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There is a critical need for novel therapies to treat patients with advanced biliary tract cancer (BTC). This systematic review summarizes the evidence-based knowledge for the potential role of PD-1 and PD-L1 monoclonal antibodies in the treatment of patients with early-stage and advanced BTC. An Embase database search was conducted, identifying 15 eligible phase II/III clinical trials for review. Results from recent phase III trials show a statistically significant overall survival (OS) benefit from the addition of PD-1/PD-L1 inhibitors to chemotherapy in the first-line management of advanced BTC. Future research should concentrate on the discovery of biomarkers to identify patients who would benefit most from these therapies.

Background: Co-existing frailty in older patients with hepatopancreaticobiliary (HPB) malignancies is common. This study assessed the relationship between the Rockwood Clinical Frailty scale (CFS) and systemic anti-cancer therapy dose intensity (SACT-DI) and overall survival (OS) in patients with advanced HPB malignancies. Research design and methods: CFS was assessed prospectively for consecutive patients with newly diagnosed advanced HPB malignancy (The Christie; Sep-2019 to June-2020). Mann-Whitney U test assessed association between CFS, ECOG Performance Status (ECOG PS), and SACT-DI and Spearman’s rank assessed the association between ECOG PS, age, and frailty. Survival analysis was performed using Kaplan-Meier and Cox regression. Results: Two hundred patients met inclusion criteria. SACT-DI was higher in Group-1 (not frail) (CFS 1–3)(median = 61%) than Group-2 (vulnerable/mildly frail) (CFS 4–5)(median = 25.1%), p

Background Everolimus-induced pneumonitis (EiP) has been poorly studied in patients with neuroendocrine neoplasms (NEN) outside clinical trials. The aim of this study was to evaluate the incidence, risk factors, and outcomes of EiP in patients with NENs using real-world data. Methods Retrospective study of everolimus-treated patients with advanced NENs. Imaging reports were systematically reviewed for the presence of pneumonitis. Clinical features and treatment profiles for EiP were summarized. Overall survival (OS) was calculated from the initiation of everolimus to the date of death or last follow-up using the Kaplan-Meier method. Results A total of 122 patients were included. Median age at start of everolimus was 62 (19-86) years, 62% (76/122) were male, and half were from pancreatic origin (62, 51%). Twenty-eight patients (23%) developed EiP: 82% grade (G)1 or G2, 14% G3 and 4% G4. The median time to EiP was 3.6 (0.8-51) months. Primary tumor site, concurrent lung disease, smoking history, and prior therapies were not associated with the onset of EiP. Patients who developed EiP had longer time on everolimus treatment (median 18 months vs 6 months; P = .0018) and OS (77 months vs 52 months; P = .093). Everolimus-induced pneumonitis was a predictor of improved OS by multivariable analysis (HR 0.39, 95% CI 0.19-0.82; P = .013). Conclusion Everolimus-induced pneumonitis in the real-world clinical setting is present in one quarter of patients with NENs receiving everolimus and often occurs early. While risk factors for EiP were not identified, patients with EiP had improved survival.

Poorly differentiated neuroendocrine carcinomas (PD-NEC) are rare cancers garnering interest as they become more commonly encountered in the clinic. This is due to improved diagnostic methods and the increasingly observed phenomenon of “NE lineage plasticity,” whereby nonneuroendocrine (non-NE) epithelial cancers transition to aggressive NE phenotypes after targeted treatment. Effective treatment options for patients with PD-NEC are challenging for several reasons. This includes a lack of targetable, recurrent molecular drivers, a paucity of patient-relevant preclinical models to study biology and test novel therapeutics, and the absence of validated biomarkers to guide clinical management. Although advances have been made pertaining to molecular subtyping of small cell lung cancer (SCLC), a PD-NEC of lung origin, extrapulmonary (EP)-PD-NECs remain understudied. This review will address emerging SCLC-like, same-organ non-NE cancer-like and tumor-type–agnostic biological vulnerabilities of EP-PD-NECs, with the potential for therapeutic exploitation. The hypotheses surrounding the origin of these cancers and how “NE lineage plasticity” can be leveraged for therapeutic purposes are discussed. SCLC is herein proposed as a paradigm for supporting progress toward precision medicine in EP-PD-NECs. The aim of this review is to provide a thorough portrait of the current knowledge of EP-PD-NEC biology, with a view to informing new avenues for research and future therapeutic opportunities in these cancers of unmet need.

PDF file - 233K, Search strategies. Supplementary Figure 1. Funnel plot of hazard ratio for overall survival for high neutrophil-to-lymphocyte ratio (horizontal axis) and the standard error for the hazard ratio (vertical axis). Supplementary Figure 2. Study-level (i.e., at the individual publication level) association study quality and the hazard ratio for overall survival.

Background: Inflammation influences cancer development and progression. An elevated platelet to lymphocyte ratio (PLR), a marker of inflammation, has been linked to poor prognosis in several malignancies. Here, we quantify the prognostic impact of this biomarker.Methods: A systematic review of databases was conducted to identify publications exploring the association of blood PLR and overall survival (OS) in solid tumors. Data were pooled in a meta-analysis. Pooled HRs for OS by disease group and by PLR cutoff groups were computed and weighted using generic inverse-variance and random-effect modeling.Results: Twenty studies comprising 12,754 patients were assessed. Cutoffs for PLR defining risk groups ranged from 150 to 300 and were dichotomous (12 studies; group 1) or split into three groups (300, 8 studies; group 2). Higher PLR was associated with significantly worse OS in group 1 [HR = 1.87; 95% confidence interval (CI, 1.49–2.34); P < 0.001] and with a nonsignificant association in group 2 (HR per higher category = 1.21; 95%CI, 0.97–1.50; P = 0.10). The size of effect of PLR on OS was greater for metastatic disease (HR[group 1] = 2.0; 95% CI, 1.6–2.7; HR[group 2] = 1.6; 95% CI, 1.1–2.4) than for early-stage disease (HR[group 1] = 1.5; 95% CI, 1.0–2.2; HR[group 2] = 1.0; 95% CI, 0.8–1.3). A significant association was observed for colorectal, hepatocellular, gastroesophageal, ovarian, and pancreatic carcinoma in group 1 and for colorectal cancers in group 2.Conclusion: A high PLR is associated with worse OS in various solid tumors. Further research of its regulation and relevance in daily practice is warranted.Impact: PLR is a readily available and inexpensive biomarker with independent prognostic value in solid tumors. Cancer Epidemiol Biomarkers Prev; 23(7); 1204–12. ©2014 AACR.

The majority of patients diagnosed with cancer are ≥65 years. However, inclusion of older patients with cancer in clinical trials is limited, and so there is less evidence to guide systemic therapeutic decisions in these patients. There is also debate surrounding the definition of “older patients”. Additionally, comorbidities, as well as life expectancy will influence compliance to any treatment, and physicians may favour less intense regimens for these patients or best supportive care alone. In patients with biliary tract cancer (BTC), surgery followed by adjuvant capecitabine (BILCAP phase 3 trial) is the only potentially curative option, but patients often present with advanced disease, and palliative systemic treatment is given. The availability of novel targeted therapies (oral and monotherapy) in selected populations of patients with BTC may increase the therapeutic artillery for these older patients. Trials to date in patients with BTC have not been age-specific and have not always included age subgroup analysis, and so the evidence to support treatment of older patients is derived via extrapolation, primarily, with only 35% being >60 years in the adjuvant BILCAP study, for example. When this evidence is provided, treated patients tend to gain equivalent survival benefit, irrespective of age. A comprehensive clinical geriatric assessment is recommended. Revision of existing BTC treatment guidelines should incorporate some reference to best practice in older patients with BTC. Observational data may also provide valuable insights in this population. Age sub-group analysis should be encouraged in prospective clinical trials including patients with BTC, with age-specific trials favoured.

