Pancreatic cancer: Are 'liquid biopsies' ready for prime-time?

Pancreatic cancer is a disease that carries a poor prognosis. Accurate tissue diagnosis is required. Tumours contain a high content of stromal tissue and therefore biopsies may be inconclusive. Circulating tumour cells(CTCs) have been investigated as a potential "liquid biopsy" in several malignancies and have proven to be of prognostic value in breast, prostate and colorectal cancers. They have been detected in patients with localised and metastatic pancreatic cancer with sensitivities ranging from 38%-100% using a variety of platforms. Circulating tumour DNA(ct DNA) has also been detected in pancreas cancer with a sensitivity ranging from 26%-100% in studies across different platforms and using different genetic markers. However, there is no clear consensus on which platform is the most effective for detection, nor which genetic markers are the most useful to use. Potential roles of liquid biopsies include diagnosis, screening, guiding therapies and prognosis. The presence of CTCs or ct DNA has been shown to be of prognostic value both at diagnosis and after treatment in patients with pancreatic cancer. However, more prospective studies are required before this promising technology is ready for adoption into routine clinical practice.

Review of the diagnosis,classification and management of autoimmune pancreatitis

Autoimmune pancreatitis(AIP)is a rare form of chronic pancreatitis,with as yet undetermined incidence and prevalence in the general population.Our understanding of it continues to evolve.In the last few years,2separate subtypes have been identified:type 1 AIP has been recognised as the pancreatic manifestation of a multiorgan disease,named immunoglobulin G4(IgG4)-related disease while type 2 AIP is a pancreas specific disorder not associated with IgG4.International criteria for the diagnosis of AIP have been defined:the HISORt criteria from the Mayo clinic,the Japan consensus criteria and,most recently,the international association of pancreatology"International Consensus Diagnostic Criteria".Despite this,in clinical practice it can still be very difficult to confirm the diagnosis and differenti-ate AIP from a pancreatic cancer.There are no large studies into the long-term prognosis and management of relapses of AIP,and there is even less information at present regarding the Type 2 AIP subtype.Further studies are necessary to clarify the pathogenesis,treatment and long-term outcomes of this disease.Critically for clinicians,making the correct diagnosis and differentiating the disease from pancreatic cancer is of the utmost importance and the greatest challenge.

Observation or resection of pancreatic intraductal papillary mucinous neoplasm:An ongoing tug of war

An increasing number of patients are being referred to pancreatic centres around the world due to often incidentally discovered cystic neoplasms of the pancreas.The evaluation and management of pancreatic cystic neoplasms is a controversial topic and with existing guidelines based on a lack of strong evidence there is discordance between centres and guidelines with regard to when to offer surgery and when to favour surveillance.The frequency,duration and modality of surveillance is also controversial as this is resource-consuming and must be balanced against the perceived benefits and risks involved.While there is consensus that the risk of malignancy should be balanced against the lifeexpectancy and comorbidities,the indications for surgery and surveillance strategies vary among the guidelines.Thus,the tug of war between surveillance or resection continues.Here we discuss the recommendations from guidelines with further accumulating data and emerging reports on intraductal papillary mucinous neoplasm in the literature.

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.

Personalising pancreas cancer treatment:When tissue is the issue

The treatment of advanced pancreatic cancer has not moved much beyond single agent gemcitabine until recently when protocols such as FOLFIRINOX(fluorouracil,leucovorin,irinotecan and oxaliplatin)and nab-paclitaxelgemcitabine have demonstrated some improved outcomes.Advances in technology especially in massively parallel genome sequencing has progressed our understanding of the biology of pancreatic cancer especially the candidate signalling pathways that are involved in tumourogenesis and disease course.This has allowed identification of potentially actionable mutations that may be targeted by new biological agents.The heterogeneity of pancreatic cancer makes tumour tissue collection important with the aim of being able to personalise therapies for the individual as opposed to a one size fits all approach to treatment of the condition.This paper reviews the developments in this area of translational research and the ongoing clinical studies that will attempt to move this into the everyday oncology practice.

人乳头瘤病毒与结直肠癌关系的研究进展

结直肠癌是世界上排名第3位的恶性肿瘤，在癌症相关病死率中排第4位，占所有癌症的9．4％。据估算全球每年的新发病例超过120万例，并且每年有大约60万人死于结直肠癌。一般认为西方发达国家是结直肠癌的高发区，而我国的发生率则相对较低。但是随着我国人民生活水平的不断提高，结直肠癌的发生率也在升高，并有年轻化的趋势。

HPV分子生物学检测方法研究进展

人乳头状瘤病毒(human papillomaviruses,HPV)属乳多空病毒科的双链环状DNA病毒,其基因组有大约8000个碱基对[1]。按照DNA序列差异分为5个属,即α、β、γ、Mu、Nu,每个属包括若干亚型。目前发现了200多种亚型,其中α属65种[2]。对人类致病的HPV主要就是α属。

