Biliary Cancer Research Articles

Integrated analysis of genomic and transcriptomic profiles to examine CD73/NT5E as a driver of drug-resistance and immunosuppression in biliary cancer (BTC).

606 Background: Despite the improved outcome achieved by the addition of the anti-PD-L1 durvalumab to standard chemotherapy, the vast majority of BTC do not benefit from chemo-immunotherapy. Immunosuppressive microenvironment is a dominant feature of BTC, involved in tumour progression and drug resistance. Here, we investigated the biological role and treatment implications of the adenosine-producing enzyme CD73 in a clinically-annotated cohort of BTC. CD73, an ecto-5’-nucleotidase (NT5E), creates an immunosuppressive tumour-promoting microenvironment by converting ATP to adenosine. Methods: Immunohistochemistry for CD73, CD4/CD8 and FOXP3 as well as whole-exome and transcriptomic sequencing were performed on resected specimens of 80 BTC (Illumina Platform). Spatial Transcriptomics was performed by using Visium Spatial Gene Expression-10x Genomics). Silencing of CD73 was obtained by transient transfection od CD73-siRNA, while genetic Knock-out by using CRISPR-Cas system technology in two BTC cell lines. Tumor growth was assessed in 2D and in 3D cell culture by using MTS assay and spheroid growth analysis before and after treatment with selected drugs. Statistical and Survival, correlation analyses were performed. Results: High CD73 expression (CD73high) was associated with older age (>70 years, p=0.01), gallbladder subsite (p=0.03), and nodal involvement (p=0.04). CD73high tumours were significantly enriched in infiltrating FOXP3+ T lymphocytes (p<0.001). CD73high status was independent predictor of poorer prognosis at the multivariate analysis (p=0,03) together with ECOG PS ≥2 (p=0,001) and the pathological stage (p=0,025) and was associated with a remarkably shorter RFS in patients treated with adjuvant chemotherapy (p=0,011). At the transcriptomic level, CD73high tumours were significantly enriched in upregulated EMT, TNF-alfa/NFKB, hypoxia and G2/M checkpoint signaling pathways and p53, BMI1, MEL18, EGFR and K-RAS genes. In in vitro models, siRNA-mediated depletion and CRISPR-CAS9 gene KO of CD73 sensitized both BTC 2D and 3D culture to cisplatin/gemcitabine treatment. The pharmacological inhibition of CD73 by AMCP improved the sensitivity of BTC cell lines to cisplatin/gemcitabine treatment. Finally, Spatially resolved transcriptomics of CD73high revealed a critical role of CD73 in tumor immunity and therapeutic response. Conclusions: We showed that CD73high BTC display aggressive biological features, poorer prognosis and resistance to standard chemotherapy. The therapeutic targeting of this adenosinergic ectonucleotidase by clinically-available compounds has the potential to enhance the efficacy of conventional treatment in BTC.

Significance of alterations in DNA damage repair (DDR) genes in advanced biliary cancers (ABCs) treated with second-line active-symptom-control (ASC) alone or ASC with oxaliplatin/5-FU chemotherapy (ASC+FOLFOX) in the randomised phase III, multicentre, open-label ABC-06 trial.

593 Background: The ABC-06 clinical trial established ASC+mFOLFOX as the standard of care treatment after Cisplatin and Gemcitabine (CisGem) for ABC. Translational research explored the role of alterations in DDR-related genes in the context of the ABC-06 clinical trial. Methods: Translational research using samples collected from the ABC-06 trial included all recruited patients with tissue sample containing >20% tumour cellularity with sufficient DNA extracted for analysis. Primary objective: assess the prevalence of somatic mutations within DDR genes in ABC. Secondary objectives: explore the impact of somatic mutations in DDR genes on: A) Patient’s response to platinum-based chemotherapy (predictive biomarker): 1) Retrospectively, using progression-free survival (PFS) data from 1st-line chemotherapy and 2) Prospectively, by assessing the impact on PFS/radiological response to 2nd-line FOLFOX (vs. control) and B) Overall survival (prognostic biomarker). Survival analysis was performed with Kaplan-Meier and Cox Regression. Results: Of 162 pts randomised, 83 had a sample available for analysis; of these, analysis failed in 24 despite >20% tumour content. Thus, a total of 59 patients (30 ASC arm, 29 ASC+FOLFOX arm) were eligible for this translational analysis: male 50.85%, metastatic 77.97%, intrahepatic cholangiocarcinoma 47.46%, adenocarcinoma 91.53%, median age 65.84 years (95% CI 63.36-68.91). Pathogenic mutations in DDR genes were identified in 22 patients (37.29%). PFS did not vary depending on the DDR-gene alterations either in the first-line setting with CisGem (n=59; 8.73 months vs 8.18 months; p-value 0.155) or with second-line FOLFOX (n=29; 3.19 months vs 3.45 months; p-value 0.098). Median OS for DDR-altered patients was 4.59 months (95% CI 2.17-5.88) (vs 7.23 months (95% CI 5.45-8.28) for DDR-wild-type); HR 2.63 (95% CI 1.48-4.67); p-value 0.001. This prognostic impact was confirmed when the prognostic model was adjusted for treatment arm and stratification factors (HR 3.75 (95% CI 1.99-7.09); p-value <0.001). Conclusions: For ABC patients, the presence of DDR-related gene pathogenic mutations are present in around one third of patients. Despite presence of DDR-mutations having a negative prognostic impact, their predictive role is not confirmed either for first-line CisGem or second-line FOLFOX. Clinical trial information: NCT01926236 .

