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.

Impact of biliary stent-related events in patients diagnosed with advanced pancreatobiliary tumours receiving palliative chemotherapy

AIM: To determine the impact(morbidity/mortality) of biliary stent-related events(SRE)(cholangitis or stent obstruction) in chemotherapy-treated pancreaticobiliary patients.METHODS: All consecutive patients with advanced pancreatobiliary cancer and a biliary stent in-situ prior to starting palliative chemotherapy were identified retrospectively from local electronic case-note records(Jan 13 to Jan 15). The primary end-point was SRE rate and the time-to-SRE(defined as time from first stenting before chemotherapy to date of SRE). Progressionfree survival and overall survival were measured from the time of starting chemotherapy. Kaplan-Meier, Cox and Fine-Gray regression(univariate and multivariable) analyses were employed, as appropriate. For the analysis of time-to-SRE, death was considered as a competing event.RESULTS: Ninety-six out of 693 screened patients were eligible; 89% had a metal stent(the remainder were plastic). The median time of follow-up was 9.6 mo(range 2.2 to 26.4). Forty-one patients(43%)developed a SRE during follow-up [cholangitis(39%), stent obstruction(29%), both(32%)]. There were no significant differences in baseline characteristics between the SRE group and no-SRE groups. Recorded SRE-consequences were: none(37%), chemotherapy delay(24%), discontinuation(17%) and death(22%). The median time-to-SRE was 4.4 mo(95%CI: 3.6-5.5). Patients with severe comorbidities(P < 0.001) and patients with ≥ 2 baseline stents/biliary procedures [HR = 2.3(95%CI: 1.2-4.44), P = 0.010] had a shorter time-to-SRE on multivariable analysis. Stage was an independent prognostic factor for overall survival(P = 0.029) in the multivariable analysis adjusted for primary tumour site, performance status and development of SRE(SRE group vs no-SRE group).CONCLUSION: SREs are common and impact on patient's morbidity. Our results highlight the need for prospective studies exploring the role of prophylactic strategies to prevent/delay SREs.

胆道肿瘤:过去、现在和未来(英文)

Tumors of the biliary tract (gallbladder tumors, cholangiocarcinomas and ampullary carcinomas) are low incidence tumors with poor prognosis. The five-year overall survival is 50% for stage Ⅰ, 30% stage Ⅱ, 10% stage Ⅲ and 0% stage Ⅳ. Treatment is based on surgery for potentially resectable tumors. Chemotherapy and chemo-radiotherapy is the treatment of choice when surgery is not amenable, however it has not achieved encouraging results. These patients use to have very few symptoms, which is the reason for the delay in diagnosis and the poor prognosis. They frequently develop biliary obstruction: obstructive jaundice, right upper quadrant pain and weight loss. Ampullary carcinomas are frequently related to steatorrhea due to malabsorption. The most effective chemotherapy drugs used in monotherapy are 5FU (response rate 20%) and gemcitabine (response rate of 13%-60%), so they have been selected for further development in multiple phase Ⅱ clinical trials to explore their efficacy and safety in combination with other agents. In a phase Ⅲ clinical trial, combination of gemcitabine and cisplatin has been selected as the schedule of choice. Target therapies are also being developed in this malignancy. The present work reviews the most current knowledge of the pathogenesis, diagnosis and natural history of biliary tract tumors. Further, review of surgery, current adjuvant treatment and therapies for unresectable and advanced disease is provided. The most recent understanding for target therapies and molecular biology is also summarized.

Advanced small-bowel well-differentiated neuroendocrine tumours:An international survey of practice on 3rd-line treatment

BACKGROUND Somatostatin analogues are an established first-line therapy for well differentiated small bowel neuroendocrine tumours(Wd-SBNETs),while and peptide receptor radionuclide therapy(PRRT)is frequently used as a second-line therapy.Adequate treatment selection of third-line treatment remains challenging due to the limited prospective data currently available on the best therapeutic sequence.AIM To understand current practice and rationale for decision-making by physicians in the 3rd-line setting by building an online survey.METHODS Weighted average(WA)of likelihood of usage between responders(1 very unlikely;4 very likely)was used to reflect the relevance of factors explored.RESULTS Replies from representatives of 28 centers were received(5/8/2020-21/9/2020);medical oncologist(53.6%),gastroenterologist(17.9%);United Kingdom(21.4%),Spain(17.9%),Italy(14.3%).Majority from European Neuroendocrine Tumor Society(ENETS)Centres of Excellence(57.1%),who followed ENETS guidelines(82.1%).Generally speaking,3rd-line treatment for Wd-SBNETs was:everolimus(EVE)(66.7%),PRRT(18.5%),liver embolization(LE)(7.4%)and interferon-alpha(IFN)(3.7%);chemotherapy(0%);decision was based on clinical trial data(59.3%),or personal experience(22.2%).EVE was most likely used if Ki-67<10%(WA 3.27/4)or age<70 years(WA 3.23/4),in the 3rd-line setting(WA 3.23/4);regardless of presence/absence of carcinoid syndrome(CS),rate of progression or extent of disease.Chemotherapy was mainly utilised only if rapid progression(within 6 mo)(WA 3.35/4),Ki-6710%-20%(WA 2.77/4),negative somatostatin receptor imaging(WA 2.65/4)or high tumour burden(WA 2.77/4);temozolomide or streptozocin was used with capecitabine or 5-fluorouracil(5-FU)(57.7%),FOLFOX(5-FU combined with oxaliplatin)(23.1%).LE was selected if presence of CS(WA 3.24/4)or Ki-67<10%(WA 2.8/4),after progression to other treatments(WA 2.8/4).IFN was rarely used(WA 1.3/4).CONCLUSION Everolimus was the most frequently used therapeutic option in the third-line setting.The most important factors for decision-making included Ki-67,rate of progression,functionality and tumour burden;since this decision is based on multiple factors,it highlights the need for a multidisciplinary assessment.

Pancreatic biomarkers:Could they be the answer?

Pancreatic ductal adenocarcinoma(PDA)is known for its poor prognosis.Most of the patients are diagnosed with advanced stages,when no curative treatment is available.Currently,despite extensive clinical research on PDA,the median overall survival remains short.Diagnosis delay and primary chemo-resistance due to its intrinsic biological nature may explain the challenges to improve our results.Our knowledge about the molecular biology of PDA has exponentially increased during the last decades and its use for the development of biomarkers could help to reach better results in the clinical setting.These biomarkers could be the clue for the improvement in PDA clinical research by earlier detection strategies with diagnostic biomarkers,and by an individualization of treatment approach with prognostic and predictive biomarkers.This review summarizes the current knowledge about the molecular biology of PDA and the status of the most important prognostic and predictive biomarkers.

Identification of patients with pancreatic adenocarcinoma due to inheritable mutation:Challenges of daily clinical practice

BACKGROUND Identification of germ-line mutations in pancreatic ductal adenocarcinoma(PDAC) could impact on patient/family.AIM To assess the referral pathways for genetic consultations in PDAC.METHODS Electronic 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.RESULTS Four-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.CONCLUSIONEarlier referrals and increased awareness may be able to overcome the low rate of successful genetic appointments.

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.

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.

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.