MicroRNA in pancreatic ductal adenocarcinoma and its precursor lesions

Pancreatic ductal adenocarcinoma (PDAC) is the 4^th deadliest cancer in the United States, due to its aggressive nature, late detection, and resistance to chemotherapy. The majority of PDAC develops from 3 precursor lesions, pancreatic intraepithelial lesions (PanIN), intraductual papillary mucinous neoplasm (IPMN), and mucinous cystic neoplasm. Early detection and surgical resection can increase PDAC 5-year survival rate from 6% for Stage IV to 50% for Stage I. To date, there are no reliable biomarkers that can detect PDAC. MicroRNAs (miRNA) are small noncoding RNAs (18-25 nucleotides) that regulate gene expression by affecting translation of messenger RNA (mRNA). A large body of evidence suggests that miRNAs are dysregulated in various types of cancers. MiRNA has been profiled as a potential biomarker in pancreatic tumor tissue, blood, cyst fluid, stool, and saliva. Four miRNA biomarkers (miR-21, miR-155, miR-196, and miR-210) have been consistently dysregulated in PDAC. MiR-21, miR-155, and miR-196 have also been dysregulated in IPMN and PanIN lesions suggesting their use as early biomarkers of this disease. In this review, we explore current knowledge of miRNA sampling, miRNA dysregulation in PDAC and its precursor lesions, and advances that have been made in using miRNA as a biomarker for PDAC and its precursor lesions.     

Validation of the clinical utility of 4 guidelines in the initial triage of mucinous cystic lesions of the pancreas based on cross-sectional imaging: Experience with 188 surgically-treated patients

IntroductionOver the years, several guidelines have been introduced to guide management of mucinous pancreatic cystic neoplasms (mPCN). In this study, we aimed to evaluate and compare the clinically utility of the Sendai-06, Fukuoka-12, Fukuoka-17 and European-18 guidelines in predicting malignancy of mPCN.MethodsOne hundred and eighty-eight patients with mucinous cystic neoplasms (MCN) or intraductal papillary mucinous neoplasm (IPMN) who underwent surgery were retrospectively reviewed and classified under the 4 guidelines. Malignancy was defined as high grade dysplasia and invasive carcinoma.ResultsRaised CA19-9>37U/ml, enhancing mural nodule≥5 mm and main pancreatic duct≥10 mm were significantly associated with malignancy on multivariate analysis. Increasing number of high risk features, absolute indications (European-18), worrisome risk or relative indications (European-18) were significantly associated with an increased likelihood of malignancy. The positive predictive values (PPV) of high risk features for Sendai-06, Fukuoka-12, Fukuoka-17 and absolute indications (European-18) for malignancy were 53%, 76%, 78% and 78% respectively. The negative predictive values (NPV) of the Sendai-06, Fukuoka-12 and Fukuoka-17 were 100%, while that of the European-18 was 92%. Risk of malignancy for patients with ≥4 worrisome features (Fukuoka-17) and ≥3 relative indications (European-18) was 66.7% and 75.0% respectively.ConclusionsAll 4 guidelines studied were useful in the initial triage of mPCN for the risk stratification of malignancy. The Fukuoka-17 had the highest PPV and NPV.     

Primary pancreatic cystic neoplasms revisited: part II. Mucinous cystic neoplasms

Mucinous cystic neoplasms (MCNs) of the pancreas represent one of the most common primary pancreatic cystic neoplasms, accounting for approximately half of these cases. MCNs are observed almost exclusively in women, and most commonly are located in the body/tail of the pancreas. In contrast to SCNs, MCNs have malignant potential. Proliferative changes (hyperplasia with or without atypia, borderline changes, non-invasive or carcinomas in-situ, and invasive carcinomas) can often be observed within the same neoplasm. Several risk factors for the presence of underlying malignancy within an MCN have recently been recognized. Cross-sectional imaging is of key importance for the diagnostic evaluation of patients with a cystic pancreatic lesion. Cyst fluid examination (cytology, biochemical/genetic analysis) is possible by using fine needle aspiration of the MCN, usually under endoscopic guidance, and may provide useful information for the differential diagnosis. Since MCNs have malignant potential, surgical resection is the treatment of choice.     