Autoimmune diseases as comorbidities for liver, gallbladder, and biliary duct cancers in Sweden.

Autoimmune diseases are associated with many cancers but there is a lack of population-based studies with different autoimmune diseases that have a long follow-up. This is also true of hepatobiliary cancers, which include hepatocellular cancer (HCC) and rarer entities of gallbladder cancer (GBC), intra- and extrahepatic cholangiocarcinoma (iCCA and eCCA), and ampullary cancer. Diagnostic data on 43 autoimmune diseases were collected from the Swedish Inpatient Register from 1987 to 2018, and cancer data were derived from the national cancer registry from 1997 onward. Relative risks were expressed as standardized incidence ratios (SIRs). In a population of 13.6million, 1.1million autoimmune diseases were diagnosed and subsequent hepatobiliary cancer was diagnosed in 3191 patients (17.2% of cancers). SIRs for HCC were 2.73 (men) and 2.86 (women), 3.74/1.96 for iCCA, 2.65/1.37 for GBC, 2.38/1.64 for eCCA, and 1.80/1.85 for ampullary cancer. Significant associations between autoimmune disease and HCC were observed for 13 autoimmune diseases, with the highest risks being for autoimmune hepatitis (48.92/73.53, men/women) and primary biliary cirrhosis (38.03/54.48). GBC was increased after six autoimmune diseases, with high SIRs for ulcerative colitis (12.22/3.24) and men with Crohn disease (9.16). These autoimmune diseases were also associated with a high risk of iCCA, which had seven other associations, and eCCA, which had five other associations. Ampullary cancer occurrence was increased after four autoimmune diseases. An autoimmune disease is a common precursor condition for hepatobiliary cancers. This calls for careful control of autoimmune disease symptoms in each patient and encouragement to practice a healthy lifestyle.

The 10-month mortality rate among older patients treated for digestive system cancer during the first wave of the COVID-19 pandemic: The CADIGCOVAGE multicentre cohort study

IntroductionThe coronavirus disease 2019 (COVID-19) pandemic has had a dramatic impact on cancer diagnosis and care pathways. Here, we assessed the mid-term impact of the COVID-19 pandemic on older adults with cancer before, during and after the lockdown period in 2020. Materials and MethodsWe performed a retrospective, observational, multicentre cohort study of prospectively collected electronic health records. All adults aged 65 or over and having been newly treated for a digestive system cancer in our institution between January 2018 until August 2020 were enrolled. ResultsData on 7,881 patients were analyzed. Although the overall 10-month mortality rate was similar in 2020 vs. 2018–2019, the mortality rate among for patients newly treated in the 2020 post-lockdown period was (after four months of follow-up) significantly higher. A subgroup analysis revealed higher mortality rates for (i) patients diagnosed in the emergency department during the pre-lockdown period, (ii) patients with small intestine cancer newly treated during the post-lockdown period, and (iii) patients having undergone surgery with curative intent during the post-lockdown period. However, when considering individuals newly treated during the lockdown period, we observed lower mortality rates for (i) patients aged 80 and over, (ii) patients with a biliary or pancreatic cancer, and (iii) patients diagnosed in the emergency department. DiscussionThere was no overall increase in mortality among patients newly treated in 2020 vs. 2018–2019. Longer follow-up is needed to assess the consequences of the pandemic. A subgroup analysis revealed significant intergroup differences in mortality.

Reducing relapse through maintenance steroid treatment can decrease the cancer risk in patients with IgG4-sclerosing cholangitis: Based on a Japanese nationwide study.

