was recorded. ADI administration showed a significant increases in ER-β protein (0.822 ± 0.08 vs 0.768 ± 0.10, P = 0.04) and a general trend to an increase in ER-β LI (39.222 ± 2.69vs 37.708 ± 5.31,P = 0.06), ER-β/ER-α LI ratio (6.564 ± 10.04 vs 2.437 ± 1.53, P = 0.06), terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (35.592 ± 14.97 vs 31.541 ± 11.54, P = 0.07) and Ki-67 (53.923 ± 20.91 vs 44.833 ± 10.38, P = 0.07) approximating statistical significance. A significant increase of ER-β protein (0.805 ± 0.13 vs 0.773 ± 0.13,P = 0.04), mRNA (2.278 ± 1.19vs 1.105 ± 1.07, P < 0.02) and LI (47.533 ± 15.47 vs 34.875 ± 16.67,P < 0.05) and a decrease of ER-α protein (0.423 ± 0.06vs 0.532 ± 0.11,P < 0.02) as well as a trend to increase of ER-β/ER-α protein in ADI vs placebo group were observed in patients without polyps (1.734 ± 0.20 vs 1.571 ± 0.42, P = 0.07). CONCLUSION:The role of ER-β on the control of apoptosis, and its amenability to dietary intervention, are supported in our study.
文摘AIM:To investigate the progression of hepatic histopathology in serial liver biopsies from Wilson disease(WD)patients.METHODS:We report a group of 12 WD patients treated with zinc and/or penicillamine who underwent multiple follow-up liver biopsies.Demographic,clinical and laboratory data were gathered and all patients underwent an initial biopsy and at least one repeat biopsy.RESULTS:Time to repeat biopsy ranged from 2 to 12 years.Six patients(non-progressors)showed stable hepatic histology or improvement.In one case,we observed improvement of fibrosis from stage 2 to 0.Six patients(progressors)had worsening of fibrosis.There was no significant correlation between the histological findings and serum aminotransferases or copper me-tabolism parameters.The hepatic copper concentration reached normal levels in only two patients:one from the non-progressors and one from the progressors group.The estimated rate of progression of hepatic fibrosis in the entire group was 0 units per year in the time frame between the first and the second liver biopsy(4 years),and 0.25 between the second and the third(3 years).In the progressors group,the rate of progression of liver fibrosis was estimated at 0.11 fibrosis units per year between the first and second biopsy and,0.6 fibrosis units between the second and third biopsy.CONCLUSION:The inability of clinical tools to detect fibrosis progression in WD suggests that a liver biopsy with hepatic copper quantification every 3 years should be considered.
