Pathogenesis of alcoholic liver disease:Role of oxidative metabolism

Alcohol consumption is a predominant etiological factor in the pathogenesis of chronic liver diseases, resulting in fatty liver, alcoholic hepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma (HCC). Although the pathogenesis of alcoholic liver disease (ALD) involves complex and still unclear biological processes, the oxidative metabolites of ethanol such as acetaldehyde and reactive oxygen species (ROS) play a preeminent role in the clinical and pathological spectrum of ALD. Ethanol oxidative metabolism influences intracellular signaling pathways and deranges the transcriptional control of several genes, leading to fat accumulation, fibrogenesis and activation of innate and adaptive immunity. Acetaldehyde is known to be toxic to the liver and alters lipid homeostasis, decreasing peroxisome proliferator-activated receptors and increasing sterol regulatory element binding protein activity via an AMP-activated protein kinase (AMPK)-dependent mechanism. AMPK activation by ROS modulates autophagy, which has an important role in removing lipid droplets. Acetaldehyde and aldehydes generated from lipid peroxidation induce collagen synthesis by their ability to form protein adducts that activate transforming-growth-factor-β-dependent and independent profibrogenic pathways in activated hepatic stellate cells (HSCs). Furthermore, activation of innate and adaptive immunity in response to ethanol metabolism plays a key role in the development and progression of ALD. Acetaldehyde alters the intestinal barrier and promote lipopolysaccharide (LPS) translocation by disrupting tight and adherent junctions in human colonic mucosa. Acetaldehyde and LPS induce Kupffer cells to release ROS and proinflammatory cytokines and chemokines that contribute to neutrophils infiltration. In addition, alcohol consumption inhibits natural killer cells that are cytotoxic to HSCs and thus have an important antifibrotic function in the liver. Ethanol metabolism may also interfere with cell-mediated adaptive immunity by impairing proteasome function in macrophages and dendritic cells, and consequently alters allogenic antigen presentation. Finally, acetaldehyde and ROS have a role in alcohol-related carcinogenesis because they can form DNA adducts that are prone to mutagenesis, and they interfere with methylation, synthesis and repair of DNA, thereby increasing HCC susceptibility.

Molecular mechanism of hepatitis B virus-induced hepatocarcinogenesis

Hepatitis B virus(HBV) infection is a global public health problem with approximately 2 billion people that have been exposed to the virus. HBV is a member of a family of small, enveloped DNA viruses called hepadnaviruses, and has a preferential tropism for hepatocytes of mammals and birds. Epidemiological studies have proved a strong correlation between chronic hepatitis B virus infection and the development of hepatocellular carcinoma(HCC). HCC is the fifth most common malignancy with about 700000 new cases each year, and more than 50% of them arise in HBV carriers. A large number of studies describe the way in which HBV can contribute to HCC development. Multiple mechanisms have been proposed, including the accumulation of genetic damage due to immune-mediated hepatic inflammation and the induction of oxidative stress. There is evidence of the direct effects of the viral proteins HBx and HBs on the cell biology. Integration of HBV-DNAinto the human genome is considered an early event in the carcinogenic process and can induce, through insertional mutagenesis, the alteration of gene expression and chromosomal instability. HBV has also epigenetic effects through the modification of the genomic methylation status. Furthermore, the virus plays an important role in the regulation of microRNA expression. This review will summarize the many mechanisms involved in HBV-related liver carcinogenesis.