Background Cisplatin/gemcitabine is standard first-line treatment for patients with advanced biliary tract cancer (ABC). NUC-1031 (phosphoramidate transformation of gemcitabine) is designed to enhance efficacy by maximizing intratumoral active metabolites. Methods Patients with untreated ABC, Eastern Cooperative Oncology Group performance status 0–1 received NUC-1031 (625 or 725 mg/m2) and cisplatin (25 mg/m2) on days 1 and 8, every 21 days. Primary objectives were safety and maximum tolerated dose; secondary objectives were objective response rate (ORR), pharmacokinetics, progression-free survival (PFS), and overall survival (OS). Results Twenty-one patients (median age 61 years, n = 13 male; 17 cholangiocarcinoma, 2 ampullary, and 2 gallbladder cancer) received NUC-1031 625 mg/m2 (n = 8 and expansion n = 7; median six cycles) or 725 mg/m2 (n = 6; median 7.5 cycles). Treatment was well tolerated; most common treatment-emergent grade 3–4 adverse events occurring in more than one patient with 625 mg/m2 NUC-1031 were increased gamma-glutamyl transferase (GGT), 40%; alanine aminotransferase, 20%; bilirubin, 13%; neutropenia, 27%; decreased white cell count, 20%; thrombocytopenia, 13%; nausea, 13%; diarrhea, 13%; fatigue, 13%; and thrombus, 20% and with 725 mg/m2, increased GGT, 67%, and fatigue, 33%. NUC-1031 725 mg/m2 was selected as the recommended dose with cisplatin in ABC. ORR was 33% (one complete response, six partial responses), DCR was 76%, median PFS was 7.2 months (95% confidence interval [CI], 4.3–10.1), and median OS was 9.6 months (95% CI, 6.7–13.1). The median estimates of area under the plasma concentration–time curve from time 0 to last measurable time and maximum concentration were highest for NUC-1031 (218–324 μg•h/mL and 309–889 μg/mL, respectively) and lowest for di-fluoro-deoxycytidine (0.47–1.56 μg•h/mL and 0.284–0.522 μg/mL, respectively). Conclusion This is the first study reporting on the combination of NUC-1031 with cisplatin in ABC and demonstrated a favorable safety profile; 725 mg/m2 NUC-1031 in combination with cisplatin is undergoing phase III trial evaluation in ABC. (ClinicalTrials.gov ID: NCT02351765; EudraCT ID: 2015-000100-26). Implications for Practice The prognosis for patients with advanced biliary tract cancer (ABC) is approximately 1 year, and new treatment options are required. The cisplatin/gemcitabine combination is standard first-line treatment for patients with ABC. NUC-1031 is a phosphoramidate transformation of gemcitabine and is designed to enhance efficacy by maximizing intratumoral active metabolites. This phase Ib study (ABC-08) demonstrated a favorable safety profile of NUC-1031 in combination with cisplatin for the first-line treatment of patients with ABC, and 725 mg/m2 NUC-1031 was recommended in combination with cisplatin for phase III trial evaluation; the NuTide:121 global randomized study is currently enrolling.

Weight loss at diagnosis is common in pancreatic cancer (PC) and can adversely affect overall survival (OS). Little is known about the impact of weight loss occurring during palliative treatment. This study aimed to investigate if early weight loss during chemotherapy for inoperable PC affects OS.This retrospective study included patients newly-diagnosed with inoperable PC. Consecutive patients initiating first-line palliative chemotherapy between Jan'15 - Jan'19 with data on percentage weight loss at week 4 of treatment (%WLWeek4) were eligible. %WLWeek4 was dichotomised using 5% cut-off. OS was measured from chemotherapy initiation. Survival analysis was performed using Cox regression.Eligible patients (n = 255); 59.2% with head/neck PC; 52.6% metastatic; received triplet (32.2%), doublet (42.7%) or single-agent (25.1%) palliative chemotherapy. Median %WLWeek4 was -2.05% (95% confidence interval (CI) -2.58 to -1.56); %WLWeek4 was ≥5% in 23.1% patients. Patients on triplet chemotherapy were more likely to develop %WLWeek4 of ≥5% [35.4% (triplet) vs. 19.3% (doublet) vs 14.1% (monotherapy); multivariable Odds Ratio (triplet vs monotherapy) =3.25; 95% CI 1.40-7.56; p-value 0.006]. Median OS was 9.7 months (95% CI 8.54-10.41). Multivariable Cox regression demonstrated shorter OS if %WLWeek4 ≥5% (median OS 7.4 months (95% CI 6.27-10.01) vs. 9.9 months (95% CI 9.20-12.05); HR 2.37 (95% CI 1.64-3.42), P 0.001); this was independent from other factors (stage, age, number of chemotherapy drugs, ECOG-PS), including response to therapy (supporting that %WLWeek4 impacted on OS regardless of response to therapy).In advanced PC treated with palliative chemotherapy, a %WLWeek4 ≥5% was more prevalent in patients undergoing triplet chemotherapy, and was associated with shorter OS, regardless of response/progression to therapy. Early identification and intervention of weight loss seems to be key to improve patient outcomes.

Background: Biliary Tract Cancers (BTC) are rare malignancies with a poor prognosis. There are many challenges encountered in treating these patients in daily practice as well as in clinical, translational and basic research. Objective: This review summarises the most relevant challenges in clinical and translational research in BTCs and suggests potential solutions towards an improvement in quality of life and outcomes of patients diagnosed with such malignancies. Findings: The main challenge is the low number of patients with BTCs, complicated by the aggressive natural behaviour of cancer and the lack of funding sources for research. In addition, the clinical characteristics of these patients and the specific cancer-related complications challenge clinical research and clinical trial recruitment. It is worth highlighting that BTCs are a group of different malignancies (cholangiocarcinoma, gallbladder cancer and ampullary cancer) rather than a unique homogeneous disease. These subgroups differ not only in molecular aspects, but also in clinical and demographic characteristics. In addition, tailored imaging and quality of life assessment are required to tackle some of the issues specific to BTCs. Finally, difficulties in tissue acquisition both in terms of biopsy size and inclusion of sufficient tumour within the samples, may adversely impact translational and basic research. Conclusion: Increasing awareness among patients and clinicians regarding BTC and the need for further research and treatment development may address some of the main challenges in BTC research. International collaboration is mandatory to progress the field.