Pancreatic cancer screening in patients with presumed branch-duct intraductal papillary mucinous neoplasms

Because delayed diagnosis is one of the causes of poor prognosis in pancreatic ductal adenocarcinoma (PDAC), early detection is a key for overall improvement of prognosis. Towards this end, periodic screening is recommended for individuals considered high-risk for PDAC. Advances in diagnostic imaging modalities have increased the frequency of incidental findings of pancreatic cysts, including the intraductal papillary mucinous neoplasm (IPMN) - a major risk factor of PDAC, having 1% annual prevalence of concomitance with IPMN. Proper retainment of patients with IPMN and regular follow-up by routine imaging examination will likely improve early detection and better prognosis of PDAC. Unfortunately, current guidelines only address management of PDAC derived from IPMN and overlook PDAC concomitant with IPMN. Screening of patients with IPMN, by endoscopic ultrasonography (currently the most reliable modality for detecting small PDAC), may facilitate early detection of both IPMN-derived and -concomitant PDAC. Prospective studies to evaluate the usefulness of endoscopic ultrasonography in screening of IPMN-concomitant PDAC will also help in determining the optimal surveillance strategy for more widespread applications.     

胰腺囊性肿瘤222例临床诊治分析

目的 总结本中心收治的胰腺囊性肿瘤（PCN）的诊治情况及预后,为PCN的临床处理提供一定依据。方法 回顾性分析2005年1月至2016年10月南京鼓楼医院收治的PCN病例,分析各类PCN的临床特征、超声内镜下表现、治疗方式及预后情况。结果 本研究共纳入222例PCN病例,包括94例导管内乳头状黏液瘤（IPMN）,58例黏液性囊性肿瘤（MCN）,43例浆液性囊性肿瘤（SCN）及27例实性假乳头状肿瘤（SPN）。各型PCN患者的男女比例1∶1.55,平均年龄为（56.0±15.7）岁,大部分PCN患者（64.0％,142／222）在就诊时有临床表现,其中以腹痛最常见（47.3％,105／222）。各型PCN术后病理提示分别有7例IPMN（16.3％,7／43）和5例MCN（9.1％,5／55）为恶性（伴浸润性癌或重度异型增生）,而SCN和SPN术后病理均为良性（P=0.027）。未手术的PCN患者中,分别有4例IPMN（8.3％,4／48）和2例SPN（66.7％,2／3）在随访过程中发生癌变。获随访的188例PCN患者的5年生存率为86.0％。124例PCN患者术后的5年生存率为90.0%,SCN、MCN和SPN的术后5年生存率分别为100.0％、92.1％和938％,而IPMN仅为74.0％,差异有统计学意义（P=0.003）。结论 PCN好发于中年女性,大部分患者就诊时有临床症状,最常表现为腹痛。MCN、IPMN和SPN具有恶变倾向,应在符合手术条件的情况下行手术切除;而SCN则可采取保守治疗。各类PCN预后差异显著,IPMN预后最差,MCN、SCN及SPN术后预后均较好。     

Primary pancreatic cystic neoplasms revisited. Part I: serous cystic neoplasms

Primary pancreatic cystic neoplasms have been recognized increasingly during the two recent decades and include mainly serous cystic neoplasms, mucinous cystic neoplasms, and intraductal papillary mucinous neoplasms. Serous cystic neoplasms represent about 30% of all cystic neoplasms of the pancreas and are characterized by their microcystic appearance (on imaging, macroscopically, and microscopically) and their benign biologic behavior. Modern diagnostic methodology allows the preoperative diagnosis with an acceptable accuracy. Currently, indications for resection of serous cystic neoplasms of the pancreas include the presence of symptoms, size > 4 cm (because these ‘large’ neoplasms have a more rapid growth rate and probably will soon become symptomatic), and any uncertainty about the diagnosis of a serous versus a mucinous cystic neoplasm. Resection should also be considered for lesions in the body/tail of the pancreas. Conservative treatment is a reasonable option in selected patients (for example in the presence of small, asymptomatic lesions in the pancreatic head, especially in the frail or elderly patient).     

Pancreatic intraductal papillary mucinous neoplasms: Current diagnosis and management

Intraductal papillary mucinous neoplasms (IPMNs) represent approximately 1% of all pancreatic neoplasms and 25% of cystic neoplasms. They are divided into three types: main duct-IPMN (MD-IPPMN), branch duct-IPMN (BD-IPMN), and mixed type-IPMN. In this review, diagnostics, including clinical presentation and radiological investigations, were described. Magnetic resonance imaging is the most useful for most IPMNs. Management depends on the type and radiological features of IPMNs. Surgery is recommended for MD-IPMN. For BD-IPMN, management involves surgery or surveillance depending on the tumor size, cyst growth rate, solid components, main duct dilatation, high-grade dysplasia in cytology, the presence of symptoms (jaundice, new-onset diabetes, pancreatitis), and CA 19.9 serum level. The patient’s age and comorbidities should also be taken into consideration. Currently, there are different guidelines regarding the diagnosis and management of IPMNs. In this review, the following guidelines were presented: Sendai International Association of Pancreatology guidelines (2006), American Gastroenterological Association guidelines, revised international consensus Fukuoka guidelines (2012), revised international consensus Fukuoka guidelines (2017), and European evidence-based guidelines according to the European Study Group on Cystic Tumours of the Pancreas (2018). The Verona Evidence-Based Meeting 2020 was also presented and discussed.     

