Clinical relevance of biomarkers in cholangiocarcinoma: critical revision and future directions

Cholangiocarcinoma (CCA) is a malignant tumour arising from the biliary system. In Europe, this tumour frequently presents as a sporadic cancer in patients without defined risk factors and is usually diagnosed at advanced stages with a consequent poor prognosis. Therefore, the identification of biomarkers represents an utmost need for patients with CCA. Numerous studies proposed a wide spectrum of biomarkers at tissue and molecular levels. With the present paper, a multidisciplinary group of experts within the European Network for the Study of Cholangiocarcinoma discusses the clinical role of tissue biomarkers and provides a selection based on their current relevance and potential applications in the framework of CCA. Recent advances are proposed by dividing biomarkers based on their potential role in diagnosis, prognosis and therapy response. Limitations of current biomarkers are also identified, together with specific promising areas (ie, artificial intelligence, patient-derived organoids, targeted therapy) where research should be focused to develop future biomarkers

Molecular profile and its clinical impact of IDH1 mutated versus IDH1 wild type intrahepatic cholangiocarcinoma

IDH1-mutated cholangiocarcinomas (CCAs) are an interesting group of neoplasia with particular behavior and therapeutic implications. The aim of the present work is to highlight the differences characterizing IDH1m and IDH1wt CCAs in terms of genomic landscape. 284 patients with iCCA treated for resectable, locally advanced or metastatic disease were selected and studied with the FOUNDATION Cdx technology. A comparative genomic analysis and survival analyses for the most relevant altered genes were performed between IDH1m and IDH1wt patients. Overall, 125 patients were IDH1m and 122 IDH1wt. IDH1m patients showed higher mutation rates compared to IDH1wt in CDKN2B and lower mutation rates in several genes including TP53, FGFR2, BRCA2, ATM, MAP3K1, NOTCH2, ZNF703, CCND1, NBN, NF1, MAP3KI3, and RAD21. At the survival analysis, IDH1m and IDH1wt patients showed no statistically differences in terms of survival outcomes, but a trend in favor of IDH1wt patients was observed. Differences in prognostic values of the most common altered genes were reported. In surgical setting, in IDH1m group the presence of CDKN2A and CDKN2B mutations negatively impact DFS, whereas the presence of CDKN2A, CDKN2B, and PBRM1 mutations negatively impact OS. In advanced setting, in the IDH1m group, the presence of KRAS/NRAS and TP53 mutations negatively impact PFS, whereas the presence of TP53 and PIK3CA mutations negatively impact OS; in the IDH1wt group, only the presence of MTAP mutation negatively impact PFS, whereas the presence of TP53 mutation negatively impact OS. We highlighted several molecular differences with distinct prognostic implications between IDH1m and IDH1wt patients

Histological and serological features of acute liver injury after SARS-CoV-2 vaccination

Codoni G, Kirchner T, Engel B, Villamil AM, Efe C, Stättermayer AF, Weltzsch JP, Sebode M, Bernsmeier C, Lleo A, Gevers TJ, Kupčinskas L, Castiella A, Pinazo J, De Martin E, Bobis I, Sandahl TD, Pedica F, Invernizzi F, Del Poggio P, Bruns T, Kolev M, Semmo N, Bessone F, Giguet B, Poggi G, Ueno M, Jang H, Elpek GÖ, Soylu NK, Cerny A, Wedemeyer H, Vergani D, Mieli-Vergani G, Lucena MI, Andrade RJ, Zen Y, Taubert R, Beretta-Piccoli BT, Histological and serological features of acute liver injury after SARS-CoV-2 vaccination, JHEP Reports (2022), doi: https://doi.org/10.1016/j.jhepr.2022.100605.Liver injury with autoimmune features after vaccination against Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2) is increasingly reported. We investigated a large international cohort of patients with acute hepatitis arising after SARS-CoV-2 vaccination, focusing on histological and serological features

Characterization of neoplastic and non-neoplastic microenvironment in liver, lung and bone marrow through the study of class III \u3b2-tubulin