Peroxisome proliferator activated receptors at the crossroad of obesity, diabetes, and pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is the fourth cause of cancer death with an overall survival of 5% at five years. The development of PDAC is characteristically associated to the accumulation of distinctive genetic mutations and is preceded by the exposure to several risk factors. Epidemiology has demonstrated that PDAC risk factors may be non-modifiable risks (sex, age, presence of genetic mutations, ethnicity) and modifiable and co-morbidity factors related to the specific habits and lifestyle. Recently it has become evident that obesity and diabetes are two important modifiable risk factors for PDAC. Obesity and diabetes are complex systemic and intertwined diseases and, over the years, experimental evidence indicate that insulin-resistance, alteration of adipokines, especially leptin and adiponectin, oxidative stress and inflammation may play a role in PDAC. Peroxisome proliferator activated receptor-γ (PPARγ) is a nuclear receptor transcription factor that is implicated in the regulation of metabolism, differentiation and inflammation. PPARγ is a key regulator of adipocytes differentiation, regulates insulin and adipokines production and secretion, may modulate inflammation, and it is implicated in PDAC. PPARγ agonists are used in the treatment of diabetes and oxidative stress-associated diseases and have been evaluated for the treatment of PDAC. PPARγ is at the cross-road of diabetes, obesity, and PDAC and it is an interesting target to pharmacologically prevent PDAC in obese and diabetic patients.

Nuclear receptors and pathogenesis of pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a median overall survival time of 5 mo and the five years survival less than 5%, a rate essentially unchanged over the course of the years. A well defined progression model of accumulation of genetic alterations ranging from single point mutations to gross chromosomal abnormalities has been introduced to describe the origin of this disease. However, due to the its subtle nature and concurring events PDAC cure remains elusive. Nuclear receptors (NR) are members of a large superfamily of evolutionarily conserved ligand-regulated DNA-binding transcription factors functionally involved in important cellular functions ranging from regulation of metabolism, to growth and development. Given the nature of their ligands, NR are very tempting drug targets and their pharmacological modulation has been widely exploited for the treatment of metabolic and inflammatory diseases. There are now clear evidences that both classical ligand-activated and orphan NR are involved in the pathogenesis of PDAC from its very early stages; nonetheless many aspects of their role are not fully understood. The purpose of this review is to highlight the striking connections that link peroxisome proliferator activated receptors, retinoic acid receptors, retinoid X receptor, androgen receptor, estrogen receptors and the orphan NR Nur, chicken ovalbumin upstream promoter transcription factor II and the liver receptor homologue-1 receptor to PDAC development, connections that could lead to the identification of novel therapies for this disease.

Antidiabetic thiazolidinediones induce ductal differentiation but not apoptosis in pancreatic cancer cells

AIM: Thiazolidinediones (TZD) are a new class of oral antidiabetic drugs that have been shown to inhibit growth of same epithelial cancer cells. Although TZD were found to be ligands for peroxisome proliferator-activated receptor γ (PPARγ), the mechanism by which TZD exert their anticancer effect is presently unclear. In this study, we analyzed the mechanism by which TZD inhibit growth of human pancreatic carcinoma cell lines in order to evaluate the potential therapeutic use of these drugs in pancreatic adenocarcinoma. METHODS: The effects of TZD in pancreatic cancer cells were assessed in anchorage-independent growth assay. Expression of PPARy was measured by reverse-transcription polymerase chain reaction and confirmed by Western blot analysis. PPARy activity was evaluated by transient reporter gene assay. Flow cytometry and DMA fragmentation,assay were used to determine the effect of TZD on cell cycle progression and apoptosis respectively. The effect of TZD on ductal differentiation markers was performed by Western blot. RESULTS: Exposure to TZD inhibited colony formation in a PPARγ-dependent manner. Growth inhibition was linked to G1 phase cell cycle arrest through induction of the ductal differentiation program without any increase of the apoptotic rate. CONCLUSION: TZD treatment in pancreatic cancer cells has potent inhibitory effects on growth by a PPAR-dependent induction of pacreatic ductal differentiation.

