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1
Abdalla, Eddie K., Christopher E. Forsmark, Gregory Y. Lauwers, and J. Nicolas Vauthey. "Monolobar Caroli's Disease and Cholangiocarcinoma." HPB Surgery 11, no. 4 (January 1, 1999): 271–77. http://dx.doi.org/10.1155/1999/70985.
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Caroli's Disease (CD) is a rare congenital disorder characterized by cystic dilatation of the intrahepatic bile ducts. This report describes a patient with cholangiocarcinoma arising in the setting of monolobar CD. In spite of detailed investigations including biliary enteric bypass and endoscopic retrograde cholangiography, the diagnosis of mucinous cholangiocarcinoma (CCA) was not made for almost one year. The presentation, diagnosis and treatment of monolobar CD and the association between monolobar CD and biliary tract cancer are discussed. Hepatic resection is the treatment of choice for monolobar CD.
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Zhu, Yan, and Lawrence N. Kwong. "IDH1 Inhibition Reawakens the Immune Response against Cholangiocarcinoma." Cancer Discovery 12, no. 3 (March 1, 2022): 604–5. http://dx.doi.org/10.1158/2159-8290.cd-21-1643.
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Summary: Isocitrate dehydrogenase 1 mutations (mIDH1) are common in cholangiocarcinoma, but their exact mechanisms in cholangiocarcinoma initiation and maintenance are unclear. In this issue of Cancer Discovery, Wu and colleagues identify immune suppression via TET2 inactivation as the primary means by which mIDH1 maintains cholangiocarcinoma survival, leading to an efficacious new combination of mIDH1 inhibitors and immune checkpoint blockade targeting regulatory T cells. See related article by Wu et al., p. 812 (9).
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Peerawong, Thanarpan, Chonlakiet Khorprasert, Sivalee Suriyapee, Taweap Sanghangthum, Isra Israngkul Na Ayuthaya, and Kanjana Shotelersuk. "Dosimetry of conformal dynamic arc radiotherapy and intensity modulated radiotherapy in unresectable cholangiocarcinoma." Asian Biomedicine 4, no. 1 (February 1, 2010): 131–39. http://dx.doi.org/10.2478/abm-2010-0015.
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Abstract Background: Radiotherapy in cholangiocrcinoma has to overcome organ tolerance of the upper abdomen. Hi-technology radiotherapy may improve conformity and reduce dose to those organ. Objective: Quantitatively compare the dosimetry of conformal dynamic arc radiotherapy (CD-arcRT) and intensity modulated radiotherapy (IMRT) in unresectable cholangiocarcinoma. Material and methods: Eleven cases of unresectable cholangiocarcinoma were re-planned with IMRT and CDarcRT at King Chulalongkhorn Memorial Hospital between 20 September 2004 and 31 December 2005. Both the planning techniques were evaluated using the dose volume histogram of the planning target volume and organ at risk. The conformation number and dose to critical normal structures were used to determine the techniques. Results: IMRT technique was significantly conformed to the planning target volume than CD-arcRT in term of conformation number. For critical structure, IMRT significantly reduced the radiation dose to liver in terms of mean liver dose, V30Gy and V20Gy of the right kidney. Conclusion: The advantage of IMRT was more conformity and reduced dose to critical structure compared with CD-arcRT, but there was no difference between these techniques in terms of V20Gy of left kidney and maximum dose to the spinal cord.
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Patowary, BN, S. Kumar, A. Pun, P. Kafle, and PK Chhetri. "Caroli's Disease: A case report." Journal of College of Medical Sciences-Nepal 8, no. 3 (September 20, 2013): 51–54. http://dx.doi.org/10.3126/jcmsn.v8i3.8685.
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Caroli's disease (CD) is a rare congenital abnormality characterized by dilatation of intra-hepatic bile ducts, recurrent cholangitis, formation of calculi inside these ducts with normal extra hepatic ducts and higher risk for cholangiocarcinoma. Association of this disease with congenital hepatic fibrosis is named as Caroli's syndrome. We reported 30 years old women with recurrent epigastric pain for 2 years with normal Liver function Test however involving both lobes of liver who developed cholangiocarcinoma approximately 6 months later. Journal of College of Medical Sciences-Nepal, 2012, Vol-8, No-3, 51-54 DOI: http://dx.doi.org/10.3126/jcmsn.v8i3.8685
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Wu, Meng-Ju, Lei Shi, Juan Dubrot, Joshua Merritt, Vindhya Vijay, Ting-Yu Wei, Emily Kessler, et al. "Mutant IDH Inhibits IFNγ–TET2 Signaling to Promote Immunoevasion and Tumor Maintenance in Cholangiocarcinoma." Cancer Discovery 12, no. 3 (March 1, 2022): 812–35. http://dx.doi.org/10.1158/2159-8290.cd-21-1077.
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Abstract Isocitrate dehydrogenase 1 mutations (mIDH1) are common in cholangiocarcinoma. (R)-2-hydroxyglutarate generated by the mIDH1 enzyme inhibits multiple α-ketoglutarate–dependent enzymes, altering epigenetics and metabolism. Here, by developing mIDH1-driven genetically engineered mouse models, we show that mIDH1 supports cholangiocarcinoma tumor maintenance through an immunoevasion program centered on dual (R)-2-hydroxyglutarate–mediated mechanisms: suppression of CD8+ T-cell activity and tumor cell–autonomous inactivation of TET2 DNA demethylase. Pharmacologic mIDH1 inhibition stimulates CD8+ T-cell recruitment and interferon γ (IFNγ) expression and promotes TET2-dependent induction of IFNγ response genes in tumor cells. CD8+ T-cell depletion or tumor cell–specific ablation of TET2 or IFNγ receptor 1 causes treatment resistance. Whereas immune-checkpoint activation limits mIDH1 inhibitor efficacy, CTLA4 blockade overcomes immunosuppression, providing therapeutic synergy. The findings in this mouse model of cholangiocarcinoma demonstrate that immune function and the IFNγ–TET2 axis are essential for response to mIDH1 inhibition and suggest a novel strategy for potentiating efficacy. Significance: Mutant IDH1 inhibition stimulates cytotoxic T-cell function and derepression of the DNA demethylating enzyme TET2, which is required for tumor cells to respond to IFNγ. The discovery of mechanisms of treatment efficacy and the identification of synergy by combined CTLA4 blockade provide the foundation for new therapeutic strategies. See related commentary by Zhu and Kwong, p. 604. This article is highlighted in the In This Issue feature, p. 587
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Smyth, Elizabeth C., Irina S. Babina, and Nicholas C. Turner. "Gatekeeper Mutations and Intratumoral Heterogeneity in FGFR2-Translocated Cholangiocarcinoma." Cancer Discovery 7, no. 3 (March 2017): 248–49. http://dx.doi.org/10.1158/2159-8290.cd-17-0057.
