Timeline of Development of Pancreatic Cancer and Implications for Successful Early Detection in High-Risk Individuals.

BACKGROUND & AIMS: To successfully implement imaging-based pancreatic cancer (PC) surveillance, understanding the timeline and morphologic features of neoplastic progression is key. We aimed to investigate the progression to neoplasia from serial prediagnostic pancreatic imaging tests in high-risk individuals and identify factors associated with successful early detection. METHODS: We retrospectively examined the development of pancreatic abnormalities in high-risk individuals who were diagnosed with PC or underwent pancreatic surgery, or both, in 16 international surveillance programs. RESULTS: Of 2552 high-risk individuals under surveillance, 28 (1%) developed neoplastic progression to PC or high-grade dysplasia during a median follow-up of 29 months after baseline (interquartile range [IQR], 40 months). Of these, 13 of 28 (46%) presented with a new lesion (median size, 15 mm; range 7-57 mm), a median of 11 months (IQR, 8; range 3-17 months) after a prior examination, by which time 10 of 13 (77%) had progressed beyond the pancreas. The remaining 15 of 28 (54%) had neoplastic progression in a previously detected lesion (12 originally cystic, 2 indeterminate, 1 solid), and 11 (73%) had PC progressed beyond the pancreas. The 12 patients with cysts had been monitored for 21 months (IQR, 15 months) and had a median growth of 5 mm/y (IQR, 8 mm/y). Successful early detection (as high-grade dysplasia or PC confined to the pancreas) was associated with resection of cystic lesions (vs solid or indeterminate lesions (odds ratio, 5.388; 95% confidence interval, 1.525-19.029) and small lesions (odds ratio, 0.890/mm; 95% confidence interval 0.812-0.976/mm). CONCLUSIONS: In nearly half of high-risk individuals developing high-grade dysplasia or PC, no prior lesions are detected by imaging, yet they present at an advanced stage. Progression can occur before the next scheduled annual examination. More sensitive diagnostic tools or a different management strategy for rapidly growing cysts are needed.

Significant detection of new germline pathogenic variants in Australian Pancreatic Cancer Screening Program participants.

BACKGROUND: The Australian Pancreatic Cancer Screening Program (APCSP) offers endoscopic ultrasound surveillance for individuals at increased risk of pancreatic ductal adenocarcinoma (PDAC) with all participants requiring assessment by a Familial Cancer Service before or after study enrolment. METHODS: Individuals aged 40-80 years (or 10 years younger than the earliest PDAC diagnosis) were eligible for APCSP study entry if they had 1) ≥ two blood relatives with PDAC (at least one of first-degree association); 2) a clinical or genetic diagnosis of Hereditary Pancreatitis or Peutz-Jeghers syndrome irrespective of PDAC family history; or 3) a known PDAC predisposition germline pathogenic variant (BRCA2, PALB2, CDKN2A, or Lynch syndrome) with ≥one PDAC-affected first- or second-degree relative. Retrospective medical record review was conducted for APCSP participants enrolled at the participating Australian hospitals from January 2011 to December 2019. We audited the genetic investigations offered by multiple Familial Cancer Services who assessed APCSP participants according to national guidelines, local clinical protocol and/or the availability of external research-funded testing, and the subsequent findings. Descriptive statistical analysis was performed using Microsoft Excel. RESULTS: Of 189 kindreds (285 participants), 50 kindreds (71 participants) had a known germline pathogenic variant at enrolment (BRCA2 n = 35, PALB2 n = 6, CDKN2A n = 3, STK11 n = 3, PRSS1 n = 2, MLH1 n = 1). Forty-eight of 136 (35%) kindreds with no known germline pathogenic variant were offered mutation analysis; 89% was clinic-funded, with increasing self-funded testing since 2016. The relatively low rates of genetic testing performed reflects initial strict criteria for clinic-funded genetic testing. New germline pathogenic variants were detected in five kindreds (10.4%) after study enrolment (BRCA2 n = 3 kindreds, PALB2 n = 1, CDKN2A n = 1). Of note, only eight kindreds were reassessed by a Familial Cancer Service since enrolment, with a further 21 kindreds identified as being suitable for reassessment. CONCLUSION: Germline pathogenic variants associated with PDAC were seen in 29.1% of our high-risk cohort (55/189 kindreds; 82/285 participants). Importantly, 10.4% of kindreds offered genetic testing were newly identified as having germline pathogenic variants, with majority being BRCA2. As genetic testing standards evolve rapidly in PDAC, 5-yearly reassessment of high-risk individuals by Familial Cancer Services is warranted.