Effect of a counseling-supported treatment with the Mediterranean diet and physical activity on the severity of the non-alcoholic fatty liver disease

AIM To determine the clinical effectiveness of nutritional counseling on reduction of non-alcoholic fatty liver disease(NAFLD) severity, weight loss, metabolic and anthropometric indexes and liver enzymes.METHODS Forty-six adults with NAFLD received a 6-mo clinical and a dietary intervention(based on Mediterranean diet) carried out respectively by a gastroenterologist and a nutritionist with counseling license. The counseling process consisted of monthly meeting(about 45 min each). The effect of the treatment was evaluated monitoring liver enzymes, metabolic parameters, cardiovascular risk indexes, NAFLD severity [assessed by ultrasound(US)] and related indexes. All parameters were assessed at baseline. Biochemistry was also assessed at mid-and end-interventions and US was repeated at end-intervention.RESULTS The percentage of patients with steatosis grade equal or higher than 2 was reduced from 93% to 48% and steatosis regressed in 9 patients(20%). At the end of the treatment the end-point concerning the weight(i.e., a 7% weight reduction or achievement/maintenance of normal weight) was accomplished by 25 out of 46 patients(i.e., 54.3%). As far as the liver enzymes is concerned, all three liver enzymes significantly decrease during the treatment the normalization was particularly evident for the ALT enzyme(altered values reduced from 67% down to 11%). Several parameters, i.e., BMI, waist circumference, waist-to-hip ratio, AST, ALT, GGT, HDL, serum glucose, Tot-Chol/HDL, LDL/HDL, TG/HDL, AIP, HOMA, FLI, Kotronen index, VAI, NAFLD liver fat score and LAP, showed a significant improvement(P < 0.01) between baseline and end-treatment.CONCLUSION Outcomes of this study further strengthen the hypothesis that Med Diet and more active lifestyle can be considered a safe therapeutic approach for reducing risk and severity of NAFLD and related disease states. The proposed approach may be proposed as a valid and recommended approach for improving the clinical profile of NAFLD patients.

Chemotherapy for hepatocellular carcinoma:The present and the future

Hepatocellular carcinoma(HCC) is the most common primary tumor of the liver. Its relationship to chronic liver diseases, in particular cirrhosis, develops on a background of viral hepatitis, excessive alcohol intake or metabolic steatohepatitis, leads to a high incidence and prevalence of this neoplasia worldwide. Despite the spread of HCC, its treatment it's still a hard challenge, due to high rate of late diagnosis and to lack of therapeutic options for advanced disease. In fact radical surgery and liver transplantation, the most radical therapeutic approaches, are indicated only in case of early diagnosis. Even local therapies, such as transarterial chemoembolization, find limited indications, leading to an important problem regarding treatment of advanced disease. In this situation, until terminal HCC occurs, systemic therapy is the only possible approach, with sorafenib as the only standard treatment available. Anyway, the efficacy of this drug is limited and many efforts are necessary to understand who could benefit more with this treatment. Therefore, other molecules for a targeted therapy were evaluated, but only regorafenib showed promising results. Beside molecular target therapy, also cytotoxic drugs, in particular oxaliplatinand gemcitabine-based regimens, and immune-checkpoint inhibitors were tested with interesting results. The future of the treatment of this neoplasia is linked to our ability to understand its mechanisms of resistance and to find novel therapeutic targets, with the objective to purpose individualized approaches to patients affected by advanced HCC.