IgG4-related sclerosing cholangitis (IgG4-SC) is recognized as a benign steroid-responsive disease; however, little is known about the risk of development of cancer in patients with IgG4-SC and about how to counter this risk. We conducted a retrospective review of the data of 924 patients with IgG4-SC selected from a Japanese nationwide survey. The incidence, type of malignancy, and risk of malignancy in these patients were examined. Then, the standardized incidence ratio (SIR) of cancer in patients with IgG4-SC was calculated. Relapse was recognized in 19.7% (182/924) of patients, and cancer development was noted in 15% (139/924) of patients. Multivariate analysis identified only relapse as an independent risk factor for the development of cancer. In most of these patients with pancreato-biliary cancer, the cancer developed within 8years after the diagnosis of IgG4-SC. The SIR for cancer after the diagnosis of IgG4-SC was 12.68 (95% confidence interval [CI] 6.89-8.79). The SIRs of cancers involving the biliary system and pancreas were 27.35 and 18.43, respectively. The cumulative survival rate was significantly better in the group that received maintenance steroid treatment (MST) than in the group that did not; thus, MST influenced the prognosis of these patients. Among the cancers, the risk of pancreatic and biliary cancers is the highest in these patients. Because of the elevated cancer risk, surveillance after the diagnosis and management to prevent relapse are important in patients with IgG4-SC to reduce the risk of development of cancer.

Prevalence of Cancer in Patients with Venous Thromboembolism: A Retrospective Nationwide Case-Control Study in Sweden.

Cancer is a risk factor for venous thromboembolism (VTE). We aimed to define sex-specific risk of preceding cancer in patients with a first-time VTE by conducting a nationwide Swedish registry-based study including 298 172 patients with VTE and 1 185 079 matched controls. This included 44 685 patients with a diagnosis of cancer at/or within 1 year before a VTE diagnosis. Female patients with VTE had a higher multivariable adjusted odds ratios of preceding cancer than male patients with VTE (5.5 [99% confidence interval 5.4-5.7] vs 3.9 [3.8-4.0]). The highest risk of cancer in patients with VTE were found for pancreatic cancer (women: 19.6 [15.8-24.4]; men: 17.2 [13.7-21.6]) and brain cancer (women: 17.4 [12.9-23.4]; men: 17.5 [13.8-22.2]). Weak associations were seen between VTE and bladder/urothelial cancer (women: 1.31 [1.12-1.53]; men: 1.34 [1.23-1.47]), prostate cancer (men: 2.17 [2.07-2.27]), malignant melanoma (women: 2.51 [2.07-3.05]; men: 2.67 [2.23-3.18]), and kidney cancer (women: 3.20 [2.49-4.11]; men: 3.33 [2.79-4.07]). In conclusion, associations with VTE were weak for bladder/urothelial cancer and kidney cancer, and strong for pancreatic, brain, and biliary cancers.

Tobacco smoking and cancer risk

Smoking tobacco is the most important and potentially modifiable risk factor for cancer in Germany. Combining tobacco with alcohol can multiply cancer risks. Up to 30 % of cancer deaths are due to tobacco smoking. 23,3 % of 18-64 year-old Germans are current smokers; in addition, 11 % of the population are regularly exposed to secondhand tobacco smoke. Tobacco smoking is causally associated with oropharyngeal, laryngeal, nose, paranasal sinus, lung, esophageal, gastric, pancreatic, hepatocellular, biliary, colorectal, kidney, ureter, urinary bladder, uterine cervix and ovary cancers and leukemia. Smokers should be supported to stop smoking and join programmes of cancer screening. Smoking cessation effectively reduces tobacco-associated cancer risk.

Genomic alterations in intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (iCCA) is an aggressive and heterogeneous biliary cancer with a poor prognosis and limited treatment options. The molecular pathogenesis of iCCA involves a highly complex process entailing multiple genetic alterations and dysregulation of signaling pathways. Recent advancements in our understanding of the genetic landscape of iCCA have opened new opportunities for therapeutic interventions. Technologies such as next-generation sequencing (NGS) have contributed to elucidating the genetic heterogeneity of iCCA, leading to the identification of numerous potentially actionable genetic alterations. Despite these advances, the prognosis of iCCA patients remains dismal. In this review, we provide an extensive summary of the current knowledge on genetic alterations in iCCA, their biological impact on patients, potential therapeutic targets, approved targeted therapies, and ongoing clinical trials with targeted agents. Furthermore, we discuss the main technologies available for studying genetic alterations and their advantages and limitations. Finally, we highlight future directions in studying genetic alterations and the development of new targeted therapies and personalized medicine approaches.