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Jusakul, Apinya, Ioana Cutcutache, Chern Han Yong, Jing Quan Lim, Mi Ni Huang, Nisha Padmanabhan, Vishwa Nellore, et al. "Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma." Cancer Discovery 7, no. 10 (June 30, 2017): 1116–35. http://dx.doi.org/10.1158/2159-8290.cd-17-0368.
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Tamai, Keiichi, Mao Nakamura, Masamichi Mizuma, Mai Mochizuki, Misa Yokoyama, Hiroyuki Endo, Kazunori Yamaguchi, et al. "Suppressive expression of CD 274 increases tumorigenesis and cancer stem cell phenotypes in cholangiocarcinoma." Cancer Science 105, no. 6 (May 8, 2014): 667–74. http://dx.doi.org/10.1111/cas.12406.
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Saha, Supriya K., John D. Gordan, Benjamin P. Kleinstiver, Phuong Vu, Mortada S. Najem, Jia-Chi Yeo, Lei Shi, et al. "Isocitrate Dehydrogenase Mutations Confer Dasatinib Hypersensitivity and SRC Dependence in Intrahepatic Cholangiocarcinoma." Cancer Discovery 6, no. 7 (May 26, 2016): 727–39. http://dx.doi.org/10.1158/2159-8290.cd-15-1442.
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Chagani, Sharmeen, and Lawrence N. Kwong. "Cholangiocarcinoma Risk Factors Open the Floodgates for Gut Microbes and Immunosuppressive Myeloid Cells." Cancer Discovery 11, no. 5 (May 2021): 1014–15. http://dx.doi.org/10.1158/2159-8290.cd-21-0187.
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Goyal, Lipika, Supriya K. Saha, Leah Y. Liu, Giulia Siravegna, Ignaty Leshchiner, Leanne G. Ahronian, Jochen K. Lennerz, et al. "Polyclonal Secondary FGFR2 Mutations Drive Acquired Resistance to FGFR Inhibition in Patients with FGFR2 Fusion–Positive Cholangiocarcinoma." Cancer Discovery 7, no. 3 (December 29, 2016): 252–63. http://dx.doi.org/10.1158/2159-8290.cd-16-1000.
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Goyal, Lipika, Lei Shi, Leah Y. Liu, Ferran Fece de la Cruz, Jochen K. Lennerz, Srivatsan Raghavan, Ignaty Leschiner, et al. "TAS-120 Overcomes Resistance to ATP-Competitive FGFR Inhibitors in Patients with FGFR2 Fusion–Positive Intrahepatic Cholangiocarcinoma." Cancer Discovery 9, no. 8 (May 20, 2019): 1064–79. http://dx.doi.org/10.1158/2159-8290.cd-19-0182.
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Merchan, Jaime R., Derek Ostertag, Douglas J. Jolly, Dalissa Tejera, Harry E. Gruber, and Jolene Shorr. "Toca 511 and Toca FC in patients with gastrointestinal tumors in the Toca 6 study." Journal of Clinical Oncology 36, no. 4_suppl (February 1, 2018): TPS880. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.tps880.
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TPS880 Background: Toca 511 (vocimagene amiretrorepvec) is an investigational, conditionally lytic, retroviral replicating vector (RRV). RRVs selectively infect cancer cells due to defects in innate and adaptive immune responses found in cancers that support virus replication, and the requirement for cell division for virus integration into the genome. Toca 511 spreads through tumors, stably delivering an optimized cytosine deaminase (CD) gene that converts the prodrug, Toca FC (investigational, extended-release 5-FC) into 5-FU. 5-FU kills infected dividing cancer cells and diffuses and kills surrounding cancer cells, myeloid derived suppressor cells, and tumor associated macrophages, thus reestablishing tumor immunity (Cloughesy et al. Neuro Oncol 2016). In a Phase 1 study, resected high grade glioma tumors expressed CD protein following intravenous (IV) Toca 511.1 In animal models of metastatic colorectal cancer, IV Toca 511 infected metastatic sites, and subsequent 5-FC treatment resulted in decreased tumor size and improved survival (Yagiz et al. Mol Therapy 2015). Methods: Toca 6 is a Phase 1b, multicenter, open-label study (NCT02576665) that aims to investigate changes in immune activity after treatment with Toca 511 & Toca FC in patients with solid tumors, including gastrointestinal tumors. A total of 30 patients who have advanced malignancies, including colorectal and pancreatic cancer, with molecular characteristics that may increase sensitivity to 5-FU or viral infection, or IDH1 mutated solid tumors (e.g., intrahepatic cholangiocarcinoma) will be enrolled. In these patients, Toca 511 is injected IV daily for 3 days, then intratumorally after biopsy. Oral Toca FC is started ~4 weeks later and repeated every 4-6 weeks. Changes from baseline in intratumoral immune activity (infiltrating T-cell subpopulations, B cells, monocytes) at 4 weeks after start of Toca FC are assessed. Contemporaneous peripheral blood is analyzed for effector, memory, Treg, and myeloid lineage cells. Viral RNA, DNA, and CD protein expression in tumor after IV Toca 511 are measured. Safety and efficacy will be determined. Concomitant checkpoint inhibitor therapy may be given following immune activity assessments. The study has enrolled 3 patients. Clinical trial information: NCT02576665.
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Catassi, G., G. D'Arcangelo, L. Norsa, M. Bramuzzo, I. Hojsak, K. L. Kolho, C. Romano, et al. "P210 Long-term outcome of very early onset inflammatory bowel disease associated with primary sclerosing cholangitis: a multicenter study from the Pediatric IBD Porto Group of ESPGHAN." Journal of Crohn's and Colitis 17, Supplement_1 (January 30, 2023): i361—i362. http://dx.doi.org/10.1093/ecco-jcc/jjac190.0340.
