Cholangiocarcinoma landscape in Europe: Diagnostic, prognostic and therapeutic insights from the ENSCCA Registry

Journal of Hepatology, Год журнала: 2022, Номер 76(5), С. 1109 - 1121

Опубликована: Фев. 12, 2022

Cholangiocarcinoma (CCA) is a rare and heterogeneous biliary cancer, whose incidence related mortality increasing. This study investigates the clinical course of CCA subtypes (intrahepatic [iCCA], perihilar [pCCA], distal [dCCA]) in pan-European cohort.The ENSCCA Registry multicenter observational study. Patients were included if they had histologically proven diagnosis between 2010-2019. Demographic, histomorphological, biochemical, studies performed.Overall, 2,234 patients enrolled (male/female=1.29). iCCA (n = 1,243) was associated with overweight/obesity chronic liver diseases involving cirrhosis and/or viral hepatitis; pCCA 592) primary sclerosing cholangitis; dCCA 399) choledocholithiasis. At diagnosis, 42.2% local disease, 29.4% locally advanced disease (LAD), 28.4% metastatic (MD). Serum CEA CA19-9 showed low diagnostic sensitivity, but their concomitant elevation increased risk presenting LAD (odds ratio 2.16; 95% CI 1.43-3.27) or MD 5.88; 3.69-9.25). undergoing resection (50.3%) best outcomes, particularly negative-resection margin (R0) (median overall survival [mOS] 45.1 months); however, involvement (R1) (hazard 1.92; 1.53-2.41; mOS 24.7 months) lymph node invasion 2.13; 1.55-2.94; 23.3 compromised prognosis. Among unresectable (49.6%), 10.6 months for those receiving active palliative therapies, mostly chemotherapy (26.2%), 4.0 supportive care (20.6%). iCCAs worse outcomes than p/dCCAs. ECOG performance status, independent prognostic factors.CCA frequently diagnosed at an stage, proportion fail to receive cancer-specific prognosis remains dismal. Identification preventable factors implementation surveillance high-risk populations are required decrease cancer-related mortality.This is, date, largest international (pan-European: 26 hospitals 11 countries) study, which cholangiocarcinoma has been investigated, comparing 3 based on latest International Classification Diseases 11th Edition (ICD-11) (i.e., intrahepatic [2C12], [2C18], [2C15] affected bile ducts), come into effect 2022. General tumor-type specific features factors, biomarker accuracy, as well patient management presented compared, outlining current state Europe.

Язык: Английский

---

Lipid alterations in chronic liver disease and liver cancer

JHEP Reports, Год журнала: 2022, Номер 4(6), С. 100479 - 100479

Опубликована: Март 26, 2022

Lipids are a complex and diverse group of molecules with crucial roles in many physiological processes, as well the onset, progression, maintenance cancers. Fatty acids cholesterol building blocks lipids, orchestrating these metabolic processes. In liver, lipid alterations prevalent cause consequence chronic hepatitis B C virus infections, alcoholic hepatitis, non-alcoholic fatty liver disease steatohepatitis. Recent developments lipidomics have also revealed that dynamic changes triacylglycerols, phospholipids, sphingolipids, ceramides, acids, involved development progression primary cancer. Accordingly, transcriptional landscape metabolism suggests carcinogenic role increasing sterol synthesis. However, limited mechanistic insights into nature hepatic lipidome so far hindered effective therapies.