La seguente tesi di Dottorato in Patologia Oncologica e Cellule Staminali \ue8 incentrata sullo studio di beta-tubulina classe III (tubb3), che \ue8 stata prevalentemente studiata in ambito oncologico nei tumori epiteliali come marcatore di resistenza alla terapia con taxani e di aggressivit\ue0. Recentemente \ue8 stata poi descritta come marker dei periciti, cellule che indicano maturit\ue0 della struttura vascolare in cui sono presenti, ma anche cellule particolari dotate di contrattilit\ue0 e con una morfologia che richiama il miofibroblasto. L\u2019osservazione di positivit\ue0 per tubb3 solo in rari casi di carcinoma epatocellulare, a differenza di molti altri carcinomi e la peculiare positivit\ue0 nel contesto dei vasi neoformati di questo tumore, ha suggerito di considerare tubb3 come un marker con superiori potenzialit\ue0 rispetto a quanto descritto in letteratura. Per tale motivo abbiamo pensato di sviluppare 3 progetti paralleli su patologie diverse tra loro, sia in ambito non neoplastico (fibrosi polmonare idiopatica) che neoplastico (carcinoma epatocellulare e mielofibrosi primitiva idiopatica), accumunate dalla presenza di una popolazione cellulare fusata con aspetto simil-miofibroblastico. In particolare nella fibrosi polmonare idiopatica, tubb3 marca i miofibroblasti che fanno parte del focus fibroblastico, lesione patognomonica della malattia. Lo studio ha portato alla stesura di un articolo scientifico che \ue8 tutt\u2019ora submitted. Nel carcinoma epatocellulare tubb3 si trova solo raramente nelle cellule neoplastiche, spesso al fronte di avanzamento del tumore e in circa 1/3 dei casi nei vasi peritumorali e peritumorali. La peculiarit\ue0 di questi risultati ha portato allo sviluppo di un secondo studio su colture cellulari dinamiche in 3D con Bioreattore con lo scopo di capire come si comportassero i vasi tumorali in coltura una volta sottoposti al farmaco attualmente riconosciuto come unica terapia dall\u2019FDA per il carcinoma epatocellulare avanzato, ovvero Sorafenib. Questo progetto \ue8 tutt\u2019ora in fase di sviluppo con il gruppo di studio del Tumor Microenvironment dell\u2019Ospedale San Raffaele di Milano, dove \ue8 presente il Bioreattore. Per quanto riguarda la mielofibrosi primitiva idiopatica, \ue8 lo stesso nome della malattia che ha suggerito di testare l\u2019anticorpo e, visti i primi risultati incoraggianti, ci ha portato ad avviare una collaborazione con l\u2019Ematologia del Policlinico GB Rossi allo scopo di capire se i pazienti che presentano una popolazione tubb3 nel contesto della biopsia midollare abbiano una biologia di malattia diversa e se questa eterogeneit\ue0 abbia qualche correlazione con l\u2019assetto mutazionale.The following PhD thesis on Human Oncological Pathology and Stem Cell is focused on class III beta-tubulin (tubb3) that has been mainly investigated in oncological context for epithelial tumors as a marker of resistance to taxane and aggressiveness. Recently it has also been described as marker for pericytes, Recentemente \ue8 stata poi descritta come marker dei pericytes, which are cells indicating the maturity of vessels but have also contractility properties and morphologically recalls myofibroblasts. The presence of tubb3 in rare cases of hepatocellular carcinoma, differently compared to other carcinomas e the peculiar positivity in newly formed tumoral vessels, has suggested the possible wide potentiality of this marker compared to what has already been described in literature. For this reason we have decided to develop 3 projects in parallel on different diseases, both non-neoplastic (idiopathic pulmonary fibrosis) and neoplastic (hepatocellular carcinoma and primary myelofibrosis) conditions, that are in a way accumunated by the presence of a spindle population of cells resembling myofibroblasts. In pulmonary fibrosis, tubb3 identify the myofibroblasts forming fibroblastic foci, that are a pathognomonic lesion of the disease. This study has produced an original article that has been submitted. In Hepatocellular carcinoma, tubb3 is found only rarely in neoplastic cells, often at the front of edge of the tumor and in 1/3 of cases in peritumoral and intratumoral vessels. The peculiarity of these results has driven the idea of another study on dynamic 3D-cultures with Bioreactor, to investigate how tumoral vessels behave in dynamic cultures also when they are subjected to drug, such as Sorafenib. This study is on-going with the group of Tumor Microenvironment of \u2019Ospedale San Raffaele in Milano, where the Bioreactor is available. Concerning primary myelofibrosis, it was the name of the disease that suggested us to investigate this process with tubb3. Thank to the intial encouraging results, we have initiated a collaboration with the the Department of Haematology of Policlinico GB Rossi in Verona to understand id the patients that present a tubb3 positive population in the context of bone marrow biopsy have a different type of disease compared to other myelofibrosis and if this heterogeneity has some relation to mutational status