The prognosis for patients with biliary tract cancers (cholangiocarcinoma and gallbladder cancer) is poor, while the incidence of these cancers is increasing. Most patients are diagnosed with advanced disease when treatment options are limited to palliative approaches, mainly focused on chemotherapy. In recent years, novel treatment targets of relevance to biliary tract cancers, mainly present in patients with intrahepatic cholangiocarcinoma, have been identified and are rapidly changing the field. These include fibroblast growth factor receptor (FGFR) fusions and isocitrate dehydrogenase (IDH)-1 and -2 mutations which are each present in around 10–20% of patients with intrahepatic cholangiocarcinoma. In addition, inhibition of other pathways/molecules is currently being explored, including human epidermal growth factor receptor (HER) family members, the Wnt pathway, neurotropic tyrosine kinase receptor (NTRK) fusions and BRAF mutations. The IDH1 inhibitor ivosidenib has already been tested in a phase III clinical trial in pretreated cholangiocarcinoma and showed benefit in terms of progression-free survival. Multiple FGFR inhibitors have consistently shown high response rates in phase II/III trials, especially for patients harbouring FGFR2 fusions. Herein, we provide an overview of the status of targeted therapies in biliary tract cancers, discussing the current clinical development of IDH and FGFR inhibitors in detail, as well as reviewing current caveats and future steps.

Patients with extrapulmonary poorly differentiated neuroendocrine carcinomas (EP-PD-NECs) have a poor prognosis. Surgery is offered for those with localised disease, but the majority of patients present with advanced disease. Treatment strategies adopted are analogous to that of high grade NECs of the lung, with platinum/etoposide-based regimens advocated in the first-line setting for advanced disease. There is no standard second-line therapy. Research into their molecular and immune pathways may pave the way for novel drug discovery. The molecular drivers of NEC are best identified in small cell lung carcinoma, which present with near universal genomic alterations in TP53 and RB1. The genetics of EP-PD-NEC remain poorly understood; TP53, KRAS, PIK3CA/PTEN and BRAF mutations have been identified, with alterations in the BRCA pathway reported additionally in small cell NEC of the cervix and absence of argininosuccinate synthetase 1 expression in NEC of the urinary bladder. The use of cell lines and patient-derived xenografts (PDX) to predict response to treatment in NEC and the emergence of alternative biomarkers, such as circulating tumour cells and cell-free DNA, will also be explored. Despite limited published data on the immune microenvironment of EP-NEC, there are a number of clinical trials investigating the use of immune-targeted agents in this disease category, with conflicting emerging data from studies thus far. This review will summarise the treatment and available molecular and immune data in this under researched diagnosis and may stimulate the direction of future exploratory studies.

Identifying pretreatment blood markers that distinguish prognostic groups of patients with advanced pancreatic ductal adenocarcinoma (PDAC) under first-line FOLFIRINOX chemotherapy has the potential to improve management of this condition. Aim of this study was to determine the prognostic utility of a range of pretreatment, inflammation-related, blood cell markers in this group of patients. Data from a training cohort were analyzed to identify potential pretreatment blood markers correlating to survival outcomes. The most informative markers were further analyzed in a validation cohort comprised patients from a geographically separate cancer center undergoing the same treatment. A total of 138 consecutive patients receiving FOLFIRINOX chemotherapy between 2010 and 2019, constituted the training cohort. Neutrophil/lymphocyte (NLR), monocyte/lymphocyte (MLR), and platelet/lymphocyte ratio (PLR) as well as the systemic inflammatory response index (SIRI) and CA19.9 showed prognostic significance in addition to tumor stage. A pretreatment SIRI score cutoff of 2.35 differentiated between a poor prognostic group with median overall survival (mOS) 5.1 months and a better prognostic group, mOS 12.5 months. SIRI ≤/> 2.35 was predictive of mOS in patients with locally advanced and metastatic PDAC. SIRI was confirmed as a prognostic marker in a validation cohort of 67 patients with mOS of 13.4 months and 6.3 months for those with SIRI ≤ 2.35 and >2.35, respectively. Additional analysis revealed baseline SIRI as being prognostic within additional subgroups of patients in both cohorts. This large, retrospective, analysis of real-world patients receiving first-line FOLFIRINOX chemotherapy for advanced PDAC has identified the pretreatment blood SIRI as a strong prognostic marker for survival. This will allow better counseling of patients with regards to the benefits of treatment, improved stratification within clinical trials, and potentially identify groups of patients for novel therapy trials as first-line treatment.

Perihilar cholangiocarcinoma (pCCA) is the anatomical sub-group of biliary tract cancer (BTC) arising between the second-order intrahepatic bile ducts and the cystic duct. Together with distal and intrahepatic cholangiocarcinoma (dCCA and iCCA; originating distal to, and proximal to this, respectively), gallbladder cancer (GBC) and ampulla of Vater carcinoma (AVC), these clinicopathologically and molecularly distinct entities comprise biliary tract cancer (BTC). Most pCCAs are unresectable at diagnosis, and for those with resectable disease, surgery is extensive, and recurrence is common. Therefore, the majority of patients with pCCA will require systemic treatment for advanced disease. The prognosis with cytotoxic chemotherapy remains poor, driving interest in therapies targeted to the molecular nature of a given patient’s cancer. In recent years, the search for efficacious targeted therapies has been fuelled both by whole-genome and epigenomic studies, looking to uncover the molecular landscape of CCA, and by specifically testing for aberrations where established therapies exist in other indications. This review aims to provide a focus on the current molecular characterisation of pCCA, targeted therapies applicable to pCCA, and future directions in applying personalised medicine to this difficult-to-treat malignancy.

Gastrinoma; Insulinoma; Pancreatic neuroendocrine tumour Gastrinoma; Insulinoma; Tumor neuroendocrino pancreático Gastrinoma; Insulinoma; Tumor neuroendocrí pancreàtic Pancreatic neuroendocrine tumours (panNET) are heterogeneous neoplasms usually characterised by slow growth and secretion of hormones, which often cause symptoms. The effect of these symptoms on quality of life (QoL) has not previously been examined in detail. EORTC (European Organisation for Research and Treatment of Cancer) guidelines were followed in phases 1–3 to produce a potential module of questions usable for trials in panNET, focusing on three common types of panNET. For two less common types, a list of symptoms was constructed. Following an extensive literature search and phase 1a interviews with patients and healthcare workers, a long list of potential issues (169) was obtained. This list was shown to 12 patients from three countries in phase 1b interviews to check that no items were missed. The list was reduced to 57 issues. The list of issues was converted to questions, mainly from existing validated questions within the EORTC item library. The list of questions was then used in a phase 3 international study in eight countries using seven languages. A provisional module of 24 items is presented for use in nonfunctioning panNET, gastrinoma and insulinoma. This module increases knowledge concerning QoL in this condition and may be a useful adjunct in clinical trials. A phase 4 trial is being considered for validation of this questionnaire.