Язык: Английский

---

AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma

Hepatology, Год журнала: 2022, Номер 77(2), С. 659 - 702

Опубликована: Сен. 9, 2022

WHAT'S NEW SINCE THE 2010 GUIDELINES? Inclusion of guidance for the diagnosis and management cholangiocarcinoma (CCA) in patients with without primary sclerosing cholangitis (PSC) (Figures 5, 8, 9). Introduction term relevant stricture, defined as any biliary stricture common hepatic duct or ducts associated signs symptoms obstructive cholestasis and/or bacterial (Table 1). In equivocal MRI cholangiopancreatography (MRI/MRCP) findings, a repeated high‐quality MRI/MRCP should be performed diagnostic purposes. Endoscopic retrograde (ERCP) avoided PSC (Figure 2). known inflammatory bowel disease (IBD), colonoscopy histological sampling may every 5 years if IBD is not initially detected. Colon cancer surveillance begin at age 15 IBD. New clinical risk tools are available stratification, but probabilities events individual interpreted caution 4 Table 3). All considered participation trials; however, ursodeoxycholic acid (13–23 mg/kg/day) can continued well tolerated meaningful improvement alkaline phosphatase (γ‐glutamyl transferase children) 12 months treatment. ERCP brushings cytology fluorescent situ hybridization analysis obtained all suspected perihilar distal CCA. There new United Network Organ Sharing policy regarding standardization Model End‐Stage Liver Disease exceptions recurrent cholangitis. transplantation following neoadjuvant therapy recommended CCA < 3 cm radial diameter that unresectable arising setting absence intrahepatic extrahepatic metastasis TABLE 1 - Definitions Chronic, cholestatic liver likely autoimmune origin characterized by inflammation fibrosis bile ducts, leading to formation strictures, frequently Small‐duct Less variant typical features normal on cholangiography PSC–AIH overlap Concurrent clinical, biochemical, AIH Secondary Biliary strictures due identifiable causes result secondary cirrhosis IgG4 elevated IgG4‐positive plasma cells tissue serum elevation pancreatic involvement Dominant A ≤1.5 mm ≤1 High‐grade >75% reduction Relevant Any INTRODUCTION AND SCOPE OF GUIDANCE Primary cholangiopathy chronic fibroinflammatory damage tree (IBD). The majority have fibrotic cholangiogram, whereas minority small‐duct PSC, cholangiogram biopsy. small percentage overlapping hepatitis (PSC‐AIH). affects both male female individuals occur age. an disease, though pathophysiology remains poorly understood. results damage, cirrhosis, failure recur 20%–30% after transplantation. also significantly increases colorectal (CRC). Currently, there no effective medical research has been challenging, PSC‐specific International Classification Diseases (ICD)‐10 code (K83.01) only approved use since 2018. glossary key definitions, including terminology defining provided 1. This American Association Study (AASLD) provides data‐supported approach It differs from AASLD guidelines, which supported systematic reviews literature, formal rating quality evidence strength recommendations, and, appropriate, meta‐analysis using Grading Recommendations Assessment, Development, Evaluation system. contrast, this was developed consensus expert panel statements based review literature topics, oversight Practice Guidelines Committee stages development. committee chose perform topic because sufficient number randomized controlled trials were support development guideline. addition inclusion CCA, updates guideline include description emphasis imaging rather than endoscopic biopsy, prognostic models noninvasive staging practice, comprehensive PSC. EPIDEMIOLOGY Population‐based epidemiological studies limited. date North America western Europe, where estimates incidence prevalence approximately 1–1.5 cases per 100,000 person‐years 6–16 100,000, respectively.1–10 Some suggested increasing.4,11 Limited data other parts world suggest lower compared States northern Europe.12–15 Within States, African Americans appear affected rates similar Whites.16–18 Peak between ages 25 45 years, median ranging 36 39 years; age.19–21 children, rate estimated 0.2 person‐years.8,22 Overall, men account two thirds PSC; among IBD, predominance much lower.20 Women generally older diagnosis. At least 70%–80% concurrent non‐Europeans children 0.6%–4.3%.18,23–35 PSC‐AIH occurs up 35% 5% adults PSC.36–38 Studies employing universal biopsy screening yielded 8.1%–9.0% adults39,40 15.1% children,41 suggesting tens thousands undiagnosed alone. ETIOLOGY Multiple simultaneous mechanisms lead its progression clear genetic predisposition involving human leukocyte