Oncologic outcomes of minimally invasive versus open distal pancreatectomy for pancreatic ductal adenocarcinoma: A systematic review and meta-analysis

In the absence of randomized trials, uncertainty regarding the oncologic efficacy of minimally invasive distal pancreatectomy (MIDP) remains. This systematic review aimed to compare oncologic outcomes after MIDP (laparoscopic or robot-assisted) and open distal pancreatectomy (ODP) in patients with pancreatic ductal adenocarcinoma (PDAC). Matched and non-matched studies were included. Pooled analyses were performed for pathology (e.g., microscopically radical (R0) resection and lymph node retrieval) and oncologic outcomes (e.g., overall survival). After screening 1760 studies, 21 studies with 11,246 patients were included. Overall survival (hazard ratio 0.86; 95% confidence interval (CI) 0.73 to 1.01; p = 0.06), R0 resection rate (odds ratio (OR) 1.24; 95%CI 0.97 to 1.58; p = 0.09) and use of adjuvant chemotherapy (OR 1.07; 95%CI 0.89 to 1.30; p = 0.46) were comparable for MIDP and ODP. The lymph node yield (weighted mean difference (WMD) −1.3 lymph nodes; 95%CI -2.46 to −0.15; p = 0.03) was lower after MIDP. Patients undergoing MIDP were more likely to have smaller tumors (WMD -0.46 cm; 95%CI -0.67 to −0.24; p < 0.001), less perineural (OR 0.48; 95%CI 0.33 to 0.70; p < 0.001) and less lymphovascular invasion (OR 0.53; 95%CI 0.38 to 0.74; p < 0.001) reflecting earlier staged disease as a result of treatment allocation bias. Based on these results we can conclude that in patients with PDAC, MIDP is associated with comparable survival, R0 resection, and use of adjuvant chemotherapy, but a lower lymph node yield, as compared to ODP. Due to treatment allocation bias and lower lymph node yield the oncologic efficacy of MIDP remains uncertain.     

Analysis of liver metastasis after resection for pancreatic ductal adenocarcinoma

AIM:To investigate the risk factors affecting the liver metastasis(LM) of pancreatic ductal adenocarcinoma(PDAC) after resection.METHODS:We retrospectively analyzed 101 PDAC patients who underwent surgical resection at the Samsung Medical Center between January 2000 and December 2004.Forty one patients with LM were analyzed for the time of metastasis,prognostic factors affecting LM,and survival.RESULTS:LM was found in 40.6%.The median time of the LM(n = 41) was 6.0 ± 4.6 mo and most LM occurred within 1 year.In univariate analysis,tumor size,preoperative carbohydrate antigen 19-9,and perineural invasion were factors affecting LM after resection.In multivariate analysis,tumor size was the most important factor for LM.In univariate analysis,tumor cell differentiation was significant to LM in low-risk groups.CONCLUSION:LM after resection of PDAC occurs early and shows poor survival.Tumor size is the key indicator for LM after resection.     

Management of Mucin‐Producing Cystic Neoplasms of the Pancreas

During the last decade small lesions of the pancreas have been increasingly recognized in clinical practice. Among these lesions, mucin‐producing cystic neoplasms represent a recently described and unique entity among pancreatic tumors. In 1996, the World Health Organization distinguished two different types of mucinous cystic tumors: intraductal papillary mucinous neoplasms (IPMNs) of the pancreas, which are characterized by mucin production, cystic dilation of the pancreatic ducts, and intrapapillary growth, and mucinous cystic neoplasms (MCNs), which are defined by ovarian‐like stroma and in most cases do not communicate with pancreatic ducts. Further, IPMNs can be subdivided into main‐duct type, mixed‐type, and branch‐duct type tumors. Older data did not distinguish among different subsets of cystic neoplasms of the pancreas, and consequently many databases were inconsistent. Histopathologically, both IPMNs and MCNs demonstrate a wide spectrum of cellular atypia ranging from mild mucinous hyperplasia to invasive adenocarcinoma. Because mucinous cystic neoplasms of the pancreas show significant differences in clinical behavior from patient to patient, knowledge of the clinicopathologic characteristics and natural history of specific subtypes of IPMNs and MCNs has become crucial for physicians working in the field of gastroenterology. The present work offers an overview of current and generally accepted clinical guidelines for the diagnosis and treatment of IPMNs and MCNs.     