Discordance of microsatellite instability and mismatch repair immunochemistry occurs depending on the cancer type

Microsatellite instability (MSI) and deficiency of mismatch repair (dMMR) are key markers for predicting the response of immune checkpoint inhibitors (ICIs) and screening for Lynch syndrome (LS). This study examined the incidences of and factors associated with the concordance of MSI and MMR in human cancers. A total of 518 formalin-fixed cancer tissues were analyzed for MSI and MMR immunohistochemistry (IHC). MSI was analyzed by a PCR-based method using Promega markers. Concordance with MMR expression and factors associated with concordance were analyzed. In 2 colorectal cancer samples, MMR IHC failed due to inadequate staining conditions. In the remaining 516 cancers, a high level of MSI (MSI-H) was identified in 113 cases, and dMMR was identified in 112. The concordance of MSI and MMR IHC was 98.3%. Only 9 cases (4 pancreatobiliary, 3 colorectal, and 2 endometrial cancers) were discordant. Of the 113 MSI-H cases, 4 (3.5%) were proficient MMR (pMMR); of the 403 microsatellite stability (MSS) cases, 5 (1.2%) were dMMR. The independent factors associated with MSI-H/dMMR included meeting Amsterdam II criteria, assay purpose, and sampling method. Multivariate analysis revealed that cancer type (gastrointestinal cancers or others) was associated with concordance of MSI and MMR IHC. Three LS cases with pancreatic or endometrial cancer demonstrated MSS and dMMR, and one biliary cancer showed MSI-H and pMMR. Discordance between MSI and MMR IHC occasionally occurs in pancreaticobiliary and endometrial cancers. When suspected, both MSI and MMR IHC should be done to judge the ICI indication and screen for LS.

Circulating tumour DNA in gastrointestinal cancer in clinical practice: Just a dream or maybe not?

The evaluation of circulating tumor DNA (ctDNA) is increasingly integrated into the management of diagnosis and treatment of gastrointestinal cancer as it represents an innovative and minimally invasive biomarker that could allow us to reach clinical needs not met yet in randomized clinical trials. Recent research provided an interesting overview of the role of circulating tumor DNA in gastric, biliary, liver, pancreatic, and colorectal cancer. Data regarding upper gastrointestinal tumors are currently not practice changing. Tumor detection rates are low in the early stages, while in advanced stages ctDNA is useful for molecular tracking evaluation. Most of the evidence comes from colorectal cancer studies, where ctDNA was evaluated both in the early and advanced stages with the post-surgery minimal residual disease assessment and the response assessment, respectively. ctDNA qualifies as a promising tool in the era of precision medicine, with potential applications in the entire management of gastrointestinal cancer patients. Further evidence is needed to establish which setting may be influenced greatly by liquid biopsy in clinical practice.

Identification of antibody against wingless‑type MMTV integration site family member 7B as a biliary cancer tumor marker.

Biliary cancer has a poor prognosis due to a lack of specific biomarkers and difficulty in diagnosis. The present study aimed to identify serum tumor markers for the diagnosis of biliary cancer via serological identification of antigens by recombinant cDNA expression cloning. Wingless‑type MMTV integration site family, member 7 (WNT7B) was identified as a target antigen, suggesting the presence of serum antibodies against this antigen. Deletion mutants were then prepared to evaluate the response to serum antibodies. When serum antibody levels against WNT7B deletion mutants (WNT7B-92‑2, -92‑260, 2-260 and 184-260) were examined using amplified luminescence proximity homogeneous assay‑linked immunosorbent assay, the levels of the antibody against WNT7B with amino acids 184‑260 were higher in patients with biliary cancer than in healthy donors. Therefore, the region covering residues 184‑260 of WNT7B was decomposed to generate seven peptides, and the levels of antibodies against these peptides were measured. Among them, the levels of antibodies against WNT7B234‑253 and WNT7B244‑260 were higher in patients with biliary cancers than in healthy donors (WNT7B234‑253, P=0.0009; WNT7B244‑260, P=0.0005). The levels of the antibody against the former were specifically high in patients with biliary cancer but not in those with esophageal, gastric, colorectal, pancreatic, or breast cancer. Furthermore, analysis by the cutoff value of WNT7B234‑253 defined by ROC showed a high sensitivity of 70% in patients with biliary cancer. Therefore, the serum levels of the antibody against WNT7B234‑253 may be useful as a marker for biliary cancer diagnosis.