Introduction: Pancreatic exocrine insufficiency (PEI) in patients with advanced pancreatic cancer (aPC) is well documented, but there is no consensus regarding optimal screening. Methods and analysis: Patients diagnosed with aPC referred for palliative therapy were prospectively recruited. A full dietetic assessment (including Mid-Upper Arm Circumference (MUAC), handgrip and stair-climb test), nutritional blood panel, faecal elastase (FE-1) and 13C-mixed triglyceride breath tests were performed. Primary objective: prevalence of dietitian-assessed PEI (demographic cohort (De-ch)); design (diagnostic cohort (Di-ch)) and validation (follow-up cohort (Fol-ch)) of a PEI screening tool. Logistic and Cox regressions were used for statistical analysis. Results: Between 1 July 2018 and 30 October 2020, 112 patients were recruited (50 (De-ch), 25 (Di-ch) and 37 (Fol-ch)). Prevalence of PEI (De-ch) was 64.0% (flatus (84.0%), weight loss (84.0%), abdominal discomfort (50.0%) and steatorrhea (48.0%)). The derived PEI screening panel (Di-ch) included FE-1 (normal/missing (0 points); low (1 point)) and MUAC (normal/missing (>percentile 25) (0 points); low (2 points)) and identified patients at high-risk (2–3 total points) of PEI [vs. low-medium risk (0–1 total points)]. When patients from the De-ch and Di-ch were analysed together, those classified by the screening panel as “high-risk” had shorter overall survival (multivariable Hazard Ratio (mHR) 1.86 (95% CI 1.03–3.36); p-value 0.040). The screening panel was tested in the Fol-ch; 78.4% patients classified as “high-risk”, of whom 89.6% had dietitian-confirmed PEI. The panel was feasible for use in clinical practice (64.8% patients completed all assessments), with high acceptability (87.5% would repeat it). Most patients (91.3%) recommended dietetic input for all patients with aPC. Conclusions: PEI is present in most patients with aPC; early dietetic input provides a holistic nutritional overview, including, but not limited to, PEI. This proposed screening panel may help to prioritise those at higher risk of PEI, requiring urgent dietitian input. Its prognostic role needs further validation.

Cisplatin and gemcitabine (CisGem) are standard chemotherapy for advanced biliary tract cancer (BTC). The MEK inhibitor selumetinib showed synergy with gemcitabine when administered sequentially in BTC. This randomised Phase 2 trial aimed to assess the efficacy of sequential or continuous selumetinib with CisGem.Patients with advanced BTC received CisGem; arm A included selumetinib every day, arm B: selumetinib, days 1-5, 8-19 each cycle. Arm C received CisGem alone. Selumetinib was dosed at 75 mg BID but amended to 50 mg BID due to toxicity.In all, 51 participants were evaluable for response. No significant difference was seen in mean change in tumour size at 10 weeks between arms A and C (-7.8% vs -12.8%, P = 0.54) or arms B and C (-15% vs -12.8%, P = 0.78). There was no difference in median progression-free survival (6.0, 7.0, 6.3 months, P 0.95) or overall survival (11.7, 11.7, 12.8 months, P = 0.70) for arms A, B and C, respectively. More participants experienced grade 3-4 toxicities in selumetinib-containing arms. More participants in arm A required chemotherapy dose reductions (P = 0.01) with lower chemotherapy dose intensity during the first 10 weeks.Adding sequential or continuous selumetinib to CisGem failed to improve efficacy and increased toxicity in patients with advanced BTC.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a poor prognosis and significant symptom burden. This prospective observational study aimed to evaluate expectations and priorities of patients with advanced PDAC and their clinicians through a study survey and two quality of life (QoL) questionnaires (QLQ-C30 and PAN26) at three time-points: baseline (T1), before (T2) and after (T3) their 1st on-treatment CT scan. Over a 1-year period, 106 patients were approached, 71 patients and 12 clinicians were recruited. Choosing between treatment options, patients prioritised: 54% overall survival (OS), 26% balance between side-effects and OS, 15% could not choose and 5% favoured symptom control. These were significantly different from the clinician’s answers (p < 0.001). Patients who prioritised OS had higher symptom burden (p = 0.03) and shorter OS compared to those who prioritised balance (p = 0.01). Most (86%) patients had personal goals they wanted to reach; clinicians knew of these in 12% of instances. Patient and clinicians’ views regarding survival improvement from chemotherapy were significantly different: 81% of clinicians and 12% of patients thought 1–2 or 3–6 months extension, 58% of patients and 0% physicians thought 1–5 or >5 years (p < 0.001). At T1, patients had low QoL and worst symptoms were: ‘Future worries’, ‘planning of activities’, fatigue and pain. Patients were willing to accept significantly higher amounts of side-effects as a trade-off for extra time, than clinicians thought (p < 0.001). Overall, there are significant discrepancies between patient and clinicians’ views about the aims, priorities and expected extension of life.Keywords: pancreatic cancer; quality of life; patient views on treatment

Background Many patients referred with a provisional diagnosis of cancer of unknown primary (pCUP) present with presumed metastatic disease to the liver. Due to the lack of definitive histological markers, intrahepatic cholangiocarcinoma (iCCA) may be overlooked. This study assessed the frequency of iCCA within a pCUP cohort. Methods A single UK cancer-center study of sequential patients referred with pCUP from January 2017 to April 2020. Baseline diagnostic imaging was reviewed independently by a radiologist and oncologist; those with radiological features of iCCA (dominant liver lesion, capsular retraction) were identified. Results Of 228 patients referred with pCUP, 72 (32%) had malignancy involving the liver. 24/72 patients had radiological features consistent with iCCA; they were predominantly female (75%) with an average age of 63 years and 63% had an ECOG PS ≤ 2. The median overall survival (OS) of the iCCA group and the remaining liver-involved CUP group were similar (OS 4.1 vs 4.4 months, p-value = 0.805). Patients, where a primary diagnosis was subsequently determined, had better OS (10.2 months, p-values: iCCA = 0.0279: cCUP = 0.0230). Conclusions In this study, 34% of patients with liver-involved pCUP, fulfilled the radiological criteria for an iCCA diagnosis. Consideration of an iCCA diagnosis in patients with CUP could improve timely diagnosis, molecular characterisation and treatment.

ObjectivesAn algorithm was designed aiming to provide consistency of pancreatic enzyme replacement therapy (PERT) dosing/titration across healthcare professionals in pancreaticobiliary cancers (PBC). This prospective observational study aimed to validate this algorithm.MethodsConsecutive patients with inoperable or post-operative PBC with pancreatic exocrine insufficiency (PEI) symptoms, not taking PERT, or taking below the algorithm ‘starting dose’, were eligible. A dietitian or clinical nurse specialist reviewed patients for up to 3 weeks, titrating PERT as per the algorithm. Feasibility of algorithm deliverability was assessed by the percentage of patients with successful completion (primary objective). ResultsEligible patients (n = 25): at baseline 22 taking PERT [100% on suboptimal doses, 54.5% taking incorrectly], 3 initiated PERT due to PEI symptoms. Algorithm completion 20/25 (80%) patients, confirming deliverability by dietitians (11/12; 92%) and Clinical nurse specialist (9/13; 69%). Symptom resolution in 8/19 (42%), 3/7 (43%) and 1/3 (33%) patients at 1st, 2nd and 3rd reviews, respectively; advice compliance between 63-86%. ConclusionThis algorithm provides a structured method to titrate PERT. At diagnosis, all patients with PBC should be assessed for PEI and adequate PERT initiated. Regular reviews are required for timely symptom resolution and adequate escalation, facilitating differential diagnosis if refractory symptoms exist.Key wordsPancreatic Exocrine Insufficiency; Pancreatic Cancer; Pancreatic Enzyme Replacement Therapy