Hyperhomocysteinemia and hypercoagulability in primary biliary cirrhosis

AIM： To assess the hypercoagulability in PBC and its relationship with homocysteine （HCY） and various components of the haemostatic system. METHODS： We investigated 51 PBC patients （43F/8M; mean age： 63±13.9 yr） and 102 healthy subjects （86 women/16 men, 63±13 yr）, and evaluated the haemostatic process in whole blood by the Sonoclot analysis and the platelet function by PFA-100 device. We then measured HCY （fasting and after methionine loading）, tissue factor （TF）, thrombin-antithrombin complexes （TAT）, D-dimer （D-D）, thrombomodulin （TH）, folic acid, vitamin B6 and B12 plasma levels. C677T 5,10-methylenetetrahydrofolate reductase （HTHFR） polymorphism was analyzed. RESULTS： Sonoclot RATE values of patients were significantly （P〈 0.001） higher than those of controls. Sonoclot time to peak values and PFA-100 closure times were comparable in patients and controls. TAT, TF and HCY levels, both in the fasting and post-methionine loading, were significantly （P〈0.001） higher in patients than in controls. Vitamin deficiencies were detected in 45/51 patients （88.2%）. The prevalence of the homozygous TT677 MTHFR genotype was significantly higher in patients （31.4%） than in controls （17.5%） （P〈 0.05）. Sonodot RATE values correlated significantly with HCY levels and TF.CONCLUSION： In PBC, hyper-HCY is related to hypovitaminosis and genetic predisposing factors. Increased TF and HCY levels and signs of endothelial activation areassociated with hypercoagulability and may have an important role in blood clotting activation.

Clinical epidemiology of chronic viral hepatitis B:A Tuscany real-world large-scale cohort study

AIM To build a regional database of chronic patients to define the clinical epidemiology of hepatitis B virus(HBV)-infected patients in the Tuscan public health care system.METHODS This study used a cross-sectional cohort design. We evaluated chronic viral hepatitis patients with HBV referred to the outpatient services of 16 hospital units. Information in the case report forms included main demographic data, blood chemistry data, viral hepatitis markers, instrumental evaluations, and eligibility for treatment or ongoing therapy and liver transplantation. RESULTS Of 4015 chronic viral hepatitis patients, 1096(27.3%) were HBV infected. The case report form was correctly completed for only 833 patients(64% males, 36% females; mean age 50.1 ± 15.4). Of these HBV-infected patients, 73% were Caucasian, 21% Asian, 4% Central African, 1% North African and 1% American. Stratifying patients by age and nationality, we found that 21.7% of HBV-infected patients were aged < 34 years(only 2.8% were Italian). The most represented routes of transmission were nosocomial/dental procedures(23%), mother-to-child(17%) and sexual transmission(12%). The most represented HBV genotypes were D(72%) and A(14%). Of the patients, 24.7% of patients were HBe Ag positive, and 75.3% were HBe Ag negative. Of the HBV patients 7% were anti-HDV positive. In the whole cohort, 26.9% were cirrhotic(35.8% aged < 45 years), and 47% were eligible for or currently undergoing treatment, of whom 41.9 % were cirrhotic. CONCLUSION Only 27.3% of chronic viral hepatitis patients were HBV infected. Our results provide evidence of HBV infection in people aged < 34 years, especially in the foreign population not protected by vaccination. In our cohort of patients, liver cirrhosis was also found in young adults.

New constraints on the P-T path of HT/UHT metapelites from the Highland Complex of Sri Lanka

We report here rare evidence for the early prograde P-Tevolution of garnet-sillimanite-graphite gneiss(khondalite)from the central Highland Complex,Sri Lanka.Four types of garnet porphyroblasts(Grt_1,Grt_2,Grt_3 and Grt_4)are observed in the rock with specific types of inclusion features.Only Grt_3 shows evidence for non-coaxial strain.Combining the information shows a sequence of main inclusion phases,from old to young:oriented quartz inclusions at core,staurolite and prismatic sillimanite at mantle,kyanite and kyanite pseudomorph,and biotite at rim in Grt_1;fibrolitic sillimanite pseudomorphing kyanite±corundum,kyanite,and spinel+sillimanite after garnet+corundum in Grt_2;biotite,sillimanite,quartz±spinel in Grt_3;and ilmenite,rulite,quartz and sillimanite in Grt_4.The pre-melting,original rock composition was calculated through stepwise re-integration of melt into the residual,XRF based composition,allowing the early prograde metamorphic evolution to be deduced from petrographical observations and pseudosections.The earliest recognizable stage occurred in the sillimanite field at around 575℃ at 4.5 kbar.Subsequent collision associated with Gondwana amalgamation led to crustal thickening along a P-T trajectory with an average dP/dT of ~30 bar/℃ in the kyanite field,up to ~660℃ at 6.5 kbar,before crossing the wet-solidus at around 675 ℃ at 7.5 kbar.The highest pressure occurred at P > 10 kbar and T around 780℃ before prograde decompression associated with further heating.At 825℃ and 10.5 kbar,the rock re-entered into the sillimanite field.The temperature peaked at 900℃ at ca.9-9.5 kbar.Subsequent near-isobaric cooling led to the growth of Grt_4 and rutile at T ~880℃.Local pyrophyllite rims around sillimanite suggest a late stage of rehydration at T<400℃,which probably occurred after uplift to upper crustal levels.U-Pb dating of zircons by LAICPMS of the khondalite yielded two concordant ^(206)Pb/^(238)U age groups with mean values of 542±2 Ma(MSWD=0.24,Th/U=0.01-0.03)and 514±3 Ma(MSWD=0.50,Th/U=0.01-0.05)interpreted as peak metamorphism of the khondalite and subsequent melt crystallization during cooling.