Genetic counselling and personalised risk assessment in the Australian pancreatic cancer screening program.

BACKGROUND: Pancreatic cancer (PC) is an aggressive disease with a dismal 5-year survival rate. Surveillance of high-risk individuals is hoped to improve survival outcomes by detection of precursor lesions or early-stage malignancy. METHODS: Since 2011, a national high-risk cohort recruited through St Vincent's Hospital, Sydney, has undergone prospective PC screening incorporating annual endoscopic ultrasound, formal genetic counselling and mutation analysis as appropriate. PancPRO, a Bayesian PC risk assessment model, was used to estimate 5-year and lifetime PC risks for familial pancreatic cancer (FPC) participants and this was compared to their perceived chance of pancreatic and other cancers. Genetic counselling guidelines were developed to improve consistency. Follow-up questionnaires were used to assess the role of genetic counselling and testing. RESULTS: We describe the Australian PC screening program design and recruitment strategy and the results of the first 102 individuals who have completed at least one-year of follow-up. Seventy-nine participants met the FPC criteria (≥ two first-degree relatives affected), 22 individuals had both a BRCA2 pathogenic variant and a close relative with PC and one had a clinical diagnosis of Peutz-Jeghers syndrome. Participants reported a high perceived chance of developing PC regardless of their genetic testing status. PancPRO reported FPC participants' mean 5-year and lifetime PC risks as 1.81% (range 0.2-3.2%) and 10.17% (range 2.4-14.4%), respectively. Participants' perceived PC chance did not correlate with their PancPRO 5-year (r = - 0.17, p = 0.128) and lifetime PC risks (r = 0.19, p = 0.091). Two-thirds felt that current genetic testing would help them, and 91% of tested participants were glad to have undergone genetic testing. Overall, 79% of participants found genetic counselling to be helpful, and 88% reported they would recommend counselling to their relatives. CONCLUSIONS: Participants reported multiple benefits of genetic counselling and testing but continue to seek greater clarification about their individual PC risk. Extension of PancPRO is required to enable personalised PC risk assessment for all high-risk sub-groups. More detailed discussion of PC risk for BRCA2 pathogenic variant carriers, providing a written summary in all cases and a plan for genetics review were identified as areas for improvement.

Endoscopic ultrasound-guided fine needle aspiration improves the pre-operative diagnostic yield of solid-pseudopapillary neoplasm of the pancreas: an international multicenter case series (with video).

BACKGROUND/OBJECTIVES: Solid-pseudopapillary neoplasms (SPNs) are rare pancreatic tumors, which occur most frequently in young women and are associated with an excellent prognosis. Computed tomography (CT) is used most commonly to identify these lesions, but there are few studies evaluating the role of endoscopic ultrasound (EUS) and fine needle aspiration (EUS-FNA) in the assessment of SPN. The aim of the study was to determine the incremental diagnostic yield of EUS-FNA compared with CT or EUS in the evaluation of patients with SPN. METHODS: A retrospective chart review of consecutive patients diagnosed with SPN who underwent CT, EUS, and EUS-FNA at five centers from three countries from 1998 to 2013. Patient demographics, imaging, endoscopic studies, cytopathology, and histology were reviewed. RESULTS: Thirty-four patients were identified with SPN. There were 31 (91.2 %) females, with a mean age at diagnosis of 37 years (range 16-81). The most common presenting symptom was abdominal pain which was present in 59 %. SPNs were incidentally detected in 14 (41.2 %) of the patients. The median tumor size was 4.2 cm (range 1.9-9.4). No patient had evidence of local or distant metastases. The most common appearance on EUS was of a mixed solid-cystic lesion (67.6 %). The diagnostic yield of CT and EUS alone was 23.5 and 41.2 %, respectively. CT and EUS combined had a diagnostic yield of 52.9 %. The addition of EUS-FNA significantly increased the diagnostic yield to 82.4 % compared with either CT or CT and EUS (p < 0.005). There were no reported adverse events reported. CONCLUSIONS: SPNs are rare pancreatic tumors primarily affecting young women. The addition of EUS-FNA significantly increased the pre-operative diagnostic yield of SPN to 82.4 %.