Purpose: This study aimed to evaluate the feasibility and repeatability of [18F]-fluorothymidine positron emission tomography (FLT-PET) and its utility as a proliferative imaging marker to evaluate response in patients with advanced pancreatic adenocarcinoma (PDAC) receiving gemcitabine-based chemotherapy. Methods: PDAC patients due to commence gemcitabine-based chemotherapy underwent FLT-PET over 60 minutes, before (baseline) and after 28 days of chemotherapy. Repeatability was assessed by a second FLT-PET scan within 7 days of baseline scan and before starting chemotherapy. Scans were assessed by two independent physician’s to determine inter-reporter concordance. FLT-PET uptake over 45-60 minutes was estimated as maximum and mean standardised uptake values (SUVmax and SUVmean). Exploratory analysis of tissue biomarkers was performed from archival tissue samples. Results: All 18 of the 21 patients consented who were imaged had primary tumour in-situ and 83% had metastases with 60% in liver. 17 patients received gemcitabine-based treatment. Thirty-five FLT-PET scans were acquired (89% evaluable) and 26 lesions delineated (17 primary tumours, 9 liver metastases). At baseline, liver metastases showed higher uptake compared with primary tumour with mean (SD) SUVmax [7.2 (1.1) vs 4.5 (1.3); p < 0.001] and SUVmean [4.7 (0.6) vs 2.1 (0.6); p < 0.001)]. There was good intra-patient repeatability and inter-reporter concordance with mean (SD) test-retest difference and inter-reporter Lin’s concordance coefficient being 4.9% (17.6) and 0.703 for SUVmax and -5.4% (SD 9.8) and 0.710 for SUVmean, respectively. FLT uptake between baseline and post-treatment scans were variable and did not predict for benefit from gemcitabine. However, gemcitabine-capecitabine combination therapy resulted in a higher FLT uptake compared to gemcitabine alone, although this did not translate to clinical benefit. No relationship was observed between tissue markers and FLT in half subjects imaged whose tissue was available. Conclusions FLT-PET is a feasible and reproducible imaging technique in patients with PDAC to evaluate proliferation-targeting therapy, using a simplified imaging protocol in well-designed clinical trials.

BACKGROUND Mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN) is a rare diagnosis, mainly encountered in the gastro-entero-pancreatic tract. There is limited knowledge of its epidemiology, prognosis and biology, and the best management for affected patients is still to be defined. AIM To investigate clinical-pathological characteristics, treatment modalities and survival outcomes of a retrospective cohort of patients with a diagnosis of MiNEN. METHODS Consecutive patients with a histologically proven diagnosis of MiNEN were identified at 5 European centres. Patient data were retrospectively collected from medical records. Pathological samples were reviewed to ascertain compliance with the 2017 World Health Organisation definition of MiNEN. Tumour responses to systemic treatment were assessed according to the Response Evaluation Criteria in Solid Tumours 1.1. Kaplan-Meier analysis was applied to estimate survival outcomes. Associations between clinical-pathological characteristics and survival outcomes were explored using Log-rank test for equality of survivors functions (univariate) and Cox-regression analysis (multivariable). RESULTS Sixty-nine consecutive patients identified; Median age at diagnosis: 64 years. Males: 63.8%. Localised disease (curable): 53.6%. Commonest sites of origin: colon-rectum (43.5%) and oesophagus/oesophagogastric junction (15.9%). The neuroendocrine component was; predominant in 58.6%, poorly differentiated in 86.3%, and large cell in 81.25%, of cases analysed. Most distant metastases analysed (73.4%) were occupied only by a poorly differentiated neuroendocrine component. Ninety-four percent of patients with localised disease underwent curative surgery; 53% also received perioperative treatment, most often in line with protocols for adenocarcinomas from the same sites of origin. Chemotherapy was offered to most patients (68.1%) with advanced disease, and followed protocols for pure neuroendocrine carcinomas or adenocarcinomas in equal proportion. In localised cases, median recurrence free survival (RFS); 14.0 mo (95%CI: 9.2-24.4), and median overall survival (OS): 28.6 mo (95%CI: 18.3-41.1). On univariate analysis, receipt of perioperative treatment (vs surgery alone) did not improve RFS (P = 0.375), or OS (P = 0.240). In advanced cases, median progression free survival (PFS); 5.6 mo (95%CI: 4.4-7.4), and median OS; 9.0 mo (95%CI: 5.2-13.4). On univariate analysis, receipt of palliative active treatment (vs best supportive care) prolonged PFS and OS (both, P < 0.001). CONCLUSION MiNEN is most commonly driven by a poorly differentiated neuroendocrine component, and has poor prognosis. Advances in its biological understanding are needed to identify effective treatments and improve patient outcomes.

Neuroendocrine tumors (NETs) are rare cancers with an associated prolonged survival in some patients. A proportion of patients diagnosed with NETs will present with carcinoid syndrome symptoms, characterized by diarrhea, flushing and/or wheezing. This review summarizes the current treatment options for carcinoid syndrome, focusing on the latest novel treatment option, telotristat ethyl. In addition, information on patient-reported outcomes and impact of carcinoid syndrome on quality of life (QOL) and improvement of following treatment with telotristat ethyl are reviewed. This article also provides an overview of the current QOL questionnaires for patients with NETs and addresses unmet needs in this field of patient-reported outcomes.

Background & Aims The role of 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) in the diagnosis and staging of patients with biliary tract cancers (BTCs) remains controversial, so we aimed to provide robust information on the utility of 18FDG-PET in the diagnosis and management of BTC. Methods This systematic review and meta-analysis explored the diagnostic test accuracy of 18FDG-PET as a diagnostic tool for diagnosis of primary tumour, lymph node invasion, distant metastases and relapsed disease. Subgroup analysis by study quality and BTC subtype were performed. Changes in management based on 18FDG-PET and impact of maximum standardised uptake values (SUVmax) on prognosis were also assessed. A random effects model was used for meta-analyses. Results A total of 2,125 patients were included from 47 eligible studies. The sensitivity (Se) and specificity (Sp) of 18FDG-PET for the diagnosis of primary tumour were 91.7% (95% CI 89.8–93.2) and 51.3% (95% CI 46.4–56.2), respectively, with an area under the curve (AUC) of 0.8668. For lymph node invasion, Se was 88.4% (95% CI82.6–92.8) and Sp was 69.1% (95% CI 63.8–74.1); AUC 0.8519. For distant metastases, Se was 85.4% (95% CI 79.5–90.2) and Sp was 89.7% (95% CI86.0–92.7); AUC 0.9253. For relapse, Se was 90.1% (95% CI 84.4–94.3) and Sp was 83.5% (95% CI 74.4–90.4); AUC 0.9592. No diagnostic threshold effect was identified. Meta-regression did not identify significant sources of heterogeneity. Sensitivity analysis revealed no change in results when analyses were limited to studies with low risk of bias/concern. The pooled proportion of change in management was 15% (95% CI 11–20); the majority (78%) due to disease upstaging. Baseline high SUVmax was associated with worse survival (pooled hazard ratio of 1.79; 95% CI 1.37–2.33; p Conclusions There is evidence to support the incorporation of 18FDG-PET into the current standard of care for the staging (lymph node and distant metastases) and identification of relapse in patients with BTC to guide treatment selection; especially if the identification of occult sites of disease would change management, or if diagnosis of relapse remains unclear following standard of care imaging. The role for diagnosis of the primary tumour remains controversial due to low sensitivity and 18FDG-PET should not be considered as a replacement for pathological confirmation in this setting. Lay summary A positron emission tomography (PET scan), using 18F-fluorodeoxyglucose (18FDG), can help doctors identify areas of cancer in the body by highlighting "hot spots". These hotspots may be cancerous (true positive) but may also be non-cancerous, like inflammation (false positive). We show that PET scans are useful to assess how far advanced the cancer is (by assessing spread to lymph glands and to other organs) and also to identify if the cancer has recurred (for example after surgery), thus helping doctors to make treatment decisions. However, a biopsy is still needed for the initial diagnosis of a biliary tract cancer, because of the high chance of a "false positive" with PET scans.