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Abstract Background Primary sclerosing cholangitis related to inflammatory bowel disease (PSC-IBD) diagnosed under the age of 6 years (i.e., VEO-IBD) may have unique characteristics and disease course. We aimed to analyze the characteristics and natural history of children with VEO PSC-IBD and compare them to children diagnosed with PSC-IBD at an older age. Methods This was a multicenter, retrospective, study evaluating patients diagnosed with both IBD and PSC before (VEO-PSC-IBD) or after the age of 6 years (PSC-IBD), followed at 14 centers affiliated with the Porto IBD Interest group of ESPGHAN. Demographic, clinical, laboratory, endoscopic, and imaging data were collected at baseline and every six months thereafter for a minimum follow-up of 12 months. IBD-related (clinical remission, need for systemic steroids, therapy escalation and surgery) and PSC-related outcomes (biliary and portal hypertensive complications, need for treatment escalation and liver transplantation, cholangiocarcinoma, and death) were analyzed at 1, 3, and 5 years. Results A total of 69 children with both IBD and PSC were included: 28 with VEO PSC-IBD [median age 5.2 (3.7-5.9) years, 21 UC (75%), 4 IBDU (14%) and 3 (15%) CD] and 41 with PSC-IBD [median age 15.7 (13.3-16.9) years, 34 UC (83%), 6 IBDU (1.5%) and 1 (0.2%) CD]. IBD was diagnosed prior to PSC in 28 of the 69 patients (40%), simultaneously in 30 (43%), and after PSC in 11 (16%), with no significant differences between VEO PSC-IBD and PSC-IBD. Most patients with UC presented with extensive disease at diagnosis (89% in VEO PSC-UC vs. 89% in PSC-UC, p = 0.72). Both groups presented most often with mild intestinal disease at diagnosis (mean PUCAI of VEO IBD-PSC 34±16, vs 31±19 of IBD-PSC, p=0.11; mean PCDAI 31±33 vs. 21±27, respectively, p=0.14). A higher number of VEO-IBD-PSC patients were diagnosed with autoimmune sclerosing cholangitis than older children [24 (86%) vs. 27 (66%) PSC-IBD, p=0.04], whereas no other differences were found for PSC-related variables. During follow-up, no significant differences were found in major IBD outcomes. The risk of developing biliary strictures and escalating therapy to vancomycin from ursodeoxycholic acid was lower in the VEO-PSC-IBD group (Figure 1 and 2, Log-rank p=0.02 and p=0.02), while no difference was found for portal hypertension and liver transplantation at 5-year follow-up. No cases of cholangiocarcinoma or death were reported. Conclusion IBD-PSC has similar baseline characteristics whether diagnosed as VEO-IBD or thereafter. However, a milder disease course in terms of biliary complications and the need for PSC-related therapy escalation, with an overall mild intestinal disease at presentation in all patients, characterize this specific subcohort of patients.
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Haag, Florian, Anjana Manikkam, Daniel Kraft, Caroline Bär, Vanessa Wilke, Aleksander J. Nowak, Jessica Bertrand, et al. "Selective Internal Radiotherapy Changes the Immune Profiles of Extracellular Vesicles and Their Immune Origin in Patients with Inoperable Cholangiocarcinoma." Cells 11, no. 15 (July 27, 2022): 2309. http://dx.doi.org/10.3390/cells11152309.
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The incidence of cholangiocellular carcinoma (CCA) is rising worldwide. As there are no specific early symptoms or specific markers of CCA, it is often diagnosed in later inoperable stages. Accumulating evidence underlines the importance of radiation therapy in the induction of antitumor immunity. The surface protein composition on extracellular vesicles (EVs) relates to originating cells and thus may play a role in vesicle function. We assessed immune profiles of EVs and their immune origin in patients with inoperable CCA prior and after selective internal radiotherapy (SIRT). A total of 47 CCA patients receiving SIRT and 12 healthy volunteers (HV) were included. Blood was withdrawn before therapy (pre T) and after T. EVs were purified from plasma by cluster of differentiation (CD)9-, CD63-, and CD81-immunobead isolation. To detect differently abundant surface markers, dynamic range and EVs input quality were assessed. A total of 37 EVs surface markers were measured by flow cytometry and correlated either with the administered activity dose (MBq) or with the interval until death (month). EVs phenotyping identified lymphocytes, B cells, NK cells, platelets, endothelial cells, leukocyte activation, B cell activation, T and B cell adhesion markers, stem/progenitor cells, and antigen-presenting cells (APC) as EVs-parenteral cells. CD4 and CD8 significantly declined, while other markers significantly increased in CCA patients pre T vs. HV. Platelets-deriving EVs significantly decreased, normalizing to levels of HV but still significantly increasing vs. HV post SIRT. B cells-deriving EVs significantly increased pre T vs. HV, positively correlating with administered activity dose. MHCII and CD40 EVs significantly increased pre SIRT and negatively correlated with administered activity dose, while EVs from antigen presenting cells and CD49e pre SIRT positively correlated with survival time after therapy. Increased levels of CD24 and CD44 in cancer pre T were significantly decreased post T. Among the heterogeneity of EVs that was demonstrated, in particular, B cells-deriving, MHCII, and CD40 positive or APC-deriving EVs need to be further studied for their diagnostic or prognostic relevance in clinical scenarios.
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Talakokkla, Sandhya, Renuka Mahatara, Christine A. Welch, and Arun Nagarajan. "Secondary Malignancies in Mantle Cell Lymphoma." Blood 126, no. 23 (December 3, 2015): 5596. http://dx.doi.org/10.1182/blood.v126.23.5596.5596.
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Abstract Background: Mantle cell lymphoma is a B cell lymphoma (CD5 +) which represents 5-10 % of Non-Hodgkin's lymphoma. Most patients have advanced disease at presentation and thus carry a poor prognosis. This type of uncommon malignant lymphoma has a distinct and recurring cytogenetic abnormality involving t(11, 14) q(13, 32). Although extra nodal involvement is common, not many cases of MCL having concomitant other malignancies are reported. We hypothesized that patients with MCL have chronic immunosuppression, comparable to chronic lymphocytic leukemia patients, and therefore are at risk for developing secondary malignancies similar to CLL patients. The aim of our study is to report the retrospective analysis of patients diagnosed with MCL and the associated secondary malignancies before or after the diagnosis of MCL. Patients and methods: The records of 41 patients who presented with MCL to "The David Lee Cancer Center" at CAMC, WVU with MCL from 2000 - 2015 were retrospectively reviewed. The number of other malignancies presenting before or after the diagnosis of MCL were analyzed. Results: The population with MCL was represented by 41, all Caucasian patients, which were 75.6% male (n = 31) and had an average age of 68.6 ± 11.3 years. Mean follow up for all patients was 23.9 ± 32.43 months. A total of 14.6% (n=6), 83.3% males, experienced a second primary. Within the second primaries 50.0% were GI cancers which included pancreatic cancer and cholangiocarcinoma while 16.7% were prostate cancer, diffuse large B-cell lymphoma or adenocarcinoma of lungs. The time to second primaries varied with 50% of the cases being diagnosed simultaneously with MCL, while 33.3% were diagnosed prior to MCL at an average time of 34.5 months, and 16.7% were diagnosed post MCL diagnosis at an average time of 18 months. Conclusion: Patients with MCL are typically CD5 positive, CD10 negative, and CD23 negative which make it different from other lymphomas like small cell lymphoma, B-cell CLL that are CD 23 positive. Rare cases of MCL may be CD5 negative or CD23 Positive. We hypothesized that MCL patients have an increased risk for developing secondary cancers due to their disease biology and from underlying chronic immunosuppression. Patients with MCL have twice the risk of developing secondary malignancies and an increased frequency of certain types of cancers such as cholangiocarcinoma & pancreatic cancer. Disclosures No relevant conflicts of interest to declare.
