Detection of Early-Stage Pancreatic Ductal Adenocarcinoma From Blood Samples : Results of a Multiplex Biomarker Signature Validation Study

INTRODUCTION: The IMMray PanCan-d test combines an 8-plex biomarker signature with CA19-9 in a proprietary algorithm to detect pancreatic ductal adenocarcinoma (PDAC) in serum samples. This study aimed to validate the clinical performance of the IMMray PanCan-d test and to better understand test performance in Lewis-null (le/le) individuals who cannot express CA19-9. METHODS: Serum samples from 586 individuals were analyzed with the IMMray PanCan-d biomarker signature and CA19-9 assay, including 167 PDAC samples, 203 individuals at high risk of familial/hereditary PDAC, and 216 healthy controls. Samples were collected at 11 sites in the United States and Europe. The study was performed by Immunovia, Inc (Marlborough, MA), and sample identity was blinded throughout the study. Test results were automatically generated using validated custom software with a locked algorithm and predefined decision value cutoffs for sample classification. RESULTS: The IMMray PanCan-d test distinguished PDAC stages I and II (n = 56) vs high-risk individuals with 98% specificity and 85% sensitivity and distinguished PDAC stages I-IV vs high-risk individuals with 98% specificity and 87% sensitivity. We identified samples with a CA19-9 value of 2.5 U/mL or less as probable Lewis-null (le/le) individuals. Excluding these 55 samples from the analysis increased the IMMray PanCan-d test sensitivity to 92% for PDAC stages I-IV (n = 157) vs controls (n = 379) while maintaining specificity at 99%; test sensitivity for PDAC stages I and II increased from 85% to 89%. DISCUSSION: These results demonstrate the IMMray PanCan-d blood test can detect PDAC with high specificity (99%) and sensitivity (92%).Peer reviewe

Surveillance after surgery for pancreatic cancer : a global scoping review of guidelines and a nordic Survey of contemporary practice

Objectives: Most patients with pancreatic cancer who have undergone surgical resection eventually develop disease recurrence. ‍This study aimed to investigate whether there is evidence to support routine surveillance after pancreatic cancer surgery, with a secondary aim of analyzing the implementation of surveillance strategies in the Nordic countries. Materials and Methods: A scoping review was conducted to identify clinical practice guidelines globally and research studies relating to surveillance after pancreatic cancer resection. This was followed by a survey among 20 pancreatic units from four Nordic countries to assess their current practice of follow-up for operated patients. Results: Altogether 16 clinical practice guidelines and 17 research studies were included. The guidelines provided inconsistent recommendations regarding postoperative surveillance of pancreatic cancer. The clinical research data were mainly based on retrospective cohort studies with low level of evidence and lead-time bias was not addressed. Active surveillance was recommended in Sweden and Denmark, but not in Norway beyond the post-operative/adjuvant period. Finland had no national recommendations for surveillance. The Nordic survey revealed a wide variation in reported practice among the different units. About 75% (15 of 20 units) performed routine postoperative surveillance. Routine CA 19-9 testing was used by 80% and routine CT by 67% as part of surveillance. About 73% of centers continued follow-up until 5 years postoperatively. Conclusion: Evidence for routine long-term (i.e. 5 years) surveillance after pancreatic cancer surgery remains limited. Most pancreatic units in the Nordic countries conduct regular follow-up, but protocols vary.Peer reviewe

Minimally invasive versus open distal pancreatectomy for resectable pancreatic cancer (DIPLOMA):an international randomised non-inferiority trial