ObjectivesFemale physicians in medicine are increasing, but disparities in female authorship exist. The aim of this study was to characterise factors associated with female first (FF) and female senior (SF) authorship in later phase systemic oncological clinical trials in biliary tract cancer (BTC) and identify any changes over time.SettingEmbase/Medline identified trial publications in BTC (2000–2020) were included. χ2tests and log regression were used (assessed factors associated with FF and SF authorship, including changes over time (STATA V.16)).Primary outcome measureFF and SF authorship in later phase systemic oncological clinical trials in BTC.Secondary outcome measureAny changes over time?ResultsOf 501 publications, 163 met inclusion criteria. The median percentage of female author representation in publications was 25%; there were no female authors in 13% of publications. Geographic location of the home institution of the first and senior authors was Asia (42%/42%), Europe (29%/29%), USA (24%/22%) and other (4%/6%), respectively. Overall, FF and SF author representation was 20% and 10%, respectively. The median position of the first female author was second in all the publication author lists. The phase of trial, journal-impact factor, industry funding or whether the study met its primary endpoint did not impact FF/SF author representation. More SF authors had home institutions in ‘other’ geographic locations (40% in 10 trials) (p=0.02) versus Asia (6%), Europe (8%) and USA (14%). There were no significant changes in FF/SF representation over time (p=0.61 and p=0.33 respectively).ConclusionsFF and SF author representation in later phase systemic clinical trial publications in BTC is low and has not changed significantly over time. The underlying reasons for this imbalance need to be better understood and addressed.

BackgroundLocoregional treatments (LRT) including radioembolisation (SIRT), transarterial chemo-embolisation (TACE), hepatic arterial infusion (HAI) of chemotherapy, external beam radiotherapy (EBRT) and ablation have been studied for the management of intrahepatic cholangiocarcinoma (iCC). The aim of this systematic review was to provide outcome benchmarks for clinical trial design.MethodsIdentification of studies reporting outcomes of patients treated with LRT for iCC was performed using PubMed and Embase. Pooled weighted means were calculated for progression-free survival (PFS) and overall survival (OS); meta-analysis of proportions was used for estimation of pooled response rate.Results6325 entries were reviewed; 93 studies were eligible, representing 101 cohorts and 3990 patients: 15 cohorts (645 patients) for ablation, 18 cohorts (541 patients) for EBRT, 27 cohorts (1232 patients) for SIRT, 22 cohorts (1145 patients) for TACE, 16 cohorts (331 patients) for HAI and 3 cohorts (96 patients) not pooled. 74% of the studies were retrospective, 99% non-randomised.The pooled mean weighted OS was 30.2 months (95% confidence interval (CI): 21.8–38.6) for ablation, 18.9 (14.2–23.5) for EBRT, 14.1 (12.1–16.0) for SIRT, 15.9 (12.9–19.0) for TACE and 21.3 (15.4–27.1) for HAI. The pooled complete response rate was 93.9% for ablation. When analysed together, SIRT, TACE and HAI had a pooled mean weighted OS of 15.7 months, and 25.2 months for patients treated in first-line with concomitant systemic chemotherapy.ConclusionsAvailable literature on LRT for iCC was heterogeneous and of insufficient quality to make strong recommendations. Ablation achieved satisfactory outcomes, and may be recommended when surgery is not feasible.

Biliary tract cancer, comprising gallbladder cancer, cholangiocarcinoma and ampullary cancer, represents a more uncommon entity outside high-endemic areas, though global incidence is rising. The majority of patients present at a late stage, and 5-year survival remains poor. Advanced stage disease is incurable, and though palliative chemotherapy has been shown to improve survival, further diagnostic and therapeutic options are required in order to improve patient outcomes. Although certain subtypes of biliary tract cancer are relatively rich in targetable mutations, attaining tumour tissue for histological diagnosis and treatment monitoring is challenging due to locoregional anatomical constraints and patient fitness. Liquid biopsies offer a safe and convenient alternative to invasive procedures and have great potential as diagnostic, predictive and prognostic biomarkers. In this review, the current standard of care for patients with biliary tract cancer, future treatment horizons and the possible utility of liquid biopsies within a variety of contexts will be discussed. Circulating tumour DNA, circulating microRNA and circulating tumour cells are discussed with an overview of their potential applications in management of biliary tract cancer. A summary is also provided of currently recruiting clinical trials incorporating liquid biopsies within biliary tract cancer research.

IntroductionPancreatic exocrine insufficiency (PEI) in patients with pancreatic malignancy is well documented in the literature and is known to negatively impact on overall survival and quality of life. A lack of consensus opinion remains on the optimal diagnostic test that can be adapted for use in a clinical setting for this cohort of patients. This study aims to better understand the prevalence of PEI and the most suitable diagnostic techniques in patients with advanced pancreatic malignancy.Methods and analysisThis prospective observational study will be carried out in patients with pancreatic malignancy (including adenocarcinoma and neuroendocrine neoplasms). Consecutive patients with inoperable pancreatic malignancy referred for consideration of first-line chemotherapy will be considered for eligibility. The study comprises three cohorts: demographic cohort (primary objective to prospectively investigate the prevalence of PEI in patients with inoperable pancreatic malignancy); sample size 50, diagnostic cohort (primary objective to design and evaluate an optimal diagnostic panel to detect PEI in patients with inoperable pancreatic malignancy); sample size 25 and follow-up cohort (primary objective to prospectively evaluate the proposed PEI diagnostic panel in a cohort of patients with inoperable pancreatic malignancy); sample size 50. The following is a summary of the protocol and methodology.Ethics and disseminationFull ethical approval has been granted by the North West Greater Manchester East Research and Ethics Committee, reference: 17/NW/0597. This manuscript reflects the latest protocol V.8 approved 21 April 2020. Findings will be disseminated by presentation at national/international conferences, publication in peer-review journals and distribution via patient advocate groups.Trial registration number194255, NCT0361643.

Biliary tract cancers, including intra- and extra-hepatic cholangiocarcinoma as well as gallbladder cancer, are associated with poor prognosis and the majority of patients present with advanced-stage, non-resectable disease at diagnosis. Biliary tract cancer may develop through an accumulation of genetic and epigenetic alterations and can be influenced by microbial exposure. Furthermore, the liver and biliary tract are exposed to the gastrointestinal microbiome through the gut-liver axis. The availability of next-generation sequencing technology has led to an increase in studies investigating the relationship between microbiota and human disease. In particular, the interplay between the microbiome, the tumour micro-environment and response to systemic therapy is a prospering area of interest. Given the poor outcomes for patients with biliary tract cancer, this emerging field of research, through which new biomarkers may be identified, offers potential as a tool for early diagnosis, prognostication or even as a future therapeutic target. This review summarises the available evidence on the microbiome environment in patients with biliary tract cancer, including a discussion around confounding factors, implications for therapy and proposed future directions.