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Caon, A. E., C. Martins, M. Cruz, L. Leite Barros, M. Azevedo, N. Queiroz, A. Carlos, et al. "P231 Epidemiological profile and long-term outcomes from a large PSC-IBD cohort." Journal of Crohn's and Colitis 14, Supplement_1 (January 2020): S258. http://dx.doi.org/10.1093/ecco-jcc/jjz203.360.
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Abstract Background Primary sclerosing cholangitis (PSC) is a chronic and progressive cholestatic disease associated with inflammatory bowel diseases (IBD) in 70% of cases.1 When combined, they present as one distinct phenotypical disease referred to as PSC-IBD with milder clinical course, despite more extensive colonic involvement and an increased risk of malignancies. The aim of this study was to assess clinical features and long-term outcomes of PSC-IBD patients from a quaternary hospital in Brazil. Methods We retrospectively reviewed all PSC-IBD patients registered and followed-up in our outpatient clinic between January 2000 and July 2019. Conventional colonoscopic and histological criteria were used to diagnose IBD, whereas radiographic or histological criteria for PSC. Medical records were abstracted for the following data: demographic characteristics; duration, extent, and treatment of IBD; duration, extent, and treatment of PSC; colorectal neoplasia (dysplasia and cancer); surgical treatment for IBD; liver transplantation and death. Results In total, 92 patients with concurrent PSC and IBD were identified. Of 92 cases, 80 (87%) had ulcerative colitis (UC) and 12 (13%) were diagnosed with Crohn’s disease (CD). There was a slight predominance of male, 51 (55%). The mean age at both IBD and PSC diagnosis was 31 and 35 years, respectively. Most of them were diagnosed with IBD prior to PSC (53%). The mean IBD duration was 15 years and 10 years in PSC subjects. The prevalence of pancolitis in UC patients was 91%. All CD cases presented ileocolonic involvement. Present or past smoking history was reported in 6% of the cohort. Aminosalicylates were the most common treatment used for IBD in 59 patients (64%). 15 of them (16%) were on monotherapy with immunobiologics and 7 patients (8%) were on combotherapy. Only 3 subjects were on anti-integrin. In our cohort, 61 cases (66%) were treated with ursodeoxycholic acid. Colorectal neoplasia and cholangiocarcinoma were observed in 6 (7%) and 3 patients (3.3%), respectively. Colorectal dysplasia was found in 20 subjects (22%) on a routine colonoscopy. Overall, 17 patients (19%) required proctocolectomy and 11 cases (12%) have undergone orthotopic liver transplant. There were 12 deaths, mainly PSC and cancer-related. Conclusion Herein we present the largest cohort of concomitant PSC and IBD in Latin America. In our centre, we have found higher rates of extensive IBD, although few of them required colectomy. The present data on cancer and dysplasia are consistent with reports in the literature. Reference
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Donaldson, K., R. A. Mitchell, R. A. Enns, B. Bressler, G. Rosenfeld, Y. Leung, A. Ramji, and H. Ko. "A164 PATTERNS IN MEDICAL THERAPY AND CLINICAL OUTCOMES IN PATIENTS WITH CONCOMITANT INFLAMMATORY BOWEL DISEASE AND PRIMARY SCLEROSING CHOLANGITIS: A SINGLE CENTRE RETROSPECTIVE ANALYSIS." Journal of the Canadian Association of Gastroenterology 4, Supplement_1 (March 1, 2021): 173–74. http://dx.doi.org/10.1093/jcag/gwab002.162.
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Abstract Background Inflammatory bowel disease (IBD) in patients with primary sclerosing cholangitis (PSC) is characterized by pancolitis with rectal sparing and is associated with an increased risk of colorectal and biliary malignancies. Currently, pharmacologic management of IBD in the setting of PSC is the same as in IBD alone. Aims To assess patterns in medical therapy, and incidence of adverse outcomes in patients with concomitant IBD and PSC. Methods A retrospective review was conducted on all PSC-IBD patients followed between January 2010 and June 2018. The Endoscopic Mayo Score was used to grade IBD severity in PSC-ulcerative colitis (UC). Results 69 patients were identified, 44 (63.8%) were male. The mean ages of IBD and PSC diagnosis were 28.6 (SD 14.9) and 37.0 (SD 18.9) years, respectively. The median length of follow up was 12 (range 2–49) years. 52 (75.4%) patients had UC, and 17 (24.6%) had Crohn’s disease (CD). 28 (87.5%) PSC-UC patients had pancolitis, and 4 (12.5 %) had proctitis. Among those with pancolitis, 8 (28.6%) had relative rectal sparing. 4 (14.3%) patients had more severe inflammation proximally, whereas only 1 (3.6%) had more severe distal inflammation. 23 (82.1%) patients had the same degree of inflammation throughout. 14 (93.3%) PSC-CD patients had colitis/ileocolitis and 1 (6.7%) had ileitis. Among those with PSC-UC, 16 (50.0%), 12 (37.5%), and 4 (12.5%) patients had grade 1, 2, and 3 disease, respectively. 62 (89.9%) PSC-IBD patients were treated with aminosalicylates, and 26 (37.7%) with biologics at some point in their IBD course. 26 (37.7%) were treated with aminosalicylates alone. 4 (5.8%) did not require any IBD therapy. Cholangiocarcinoma, colorectal cancer, and gallbladder cancer developed in 8 (11.6%), 1 (1.4%), and 1 (1.4%) PSC-IBD patients, respectively. 16 (23.2%) patients required partial or total colectomy. Indication for surgery was inflammation or stenosis, dysplasia, and neoplasia in 13 (81.3%), 2 (12.5%), and 1 (6.3%) patients, respectively. Conclusions The majority of this cohort had UC with mild disease activity. Pancolitis was common, with frequent rectal sparing and more severe right-sided inflammation. Despite the predominance of low-grade colitis, a large portion of patients required treatment with biologics. The incidence of adverse outcomes underscores the need for strict adherence to recommended surveillance practices. Low grade endoscopic activity, typical of the quiescent IBD course in PSC-IBD, may mask low grade histologic inflammation, which in turn may contribute to the increased risk of colonic neoplasia. Further studies are needed to determine the best management strategy for IBD in patients with PSC. Funding Agencies None
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Ribaldone, D. G., S. Vieujean, M. Julsgaard, F. Zingone, E. Savarino, F. Cañete, A. Aratari, et al. "P252 Solid organ transplant (with the exception of liver) in patients with inflammatory bowel disease: An ECCO CONFER Multicentre Case Series." Journal of Crohn's and Colitis 17, Supplement_1 (January 30, 2023): i403—i404. http://dx.doi.org/10.1093/ecco-jcc/jjac190.0382.