antigen (HLA) variants,42–48 many additional non‐HLA loci implicated.46,49 about environmental risks possible link nonsmoking.25,50,51 Evidence suggests drive being epiphenomenon.52,53 few demonstrated impaired gut barrier PSC,54–56 expanding body dysbiosis intestinal microbial community PSC.57–72 Aberrant trafficking lymphocytes73,74 translocation constituents metabolites67,75,76 proposed induce activation epithelial peribiliary inflammation, consists macrophages,77,78 eosinophils,79–81 T cells.82–84 However, specific immune response yet delineated.85–87 Unconventional mucosa‐associated invariant γδ important recognition pathogens play role PSC88 localize areas fibrosis.84 IL‐17 production implicated animal models,89,90 appears significant well.88,91,92 large gland hyperplasia mesenchymal cells, acquire myofibroblast phenotype.93,94 Strictures reduced flow, increased pressure, alterations composition further progression.95–97 Still unresolved why immunosuppressive colectomy do alter course, perhaps indicating some involved initiation little influence progression.98–101FIGURE 1: Pathogenesis current model pathogenesis involves four major themes background underlying factors. (1) intestine, altered microbiome, inflamed mucosa, "leaky gut." (2) Intestinal lymphocytes, products, metabolites translocate through portal vein directly liver, activating innate adaptive responses. (3) Microbial components act activate perpetuate (4) Peribiliary glands expand, Hedgehog pathway, phenotype large‐duct fibrosis. Abbreviations: BEC, cell; MHC II, histocompatibility complex class II; TLR, toll‐like receptor; Treg, regulatory cell.DIAGNOSIS cholestasis, especially characteristic Careful exclusion required, diagnosed findings compatible presence (see "Histology" section below). variants ATP binding cassette subfamily B member 4, multidrug resistance protein 3, gene excluded.102 histologic cholangiographic overlap, AIH, considered. Conversely, unexplained laboratory nonresponse conventional glucocorticoid therapy.36 2 Etiologies Infectious HIV‐related Recurrent pyogenic Cholangitis lenta subacute nonsuppurative Parasitic • Hydatid cyst Echinococcosis Clonorchiasis opisthorchiasis Ascariasis Fascioliasis Schistosomiasis Ischemic Critically ill Hereditary hemorrhagic telangiectasis Intra‐arterial chemotherapy Hepatic artery thrombosis Malignant Cholangiocarcinoma Diffuse Langerhans cell histiocytosis Lymphoma Autoimmune Eosinophilic pseudotumor IgG4‐associated Mast Sarcoidosis Anatomic Choledocholithiasis Intrahepatic lithiasis Cystic Surgical trauma Anastomotic Portal hypertensive biliopathy pancreatitis Sickle Choledochal Drug‐induced Immunotherapy checkpoint inhibitors Pembrolizumab Nivolumab Atezolizumab FIGURE 2: Diagnostic algorithm Patients careful evaluation history, physical examination, measurement tests, followed MRI/MRCP. cholangitis, diagnostic. Equivocal prompt experienced center consideration repeat year If initial normal, diagnose versus alternative diagnoses.Symptoms Nearly half adult present constant intermittent symptoms, another 22% develop within diagnosis.103 Symptoms fatigue, abdominal pain, fever, pruritus, anxiety depression.21 Pruritus pain fluctuate depending obstruction acute Emotional distress exacerbated idiopathic nature lack therapy, risk.104,105 Assessment itself such fatigue.106 growing interest measuring patient‐reported outcome measures (PROM). Two recent PROMs specifically PSC: PRO Simple Cholestatic Complaints Score107,108; they require validation prior routine use. Biochemical serological tests markers sensitive biochemical profile enzymes, (ALP) γ‐glutamyl (GGT), seen 75% patients.40 Notably, aminotransferases necessarily unless predominant more times upper limit (ULN).109 precise criteria established. Detection autoantibodies, antinuclear, anti–smooth muscle, perinuclear antineutrophil antibodies, highly variable, representing dysregulation state.110,111 contrast (PBC) autoantibodies minimal implications PSC.112 Elevation 15% significance unclear.113,114 High‐titer (> 5.6 g/L) rare IgG4‐sclerosing IgG4/IgG1 ratio 0.24 exclude when 1.4–2.8 g/L.114,115 Imaging first modality PSC.116 scanner minimum 1.5‐Tesla field strength. T2 weighted (T2w), three‐dimensional (3D) (MRCP) 1‐mm slices preferred two‐dimensional MRCP, axial T1‐weighted (T1w) T2w sequences. Enhancement extracellular hepatobiliary agent done change status concerns insufficient recommend one type over another. study artifact blurring third‐order branches beyond delineated.117 Before advent MRI/MRCP, regarded gold standard diagnosing PSC.118 serious complications therapeutic intervention sampling.119 