OGBN P10 Laparoscopic management of cholecystoduodenal and cholecystocolic fistulas: technical considerations and postoperative outcomes

Abstract Background Cholecystoduodenal and cholecystocolic fistulas are rare complications of gallstone disease. They are usually diagnosed intraoperatively, posing significant surgical challenges. The aim of this study is to review the incidence, presentations, difficulty grading, technical aspects and their management outcomes on a unit adopting a policy of index admission cholecystectomy for all comers with biliary emergencies. Methods A prospectively maintained database of all laparoscopic cholecystectomy (LC) and laparoscopic common bile duct exploration (LCBDE) performed over a 30 years period between 1992 to 2022 by a single surgeon was reviewed. All biliary emergencies who were fit for anaesthesia were managed with an intention to treat during the index admission. Procedures involving cholecystoenteric fistulas or suspicious attachments were analysed. The clinical presentation, imaging, operative findings and outcomes were analysed. All suspicious cholecystoenteric attachments were dissected and encircled, confirming a fistula was achieved by access through the gallbladder lumen and, in most cases, obtaining either a duodenography or a colonography before disconnecting and repairing the fistula. Although staplers were not used in this series the technique may enhance the security of closure and prevent occasional complications resulting from minor intraoperative or postoperative leakage. Results 59/6000 (1%) patients had cholecystoduodenal and cholecystocolic fistulas (46) or dense fibrous attachments (13) where careful dissection revealed no obvious fistula. 67.8% were female and the median age was 68 years. 33 (56%) were emergency admissions, including 20 jaundiced and 8 with acute cholecystitis. Of 26 admitted electively 6 had previous acute cholecystitis. 32 (54.2%) had risk factors for CBD stones. ERCP was done in 5 and of cross sectional imaging in 15 patients only one suspected a cholecystocolic fistula. LCs were classified difficulty grade IV (28) or V (31). 29 (49.15) required LCBDE: 11 (18.6%) by trancystic exploration and 18 (30.5%) via choledochotomy. 12 patients had Mirizzi abnormalities and 3 had gallbladder, biliary or duodenal cancers. Subhepatic drains were used in 54 (91.5%). Median operative time was 145 minutes (range 35–375). One patient was converted to open due to significant adhesions. Perioperative complications occurred in 32%: 4 t-tube complications, 3 bile leaks, 3 chest infections, 3 intraabdominal collections requring relaparoscopy and 6 miscellaneous. The rate of complications specific to the presence of such fistulas was only 12%. There were 2 deaths with respiratory infection. Median hospital stay was 10 days (range 1–160). Conclusions When dense fibrosis and adhestions to bowel loops are encountered, a high index of suspicion is particularly important as 44% present electively with chronic symptoms. When an attachment is suspected to be a fistula it should be isolated, approached through the gallbladder lumen to confirm a fistula. Ligation is carried out before division and appropriately securing the fistula using seromuscular sutures. The laparoscopic approach to managing cholecystoduodenal and cholecystocolic fistulas is not currently widely practiced as the operative findings results in a low threshold for open conversion. However, laparoscopic resolution is feasible with appropriate training and experience thus avoiding conversion to open surgery which may help reduce the relatively high morbidity associated with such encounters.

Second line drug therapy for biliary cancer

Biliary cancer is a group of tumors that develop from the epithelium of the intra- and extrahepatic bile ducts (cholangiocarcino-ma), as well as the gallbladder. For 10 years, chemotherapy based on a combination of gemcitabine and cisplatin has remained the standard of first-line therapy in patients with locally advanced or metastatic biliary cancer, resulting in a median overall survival of 11.7 months. With the progression of the disease on the first line, effective options did not previously exist. Attempts to use various chemotherapeutic regimens, both in monotherapy and in combination, have not been successful. In order not to leave the patient without treatment, fluoropyrimidines, their combinations with oxaliplatin or irinotecan, are empirically prescribed as follow-up therapy. In recent years, different subtypes of biliary tract cancer have been defined depending on the anatomical location and genetic and/or epigenetic aberrations. Especially for intrahepatic cholangiocarcinoma novel therapeutic targets have been identified, including fibroblast growth factor receptor gene fusions 2 (FGFR2) and isocitrate dehydrogenase 1 and 2 mutations (IDH1/2), with molecularly targeted agents having shown evidence of activity in this subgroup of patients. Additionally, other pathways are being evaluated in both intrahepatic cholangiocarcinoma and other subtypes of biliary tract cancer, alongside targeting of the immune microenvironment. The growing knowledge of biliary tract cancer biology and molecular heterogeneity has paved the way for the development of new therapeutic approaches that will completely change the treatment paradigm for this disease in the near future. In this review, we review recently published data on the use of second-line therapy after progression with standard first-line therapy in patients with biliary cancer.