胰腺导管腺癌免疫治疗研究现状和展望

胰腺导管腺癌(Pancreatic ductal adenocarcinoma,PDAC)是胰腺癌最常见的类型,预后极差。手术切除是目前唯一的根治手段,但多数患者就诊时已失去手术机会。免疫治疗作为一种新兴的治疗手段,在多种实体瘤和血液系统恶性肿瘤治疗中显现出乐观前景。然而,PDAC肿瘤抗原性低以及免疫抑制微环境等特征导致其免疫治疗困难重重。本文通过综述PDAC的肿瘤微环境组成特点和目前开展的新型免疫治疗策略,为PDAC的免疫治疗研究提供新思路。     

Minimally invasive versus open pancreatoduodenectomy for pancreatic ductal adenocarcinoma: Individual patient data meta-analysis of randomized trials

ObjectiveAssessment of minimally invasive pancreatoduodenectomy (MIPD) in patients with pancreatic ductal adenocarcinoma (PDAC) is scarce and limited to non-randomized studies. This study aimed to compare oncological and surgical outcomes after MIPD compared to open pancreatoduodenectomy (OPD) for patients after resectable PDAC from published randomized controlled trials (RCTs).MethodsA systematic review was performed to identify RCTs comparing MIPD and OPD including PDAC (Jan 2015–July 2021). Individual data of patients with PDAC were requested. Primary outcomes were R0 rate and lymph node yield. Secondary outcomes were blood-loss, operation time, major complications, hospital stay and 90-day mortality.ResultsOverall, 4 RCTs (all addressed laparoscopic MIPD) with 275 patients with PDAC were included. In total, 128 patients underwent laparoscopic MIPD and 147 patients underwent OPD. The R0 rate (risk difference(RD) −1%, P = 0.740) and lymph node yield (mean difference(MD) +1.55, P = 0.305) were comparable between laparoscopic MIPD and OPD. Laparoscopic MIPD was associated with less perioperative blood-loss (MD -91ml, P = 0.026), shorter length of hospital stay (MD -3.8 days, P = 0.044), while operation time was longer (MD +98.5 min, P = 0.003). Major complications (RD -11%, P = 0.302) and 90-day mortality (RD -2%, P = 0.328) were comparable between laparoscopic MIPD and OPD.ConclusionsThis individual patient data meta-analysis of MIPD versus OPD in patients with resectable PDAC suggests that laparoscopic MIPD is non-inferior regarding radicality, lymph node yield, major complications and 90-day mortality and is associated with less blood loss, shorter hospital stay, and longer operation time. The impact on long-term survival and recurrence should be studied in RCTs including robotic MIPD.     

Serum biomarkers for the differentiation of autoimmune pancreatitis from pancreatic ductal adenocarcinoma

Autoimmune pancreatitis(AIP), a chronic inflammation caused by the immune system attacking the pancreas, usually presents imaging and clinical features that overlap with those of pancreatic ductal adenocarcinoma(PDAC). Serum biomarkers, substances that quantitatively change in sera during disease development, are a promising non-invasive tool with high utility for differentiating between these diseases. In this way, the presence of AIP is currently suspected when serum concentrations of immunogl...     

High expression of DDR1 is associated with the poor prognosis in Chinese patients with pancreatic ductal adenocarcinoma

Background

Discoidin domain receptors 1 (DDR1), a subtype of DDRs, has been reported as a critical modulator of cellular morphogenesis, differentiation, migration and invasion.

Methods and results

In this study, we investigated the expression of DDR1 and its clinical association in Chinese patients with pancreatic ductal adenocarcinoma (PDAC). Across a cohort of 30 patients, we examined DDR1 expression in paired PDAC and corresponding adjacent non-tumor tissues by real-time quantitative PCR (RT-qPCR), or western blotting. DDR1 expression is significantly higher in PDAC, as compared to normal adjacent tissue, confirming results from the Oncomine databases. We validated DDR1 expression by immunohistochemistry across a non-overlapping cohort of 205 PDAC specimens. Kaplan-Meier survival curves indicate that increased expression of DDR1 is associated with a poor prognosis in PDAC patients (P = 0.013). Multivariate Cox regression analysis identified DDR1 expression, age, N classification and liver metastasis as independent prognostic factors in PDAC.