Biomarkers in the diagnosis of pancreatic cancer: Are we closer to finding the golden ticket?

Pancreatic cancer (PC) is a leading cause of cancer related mortality on a global scale. The disease itself is associated with a dismal prognosis, partly due to its silent nature resulting in patients presenting with advanced disease at the time of diagnosis. To combat this, there has been an explosion in the last decade of potential candidate biomarkers in the research setting in the hope that a diagnostic biomarker may provide a glimmer of hope in what is otherwise quite a substantial clinical dilemma. Currently, serum carbohydrate antigen 19-9 is utilized in the diagnostic work-up of patients diagnosed with PC however this biomarker lacks the sensitivity and specificity associated with a gold-standard marker. In the search for a biomarker that is both sensitive and specific for the diagnosis of PC, there has been a paradigm shift towards a focus on liquid biopsy and the use of diagnostic panels which has subsequently proved to have efficacy in the diagnosis of PC. Currently, promising developments in the field of early detection on PC using diagnostic biomarkers include the detection of microRNA (miRNA) in serum and circulating tumour cells. Both these modalities, although in their infancy and yet to be widely accepted into routine clinical practice, possess merit in the early detection of PC. We reviewed over 300 biomarkers with the aim to provide an in-depth summary of the current state-of-play regarding diagnostic biomarkers in PC (serum, urinary, salivary, faecal, pancreatic juice and biliary fluid).

Macrophage inhibitory cytokine-1/growth differentiation factor-15 in premalignant and neoplastic tumours in a high-risk pancreatic cancer cohort.

BACKGROUND: Pancreatic cancer (PC) is a leading cause of cancer related mortality worldwide, with poor survival due to late diagnosis. Currently, biomarkers have limited use in early diagnosis of PC. Macrophage inhibitory cytokine-1 or growth differentiation factor-15 (MIC-1/GDF15) has been implicated as a potential serum biomarker in PC and other malignancies. AIM: To determine the role of MIC-1/GDF15 in detecting pre-malignant pancreatic lesions and neoplastic tumours in an asymptomatic high-risk cohort part of Australian Pancreatic Cancer Screening Program. METHODS: A feasibility prospective single centre cohort study was performed. Participants recruited for yearly surveillance with endoscopic ultrasound (EUS) had serial fasting blood samples collected before EUS for MIC-1/GDF15, C-reactive protein and carbohydrate antigen 19-9. Patients were stratified into five groups based on EUS findings: Normal; pancreatic cysts, branch-duct intraductal papillary mucinous neoplasm; diffuse non-specific abnormalities; and neoplastic tumours. MIC-1/GDF15 serum levels were quantified using ELISA. Participants in whom EUS demonstrated abnormalities but not malignancy were closely followed up with magnetic resonance imaging (MRI) or computed tomography. RESULTS: One hundred twenty participants were prospectively recruited from 2011-2018. Forty-seven participants (39.2%) had an abnormal EUS and five participants (4.2%) were diagnosed with neoplastic tumours, three by EUS (two pancreatic and one liver) and two by MRI/computed tomography (breast cancer, bladder cancer), which were performed for follow up of abnormal EUS. Baseline serum MIC-1/GDF15 was a significant predictor of neoplastic tumours on receiver operator characteristic curve analysis [area under curve (AUC) = 0.814, P = 0.023]. Baseline serum MIC-1/GDF15 had moderate predictive capacity for branch-duct intraductal papillary mucinous neoplasm (AUC = 0.644) and neoplastic tumours noted on EUS (AUC = 0.793), however this was not significant (P = 0.188 and 0.081 respectively). Serial serum MIC-1/GDF15 did not demonstrate a significant percentage change between a normal and abnormal EUS (P = 0.213). Median baseline MIC-1/GDF15 was greater in those with neoplastic tumours (Median = 1039.6, interquartile range = 727.0-1977.7) compared to those diagnosed with a benign lesion (Median = 570.1, interquartile range = 460.7-865.2) on EUS and MRI (P = 0.012). CONCLUSION: In this pilot study MIC-1/GDF15 has predictive capacity for neoplastic tumours in asymptomatic individuals with a genetic predisposition for PC. Further imagining may be warranted in patients with abnormal EUS and raised serum MIC-1/GDF15. Larger multicentric prospective studies are required to further define the role of MIC-1/GDF15 as a serological biomarker in pre-malignant pancreatic lesions and neoplastic tumours.

