Potential utility of liquid biopsies in the management of patients with biliary tract cancers:A review

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.

Health-related quality of life, anxiety, depression and impulsivity in patients with advanced gastroenteropancreatic neuroendocrine tumours

AIM To compare health-related quality of life(HRQoL),anxiety, depression, and impulsivity scores in patients with and without carcinoid syndrome(CS), and correlated them with serum 5-hydroxyindoleacetic acid(5-HIAA) levels.METHODS Patients with advanced gastroenteropancreatic neuroendocrine tumours(GEPNET), with and without CS completed HRQoL QLQ-C30 and QLQ-GI.NET21, Hospital Anxiety and Depression Scale(HADS) and Barratt Impulsivity Scale(BIS) questionnaires. Twosample Wilcoxon test was applied to assess differences in serum 5-HIAA levels, two-sample Mann-Whitney U test for HRQoL and BIS, and proportion test for HADS, between those with and without CS.RESULTS Fifty patients were included; 25 each with and without CS. Median 5-HIAA in patients with and without CS was 367 nmol/L and 86 nmol/L, respectively(P = 0.003). Scores related to endocrine symptoms were significantly higher amongst patients with CS(P = 0.04) and scores for disease-related worries approached significance in the group without CS, but no other statistically-significant differences were reported between patients with and without CS in responses on QLQ-C30 or QLQ-GI.NET21. Fifteen patients(26%) scored ≥ 8/21 on anxiety scale, and 6(12%) scored ≥ 8/21 on depression scale. There was no difference in median 5-HIAA between those scoring < or ≥ 8/21 on anxiety scale(P = 0.53). There were no statistically significant differences between groups in first or second-order factors(BIS) or total sum(P = 0.23).CONCLUSION Excepting endocrine symptoms, there were no significant differences in HRQoL, anxiety, depression or impulsivity between patients with advanced GEPNET, with or without CS. Over one quarter of patients had high anxiety scores, unrelated to peripheral serotonin metabolism.

Prognostic importance of lymph node yield after curative resection of gastroenteropancreatic neuroendocrine tumours

BACKGROUND The prognostic significance of lymph nodes(LNs)metastases and the optimum number of LN yield in gastroenteropancreatic neuroendocrine tumours(GEP NETs)undergoing curative resection is still debatable.Many studies have demonstrated that cure rate for patients with GEP NETs can be improved by the resection of the primary tumour and regional lymphadenectomy AIM To evaluate the effect of lymph node(LN)status and yield on relapse-free survival(RFS)and overall survival(OS)in patients with resected GEP NETs.METHODS Data on patients who underwent curative resection for GEP NETs between January 2002 and March 2017 were analysed retrospectively.Grade 3 tumours(Ki67>20%)were excluded.Univariate Cox proportional hazard models were computed for RFS and OS and assessed alongside cut-point analysis to distinguish a suitable binary categorisation of total LNs retrieved associated with RFS.RESULTS A total of 217 patients were included in the study.The median age was 59 years(21-97 years)and 51%(n=111)were male.Primary tumour sites were small bowel(42%),pancreas(25%),appendix(18%),rectum(7%),colon(3%),gastric(2%),others(2%).Median follow up times for all patients were 41 mo(95%CI:36-51)and 71 mo(95%CI:63–76)for RFS and OS respectively;50 relapses and 35 deaths were reported.LNs were retrieved in 151 patients.Eight or more LNs were harvested in 106 patients and LN positivity reported in 114 patients.Three or more positive LNs were detected in 62 cases.The result of univariate analysis suggested perineural invasion(P=0.0023),LN positivity(P=0.033),LN retrieval of≥8(P=0.047)and localisation(P=0.0049)have a statistically significant association with shorter RFS,but there was no effect of LN ratio on RFS:P=0.1 or OS:P=0.75.Tumour necrosis(P=0.021)and perineural invasion(P=0.016)were the only two variables significantly associated with worse OS.In the final multivariable analysis,localisation(pancreas HR=27.33,P=0.006,small bowel HR=32.44,P=0.005),and retrieval of≥8 LNs(HR=2.7,P=0.036)were independent prognostic factors for worse RFS.CONCLUSION An outcome-oriented approach to cut-point analysis can suggest a minimum number of adequate LNs to be harvested in patients with GEP NETs undergoing curative surgery.Removal of≥8 LNs is associated with increased risk of relapse,which could be due to high rates of LN positivity at the time of surgery.Given that localisation had a significant association with RFS,a prospective multicentre study is warranted with a clear direction on recommended surgical practice and follow-up guidance for GEP NETs.