Tumour tissue as a source for molecular profiling and for in vivo models has limitations (e.g., difficult access, limited availability, single time point, potential heterogeneity between primary and metastatic sites). Conversely, liquid biopsies provide an easily accessible approach, enabling timely and longitudinal interrogation of the tumour molecular makeup, with increased ability to capture spatial and temporal intra-tumour heterogeneity compared to tumour tissue. Blood-borne biomarker assays (e.g., circulating tumour cells (CTCs), circulating free/tumour DNA (cf/ctDNA)) pose unique opportunities for aiding in the molecular characterisation and phenotypic subtyping of neuroendocrine neoplasms and will be discussed in this article.

Background: Neuroendocrine tumours (NETs) are a rare and heterogeneous group of neoplasms that mainly originate from the gastroenteropancreatic tract (GEP-NETs). The vast majority of NETs tend to overexpress somatostatin receptors (SSTRs), which can be targeted by somatostatin analogues (SSAs). 68Gallium DOTA SSTR peptide positron emission tracer computed tomography (68Ga PET-CT) has emerged as superior to other imaging modalities in identifying SSTRs. This study aimed to assess whether patients with GEP- NETs treated with SSAs have similar outcomes irrespective of tracer uptake intensity on 68Ga PET-CT.Methods: Patient cases undergoing 68Ga PET-CT imaging between November 2015 and September 2020 at The Christie NHS Foundation Trust, with diagnosis of histologically-confirmed advanced GEP-NETs receiving SSAs, were reviewed retrospectively. Kaplan-Meier and Cox regression were utilised to analyse progression free (PFS) and overall survival (OS).Results: Of 644 patients imaged with 68Ga PET-CT, 132 met inclusion criteria. The median age of patients was 62 years; ECOG performance status 0: 62 (47%), 1: 56 (42%), 2: 13 (10%); primary sites: ileum: 54 (41%), pancreas: 26 (20%), cancer of unknown primary: 20 (15%), Grade (G)1: 63 (47%), G2: 56 (42%), G3: 3 (2%), unknown: 11 (8%); 68Ga PET-CT tracer uptake increased: 124 (94%), no increased tracer uptake: 8 (6%). 66 patients (50%) progressed, and 99 (74%) were alive at analysis. Median PFS on SSAs was 20.82 months (95% confidence interval (CI) 12.2–30.03) for patients with increased tracer uptake (n=63) and 8.26 months (95% CI 4.55-not available (NA)) for patients with no increased tracer uptake (n=3) (Hazard Ratio (HR): 4.19 (95% CI 1.238–14.28), P=0.022). Median OS from commencement of SSA was: 99.51 months (95% CI 95.96 – NA) for patients with increased tracer uptake and 47.67 months for patients with no increased tracer uptake (95% CI 13.41 – NA) (HR 2.93 (95% CI 1.011–8.49), P=0.048).Conclusions: 68Ga PET-CT scans are an accurate tool for diagnosis and localisation of NETs. Median PFS and OS appears to be greater in patients receiving SSAs with increased uptake on the 68Ga PET-CT. However, further evaluation in larger cohorts is needed to definitively assess clinical benefit of SSAs in the 68Ga PET-CT negative cohort.

BACKGROUND Brain metastases (BMs) incidence in patients with extra-pulmonary neuroendocrine neoplasms (EP-NENs) is unclear, with no available management recommendations. This study aimed to review the clinical presentation, management and survival outcomes of patients with EP-NENs and BMs at a European Centre of Excellence. METHODS A retrospective single-centre analysis of consecutive patients with EP-NENs (Aug 2004-Feb 2020) was conducted. Median overall survival (OS)/survival from BMs diagnosis were estimated (Kaplan Meier). RESULTS Of 786 patients, 15 (1.9%) had BMs, median age 61y (range 15–77); 8 (53%) male, primary NEN site: unknown 40%; oesophageal 13%; small bowel 13%; pancreas 13%; gastric 7%; cervix 7% and bladder 7%. Most patients with BMs had grade 3 (G3) NENs (11, 73%), 3 (20%) were G2 and 1 (7%)G1. Eight (53%) had poorly-differentiated NENs, 6 well-differentiated and 1 not recorded. Two (13%) patients had synchronous BMs at diagnosis, whilst 13 (87%) developed BMs metachronously. Median time to development of BMs after initial NEN diagnosis: 15.9 months (range 2.5–139.5). Five patients had a solitary BM, 4 had 2–9 lesions and 6 had >10 BMs. The most commonly affected sites were the cerebrum (13, 87%), cerebellum (6, 40%), leptomeninges (2, 13%) and orbit (1, 7%). The most common presenting symptoms were limb weakness, headache, confusion, visual disturbance (each n=3, 20%), seizures (2, 13%), word-finding difficulty (2, 13%) and facial weakness/ptosis (1, 7%). Median OS from initial NEN diagnosis was 23.6-months [95%-CI 15.2–31.3]; median time to death from BMs diagnosis was 3.0-months [95%-CI 0.0–8.3]. Treatment of BMs was surgery (n=3); radiotherapy (n=6); 5 had WBRT, one localised radiotherapy (orbit). Six (40%) had best supportive care. CONCLUSION BMs in patients with EP-NENs are rare and predominantly in G3 NENs, with diverse intracranial distribution. Although uncommon, BMs from NENs behave aggressively and greater understanding is needed to improve therapeutic outcomes.

Background: Molecular profiling is becoming increasingly relevant in the management of patients with advanced cancer, to identify targetable aberrations and prognostic markers to enable a precision medicine strategy. Methods: Eligible patients were those diagnosed with advanced biliary tract cancer (BTC) including intrahepatic (iCCA) and extrahepatic cholangiocarcinoma (eCCA), gallbladder cancer (GBC), and ampullary carcinoma (Amp) who underwent molecular profiling between April 2017 and June 2020 based on analysis of either tumour samples (FoundationOne CDx&reg, /Oncomine&reg, platforms) or ctDNA (FoundationOne Liquid&reg, platform (Foundation Medicine, Cambridge, MA, USA)). Baseline patient characteristics and molecular profiling outcomes were extracted. The primary aim was to describe sample failure rate. Secondary aims included description of reason for sample failure, summary of findings derived from molecular profiling, and assessment of concordance between paired tissue and ctDNA samples. Results: A total of 149 samples from 104 individual patients diagnosed with advanced BTC were identified and eligible for this analysis: 68.2% iCCA, 100% advanced stage, 94.2% received palliative therapy. The rate of sample failure was 26.8% for tissue and 15.4% for ctDNA, p-value 0.220, predominantly due to insufficient (defined as &lt, 20%) tumour content in the sample (the reason for 91.2% of tissue sample failure). Of the 112 samples successfully analysed, pathological molecular findings were identified in the majority of samples (88.4%) and identification of pathological findings using ctDNA, was possible regardless of whether the patient was on active treatment at time of blood acquisition or not (p-value 1.0). The rate of targetable alterations identified was 40.2% across all successfully-analysed samples (39 iCCA, 6 non-iCCA): IDH1 mutations (19.1% of individual patients), FGFR2 alterations (10.1% and 5.6% of individual patients had FGFR2 fusions and mutations, respectively), 10.6% of all patients (12.4% of patients with successfully analysed samples) entered trials with matched targeted therapies as a consequence. Concordance of findings for paired tissue and paired tissue-ctDNA was high (3/3, 100% and 6/6, 100%, respectively). Twelve ctDNA samples were taken prior to palliative treatment initiation, median maximum mutant allele frequency (MAF) was 0.47 (range 0.21&ndash, 19.8), no significant association between reported maximum MAF and progression-free survival (PFS) or overall survival (OS) (all Cox regression p-values &gt, 0.273). A total of 15 patients (16.6%) harboured alterations in DNA damage repair (DDR) genes, when treated with platinum-based chemotherapy, there was a trend towards increased partial response rate (21.4% vs. 15.9%, p-value 0.653), radiological benefit rate (64.3% vs. 36.2%, p-value 0.071), and longer OS (median OS 20.4 months (95% CI 7.9&ndash, 26.7) vs. 13.3 (95 CI 11.0&ndash, 16.4), Cox Regression HR 0.79 (95% CI 0.39&ndash, 1.61), p-value 0.527). Conclusions: Molecular profiling is of use for identification of novel therapeutic strategies for patients with advanced BTC (mainly iCCA). One in four archived tissue samples may have insufficient tumour content for molecular profiling, ctDNA-based approaches may overcome these obstacles.