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Abstract Background There are limited data available on the course of IBD in patients with solid organ transplantation. The aim of this ECCO CONFER study was to evaluate the trend of IBD before and after solid organ transplantation but liver. Methods This was a retrospective observational multicentre study that collected cases through the CONFER project. Patients with an established IBD diagnosis who underwent a solid organ transplantation (with the exception of liver) were eligible candidates. Results 33 patients with solid organ transplantation (67% male; 55% CD) were collected from 12 referral centres in five different countries. Mean age was 53 ± 16 years. 34 organs were transplanted in 33 patients. Most of the patients underwent kidney transplantation (n=27, 82%). 4 (12%) received a heart and 1 (3%) underwent lung transplantation; 1 (3%) underwent a combined heart and kidney transplant. The mean duration of IBD was 18.4 ± 14.7 months. Clinical characteristics are summarized in Table 1. The median follow-up after transplantation was 4.3 years (IQR 3.25 – 10.7). 7/33 patients (21.2%) experienced organ rejection, with 1 kidney retransplant. Regarding immunosuppressive therapy, 29/33 patients (88%) were treated with tacrolimus, 25 (76%) with systemic steroids, 22 (67%) with mycophenolate mofetil, 11 (33%) with everolimus, 6 with cyclosporine (18%), 3 (9%) with thiopurines. Regarding biologics, 1 patient was treated with infliximab, 2 with adalimumab, 2 with vedolizumab, 1 with ustekinumab. Defining a severe IBD course the need for biologic therapy or bowel resection or hospitalization, 4 patients (11.7%) had a severe disease course after transplantation versus 3 patients (9.3%) in the first 51 months of disease before transplantation (p = 0.26). Univariate analysis is reported in Table 2. 1 case of low-grade dysplasia was found 10 years after the transplantation. 1 case of colorectal cancer was found in a patient affected by CD five years after kidney transplantation. The other cases of tumours after transplantation are reported in Table 3. The first serious infectious episode after transplantation is shown in Table 4: 17 of 33 patients (51.5%) reported at least 1 episode of serious infection. In total 29 different serious infectious episodes after transplantation were recorded, compared to 28 episodes in the pre-transplantation period. At the last follow-up visit, 6/33 (18.2%) patients had died: 1 due to cholangiocarcinoma, 1 amyloidosis, 1 heart failure, 1 myocardial infection (2 not available). Conclusion Solid organ transplantation appears to have a satisfactory course for both the transplanted organ and IBD, in terms of organ survival and IBD severity; furthermore, the use of biologics in these patients does not appear to be linked to a worse outcome.
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Kim, Edward Jae-Hoon, Corey Allan Carter, Tony R. Reid, Scott Caroen, Bryan Oronsky, Nacer D. Abrouk, Mary Flanagan Quinn, and Elizabeth Poplin. "Phase I study (PAYLOAD) of RRx-001 + irinotecan in patients with advanced solid malignancies." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e16031-e16031. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e16031.
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e16031 Background: RRx-001 is a downregulator of CD-47 and SIRP-alpha, which demonstrated a clinically meaningful improvement in OS and PFS vs. regorafenib when dosed sequentially with irinotecan in a 3rd/4th line colorectal cancer randomized trial called ROCKET (NCT02096354). Recently, RRx-001 has been shown to downregulate PD-L1 on circulating tumor cells. This phase 1 trial named PAYLOAD (NCT02801097) was performed to assess the safety and tolerability of the combination of RRx-001 and irinotecan and to determine a recommended phase II dose (RP2D). Methods: Eligible patients (pts) had adequate organ and bone marrow functions and an ECOG of 0-2 and evaluable refractory advanced solid tumors. RRx-001 was administered once per week for 3 weeks and thereafter once every two weeks. RRx-001 was administered as a 10-15 min IV infusion with irinotecan, which began on Week 4 and which was also given every other week, staggered with RRx-001 . Dose escalation followed a standard 3 + 3 design with co-escalation of RRx-001 and irinotecan as follows: 1: Irinotecan 120 mg/m2 + RRx-001, 0.5 mg 2: Irinotecan 120 mg/m2 + RRx-001, 2 mg 3: Irinotecan 120 mg/m2 + RRx-001, 4 mg 4: Irinotecan 150 mg/m2 + RRx-001, 4 mg Radiological imaging was performed every 8 weeks. Results: 12 pts; 1 gallbladder, 1 ampullary carcinoma, 1 cholangiocarcinoma, 5 colon, 1 GE junction, 2 pancreatic and 2 rectal cancers were enrolled from January 2018 to November 2018. 1 and 18 doses (median: 6 doses) of the combination of RRx-001 and irinotecan were received. The median number of prior treatments was 4 (range 1-5). There were 2 Grade 3 events, leukopenia and anemia, judged not related to RRx-001 but related to irinotecan, 1 Grade 4 event, leukopenia, judged not related to RRx-001 but related to irinotecan and 1 Grade 5 event, neutropenic enterocolitis, also judged not related to RRx-001 but related to irinotecan. No dose-limiting toxicities were identified. The median overall survival was ~ 6.5 months. Conclusions: Alternating weekly infusions of 150 mg/m2 of irinotecan and 4 mg of RRx-001 were well tolerated. No Grade 2 or above diarrhea was observed with irinotecan treatment, which suggests that RRx-001 may protect against gastrointestinal (GI) toxicities, since RRx-001 has also demonstrated anti- oral mucositis and anti-diarrheal properties in other studies.This dose level is the recommended phase 2 dose for future trials. Clinical trial information: NCT02801097 .
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"Infigratinib Approved for Cholangiocarcinoma." Cancer Discovery, June 25, 2021. http://dx.doi.org/10.1158/2159-8290.cd-nb2021-0364.
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Wu, Qibiao, Yuanli Zhen, Lei Shi, Phuong Vu, Patricia Greninger, Ramzi Adil, Joshua Merritt, et al. "EGFR Inhibition Potentiates FGFR Inhibitor Therapy and Overcomes Resistance in FGFR2 Fusion–Positive Cholangiocarcinoma." Cancer Discovery, April 14, 2022, OF1—OF18. http://dx.doi.org/10.1158/2159-8290.cd-21-1168.