HPV相关癌症治疗性疫苗的研究进展

人乳头瘤病毒(HPV)感染所致癌症大约占所有恶性肿瘤的4.5%~5.0%.其高危亚型的持续性感染与宫颈癌、阴茎癌、肛管癌及口咽部等多种恶性肿瘤的发生有关.HPV预防性疫苗虽然可以有效预防常见HPV亚型的感染,但不能覆盖所有高危亚型且对已发生的感染没有治疗效果.针对具有致癌潜力的HPV高危亚型,当前处于研发阶段的HPV相关癌症治疗性疫苗分为核酸疫苗(包括DNA疫苗、RNA疫苗)、肽类疫苗、蛋白质疫苗、活载体疫苗(包括细菌性活载体疫苗、病毒性活载体疫苗)和基于细胞的HPV治疗疫苗等.以上各类疫苗均已经进入了不同的临床试验阶段.尤其是活载体疫苗中的病毒性活载体疫苗,部分产品已经在Ⅲ期临床试验中取得了比较满意的治疗效果.本文对前述不同种类HPV相关癌症治疗性疫苗的研发进展进行了系统的综述.

Highlights of the 2nd International Symposium on Tribbles and Diseases: tribbles tremble in therapeutics for immunity, metabolism, fundamental cell biology and cancer

The Tribbles(TRIB) family of pseudokinase proteins has been shown to play key roles in cell cycle, metabolic diseases, chronic inflammatory disease, and cancer development. A better understanding of the mechanisms of TRIB pseudokinases could provide new insights for disease development and help promote TRIB proteins as novel therapeutic targets for drug discovery. At the 2 nd International Symposium on Tribbles and Diseases held on May 7–9, 2018 in Beijing, China, a group of leading Tribbles scientists reported their findings and ongoing studies about the effects of the different TRIB proteins in the areas of immunity, metabolism, fundamental cell biology and cancer. Here, we summarize important and insightful overviews from 4 keynote lectures, 13 plenary lectures and 8 short talks that took place during this meeting. These findings may offer new insights for the understanding of the roles of TRIB pseudokinases in the development of various diseases.

A monolithic single-chip point-of-care platform for metabolomic prostate cancer detection

There is a global unmet need for rapid and cost-effective prognostic and diagnostic tools that can be used at the bedside or in the doctor’s office to reduce the impact of serious disease.Many cancers are diagnosed late,leading to costly treatment and reduced life expectancy.With prostate cancer,the absence of a reliable test has inhibited the adoption of screening programs.We report a microelectronic point-of-care metabolite biomarker measurement platform and use it for prostate cancer detection.The platform,using an array of photodetectors configured to operate with targeted,multiplexed,colorimetric assays confined in monolithically integrated passive microfluidic channels,completes a combined assay of 4 metabolites in a drop of human plasma in under 2 min.A preliminary clinical study using L-amino acids,glutamate,choline,and sarcosine was used to train a cross-validated random forest algorithm.The system demonstrated sensitivity to prostate cancer of 94%with a specificity of 70%and an area under the curve of 0.78.The technology can implement many similar assay panels and hence has the potential to revolutionize low-cost,rapid,point-of-care testing.

Perioperative immunotherapy for pancreatic cancer is on its way

Interdisciplinary perioperative treatment has greatly improved the outcome of pancreatic cancer patients.Based on randomized,controlled phase III clinical trials,adjuvant chemotherapy with mFOLFIRINOX(PRODIGE-24 study),gemcitabine/capecitabine(ESPAC-4)or 5-fluorouracil/gemcitabine monotherapy(ESPAC-1,CONKO-001,ESPAC-3)is now the clinical standard after curative resection(1).

The role of endosomal cholesterol trafficking protein, StAR-related lipid transfer domain 3 （StarD3/MLN64）, in BRIN-BD11 insulinoma cells

Dear Editor, Insulin secretion by pancreatic β-cells is modulated by altering the cellular content and distribution of cholesterol, which is tightly regulated by a network of transcription factors, enzymes, receptors, transporters and cholesterol trafficking proteins. Inhibition of cellular biosynthesis by ＇statin＇ drugs, or depletion of plasma membrane cholesterol by methyl-β-cyclodextrin （MCD）, reduce glucose-stimulated insulin secretion （GSIS） and content in β-cells and islets;

Blood：借助细胞外囊泡诊断儿童白血病潜力大

曼彻斯特大学的研究人员最近开发了一种新的白血病诊断检测方法，该方法的出现或将使得医生对一种常见的儿童白血病的诊断发生革命性变化。研究人员表示急性淋巴细胞白血病细胞能够产生和释放一种特殊的细胞外结构，可以在血液中进行追踪。该发现或对这种儿童白血病的诊断，药物输送和治疗有重要启示。相关研究结果发表在国际学术期刊Blood上。

SERIneALanine Killer:SPT promiscuity inhibits tumour growth via intra-tumoral deoxysphingolipid production

In a recent article in Nature,Muthusami et al.1 highlight the promiscuity of serine palmitoyltransferase(SPT)for non-essential amino acids under low serine conditions,illustrating a previously unappreciated mechanism for inhibition of tumour growth—increased levels of deoxysphingolipids.