Genetic features and therapeutic relevance of emergent circulating tumor DNA alterations in refractory non-colorectal gastrointestinal cancers

Acquired resistance to systemic treatments is inevitable in most cancers, but the genetic basis for this in many cancer types has remained elusive due to constraints in obtaining tissue specimens longitudinally. In the management of gastrointestinal cancers, molecular profiling is conventionally performed at a single time point, although serial evaluations may yield biological insights that inform treatment decisions. We characterize genetic changes in serial liquid biopsies which provide real-time snapshots of tumor genetics and heterogeneity in refractory non-colorectal gastrointestinal cancers, and determine the clinical utility of repeat circulating tumor DNA (ctDNA) testing. In a national cohort of 449 patients with pancreatic, biliary, esophagogastric, and hepatocellular cancers, resistance to conventional therapies is broadly associated with tumor evolution. Emergent ctDNA alterations only detectable at progression occurs in 63% of patients and are frequently associated with treatment actionability. Tumor mutation burden is dynamic in cancers undergoing treatment, but is not associated with time to progression. Objective tumor responses in a case series of patients receiving treatment matched to emergent alterations show that repeat liquid biopsies may have clinical benefit by expanding treatment options in advanced gastrointestinal cancers.

Risks of colorectal cancer and biliary cancer according to accompanied primary sclerosing cholangitis in Korean patients with ulcerative colitis: a nationwide population-based study.

We conducted a nationwide population-based study to investigate incidence rates of colorectal and biliary cancers according to accompanying primary sclerosing cholangitis in Korean ulcerative colitis patients. We used the Health Insurance Review and Assessment claim database from January 2007 to April 2020. Standardized incidence ratios of colorectal and biliary cancers in ulcerative colitis patients were calculated. Among 35,189 newly diagnosed ulcerative colitis patients, 1,224 patients were diagnosed with primary sclerosing cholangitis. During the study period, 122 and 52 patients were diagnosed with colorectal and biliary cancers, respectively. Incidences of colorectal cancer were not higher in ulcerative colitis patients than those in the general population (standardized incidence ratios, 0.83; 95% confidence interval, 0.69-0.99), regardless of accompanied primary sclerosing cholangitis (standardized incidence ratio, 0.73; 95% confidence interval, 0.24-1.71). While incidences of biliary cancer were not higher in ulcerative colitis patients than those in the general population (standardized incidence ratio, 1.14; 95% confidence interval, 0.80-1.58), these were much higher with accompanied primary sclerosing cholangitis (standardized incidence ratio, 10.07; 95% confidence interval, 5.75-16.36). Cumulative incidences of colorectal and biliary cancers increased in patients who were diagnosed with ulcerative colitis at an older age. In Korean ulcerative colitis patients, colorectal cancer incidences were not higher than those in the general population regardless of accompanied primary sclerosing cholangitis. However, biliary cancer incidences were much higher in ulcerative colitis patients with primary sclerosing cholangitis than in those without, or in the general population.

Infectious complications of non-surgical biliary tract manipulation in paediatric patients. Role of antibiotic prophylaxis

BackgroundInfections related to non-surgical manipulation of the biliary tract (NSMBT) are common events despite periprocedural antibiotic prophylaxis (PAP). Since June 2017, our local protocol has indicated a 24-h regimen of intravenous piperacillin–tazobactam for this purpose. ObjectiveWe aimed to describe the incidence and characteristics of NSMBT-related paediatric infections, define risk factors for their development, and analyse adherence to our PAP protocol. Materials and methodsEpidemiological, clinical, and microbiological data were collected in consecutive NSMBT procedures performed in paediatric patients (<18 years) in our centre (2010–2019). Results113 procedures in 37 patients, median age 4 years (IQR 1–8), were included. Main underlying diseases were biliary atresia (32%) and cancer (14%). Sixty-eight percent had undergone liver transplant and 70% hepaticojejunostomy. In 44 procedures (39%), the intervention was performed during the course of infection and previously prescribed antibiotic treatment was maintained. In the other 69, PAP was specifically indicated for NSMBT; antibiotic adequacy increased from 35% to 100% after June 2017. In total, 32 NSMBT-related infections (28%) occurred, mainly in the first 24h post-procedure (72%); no deaths happened. Causative pathogens were Gram-negative rods (64%), Gram-positive cocci (28%), and Candida spp. (8%). Main related risk factors were hepaticojejunostomy, biliary obstruction, and liver transplant. ConclusionsNSMBT in children entails a significant infection risk, even under antibiotic prophylaxis, being hepaticojejunostomy the main risk factor. Infectious complications mainly occurred immediately after the procedure. After establishing a PAP protocol, 100% of interventions received appropriate prophylaxis, decreasing antibiotic exposure time and potentially, the length of hospital stay.

A comparison of DNA sequencing and gene expression profiling to assist tissue of origin diagnosis in cancer of unknown primary.