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Abstract FGFR inhibitors are approved for the treatment of advanced cholangiocarcinoma harboring FGFR2 fusions. However, the response rate is moderate, and resistance emerges rapidly due to acquired secondary FGFR2 mutations or due to other less-defined mechanisms. Here, we conducted high-throughput combination drug screens, biochemical analysis, and therapeutic studies using patient-derived models of FGFR2 fusion–positive cholangiocarcinoma to gain insight into these clinical profiles and uncover improved treatment strategies. We found that feedback activation of EGFR signaling limits FGFR inhibitor efficacy, restricting cell death induction in sensitive models and causing resistance in insensitive models lacking secondary FGFR2 mutations. Inhibition of wild-type EGFR potentiated responses to FGFR inhibitors in both contexts, durably suppressing MEK/ERK and mTOR signaling, increasing apoptosis, and causing marked tumor regressions in vivo. Our findings reveal EGFR-dependent adaptive signaling as an important mechanism limiting FGFR inhibitor efficacy and driving resistance and support clinical testing of FGFR/EGFR inhibitor therapy for FGFR2 fusion–positive cholangiocarcinoma. Significance: We demonstrate that feedback activation of EGFR signaling limits the effectiveness of FGFR inhibitor therapy and drives adaptive resistance in patient-derived models of FGFR2 fusion–positive cholangiocarcinoma. These studies support the potential of combination treatment with FGFR and EGFR inhibitors as an improved treatment for patients with FGFR2-driven cholangiocarcinoma.
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"Ivosidenib Boosts OS in Cholangiocarcinoma." Cancer Discovery 11, no. 12 (October 11, 2021): 2953–54. http://dx.doi.org/10.1158/2159-8290.cd-nb2021-0389.
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Zhang, Qianfei, Chi Ma, Yi Duan, Bernd Heinrich, Umberto Rosato, Laurence P. Diggs, Lichun Ma, et al. "Gut microbiome directs hepatocytes to recruit MDSC and promote cholangiocarcinoma." Cancer Discovery, December 15, 2020, CD—20–0304. http://dx.doi.org/10.1158/2159-8290.cd-20-0304.
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Lin, Youpei, Lihua Peng, Liangqing Dong, Dongbing Liu, Jiaqiang Ma, Jian Lin, Xiaofang Chen, et al. "Geospatial immune heterogeneity reflects the diverse tumor-immune interactions in intrahepatic cholangiocarcinoma." Cancer Discovery, July 19, 2022. http://dx.doi.org/10.1158/2159-8290.cd-21-1640.
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Abstract Intrahepatic cholangiocarcinoma (iCCA) exhibits extensive intratumoral heterogeneity and extremely high mortality rate. Here, we performed WES, RNA-seq, TCR-seq and multiplexed immunofluorescence on 207 tumor regions from 45 iCCA patients. Over half of iCCA displayed intratumoral heterogeneity of immune infiltration, and iCCA were classified into sparsely, heterogeneously, and highly infiltrated subgroups with distinct immunogenomic characteristics. Sparsely infiltrated tumors displayed active copy number loss of clonal neoantigens and heterogeneous immune infiltration played an important role in the subclonal evolution across tumor subregions. Highly infiltrated tumors were characterized by extensive immune activation and similar TCR repertoire across tumor subregions, but counteracted with T cell exhaustion and pervasive antigen presentation defects. Notably, FGFR2 mutations and fusions correlated with low mutation burden and reduced immune infiltration. Our work sculpted the dynamic tumor-immune interactions and developed a robust classification system to divide iCCA patients into high and low immune evasion groups with different prognosis.
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Arora, A., SJ Storr, H. Reddy, DN Lobo, S. Madhusudan, and AM Zaitoun. "O085 CD10 expression in carcinomas of the pancreas, bile duct and ampulla." British Journal of Surgery 109, Supplement_4 (July 22, 2022). http://dx.doi.org/10.1093/bjs/znac242.085.
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Abstract Introduction Pancreatic cancer and cholangiocarcinoma including, cancer of ampulla of Vater, are very aggressive and have a dismal prognosis; hence improved methods of patient stratification are required. Methods We assessed the expression of CD10 in stromal and epithelial cells of two patient cohorts using immunohistochemistry on tissue microarrays. The first cohort was composed of 68 pancreatic adenocarcinomas and the second cohort was composed of 120 cancers of the bile duct and ampulla. Results In bile duct and ampullary carcinomas an association was observed between CD10 stromal expression and patient age (p =0.009). The CD10 stromal expression was associated with poor disease specific survival (DSS) (p =0.05). In multivariate Cox model for DSS, stromal CD10 expression (p = 0.037) was independently associated with poor outcome. In multivariate Cox model for disease free survival (DFS), CD10 stromal expression (p = 0.012), and nodal status (p = 0.025) were independently associated with poor outcome. In pancreatic cancer, no statistically significant association was observed between CD 10 stromal expression and clinicopathological variables such as tumour size (p = 0.099), T stage (p = 0.393), N stage (p = 0.860), Vascular invasion (p = 0.904), perineural invasion (p = 0.532) and grade (0.168). In multivariate Cox model for DSS, T stage (p = 0.042) was independently associated with poor outcome. Conclusion The results suggest that CD10 stromal expression may have prognostic significance in cholangiocarcinoma. The findings of this study warrant a larger follow-up study. Take-home message The results suggest that CD10 stromal expression may have prognostic significance in cholangiocarcinoma. The findings of this study warrant a larger follow-up study.
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Silverman, Ian M., Antoine Hollebecque, Luc Friboulet, Sherry Owens, Robert C. Newton, Huiling Zhen, Luis Feliz, Camilla Zecchetto, Davide Melisi, and Timothy C. Burn. "Clinicogenomic analysis of FGFR2-rearranged cholangiocarcinoma identifies correlates of response and mechanisms of resistance to pemigatinib." Cancer Discovery, November 20, 2020, CD—20–0766. http://dx.doi.org/10.1158/2159-8290.cd-20-0766.
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Cleary, James M., Srivatsan Raghavan, Qibiao Wu, Yvonne Y. Li, Liam F. Spurr, Hersh V. Gupta, Douglas A. Rubinson, et al. "FGFR2 Extracellular Domain In-Frame Deletions are Therapeutically Targetable Genomic Alterations that Function as Oncogenic Drivers in Cholangiocarcinoma." Cancer Discovery, April 29, 2021, candisc.1669.2020. http://dx.doi.org/10.1158/2159-8290.cd-20-1669.