Challenges in diagnosis of pancreatic cancer.

Pancreatic cancer is a growing source of cancer related death, yet has poor survival rates which have not improved in the last few decades. Its high mortality rate is attributed to pancreatic cancer biology, difficulty in early diagnosis and the lack of standardised international guidelines in assessing suspicious pancreatic masses. This review aims to provide an update in the current state of play in pancreatic cancer diagnosis and to evaluate the benefits and limitations of available diagnostic technology. The main modalities discussed are imaging with computed tomography, magnetic resonance imaging, endoscopic ultrasound and positron emission tomography and tissue acquisition with fine needle aspiration. We also review the improvements in the techniques used for tissue acquisition and the opportunity for personalised cancer medicine. Screening of high risk individuals, promising biomarkers and common mimickers of pancreatic cancer are also explored, as well as suggestions for future research directions to allow for earlier detection of pancreatic cancer. Timely and accurate diagnosis of pancreatic cancer can lead to improvements in the current poor outcome of this disease.

Clinical predictors for sessile serrated polyposis syndrome: A case control study.

AIM: To compared individuals with serrated polyposis syndrome (SPS) to those with sessile serrated adenoma (SSA) and adenomas in the setting of endoscopists with high adenoma detection rates at a secondary and tertiary academic centre. METHODS: Retrospectively we collated the clinical, endoscopic and histological features of all patients with SPS at St Vincent's public and private hospital in the last 3 years. Patients were identified by searching through 2 pathology databases. Variables explored included smoking status, symptoms, and family history of concurrent colorectal cancer, number and location of polyps. Patients with SPS were matched to two cohorts (1) patients with SSA not meeting World Health Organization (WHO) criteria for SPS over 3 years; and (2) patients with exclusively adenomas. The control cases were also matched according to gender and endoscopist. Adenoma detection rates ranged from 25% to 40%. RESULTS: Forty patients with SPS were identified and matched with 40 patients in each control group. In total 15452 colonoscopies were performed over the study period which amounts to a prevalence of 1: 384 patients (0.26%) with SPS. Fourteen patients (35%) required more than 1 year to accumulate enough polyps to reach WHO criteria for SPS. The diagnosis of SPS was largely incidental and 5% SPS patients were diagnosed with colorectal cancer over 3 years. The chance of detecting a meta-synchronous adenoma was similar in those with SPS (42%) and those with SSA (55%), P = 0.49. The majority of patients (75%) meeting criteria for SPS were women. The mean age of those with SPS (45 years) was significantly lower than both cohorts with SSA (57 years) and adenomas (63 years), P = 0.01. On univariate analysis cigarette exposure, first-degree family history of colorectal cancer and a high BMI weren't significantly more associated with SPS compared to patients with SSA or patients with adenomas. However, patients with SPS (97%) and patients with SSAs not meeting SPS criteria (98%) were significantly more likely to be Caucasian compared to patients with adenomas (79%), P = 0.01. CONCLUSION: The prevalence of SPS in our study was 0.26%. The vast majority of patients diagnosed with SPS were women. As a group, they were significantly younger compared to patients with SSA not meeting WHO criteria and patients with adenomatous polyps by more than a decade. Patients with SPS were no more likely to have a first degree relative with colorectal cancer or smoking history than the other two groups. Patients with serrated polyps were more likely to be Caucasian than patients with adenomas.