shown comparable accuracy ERCP.120 Importantly, patient high pretest probability 30% even MRCP negative.120 Thus, suboptimal equivocal, repeated, preferably 3D reconstruction.116,120 Transabdominal ultrasound (US) usually nondiagnostic, although wall thickening focal dilatations demonstrated.121 CT limited assessment ducts.122 US rule out probably related stage process 3).123,124 Specific terms stenosis, dilatation imprecise descriptions beaded, pruned‐tree appearance, irregularity ducts.124 Early course diffusely distributed, short, alternating slightly dilated segments demonstrated.125,126 Contrast‐enhanced T1w images demonstrate mural enhancement ducts.127 As progresses, worsen become obliterated. With worsening signal abnormalities parenchyma diffusion‐weighted inflammation. Fibrosis parenchymal atrophy dysmorphy, lobe, lobulations surface, increase caudate:right lobe ratio.124FIGURE 3: (top left) demonstrates multiple severe (arrows) high‐grade main (arrowhead). (bottom dysmorphy marked enlargement caudate intensity right lobe. right) (arrows). heterogeneity left lobes comparison C, lobe; L, R, lobe.A dominant stenosis ERCP.128,129 used definition.130,131 reports spatial resolution basic differences ERCP, high‐pressure injection. observed lumen >75%.117,124 need describe relevance meet strict stricture. Therefore, introduced refer Histology Modern modalities decreased PSC.132 concern AIH. Concentric "onion skin" periductal infrequent feature cholangiopathies. Typical fibro‐obliterative lesions, loss, ductular reaction (also referred proliferation), pattern interface activity, changes periportal hepatocytes.133,134 these basis normal.8,135 Histologic lymphoplasmacytic signify AIH.22,136–138 Over 70% ulcerative colitis third Crohn's indeterminate colitis.1,20,33,139,140 (PSC‐IBD) localized colon notable backwash ileitis.141,142 often asymptomatic despite activity.143,144 found quiescent colitis.145 addition, frequent.146 who undergo ileocolonoscopy biopsies time screen colitis. detected, 5‐year intervals suggestive PSC‐IBD less aggressive frequent immunosuppression.52,147 prone developing pouchitis ileoanal anastomosis,148 hypertension peristomal stomal varices.149 Guidance evaluate segments. 2. unclear. 3. 4. levels measured 5. except overlap. 6. Ileocolonoscopy previous subsequent whenever occur. NATURAL HISTORY heterogenous variable complicated CRC. Most slowly progressive increasing fibrosis, eventually end‐stage disease. Median death (LT) reported low 9 referral centers, population‐based estimate it 21 longer.19 proportion transplanted, deaths decreased, unchanged.150 increasingly early stage,150,151 awareness function general population people remain undiagnosed.40,41,152–154 Patient demographics progression. Younger sex better outcomes.20 under 20 2.5 longer transplant‐free survival 17 60.155 LT those alone.20 favorable prognosis until malignancy.20,135 Twenty‐three percent 5–14 years.135 Whether represents separate entity early/mild form controversial. Nonetheless, monitored 3–5 Presence ALP worse prognosis. earlier stages, so progression.103,154 Although fluctuates during course,151,156 persistently normal/low (ALP 1.5 × ULN) prognosis.157–161 invalid wide fluctuations values bone growth, instead GGT used. Like adults, spontaneous normalization (GGT 50 U/L) prognosis.162,163 Progressive fibrosis/cirrhosis Accumulation slow. 2‐year trial simtuzumab, direct indirect stable most patients; Ishak serial improved 29%, remained unchanged 34%, worsened 37%.164 Similarly, 141 had 12–18 apart, Batts‐Ludwig 17%, 64%, 19%,165 confirming smaller demonstrating 1–5 years.166–174 Cholangitis/gallstones required lacking, case series report 6% nearly 40% experience complication course. During trial, disease‐related complication, occurring 12% years.164 importance positive culture prognosis,175 awaiting LT.176 Candida poor sign.175 Gallstones, sludge, cholecystitis, gallbladder polyps near PSC.177,178 calculi 8% patients, interventions stones sludge contribute obstruction.179 Development tree, effects natural history jaundice, fevers. Up 45% will strictures.128,129 seem outcome. prestenotic poorer outcomes.123 ERCP180 rapid CCA.118 Further, malignancy, reduces survival.175 Malignancy highest (2.5%) thereafter 1%–1.5% year.19,181 study, cumulative 10, 20, 30 6%, 14%, 20%, respectively.19 Compared population, 160–400 greater.3,19,182 largest (N = 2588), 28 greater PSC.33 Rapid weight loss raise suspicion completely asymptomatic. differ disease.183 consistent factor rarely pediatric Other factors sex, comorbidity along bilirubin levels.19,20,33,103,183–187 impact smoking alcohol uncer