Main factors influencing long-term outcomes of liver transplantation in 2022

Liver transplant(LT)outcomes have markedly improved in the recent decades,even if long-term morbidity and mortality are still considerable.Most of late deaths are independent from graft function and different comorbidities,including complications of metabolic syndrome and de novo neoplasms,seem to play a key role in determining long-term outcomes in LT recipients.This review discusses the main factors associated with late mortality and suggests possible strategies to improve long-term management and follow-up after liver transplantation.In particular,the reduction of drug toxicity,the use of tools to identify high-risk patients,and setting up a multidisciplinary team also for long-term management of LT recipients may further improve survival after liver transplantation.

Gastric and duodenal polyps in familial adenomatous polyposis patients: Conventional endoscopy vs virtual chromoendoscopy(fujinon intelligent color enhancement) in dysplasia evaluation

AIM To test the fujinon intelligent color enhancement(FICE) in identifying dysplastic or adenomatous polyps in familial adenomatous polyposis(FAP) patients.METHODS Seventy-six consecutive FAP patients, already treated by colectomy and members of sixty-five families, were enrolled. A FICE system for the upper gastro-intestinal tract with an electronic endoscope system and a standard duodenoscope(for side-viewing examination) were used by two expert examiners. Endoscopic resection was performed with diathermic loop for polyps ≥ 6 mm and with forceps for polyps < 6 mm. Formalin-fixed biopsy specimens were analyzed by two expert gastrointestinal pathologists blinded to size, location and number of FAPassociated fundic gland polyps.RESULTS Sixty-nine(90.8%) patients had gastric polyps(34 only in the corpus-fundus, 7 only in the antrum and 28 in the whole stomach) and 52(68.4%) in duodenum(7 in the bulb, 35 in second/third duodenal portion, 10 both in the bulb and the second portion of duodenum). In the stomach fundus after FICE evaluation, 10 more polyps were removed from 10 patients for suspicious features of dysplasia or adenomas, but they were classified as cystic fundic gland after histology. In the antrum FICE identified more polyps than traditional endoscopy, showing a better tendency to identify adenomas and displastic areas. In the duodenum FICE added a significant advantage in identifying adenomas in the bulb and identified more polyps in the Ⅱ/Ⅲ portion.CONCLUSION FICE significantly increases adenoma detection rate in FAP patients but does not change any Spigelman stage and thus does not modify patient's prognosis and treatment strategies.