Background: The oncological safety of minimally invasive surgery has been questioned for several abdominal cancers. Concerns also exist regarding the use of minimally invasive distal pancreatectomy (MIDP) in patients with resectable pancreatic cancer as randomised trials are lacking. Methods: In this international randomised non-inferiority trial, we recruited adults with resectable pancreatic cancer from 35 centres in 12 countries. Patients were randomly assigned to either MIDP (laparoscopic or robotic) or open distal pancreatectomy (ODP). Both patients and pathologists were blinded to the assigned approach. Primary endpoint was radical resection (R0, ≥1 mm free margin) in patients who had ultimately undergone resection. Analyses for the primary endpoint were by modified intention-to-treat, excluding patients with missing data on primary endpoint. The pre-defined non-inferiority margin of −7% was compared with the lower limit of the two-sided 90% confidence interval (CI) of absolute difference in the primary endpoint. This trial is registered with the ISRCTN registry (ISRCTN44897265). Findings: Between May 8, 2018 and May 7, 2021, 258 patients were randomly assigned to MIDP (131 patients) or ODP (127 patients). Modified intention-to-treat analysis included 114 patients in the MIDP group and 110 patients in the ODP group. An R0 resection occurred in 83 (73%) patients in the MIDP group and in 76 (69%) patients in the ODP group (difference 3.7%, 90% CI −6.2 to 13.6%; pnon-inferiority = 0.039). Median lymph node yield was comparable (22.0 [16.0–30.0] vs 23.0 [14.0–32.0] nodes, p = 0.86), as was the rate of intraperitoneal recurrence (41% vs 38%, p = 0.45). Median follow-up was 23.5 (interquartile range 17.0–30.0) months. Other postoperative outcomes were comparable, including median time to functional recovery (5 [95% CI 4.5–5.5] vs 5 [95% CI 4.7–5.3] days; p = 0.22) and overall survival (HR 0.99, 95% CI 0.67–1.46, p = 0.94). Serious adverse events were reported in 23 (18%) of 131 patients in the MIDP group vs 28 (22%) of 127 patients in the ODP group. Interpretation: This trial provides evidence on the non-inferiority of MIDP compared to ODP regarding radical resection rates in patients with resectable pancreatic cancer. The present findings support the applicability of minimally invasive surgery in patients with resectable left-sided pancreatic cancer. Funding: Medtronic Covidien AG, Johnson &amp; Johnson Medical Limited, Dutch Gastroenterology Society.</p

Minimally invasive versus open distal pancreatectomy for resectable pancreatic cancer (DIPLOMA):an international randomised non-inferiority trial

Background: The oncological safety of minimally invasive surgery has been questioned for several abdominal cancers. Concerns also exist regarding the use of minimally invasive distal pancreatectomy (MIDP) in patients with resectable pancreatic cancer as randomised trials are lacking. Methods: In this international randomised non-inferiority trial, we recruited adults with resectable pancreatic cancer from 35 centres in 12 countries. Patients were randomly assigned to either MIDP (laparoscopic or robotic) or open distal pancreatectomy (ODP). Both patients and pathologists were blinded to the assigned approach. Primary endpoint was radical resection (R0, ≥1 mm free margin) in patients who had ultimately undergone resection. Analyses for the primary endpoint were by modified intention-to-treat, excluding patients with missing data on primary endpoint. The pre-defined non-inferiority margin of −7% was compared with the lower limit of the two-sided 90% confidence interval (CI) of absolute difference in the primary endpoint. This trial is registered with the ISRCTN registry (ISRCTN44897265). Findings: Between May 8, 2018 and May 7, 2021, 258 patients were randomly assigned to MIDP (131 patients) or ODP (127 patients). Modified intention-to-treat analysis included 114 patients in the MIDP group and 110 patients in the ODP group. An R0 resection occurred in 83 (73%) patients in the MIDP group and in 76 (69%) patients in the ODP group (difference 3.7%, 90% CI −6.2 to 13.6%; pnon-inferiority = 0.039). Median lymph node yield was comparable (22.0 [16.0–30.0] vs 23.0 [14.0–32.0] nodes, p = 0.86), as was the rate of intraperitoneal recurrence (41% vs 38%, p = 0.45). Median follow-up was 23.5 (interquartile range 17.0–30.0) months. Other postoperative outcomes were comparable, including median time to functional recovery (5 [95% CI 4.5–5.5] vs 5 [95% CI 4.7–5.3] days; p = 0.22) and overall survival (HR 0.99, 95% CI 0.67–1.46, p = 0.94). Serious adverse events were reported in 23 (18%) of 131 patients in the MIDP group vs 28 (22%) of 127 patients in the ODP group. Interpretation: This trial provides evidence on the non-inferiority of MIDP compared to ODP regarding radical resection rates in patients with resectable pancreatic cancer. The present findings support the applicability of minimally invasive surgery in patients with resectable left-sided pancreatic cancer. Funding: Medtronic Covidien AG, Johnson &amp; Johnson Medical Limited, Dutch Gastroenterology Society.</p