Язык: Английский

---

Distribution and density of tertiary lymphoid structures predict clinical outcome in intrahepatic cholangiocarcinoma

Journal of Hepatology, Год журнала: 2021, Номер 76(3), С. 608 - 618

Опубликована: Ноя. 15, 2021

Язык: Английский

---

Targeting FGFR inhibition in cholangiocarcinoma

Cancer Treatment Reviews, Год журнала: 2021, Номер 95, С. 102170 - 102170

Опубликована: Фев. 26, 2021

Cholangiocarcinomas (CCAs) are rare but aggressive tumours of the bile ducts, which often diagnosed at an advanced stage and have poor outcomes on systemic therapy. Somatic alterations with therapeutic implications been identified in almost half CCAs, particular intrahepatic CCA (iCCA), subtype arising from ducts within liver. Among patients CCA, fibroblast growth factor receptor 2 (FGFR2) fusions or rearrangements occur exclusively iCCA, where they estimated to be found up 10-15% patients. Clinical trials for selective FGFR kinase inhibitors shown consistent activity these agents previously treated iCCA harbouring alterations. Current show differences their structure, mechanisms target engagement, specificities FGFR1, 2, 3 4 other related kinases. These offer potential improve FGFR-driven impact variations molecular profiles efficacy, safety, acquired resistance mechanisms, patients' health-related quality life remains fully characterized. The most common adverse event associated is hyperphosphatemia, on-target off-tumour effect FGFR1 inhibition, strategies manage this include dose adjustment, chelators, use a low phosphate diet. As targeted enter clinic testing actionable mutations monitoring emergence will essential.

Язык: Английский

---

Novel therapeutic targets for cholestatic and fatty liver disease

Gut, Год журнала: 2021, Номер 71(1), С. 194 - 209

Опубликована: Окт. 6, 2021

Cholestatic and non-alcoholic fatty liver disease (NAFLD) share several key pathophysiological mechanisms which can be targeted by novel therapeutic concepts that are currently developed for both areas. Nuclear receptors (NRs) ligand-activated transcriptional regulators of metabolic processes including hepatic lipid glucose metabolism, energy expenditure bile acid (BA) homoeostasis, as well inflammation, fibrosis cellular proliferation. Dysregulation these contributes to the pathogenesis progression cholestatic disease, placing NRs at forefront approaches. This includes BA activated such farnesoid-X receptor (FXR) peroxisome proliferator-activated receptors, respectively, high affinity ligands targeting specific or multiple isoforms have been developed. Moreover, liver-specific thyroid hormone beta 1 complete spectrum available NR-targeted drugs. Apart from FXR ligands, signalling mimetics FXR-activated fibroblast growth factor 19, modulation their enterohepatic circulation through uptake inhibitors in hepatocytes enterocytes, derivatives undergoing cholehepatic shunting (instead circulation). Other approaches more directly target inflammation and/or critical events progression. Combination strategies synergistically disturbances, may ultimately necessary successful treatment complex multifactorial disorders.