Cancer of unknown primary (CUP) is a syndrome defined by clinical absence of a primary cancer after standardised investigations. Gene expression profiling (GEP) and DNA sequencing have been used to predict primary tissue of origin (TOO) in CUP and find molecularly guided treatments; however, a detailed comparison of the diagnostic yield from these two tests has not been described. Here, we compared the diagnostic utility of RNA and DNA tests in 215 CUP patients (82% received both tests) in a prospective Australian study. Based on retrospective assessment of clinicopathological data, 77% (166/215) of CUPs had insufficient evidence to support TOO diagnosis (clinicopathology unresolved). The remainder had either a latent primary diagnosis (10%) or clinicopathological evidence to support a likely TOO diagnosis (13%) (clinicopathology resolved). We applied a microarray (CUPGuide) or custom NanoString 18-class GEP test to 191 CUPs with an accuracy of 91.5% in known metastatic cancers for high-medium confidence predictions. Classification performance was similar in clinicopathology-resolved CUPs - 80% had high-medium predictions and 94% were concordant with pathology. Notably, only 56% of the clinicopathology-unresolved CUPs had high-medium confidence GEP predictions. Diagnostic DNA features were interrogated in 201 CUP tumours guided by the cancer type specificity of mutations observed across 22 cancer types from the AACR Project GENIE database (77,058 tumours) as well as mutational signatures (e.g. smoking). Among the clinicopathology-unresolved CUPs, mutations and mutational signatures provided additional diagnostic evidence in 31% of cases. GEP classification was useful in only 13% of cases and oncoviral detection in 4%. Among CUPs where genomics informed TOO, lung and biliary cancers were the most frequently identified types, while kidney tumours were another identifiable subset. In conclusion, DNA and RNA profiling supported an unconfirmed TOO diagnosis in one-third of CUPs otherwise unresolved by clinicopathology assessment alone. DNA mutation profiling was the more diagnostically informative assay. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Socioeconomic disparities in the receipt of palliative care in biliary tract cancers.

80 Background: Biliary tract cancers are tumors arising from epithelial cells lining the biliary tract including the intrahepatic bile duct, extrahepatic bile duct, gall bladder, and ampulla of Vater. The incidence of biliary tract cancers has over the years. While there have been several advances in the diagnosis and treatment of biliary tract cancers, palliative treatment remains important in the management of these cancers. This study aims to analyze the patterns associated with the receipt of palliative care in patients with biliary tract cancers. Methods: We conducted a retrospective review of 150,007 patients in the National Cancer Database diagnosed with biliary tract cancer between 2004-2018 using ICD-O3 codes. Chi-square tests were used to assess the differences between palliative care recipients and non-recipients. Logistic regression was used to assess which variables influence the likelihood of receiving palliative care. Statistical analyses were performed using SPSS. Results: The overall palliative care utilization amongst patients with biliary tract cancers was 13%. The use of palliative care in biliary tract cancers gradually increased over the years. Patients with gall bladder cancers were less likely to receive palliative care than those with intra-hepatic biliary duct cancers (OR 0.60 p &lt; 0.001). Our study also found significant differences in the utilization of palliative care based on race. Blacks were less likely to use palliative care than whites (OR 0.89 p = 0.001). Hispanic patients were less likely to utilize palliative care than whites (OR 0.70 95% CI 0.64-0.76). There was no statistically significant difference between the use of PC between Whites and Asians (OR 1.04 95% CI 0.95-1.13 p &lt; 0.441). Privately insured patients were less likely to receive palliative care than uninsured patients (OR 0.88 p = 0.029). There were no statistically significant differences between the receipt of palliative care in uninsured patients and Medicare or Medicaid patients (OR 0.98 p = 0.69; OR 1.00 p = 0.93). Patients belonging to households with a median income (&gt; $63,333) were less likely to receive palliative care than those in low-income (&lt; $40,000) household (OR 0.67 p &lt; 0.001). There was an increased likelihood of receiving palliative care in patients from communities with higher educational status. Patients who received treatment at academic/research programs were more likely to receive palliative care than those at community cancer programs (OR 1.18 95% CI 1.08-1.29). Conclusions: Our study identified disparities in the receipt of palliative care in biliary tract cancers based on socioeconomic status. Blacks and Hispanics were less likely to receive palliative care than whites. Interestingly, uninsured patients were more likely to receive palliative care than privately insured patients. As part of quality improvement, future research should address the drivers behind these reported disparities.

ONE Liver: A unique, multidisciplinary virtual tool for prospective review of complex liver tumors.