Distinct metamorphic evolution of alternating silica-saturated and silica-deficient microdomains within garnet in ultrahigh-temperature granulites: An example from Sri Lanka

Here we report the occurrence of garnet porphyroblasts that have overgrown alternating silica-saturated and silica deficient microdomains via different mineral reactions. The samples were collected from ultrahigh-temperature(UHT) metapelites in the Highland Complex, Sri Lanka. In some of the metapelites, garnet crystals have cores formed via a dehydration reaction, which had taken place at silicasaturated microdomains and mantle to rim areas formed via a dehydration reaction at silica-deficient microdomains. In contrast, some other garnets in the same rock cores had formed via a dehydration reaction which occurred at silica-deficient microdomains while mantle to rim areas formed via a dehydration reaction at silica-saturated microdomains. Based on the textural observations, we conclude that the studied garnets have grown across different effective bulk compositional microdomains during the prograde evolution. These microdomains could represent heterogeneous compositional layers(paleobedding/laminations) in the precursor sediments or differentiated crenulation cleavages that existed during prograde metamorphism. UHT metamorphism associated with strong ductile deformation, metamorphic differentiation and crystallization of locally produced melt may have obliterated the evidence for such microdomains in the matrix. The lack of significant compositional zoning in garnet probably due to self-diffusion during UHT metamorphism had left mineral inclusions as the sole evidence for earlier microdomains with contrasting chemistry.

Telomerase activity: An attractive target for cancer therapeutics

Telomeres are non-coding tandem repeats of 1000-2000 TTAGGG nucleotide DNA sequences on the 3’ termini of human chromosomes where they serve as protective “caps” from degradation and loss of genes. The “cap” at the end of chromosome required to protect its integ-rity is a 150-200 nucleotide-long single stranded G-rich 3’ overhang that forms two higher order structures, a T-loop with Sheltering complex, or a G-quadruplex com-plex. Telomerase is a human ribonucleoprotein reverse transcriptase that continually added single stranded TTAGGG DNA sequences onto the single strand 3’ of telomere in the 5’ to 3’ direction. Telomerase activity is detected in male germ line cells, proliferative cells of renewal tissues, some adult pluripotent stem cells, embryonic cells, but in most somatic cells is not de-tected. Re-expression or up-regulation of telomerase in tumours cells is considered as a critical step in cell tumorigenesis and telomerase is widely considered as a tumour marker and a target for anticancer drugs. Dif-ferent approaches have been used in anticancer thera-peutics targeting telomerase. Telomerase inhibitors can block directly Human TElomerase Reverse Transcrip-tase （hTERT） or Human TElomerase RNA telomerase subunits activity, or G-quadruplex and Sheltering complex components, shortening telomeres and inhibiting cell proliferation. Telomerase can become an immune target and GV1001, Vx-001, I540 are the most wide-spread vaccines used with encouraging results. Another method is to use hTERT promoter to drive suicide gene expression or to control a lytic virus replication. Recently telomerase activity was used to activate pro-drugs such as Acycloguanosyl 5’-thymidyltriphosphate, a synthetic ACV-derived molecule when it is activated by telomer-ase it does not require any virus or host active immune response to induce suicide gene therapy. Advantage of all these therapies is that target only neoplastic cells without any effects in normal cells, avoiding toxicity and adverse effects of the current chemotherapy. However, as not all the approaches are equally effcient, further studies will be necessary.

Practical insights into chronic management of hepatic Wilson’s disease

Wilson’s disease(WD)is a rare inherited disorder of human copper metabolism,with an estimated prevalence of 1:30000-1:50000 and a broad spectrum of hepatic and neuropsychiatric manifestations.In healthy individuals,the bile is the main route of elimination of copper.In WD patients,copper accumulates in the liver,it is released into the bloodstream,and is excreted in urine.Copper can also be accumulated in the brain,kidneys,heart,and osseous matter and causes damage due to direct toxicity or oxidative stress.Hepatic WD is commonly but not exclusively diagnosed in childhood or young adulthood.Adherent,non-cirrhotic WD patients seem to have a normal life expectancy.Nevertheless,chronic management of patients with Wilson’s disease is challenging,as available biochemical tests have many limitations and do not allow a clear identification of non-compliance,overtreatment,or treatment goals.To provide optimal care,clinicians should have a complete understanding of these limitations and counterbalance them with a thorough clinical assessment.The aim of this review is to provide clinicians with practical tools and suggestions which may answer doubts that can arise during chronic management of patients with hepatic WD.In particular,it summarises current knowledge on Wilson’s disease clinical and biochemical monitoring and treatment.It also analyses available evidence on pregnancy and the role of low-copper diet in WD.Future research should focus on trying to provide new copper metabolism tests which could help to guide treatment adjustments.