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Wang, Si-Yuan, Nan Jiang, Jian-Ping Zeng, Shao-Qing Yu, Ying Xiao, and Shuo Jin. "Characteristic of Perineural Invasion in Hilar Cholangiocarcinoma Based on Whole-Mount Histologic Large Sections of Liver." Frontiers in Oncology 12 (March 8, 2022). http://dx.doi.org/10.3389/fonc.2022.855615.
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Background & ObjectivePerineural invasion is an important biological feature of hilar cholangiocarcinoma (HCCA). We developed a whole-mount histologic large sections (WHLS) of the liver to evaluate peripheral nerve invasion (PNI) of HCCA.MethodsUsing sampling, fixation, dehydration, embedding, sectioning, hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining, and scanning, the characteristics of intrahepatic and extrahepatic PNI in 20 patients with Bismuth type III and type IV HCCA were analyzed with WHLS. Correlation between the characteristics of nerve invasion and tumor size, vascular invasion (artery, portal vein), degree of differentiation, microvascular invasion (MVI), carbohydrate antigen19-9 (CA19-9), and differentiation degree of HCCA was statistically evaluated.ResultsThe WHLS of the liver was successfully established, which enabled us to observe intrahepatic and extrahepatic distribution of HCCA and whether surrounding tissues including nervous, blood, and lymph vessels were infiltrated. Extrahepatic and intrahepatic PNI were identified in 20 (100%) patients and 1 (5.0%) patient, respectively. Vessel density decreased in most invaded nerves presented by CD-34, which correlated with 100% of poorly differentiated and 83% of moderately differentiated tumors (P<0.008).ConclusionThis study established a WHLS of the liver that can be used for clinical diagnosis and research, and confirmed that extrahepatic PNI is prevalent, but intrahepatic nerve invasion is rare and does not accompany the invasion scope of bile ducts in types III and IV HCCA. In addition, moderately and poorly differentiated malignant tumors are more prone to PNI, independent of blood supply.
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Takahashi, Atsushi, Hiroshi Imamura, Ryota Ito, Fumihiro Kawano, Yu Gyoda, Hirofumi Ichida, Ryuji Yoshioka, et al. "A case report of fibrolamellar hepatocellular carcinoma, with particular reference to preoperative diagnosis, value of molecular genetic diagnosis, and cell origin." Surgical Case Reports 7, no. 1 (September 17, 2021). http://dx.doi.org/10.1186/s40792-021-01295-4.
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Abstract Background Fibrolamellar hepatocellular carcinoma (FL-HCC) is a liver tumor that occurs almost exclusively in young adults without underlying liver disease. In spite of its distinct clinical characteristics and specific imaging findings, preoperative diagnosis is often difficult due to the extremely low incidence of the tumor. Although FL-HCC shows particular morphological features on H&E-stained tissue sections, differential diagnosis from ordinary HCC, especially the scirrhous variant of HCC, and intrahepatic cholangiocarcinoma needs additional immunohistochemical (IHC) analyses and/or molecular genetic testing. Case presentation A 21-year-old male patient was referred to our hospital for further evaluation of a large liver mass. Abdominal ultrasound examination, contrast-enhanced computed tomography, and magnetic resonance imaging revealed a well-defined hypervascular lobulated liver mass, 11 × 11 cm in diameter, with a central scar and calcification, in segments 5/8. Under the diagnosis of FL-HCC, we carried out extended anterior sectorectomy, including a part of segment 4. On microscopic examination, the tumor was composed of proliferating polygonal cells with abundant eosinophilic granular cytoplasm containing nuclei with vesicular chromatin and enlarged nucleoli, in an abundant stroma. Collagen fibers arranged in a parallel lamellar pattern were seen in the tumor stroma. These findings, together with the results of subsequent IHC analyses using HAS, CK7, and CD 67, we made the diagnosis of FL-HCC, which was further confirmed by detection of the DNAJB1-PRKACA fusion gene in the tumor cells by RT-PCR. Conclusion FL-HCC shows distinct imaging appearances. Although it also has characteristic morphological features, combined use of IHC and/or molecular genetic studies are necessary for the final diagnosis.
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"Study Suggests Treatment Approaches for Cholangiocarcinomas." Cancer Discovery 7, no. 6 (April 19, 2017): OF6. http://dx.doi.org/10.1158/2159-8290.cd-nb2017-059.
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"Pemigatinib Is Active in Some FGFR2-Altered Cholangiocarcinomas." Cancer Discovery 10, no. 5 (April 3, 2020): 639.1–639. http://dx.doi.org/10.1158/2159-8290.cd-rw2020-050.
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Russell, Thomas, Peter Labib, and Somaiah Aroori. "HPB P12 Pancreatoduodenectomy for confirmed malignancy: A complication profile from the Recurrence After Whipple's (RAW) study." British Journal of Surgery 109, Supplement_9 (December 7, 2022). http://dx.doi.org/10.1093/bjs/znac404.109.