Pathology and molecular pathology of cholangiocarcinoma

Biliary tract cancers are a wide group of heterogeneous neoplasms of the biliary tree, composed of intrahepatic cholangiocarcinoma perihilar bile duct cancer and distal bile duct cancer, according to location. The variability in location reflects the different morphologies and molecular alterations. In particular, intrahepatic peripheral mass forming cholangiocarcinoma is represented by the “small duct type” cholangiocarcinoma, which is different from the “large duct type” cholangiocarcinoma that, although intrahepatic, behaves similar to extrahepatic bile duct cancers, perihilar and distal ones. Recently, molecular targetable alterations, mainly FGFR2 fusions and IDH1 mutations, have been described, mostly in the intrahepatic “small duct type” subgroup and have opened the way, together with rarer targetable alterations, for personalisation of therapy also in these aggressive neoplasms

HCC in metabolic syndrome: current concepts and future directions

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths globally. In recent years, the metabolic syndrome epidemic is changing the etiological landscape of HCC, with metabolic liver disease comprising an exponentially increasing proportion of HCC cases. In this review, we discuss HCC in the context of metabolic syndrome, including its epidemiology, its unique clinical and pathological characteristics, and its multifactorial pathogenesis. We also discuss HCC prevention and management as relates to these patients

Total portal vein replacement with peritoneal interposition graft during Whipple’s procedure for extrahepatic cholangiocarcinoma: a technical report

Abstract Background Aggressive surgical resection in locally advanced hepatopancreatobiliary (HPB) malignancies is frequently advocated as the only potentially curative treatment. In recent years, advances in chemotherapy regimens and surgical techniques have led to improved oncologic outcomes and overall survival, by increasing the rates of radical (R0) resections. Vascular resections are increasingly reported to further increase disease clearance rates. Within this perspective, the issue of vascular reconstruction has raised growing interest, drawing particular attention to vascular substitutes and surgical techniques for reconstruction. Case presentation A case of extrahepatic cholangiocarcinoma with high clinical suspicion of vascular infiltration of the portal trunk at preoperative assessment is reported. An autologous interposition graft, harvested from diaphragmatic peritoneum, was chosen as a vascular substitute leading to successful portal trunk reconstruction and overcoming all possible drawbacks associated with cadaveric and artificial grafts reconstructions. Conclusion This solution was strategic to ensure complete oncologic clearance averting the risk of positive margins (R1) at final pathology

3D Models as a Tool to Assess the Anti-Tumor Efficacy of Therapeutic Antibodies: Advantages and Limitations

Therapeutic monoclonal antibodies (mAbs) are an emerging and very active frontier in clinical oncology, with hundred molecules currently in use or being tested. These treatments have already revolutionized clinical outcomes in both solid and hematological malignancies. However, identifying patients who are most likely to benefit from mAbs treatment is currently challenging and limiting the impact of such therapies. To overcome this issue, and to fulfill the expectations of mAbs therapies, it is urgently required to develop proper culture models capable of faithfully reproducing the interactions between tumor and its surrounding native microenvironment (TME). Three-dimensional (3D) models which allow the assessment of the impact of drugs on tumors within its TME in a patient-specific context are promising avenues to progressively fill the gap between conventional 2D cultures and animal models, substantially contributing to the achievement of personalized medicine. This review aims to give a brief overview of the currently available 3D models, together with their specific exploitation for therapeutic mAbs testing, underlying advantages and current limitations to a broader use in preclinical oncology

Laparoscopic Surgery for Intrahepatic Cholangiocarcinoma: A Focus on Oncological Outcomes

Background: The aim of the present study was to analyze the long-term outcomes of laparoscopic and open surgery for intrahepatic cholangiocarcinoma (iCCA) in a series, collected in a tertiary referral center with a high annual volume of laparoscopic activity. Methods: Between January 2004 and June 2020, 446 liver resections (LR) were performed for iCCA: of these, 179 were performed by laparoscopic surgery (LS) and 267 with the open approach. The two groups were matched through a 1:1 propensity score using covariates representative of patient and disease characteristics. The study and control groups were compared, with specific attention given to oncological outcomes (rate of R0, depth of resection margins, overall and disease-free survival, rate, and site of recurrence). Results: The number of retrieved nodes, rate, and depth of negative resection margins were comparable between the two groups. The interval time between surgery and subsequent adjuvant treatments was significantly shorter in LS patients. No differences were shown even in the comparison between the LS and the open group in terms of median disease-free and overall survival. Moreover, the disease recurrence rate was comparable between the LS and the open groups (45.2% versus 56.7%), and the recurrence pattern was similar. Conclusions: The minimally invasive approach for iCCA was once again confirmed to be associated with advantages in terms of intraoperative and short-term outcomes, but was also proven to be oncologically non-inferior to the open counterpart. In the present study, overall and disease-free survival were found to be similar between the two approaches