Barretts esophagus - aspects on early detection of malignant transformation

Background: Barrett’s esophagus (BE) is a metaplastic mucosal transformation adjacent to the gastroesophageal junction, due to chronic reflux of gastric juices. BE is associated to an increased risk of esophageal adenocarcinoma (EAC) development, preceded by different states of dysplasia. Early detection of dysplasia is of fundamental value for the patient because of the improved chances of curative treatment. International guidelines recommend endoscopic surveillance of BE. Because of the low incidence of EAC in the BE-population, better techniques for dysplasia detection during surveillance, and biomarkers for evaluation of cancer risk, are warranted for better selection of patients that will benefit from lifelong surveillance. The renin-angiotensin system (RAS) is involved in fluid and electrolyte homeostasis as well as in hemodynamic regulation. More recently, RAS has been associated to several pathology-related conditions such as inflammation and cancer. Epidemiological studies indicate that drugs interfering with RAS may alter the EAC-risk in a BE. Objectives: The general aims of this thesis were to validate a new endoscopic technique for dysplasia detection, and to explore a number of RAS components as potential biomarkers for dysplasia in BE. Methods: Patients were recruited from the endoscopy department at Sahlgrenska University Hospital. High-definition magnifying contrast enhanced endoscopy was compared to standard white light endoscopy for dysplasia yield. Biopsies were collected for histopathological evaluation. Immunohistochemistry was performed for the localization of RAS. RAS interfering drugs (ACE inhibitor or AT1R antagonist) were administered, in a randomized setting, for three weeks to patients with dysplasia in BE. Western blot was performed for targeted protein analyses, and proteomics was performed by 2-D gel electrophoresis and tandem mass spectrometry. Results: In a randomized crossover setting, 107 patients were examined by advanced or standard endoscopy as the first investigation. An equal amount of patients were detected with dysplastic lesions in BE by the two techniques, but significantly fewer biopsies were acquired by the use of advanced endoscopy. The mucosal presence of the classical RAS components ACE, AT1R and AT2R were confirmed in both BE-patients and age matched non-BE controls. The AT1R expression was higher in the BE metaplastic mucosa of patients with dysplasia than in patients with no dysplasia. Several cancer-related proteins were found altered after three weeks of RAS-interfering medication (ACE inhibitor enalapril or AT1R antagonist candesartan) in dysplasia-bearing BE patients. A global proteomic analysis was performed in a subset of these patients, and three cancer-related proteins were identified as significantly regulated. Conclusion: Advanced endoscopic technique provides a better dysplasia yield per biopsy compared to standard technology. The altered expression of RAS components and the impact of RAS interfering drugs on certain cancer-related proteins in BE dysplasia suggest involvement in carcinogenesis and support a biomarker potential

Endoscopic Resections for Barrett’s Neoplasia: A Long-Term, Single-Center Follow-Up Study