Review of screening for pancreatic cancer in high risk individuals.

Pancreatic cancer is difficult to diagnose at an early stage and is associated with a very poor survival. Ten percent of pancreatic cancers result from genetic susceptibility and/or familial aggregation. Individuals from families with multiple affected first-degree relatives and those with a known cancer-causing genetic mutation have been shown to be at much higher risk of developing pancreatic cancer. Recent efforts have focused on detecting disease at an earlier stage to improve survival in these high-risk groups. This article reviews high-risk groups, screening methods, and current screening programs and their results.

Pancreatic solid pseudopapillary tumours - EUS FNA is the ideal tool for diagnosis.

BACKGROUND: Solid pseudopapillary tumour (SPT) is a rare tumour of the pancreas with low malignant potential affecting mainly young women difficult to diagnose preoperatively. The aim of this study is to describe the endoscopic ultrasound (EUS) features and utility of EUS-guided fine needle aspiration (FNA) in diagnosing these tumours. METHODS: A retrospective analysis of SPTs identified in a tertiary institution EUS database between April 2002 and April 2009 was performed. Medical records, imaging, EUS features, cytology and histology specimens were reviewed. Patients were followed up until April 2009. RESULTS: Seven cases of SPTs were indentified out of 2400 EUS performed. All patients were females with a mean age of 41 years (range 22-69). The tumours were solitary with a mean diameter of 2.9 cm (range 2-4.3 cm). Five tumours were located in the body and tail of the pancreas and two in the neck. All lesions were hypoechoic, heterogenous and well circumscribed, with five having a cystic component and two having a calcified rim. FNA using a 22-gauge needle was performed in six cases with no complications. A preoperative diagnosis of SPT based on cytology was obtained in 5/6 cases (83%). Surgical resection was done in six cases with confirmation of SPT and no metastatic disease. CONCLUSION: EUS-guided FNA is a minimally invasive, safe and reliable way of diagnosing SPT by providing characteristic cytological specimens. Definitive preoperative diagnosis leads to targeted and minimally invasive surgical resection.

Lactose malabsorption in the elderly: role of small intestinal bacterial overgrowth.

OBJECTIVE: The prevalence of lactose malabsorption (LM) is increased in the elderly, although the mechanisms responsible are still a matter of speculation. The objective of this study was to investigate the possible roles of reduced functional small intestinal absorptive area, lactase deficiency and small intestinal bacterial overgrowth (SIBO). MATERIAL AND METHODS: Twenty Caucasian (Anglo-Celtic), asymptomatic, well-nourished, elderly volunteers (median age 79 years, range 70-94 years) with no clinically apparent predisposition to SIBO underwent a 50 g lactose breath hydrogen test (LBHT) and mannitol absorption test, the latter as an index of functional small intestinal absorptive area. Those with LM additionally underwent bacteriological assessment of small intestinal secretions and mucosal biopsy, to assess the contribution of SIBO and lactase deficiency, respectively, to the pathogenesis of LM in individual cases. The prevalence of SIBO was also determined in elderly subjects without LM. Twenty asymptomatic younger subjects (median age 29 years, age range 18-35 years) served as controls. All subjects were "hydrogen producers" in response to lactulose. RESULTS: LM was evident in 10/20 (50%) elderly subjects and 1/20 (5%) younger subjects (p=0.003). Mannitol absorption did not differ significantly in elderly and younger subjects or in elderly subjects with and without LM. SIBO was documented in 9/10 (90%) elderly subjects with LM; eradication was associated with resolution of LM. Lactase deficiency was evident in only one elderly subject with LM. SIBO was evident in 2/10 (20%) elderly subjects without LM (p=0.005 compared to those with LM). Lactulose breath hydrogen test identified only 2/11 (18%) elderly subjects with SIBO. CONCLUSIONS: Increased prevalence of LM in the elderly is mostly due to clinically non-apparent SIBO, rather than mucosal factors. The lactulose breath hydrogen test cannot be relied upon to identify elderly subjects with SIBO, even in those without an anatomical predisposition.