Management of incidentally discovered appendiceal neuroendocrine tumors after an appendicectomy

Appendiceal neuroendocrine tumors(aNETs)are an uncommon neoplasm that is relatively indolent in most cases.They are typically diagnosed in younger patients than other neuroendocrine tumors and are often an incidental finding after an appendectomy.Although there are numerous clinical practice guidelines on management of a NETs,there is continues to be a dearth of evidence on optimal treatment.Management of these tumors is stratified according to risk of locoregional and distant metastasis.However,there is a lack of consensus regarding tumors that measure 1-2 cm.In these cases,some histopathological features such as size,tumor grade,presence of lymphovascular invasion,or mesoappendix infiltration must also be considered.Computed tomography or magnetic resonance imaging scans are recommended for evaluating the presence of additional disease,except in the case of tumors smaller than 1 cm without additional risk factors.Somatostatin receptor scintigraphy or positron emission tomography with computed tomography should be considered in cases with suspected residual or distant disease.The main point of controversy is the indication for performing a completion right hemicolectomy after an initial appendectomy,based on the risk of lymph node metastases.The main factor considered is tumor size and 2 cm is the most common threshold for indicating a colectomy.Other factors such as mesoappendix infiltration,lymphovascular invasion,or tumor grade may also be considered.On the other hand,potential complications,and decreased quality of life after a hemicolectomy as well as the lack of evidence on benefits in terms of survival must be taken into consideration.In this review,we present data regarding the current indications,outcomes,and benefits of a colectomy.

Retrospective study on mixed neuroendocrine non-neuroendocrine neoplasms from five European centres

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 months(95%CI:9.2-24.4),and median overall survival(OS):28.6 months(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 months(95%CI:4.4-7.4),and median OS;9.0 months(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.

The role of radiotherapy in metastatic bladder cancer

The management of metastatic bladder cancer is palliative.Best outcomes are achieved in those who are fit enough for systemic therapies.The place of radiotherapy in these patients is mainly for symptom control,in particular haematuria.However,a small proportion,especially those with oligometastases,will benefit from more radical treatment.In this review,we look at the evidence currently available for radiotherapy in this setting.

Editorial comment on: development and external validation of a model to predict overall survival in patients with resected gallbladder cancer

The incidence of biliary tract cancer(BTC)(1),including gallbladder cancer(GBC)(2),is increasing.Potentially curative surgery is possible in only approximately 20%,and adjuvant capecitabine,versus observation after resection,has been reported to improve survival in a prespecified sensitivity and per-protocol analyses of the phase 3 randomised trial BILCAP(capecitabine compared with observation in resected BTC)(adjusting for minimisation factors,nodal status,grade,and gender)(3,4).The prognosis for patients with advanced BTC is poor;the median overall survival(OS)for patients receiving standard of care cisplatin/gemcitabine in the first-line setting was 11.7 months in the Advanced Biliary Cancer-02(ABC-02)study(5).There has been no alteration in the established choice of first-line systemic treatment for advanced BTC for over a decade.However,a recent press release announced that the phase 3 randomised study of durvalumab in combination with cisplatin/gemcitabine versus placebo with cisplatin/gemcitabine as a first-line treatment for patients with advanced BTC(TOPAZ-1)had met its primary endpoint of OS at the interim analysis;detailed results are awaited(NCT03875235).

The promise of precision medicine:how biomarkers are shaping the future of cholangiocarcinoma treatment

Cholangiocarcinoma(CCA)is the second most frequent primary malignant neoplasm of the hepatobiliary system.Unfortunately,CCA is often diagnosed at an advanced stage,when potentially curative surgical treatments are not recommended.The probability of achieving complete resection in patients who undergo surgery is about 25%(1)and even when complete tumor removal is achieved,the risk of recurrence is greater than 50%.Identification and validation of reliable biomarkers is crucial for the early detection,accurate diagnosis,appropriate staging/prognosis,therapy selection and effective monitoring of patients with biliary tract cancers(BTCs)(Figure 1).Achieving early diagnosis remains a challenge to improve survival and,although many promising biomarkers have been identified(2),to date none have reached clinical practice.

The microbiome as a potential diagnostic biomarker for pancreatic ductal adenocarcinoma(PDAC)

Pancreatic ductal adenocarcinoma(PDAC)is a major cause of cancer-related death worldwide.Despite recent advances in treatment options,prognosis remains poor,and data estimates from the United States(US)show that PDAC will surpass colorectal cancer to become the second most common cause of cancer-related death by 2040(1).Surgery followed by adjuvant chemotherapy is the only potentially curative treatment option for patients with PDAC;however,the majority present with advanced stage,non-resectable disease.Early diagnosis could improve the dismal prognosis for this patient group,but this remains challenging due to numerous factors including a lack of approved biomarkers and screening programmes,and non-specificity or late presentation of symptoms.