Язык: Английский

---

Long-Term Outcomes and Exploratory Analyses of the Randomized Phase III BILCAP Study

Journal of Clinical Oncology, Год журнала: 2022, Номер 40(18), С. 2048 - 2057

Опубликована: Март 22, 2022

PURPOSE The BILCAP study described a modest benefit for capecitabine as adjuvant therapy curatively resected biliary tract cancer (BTC), and has become the standard of care. We present long-term data novel exploratory subgroup analyses. METHODS This randomized, controlled, multicenter, phase III recruited patients age 18 years or older with histologically confirmed cholangiocarcinoma muscle-invasive gallbladder after resection curative intent an Eastern Cooperative Oncology Group performance status < 2. Patients were randomly assigned 1:1 to receive oral (1,250 mg/m 2 twice daily on days 1-14 21-day cycle, eight cycles) observation. primary outcome was overall survival (OS). is registered EudraCT 2005-003318-13. RESULTS Between March 15, 2006, December 4, 2014, 447 enrolled; 223 BTC group 224 observation group. At cutoff January 21, 2021, median follow-up all 106 months (95% CI, 98 108). In intention-to-treat analysis, OS 49.6 35.1 59.1) in compared 36.1 29.7 44.2) (adjusted hazard ratio 0.84; 95% 0.67 1.06). protocol-specified sensitivity adjusting minimization factors, nodal status, grade, sex, 0.74 0.59 0.94). further describe prognostic impact R sex. CONCLUSION analysis supports previous suggesting that can improve when used chemotherapy surgery should be considered

Язык: Английский

---

EASL-ILCA Clinical Practice Guidelines on the management of intrahepatic cholangiocarcinoma

Journal of Hepatology, Год журнала: 2023, Номер 79(1), С. 181 - 208

Опубликована: Апрель 20, 2023

Язык: Английский

---

Cholangiocarcinoma

Pathologica, Год журнала: 2021, Номер 113(3), С. 158 - 169

Опубликована: Июнь 1, 2021

Liver cancer represents the third leading cause of cancer-related death worldwide. Cholangiocarcinoma (CCA) is second most common type liver after hepatocellular carcinoma, accounting for 10-15% all primary malignancies. Both incidence and mortality CCA have been steadily increasing during last decade. Moreover, CCAs are diagnosed at an advanced stage, when therapeutic options very limited. may arise from any tract biliary system it classified into intrahepatic, perihilar, distal CCA, according to anatomical site origin. This topographical classification also reflects distinct genetic histological features, risk factors, clinical outcomes. review focuses on histopathology its differential diagnoses, diagnostic pitfalls.

Язык: Английский

---

Harnessing Nanomaterials for Cancer Sonodynamic Immunotherapy

Advanced Materials, Год журнала: 2023, Номер 35(33)

Опубликована: Март 7, 2023

Abstract Immunotherapy has made remarkable strides in cancer therapy over the past decade. However, such emerging still suffers from low response rates and immune‐related adverse events. Various strategies have been developed to overcome these serious challenges. Therein, sonodynamic (SDT), as a non‐invasive treatment, received ever‐increasing attention especially treatment of deep‐seated tumors. Significantly, SDT can effectively induce immunogenic cell death trigger systemic anti‐tumor immune response, termed immunotherapy. The rapid development nanotechnology revolutionized effects with robust induction. As result, more innovative nanosonosensitizers synergistic modalities are established superior efficacy safe profile. In this review, recent advances immunotherapy summarized particular emphasis on how be explored harness for amplifying response. Moreover, current challenges field prospects its clinical translation also presented. It is anticipated that review provide rational guidance facilitate nanomaterials‐assisted immunotherapy, helping pave way next‐generation eventually achieve durable patients.

Язык: Английский

---