Muscle fatigue in women with primary biliary cirrhosis:Spectral analysis of surface electromyography

AIM： To evaluate the myoelectric manifestations of peripheral fatigability in patients with primary biliary cirrhosis in comparison to healthy subjects. METHODS： Sixteen women with primary biliary cirrhosis without comorbidity and 13 healthy women matched for age and body mass index （BMI） completed the selfreported questionnaire fatigue impact scale. All subjects underwent surface electromyography assessment of peripheral fatigability. Anterior tibial muscle isometric voluntary contraction was executed for 20 s at 80% of maximal voluntary isometric contraction. During the exercise electromyographic signal series were recorded and root mean square （expression of central drive） as well as mean and median of electromyographic signal frequency spectrum （estimates of muscle fatigability） were com- puted. Each subject executed the trial two times. EMG parameters were normalized, then linear regression was applied and slopes were calculated. RESULTS： Seven patients were fatigued （median fatigue impact scale score： 38, range： 26-66） and 9 were not fatigued （median fatigue impact scale score： 7, range： 0-17）. The maximal voluntary isometric contraction was similar in patients （82, 54-115 N） and controls （87, 74-101 N）, and in patients with high （81, 54-115 N） and low fatigue impact scale scores （86, 65-106 N）. Root mean square as well as mean and median of frequency spectrum slopes were compared with the Mann-Whitney U test, and no significant difference was found between fatigued and non-fatigued patients and controls. CONCLUSION： No instrumental evidence of peripheral fatigability can be found in women with primary biliary cirrhosis but no comorbidity, suggesting that fatigue in such patients may be of central origin.

Therapeutic usability of two different fiducial gold markers for robotic stereotactic radiosurgery of liver malignancies:A pilot study

AIM: To assess how the application of different types of markers affects the tracking accuracy of Cyber Knife's.METHODS: Fifteen patients were recruited and subjected to the ultrasound-guided placement of markers. Two different type of needles 25 gauge(G) and 17 G containing two different fiducial marker, gold notched flexible anchor wire 0.28 mm × 10 mm(25 G needle) and gold cylindrical grain 1 mm × 4 mm(17 G), were used. Seven days after the procedure, a Cyber Knife planning computed tomography(CT) for the simulation of radiation treatment was performed on all patients.A binary CT score was assigned to the fiducial markers visualization. Also, the CT number was calculated for each fiducial and the values compared with a specific threshold.RESULTS: For each patient from 1 to 5, intra-hepatic markers were placed(one in 2 patients, three in 8 patients, four in 3 patients, and five in 2 patients). A total of 48 needles were used(thirty-two 17 G and sixteen 25 G) and 48 gold markers were placed(32 Grain shaped markers and 16 Gold Anchor). The result showed that the CT visualization of the grain markers was better than the anchor markers(P = 5 × 10^(-9)). Furthermore, the grain markers were shown to present minor late complications(P = 3 × 10^(-6)), and the best CT threshold number(P = 0.0005). CONCLUSION: The study revealed that the Gold Anchor fiducial marker is correlated with a greater number of late minor complications and low visualization by the CT.