59 Background: Primary and secondary malignancies involving the liver represent some of the most complex cases we see in oncology. These tumors often require multi-disciplinary decision making to determine the optimal treatment. For example, the treatment plan for hepatocellular carcinoma or colorectal cancer metastatic to the liver can often include one of several liver-directed therapy options for cure and/or palliation. Obtaining multiple opinions in an expedited and patient-centered way can be challenging for community oncologists, especially those serving a rural community. We opted to create a virtual tumor board with geographical reach across Tennessee for timely comprehensive evaluation of these patients at Tennessee Oncology (TO), a community oncology network spanning over 30 clinical sites of care. Methods: In January 2021, we created a multidisciplinary team containing specialists in medical oncology, radiation oncology, hepatology, radiology, interventional radiology, and hepatobiliary surgery. Medical oncologists at any TO clinic in Tennessee or Georgia could make referrals to the program within the Electronic Health Record (EHR). The team reviewed all submitted cases bi-weekly either virtually or at a centralized location. Referring providers were not required to attend the tumor boards to expand geographical reach. Recommendations were communicated back to the referring physician by both email and letters scanned into the EHR. Results: Between January 1, 2021 and May 1, 2022, a total of 154 referrals representing 126 unique patients were placed to the ONE Liver tumor board. Thirty-three physicians referred patients across 21 practice locations across the state. The top 3 diagnoses were: metastatic colorectal cancer (53), hepatocellular carcinoma (33), and primary biliary cancers (32). The most common first line recommendations were for therapy with Y-90 embolization, further imaging workup, continued systemic therapy and/or clinical trial evaluation, and stereotactic body radiation therapy. All patients were evaluated within 2 weeks of referral with most evaluated in less than 1 week. 60% of patients evaluated lived more than 25 miles from a tertiary medical center and 28% lived more than 50 miles out. Conclusions: This initiative successfully facilitated efficient and multi-disciplinary evaluation of patients with complex liver tumors living in rural areas. Tumor boards of this type might scale disease expertise across larger geographical locations than traditional in-person tumor boards.

A preponderance of gastrointestinal cancer patients transition into cachexia syndrome.

Cancer cachexia is frequently documented by self-reported, single time-point weight histories. This approach lacks the granularity needed to fully elucidate the progression of cachexia syndrome. This study aimed to longitudinally assess body weight changes pre- and post-cancer diagnosis in gastrointestinal (GI) cancer patients. Body weights and relevant clinical data recorded in the electronic health record 12months pre- and post-GI cancer (colorectal, gastroesophageal, hepatobiliary and pancreatic) diagnosis were extracted. Weight loss was categorized by the International Consensus Definition for cachexia. A total of 879 patients were included in the final cohort including patients diagnosed with colorectal (n=317), hepatocellular (n=185), biliary (n=72), pancreatic (n=186) or gastroesophageal (n=119) cancer. Stage of disease was equally distributed. Patients without cachexia at diagnosis (n=608) remained weight stable during the 12months pre-diagnosis (+0.5±0.5% body weight; P=0.99). Patients with cachexia at diagnosis (n=271) remained weight stable 6 to 12months prior to diagnosis (+0.4±0.8%; P>0.9999) and lost 8.7±0.6% (P<0.0001) within the 6months pre-diagnosis. Patients without cachexia at diagnosis lost more weight post-diagnosis (6.3±0.6%) than patients with cachexia at diagnosis (4.7±1.0%; P=0.01). Pre-diagnosis weight trajectories did not differ between primary malignancies or stage of disease in patients without or with cachexia at diagnosis (all P≥0.05). Post-diagnosis weight trajectories did differ by primary malignancy (P≤0.0002) and stage (P<0.0001). In both patients without and with cachexia at diagnosis, colorectal patients lost the least amount of weight post-diagnosis and gastroesophageal patients lost the most amount of weight post-diagnosis. Stage 4 patients without or with cachexia at diagnosis lost the most weight post-diagnosis (P≤0.0003). Regardless of cachexia status at diagnosis, patients lost more weight when treated with systemic therapy (7.1±0.7%; P<0.0001; n=419) or radiation therapy (8.4±1.4%; P=0.02; n=116) compared to those who did not. Patients who did not have surgery lost more weight post-diagnosis (7.6±1.1%; P<0.0001; n=355) compared to those who did have surgery. By 12months post-diagnosis, 83% of the surviving GI cancer patients in this cohort had transitioned into cachexia syndrome. Significant weight loss in patients with GI cancer cachexia at diagnosis initiates at least 6months prior to diagnosis, and most patients will transition into cachexia syndrome post-diagnosis, regardless of pre-diagnosis weight change and stage of disease. These findings punctuate the importance of weight surveillance in cancer detection and earlier palliative interventions post-diagnosis in the GI cancer patient population.