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Abstract Background Pancreatoduodenectomy (PD) is recommended in fit patients with resectable cancer affecting the pancreatic head or periampullary region. This operation can provide a cure in some patients but it remains high-risk. Although perioperative mortality rates have fallen below 2.0% in high-volume centres, complications still affect up to 50% of cases. Due to the nature of the resection and the subsequent anastomoses required, a number of general and procedure-specific complications may occur. Whilst a number of smaller studies have reported on procedure-specific outcomes, no large recent studies have aimed to put together a comprehensive complication profile. This international multicentre retrospective study aimed to calculate the incidence and severity of all PD complications in a cohort of patients with confirmed pancreatic ductal adenocarcinoma (PDAC), ampullary adenocarcinoma (AA) or cholangiocarcinoma (CC). Methods Patients were included if they underwent PD for histologically-confirmed PDAC, AA or CC at one of 28 participating units between 01/06/2012 and 31/05/2015. This end date was selected so that five-year follow-up data was available for all patients. Data was collected on the following complications: clinically relevant postoperative pancreatic fistula (CR-POPF), bile leak, gastrojejunal leak, postpancreatectomy haemorrhage (PPH), delayed gastric emptying (DGE), acute kidney injury (AKI), cardiac arrythmia, chest infection, cholangitis, chyle leak, Clostridium difficile infection, ileus, intra-abdominal collection, liver abscess, myocardial infarction (MI), pancreatic necrosis, pancreatitis, portal vein (PV)/superior mesenteric vein (SMV) thrombosis, sepsis of unknown origin, splenic vein thrombosis, surgical site infection (SSI), urinary tract infection (UTI), deep vein thrombosis (DVT), and pulmonary embolism (PE). Other complications could be entered by the data collector in free text. CR-POPF, bile leak, gastrojejunal leak, PPH and DGE were defined and categorised using internationally agreed definitions. All other complications were diagnosed based on predefined clinical and/or radiological criteria. All complications were graded using the Clavien-Dindo (CD) classification. When comparing patients who developed at least one complication to those who developed no complications, medians were compared using the Mann-Whitney U test. Other comparisons were made using Fisher's exact test. Results The analysis included 1,465 patients. Median age was 67 years and 44.2% were female. In total, 49.1% of patients experienced at least one complication; 25.4% of these were CD grade I, 48.5% were grade II, 17.1% were grade III, 5.7% were grade IV and 3.2% were grade V. CR-POPF affected 7.1% of cases (grade B: 81, grade C: 23), bile leak affected 2.7% (grade A: 13, grade B: 17, grade C: 10) and gastrojejunal leak affected 1.7% (grade A: 5, grade B: 8, grade C: 7). PPH was reported in 5.6% of cases (grade A: 17, grade B: 39, grade C: 26) and 11.3% developed DGE (grade A: 73, grade B, 58, grade C: 35). Seventy-seven patients (5.2%) had an unplanned return to theatre and 90-day mortality was 3.6%. The most common cause of death was PPH, followed by POPF, intra-abdominal sepsis and renal failure. Patients who experienced morbidity were significantly more likely to be female (41.3% vs 46.9%, p=0.03) or have a preoperative cardiovascular (49.3% vs 33.7%, p<0.0001) or respiratory co-morbidity (13.6% vs 8.3%, p=0.001). They were also less commonly ASA grade I or II (62.9% vs 70.0%, p=0.005). Conclusions In our international multicentre study of patients who underwent PD for confirmed malignancy, overall morbidity was 49.1% and perioperative mortality was 3.6%. Whilst minor complications were common, severe complications were rare. The incidences of CR-POPF, bile leak, gastrojejunal leak, and PPH were 7.1%, 2.7%, 1.4% and 5.6%, respectively. The most common cause of death was PPH. It is important that surgeons who perform PD have a sound understanding of its complication profile. This will allow them to evaluate their own performance when auditing and guide the consenting process.
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Russell, Thomas, Peter Labib, and Somaiah Aroori. "HPB P63 Five-year follow-up after pancreatoduodenectomy performed for malignancy: a nine-year experience." British Journal of Surgery 109, Supplement_9 (December 7, 2022). http://dx.doi.org/10.1093/bjs/znac404.157.
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Abstract Background Pancreatic ductal adenocarcinoma (PDAC) of the pancreatic head is a leading cause of cancer-related death in the Western world and its incidence is set to rise across the globe. Unfortunately, the majority of patients present with metastatic disease and prognosis is very poor. Ampullary adenocarcinoma (AA) and cholangiocarcinoma (CC) are less common but their prognoses are only marginally better. Patients with one of these cancers may undergo pancreaticoduodenectomy (PD) providing they present with resectable disease and have an appropriate performance status. Whilst this offers some patients the possibility of a cure, it is a high-risk operation and overall morbidity is often quoted at 50%. Additionally, early recurrence rates are high and few patients achieve long-term survival. This study aimed to describe the experience of a typical tertiary hepatopancreatobiliary (HPB) unit in the United Kingdom. We aimed to a compile a complication profile and investigate the impact of selected preoperative variables on short- and long-term outcomes. We also aimed to compare patient outcomes based on their cancer type. Methods Patients were included if they underwent PD for histologically-confirmed PDAC, AA or CC at our institution between 01/09/2006 and 31/05/2015. The end date of 31/05/2015 was chosen to complete five-year follow-up for all included patients. Information was collected on the following: patient demographics, comorbidities, preoperative imaging and staging, NAT (if given), selected preoperative blood results, procedure and intraoperative findings, postoperative management and complications, histology results, adjuvant treatment (if given), cancer recurrence, palliative treatment (if given), and five-year survival. When comparing patients by their histological diagnosis, medians were compared using the Kruskal-Wallis test and other variables were compared using Fisher's exact test. Fisher's exact test was also used to investigate the association of selected preoperative variables on overall morbidity, major morbidity (Clavien-Dindo grade I and II complications excluded), 90-day mortality and five year survival. The Kaplan-Meier method was used to compare survival between patients with PDAC, AA and CC. The Mantel-Cox method was used to test for statistical significance. Fisher's exact test was used to investigate the impact of selected preoperative variables on five-year survival. A p-value of less than 0.05 was considered statistically significant. Results A total of 271 patients were included; 57.9% had a histological diagnosis of PDAC, 25.8% had AA and 16.2% had CC. Ninety-day mortality was 3.3%, 67.9% of patients experienced at least one complication and 17.3% experienced a complication which was Clavien-Dindo grade III or higher. A total of 401 postoperative complications were recorded; 27.2% were CD grade I, 53.2% were grade II, 12.7% were grade III, 4.4% were grade IV and 1.5% were grade V. Rates of CR-POPF, bile leak, gastrojejunal leak, PPH and DGE were 8.1%, 4.1%, 0.0%, 9.2% and 19.9%, respectively. Patients with a preoperative bilirubin ≤29 µmol/L less often experienced morbidity (p=0.03) or major morbidity (p=0.02) but this did not affect 90-day mortality (p=0.7). Similarly, those with a preoperative neutrophil/lymphocyte ratio (NLR) ≤3.1 had lower rates of morbidity (p=0.04) and major morbidity (p=0.01) but the difference in 90-day mortality was not significant (p=0.3). An ASA grade of III or IV correlated with increased overall morbidity (p=0.002) and major morbidity (p=0.009) but the difference in 90-day mortality was not significant (p=0.2). Overall five-year survival was 22.5%; this was not affected by age, BMI, preoperative comorbidities, ASA grade or preoperative blood tests. Conclusions In our series, most patients experienced at least one complication but less than a fifth experienced major morbidity. Rates of CR-POPF, bile leak, gastrojejunal leak, PPH and DGE were 8.1%, 4.1%, 0.0%, 9.2% and 19.9%, respectively. ASA grade III/IV patients and those with a high preoperative bilirubin and/or NLR more commonly experienced overall and major morbidity. Five-year recurrence and survival rates were 68.3% and 22.5%, respectively. The preoperative variables studied did not affect five-year survival. Surgeons who perform PD should have a sound understanding of the figures above as this will guide patient selection and the consenting process. Future research should focus on identifying patients who are likely to achieve poor long-term outcomes, this sub-group may benefit from neoadjuvant chemotherapy.