Conclusions

This study demonstrated that DDR1 can well serve as a novel prognostic biomarker in PDAC.     

Real-world costs and dynamics of surveillance in patients who underwent surgery for low-risk branch duct intraductal papillary mucinous neoplasms

Surveillance costs and appropriateness of surgery of “low-risk” BD-IPMNs are relevant issues. In this study we evaluated the rate of correct indication for pancreatectomy defined as high grade dysplasia (HGD) at histology in 961 patients who underwent surveillance for a median of 5.1 years. Undertreatment and overtreatment were defined as invasive cancer and low grade dysplasia (LGD) at histology, respectively. Of the 66 patients (6.9%) who were operated, only 16 (23.8%) had a HGD while 40 (59.7%) had a LGD and 10 (14.9%) an invasive cancer, without differences regarding timing of surgery. The mean surveillance cost was € 194.9 ± 107.6 per patient-year, with a median cost of € 277.1 ± 148.2 in the correct surgery group compared with € 222.7 ± 111.6 and € 197 ± 102.7 in the overtreatment and undertreatment groups. The surveillance mean cost from diagnosis to surgery was € 854.8. Rate of appropriate surgery in BD-IPMNs under surveillance is low.     

A systematic review of economic evaluation in pancreatic ductal adenocarcinoma

ObjectivesThe economic evaluation (EE) of healthcare interventions has become a necessity. However, high quality needs to be ensured in order to achieve validated results and help making informed decisions. Thus, the objective of the present study was to systematically identify and review published pancreatic ductal adenocarcinoma-related EEs and to assess their quality.MethodsSystematic literature research was conducted in PubMed and Cochrane to identify published EEs between 2000 and 2015. The quality of each selected EE was assessed by two independent reviewers, using the Drummond's checklist.ResultsOur systematic review was based on 32 EEs and showed a wide variety of methodological approaches, including different perspectives, time horizon, and cost effectiveness analyses. Nearly two-thirds of EEs are full EEs (n = 21), and about one-third of EEs had a Drummond score ≥7, synonymous with ‘high quality’. Close to 50% of full EEs had a Drummond score ≥7, whereas all of partial EEs had a Drummond score <7 (n = 11).ConclusionsOver the past 15 years, a lot of interest has been evinced over the EE of pancreatic ductal adenocarcinoma (PDAC) and its direct impact on therapeutic advances in PDAC. To provide a framework for health care decision-making, to facilitate transferability and to lend credibility to health EEs, their quality must be improved. For the last 4 years, a tendency towards a quality improvement of these studies has been observed, probably coupled with a context of rational decision-making in health care, a better and wider spread of recommendations and thus, medical practitioners' full endorsement.     

pT but not pN stage of the 8th TNM classification significantly improves prognostication in pancreatic ductal adenocarcinoma

The UICC TNM (tumour-node-metastasis) staging system for pancreatic ductal adenocarcinoma (PDAC) has been a matter of debate over decades because survival prediction based on T stages was weak and unreliable. To improve staging, the recently published 8th TNM edition (2016) introduced a conceptually completely changed strictly size-based T staging system and a refined N stage for PDAC. To investigate the clinical value of the novel TNM classification, we compared the prognostic impact of pT and pN stage between the 7th and 8th edition in two well-characterised independent German PDAC cohorts from different decades, including a total number of 523 patients. Former UICC T staging (7th edition 2009) resulted in a clustering of pT3 cases (72% and 85% of cases per cohort, respectively) and failed to show significant prognostic differences between the four stages in one of the investigated cohorts (p = 0.074). Application of the novel size-based T stage system resulted in a more equal distribution of cases between the four T categories with a predominance of pT2 tumours (65% and 60% of cases). The novel pT staging algorithm showed greatly improved discriminative power with highly significant overall differences between the four pT stages in both investigated cohorts in univariate and multivariate analyses (p < 0.001, each). In contrast, no prognostic differences were observed between the recently introduced pN1 and pN2 categories in both cohorts (p = 0.970 and p = 0.061).pT stage of resected PDAC patients according to the novel UICC staging protocol (8th edition) significantly improves patient stratification, whereas introduction of an extended N stage protocol does not demonstrate high clinical relevance in our cohorts.