Background The benefit from chemotherapy, specifically for patients with gallbladder cancer (GBC), has been poorly explored since GBC is mostly studied jointly with other biliary tract cancers (BTC). Methods Eligible studies reporting outcome of palliative systemic chemotherapy for advanced GBC were identified through MEDLINE, cross-referencing and conferences (PROSPERO-CRD42019155745). Meta-analysis of proportions and calculation of pooled weighted means were performed. Results 58 eligible studies (n = 1,986 patients); cisplatin/gemcitabine (33 % of patients), gemcitabine/oxaliplatin (14 %) or gemcitabine monotherapy (9%). Estimated pooled overall radiological response rate(ORR), and pooled weighted mean progression-free (PFS) and overall survivals (OS) were 23.2 % (95 %–CI 20.0−26.5) (I2: 52.5 % (p Conclusions GBC benefit from chemotherapy differs from other BTCs, with shorter PFS/OS despite higher ORR; new treatment options are urgently required for management of advanced GBC.

Pancreatic neuroendocrine tumours (PanNETs) are rare diseases and a good example of how research is not only feasible, but also of crucial importance in the scenario of rare tumours. Many clinical trials have been performed over the past two decades expanding therapeutic options for patients with advanced PanNETs. Adequate management relies on optimal selection of treatment, which may be challenging for clinicians due to the fact that multiple options of therapy are currently available. A number of therapies already exist, which are supported by data from phase III studies, including somatostatin analogues and targeted therapies (sunitinib and everolimus). In addition, chemotherapy remains an option, with temozolomide and capecitabine being one of the most popular doublets to use. Peptide receptor radionuclide therapy was successfully implemented in patients with well-differentiated gastro-entero-pancreatic neuroendocrine tumours, but with certain questions waiting to be solved for the management of PanNETs. Finally, the role of immunotherapy is still poorly understood. In this review, the data supporting current systemic treatment options for locally advanced or metastatic PanNETs are summarized. Strategies for treatment selection in patients with PanNETs based on patient, disease, or drug characteristics is provided, as well as a summary of current evidence on prognostic and predictive biomarkers. Future perspectives are discussed, focusing on current and forthcoming challenges and unmet needs of patients with these rare tumours.

Biliary tract cancers (BTCs) are rare with poor prognosis. Due to the advent of genomic sequencing, new data have emerged regarding the molecular makeup of this disease. To add to the complexity, various subtypes also harbor a varied genetic composition. The commonly mutated genes associated with this cancer are KRAS, EGFR, IDH, FGFR and BAP1. Various clinical studies are looking at targeting these genetic mutations. Another therapeutic area of note is the potential for the use of immunotherapy in patients with BTC. Although BTC may be a result of chronic inflammation, this does not necessarily translate into increased immunogenicity. This literature review discusses the diverse molecular and immune-related pathways in patients with BTC and their potential therapeutic implications.

BACKGROUNDIdentification of germ-line mutations in pancreatic ductal adenocarcinoma (PDAC) could impact on patient/family.AIMTo assess the referral pathways for genetic consultations in PDAC.METHODSElectronic records of PDAC patients were reviewed retrospectively. Patients eligible for genetic consultation referral were identified following the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC) criteria. RESULTSFour-hundred patients were eligible. Of 113 patients (28.3%) meeting EUROPAC criteria, 8.8% were referred for genetic opinion. Germ-line mutations were identified in 0.75% of the whole population.CONCLUSION Earlier referrals and increased awareness may be able to overcome the low rate of successful genetic appointments.

BACKGROUND & AIMS: Whether all patients with advanced biliary tract cancer (aBTC) should be included in prospective trials, irrespective of the anatomic site of origin, is debated. Herein, we aimed to assess the survival impact of anatomic site of origin in prospective clinical trials of aBTC using landmark survival analysis.METHODS: Patients enrolled into prospective first-line aBTC clinical trials (Jan 97-Dec 15) were included. Overall survival (OS) was analysed using Cox proportional hazard regression; landmark survival (LS) and 95% CIs were calculated.RESULTS: Overall, 1,333 patients were included: median age 63 years (range 23-85); 46% male; 84% ECOG-PS0/1; 25% with locally advanced disease, 72% with metastatic, 3% not reported (NR). Patients were treated with mono-chemotherapy (23%), cisplatin/gemcitabine (36%), other combinations (39%), or NR (2%). Median OS was 10.2 months (95% CI 9.6-10.9). All sites (treatment-adjusted) had decreased risk of death vs. gallbladder cancer (GBC) (p 0.05, p = 0.08 respectively).CONCLUSIONS: GBC is associated with worse OS than other BTC sites and should be considered as a stratification factor in clinical trials. LS rates enable adjusted prognostication for aBTC survivors.LAY SUMMARY: Patients with gallbladder cancer have worse overall survival compared to those with biliary tract cancers of different primary origin. Thus, gallbladder cancer should be considered as a stratification factor in future clinical trials. Landmark survival rates enable adjusted prognosis prediction for patients with advanced biliary tract cancer who survive for some time.

Gemcitabine/cisplatin is standard of care for first-line treatment of patients with advanced biliary tract cancer (aBTC); new treatments are needed. NUC-1031 is designed to overcome key cancer resistance mechanisms associated with gemcitabine. The tolerability/efficacy signal of NUC-1031/cisplatin in the Phase Ib ABC-08 study suggested that this combination may represent a more efficacious therapy than gemcitabine/cisplatin for patients with aBTC, leading to initiation of the global NuTide:121 study which will include 828 patients ≥18 years with untreated histologically/cytologically-confirmed aBTC (including cholangiocarcinoma, gallbladder or ampullary cancer); randomized (1:1) to NUC-1031 (725 mg/m2)/cisplatin (25 mg/m2) or gemcitabine (1000 mg/m2)/cisplatin (25 mg/m2), on days 1/8, Q21-days. Primary objectives are overall survival and objective response rate. Secondary objectives: progression-free survival, safety, pharmacokinetics, patient-reported quality of life and correlative studies. (Investigational new drug (IND) number: 139058, European Clinical Trials database: EudraCT Number 2019-001025-28, ClinicalTrials.gov identifier: NCT04163900).