Telomerase reactivation is associated with hepatobiliary and pancreatic cancers

Background:Human telomerase reverse transcriptase(hTERT)and its components play a significant role in cancer progression,but recent data demonstrated that telomeres and telomerase alterations could be found in other diseases;increasing evidence suggests a key role of this enzyme in the fields of hepatobiliary and pancreatic diseases.Data sources:We performed a PubMed search with the following keywords:telomerase,hepatocellular carcinoma,cholangiocarcinoma,pancreatic adenocarcinoma by December 2019.We reviewed the relevant publications that analyzed the correlation between telomerase activity and hepatobiliary and pancreatic diseases.Results:Telomerase reactivation plays a significant role in the development and progression of hepatobiliary and pancreatic tumors and could be used as a diagnostic biomarker for hepatobiliary and pancreatic cancers,as a predictor for prognosis and a promising therapeutic target.Conclusions:Our review summarized the evidence about the critical role of hTERT in cancerous and precancerous lesions of the alteration and its activity in hepatobiliary and pancreatic diseases.

Higher volume growth rate is associated with development of worrisome features in patients with branch duct-intraductal papillary mucinous neoplasms

BACKGROUND Branch duct-intraductal papillary mucinous neoplasms(BD-IPMNs)are the most common pancreatic cystic tumours and have a low risk of malignant transformation.Current guidelines only evaluate cyst diameter as an important risk factor but it is not always easy to measure,especially when comparing different methods.On the other side,cyst volume is a new parameter with low interobserver variability and is highly reproducible over time.AIM To assess both diameter and volume growth rate of BD-IPMNs and evaluate their correlation with the development of malignant characteristics.METHODS Computed tomography scans and magnetic resonance imaging exams were retrospectively reviewed.The diameter was measured on three planes,while the volume was calculated by segmentation:The volume of the entire cyst was determined by manually drawing a region of interest along the edge of the neoplasm on each consecutive slice covering the whole lesion;therefore,a threedimensional volume of interest was finally obtained with the calculated value expressed in cm^(3).Changes in size over time were measured.The development of worrisome features was evaluated.RESULTS We evaluated exams of 98 patients across a 40.5-mo median follow-up time.Ten patients developed worrisome features.Cysts at baseline were significantly larger in patients who developed worrisome features(diameters P=0.0035,P=0.00652,P=0.00424;volume P=0.00222).Volume growth rate was significantly higher in patients who developed worrisome features(1.12 cm^(3)/year vs 0 cm^(3)/year,P=0.0001);diameter growth rate was higher as well,but the difference did not always reach statistical significance.Volume but not diameter growth rate in the first year of follow-up was higher in patients who developed worrisome features(0.46 cm^(3)/year vs 0 cm^(3)/year,P=0.00634).CONCLUSION The measurement of baseline volume and its variation over time is a reliable tool for the follow-up of BD-IPMNs.Volume measurement could be a better tool than diameter measurement to predict the development of worrisome features.

Understanding fatigue in primary biliary cholangitis:From pathophysiology to treatment perspectives

Fatigue is considered one of the most frequent and debilitating symptoms in primary biliary cholangitis(PBC),affecting over 50%of PBC patients.One in five patients with PBC suffer from severe fatigue,which significantly impairs quality of life.Fatigue is made up of a central and a peripheral component,whose pathophysiology is still greatly unresolved.Central fatigue is characterised by a lack of self-motivation and can manifest both in physical and mental activities(lack of intention).Peripheral fatigue includes neuromuscular dysfunction and muscle weakness(lack of ability).Peripheral fatigue could be explained by an excessive deviation from aerobic to anaerobic metabolism leading to excessive lactic acid accumulation and therefore accelerated decline in muscle function and prolonged recovery time.As opposed to itching,and with the exception of endstage liver disease,fatigue is not related to disease progression.The objective of this review is to outline current understanding regarding the pathophysiology of fatigue,the role of comorbidities and contributing factors,the main tools for fatigue assessment,the failed therapeutic options,and future treatment perspectives for this disabling symptom.Since fatigue is an extremely common and debilitating symptom and there is still no licensed therapy for fatigue in PBC patients,further research is warranted to understand its causative mechanisms and to find an effective treatment.