Background and Objectives: Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are both well-established and effective treatments for dysplasia and early cancer in Barrett’s esophagus (BE). This study aims to compare the short- and long-term outcomes associated with these procedures in treating Barrett’s neoplasia. Materials and Methods: This single-center retrospective cohort study included 95 patients, either EMR (n = 67) or ESD (n = 28), treated for Barrett’s neoplasia at Sahlgrenska University Hospital between 2004 and 2019. The primary outcome was the complete (en-bloc) R0 resection rate. Secondary outcomes included the curative resection rate, additional endoscopic resections, adverse events, and overall survival. Results: The complete R0 resection rate was 62.5% for ESD compared to 16% for EMR (p p p = 0.028). There were few adverse events associated with both EMR and ESD. In both the stratified Kaplan–Meier survival analysis (Log-rank test, Chi-square = 2.190, df = 1, p = 0.139) and the multivariate Cox proportional hazards model (hazard ratio of 0.988; 95% CI: 0.459 to 2.127; p = 0.975), the treatment group (EMR vs. ESD) did not significantly impact the survival outcomes. Conclusions: Both EMR and ESD are effective and safe treatments for BE neoplasia with few adverse events. ESD resulted in higher curative resection rates with fewer AERs, indicating its potential as a primary treatment modality. However, the survival analysis showed no difference between the methods, highlighting their comparable long-term outcomes

Support for involvement of the renin–angiotensin system in dysplastic Barrett’s esophagus

<p><b>Background and aim:</b> Patients with dysplasia in Barrett’s esophagus (BE) have a considerable risk of developing esophageal adenocarcinoma (EAC). The mucosal expression of the pro-inflammatory angiotensin II receptor type 1 (AT1R) is elevated in these patients, suggesting a role in carcinogenesis. The purpose of this study was to determine whether interference with the renin–angiotensin system (RAS) would influence downstream markers of carcinogenesis.</p> <p><b>Methods:</b> Endoscopic mucosal biopsies from BE patients with low-grade dysplasia (LGD) were sampled before and after a three-week period of RAS-interfering treatment. Thirty patients were randomly allocated to enalapril (ACE inhibitor, 5 mg od), candesartan (AT1R antagonist, 8 mg od), or no drug. The expression of 12 proteins known to be associated with RAS and carcinogenesis was assessed using western blot.</p> <p><b>Results:</b> We found altered expression of several proteins after enalapril treatment (decreased: NFκB, <i>p</i> = .043; NLRP3, <i>p</i> = .050; AMACR, <i>p</i> = .017; and caspase 3, <i>p</i> = .025; increased: p53, <i>p</i> = .050). Candesartan treatment was associated with increased iNOS expression (<i>p</i> = .033). No significant changes were seen in the no-drug group.</p> <p><b>Conclusion:</b> Interference with angiotensin II formation was associated with altered expression of inflammation- and carcinogenesis-related proteins. The present results speak in favor of involvement of angiotensin II in BE dysplasia, but the role of AT1R should be investigated further.</p

EUS is accurate in characterizing pancreatic cystic lesions; a prospective comparison with cross-sectional imaging in resected cases

Abstract Background Imaging modalities for characterizing pancreatic cystic lesions (PCLs) is a known uncertainty. The aim of this prospective study was to compare the diagnostic performance of endoscopic ultrasound morphology, cytology and cyst fluid carcinoembryonic antigen (EUS-FNA-CEA) with cross-sectional imaging in resected PCLs. Methods The cross-sectional imaging and EUS-FNA-CEA results were collected in an academic tertiary referral centre using histology of the surgical specimen as the diagnostic standard. Results Of 289 patients undergoing evaluation for PCL with cross-sectional imaging and EUS-FNA between February 2007 and March 2017, 58 underwent surgical resection providing a final diagnosis of the PCLs: 45 mucinous, 5 serous, 1 pseudocyst, 2 endocrine, 2 solid pseudopapillary neoplasms and 3 other. EUS-FNA-CEA was more accurate than cross-sectional imaging in diagnosing mucinous PCLs (95% vs. 83%, p  = 0.04). Ninety-two percent of the PCLs with high-grade dysplasia or adenocarcinoma were smaller than 3 cm in diameter. The sensitivity of EUS-FNA-CEA and cross-sectional imaging for detecting PCLs with high-grade dysplasia or adenocarcinoma were 33% and 5% ( p  = 0.03), respectively. However, there was no difference in accuracy between the modalities (62% vs. 66%, p  = 0.79). The sensitivity for detecting pancreatic adenocarcinomas only was 64% for EUS-FNA-CEA and 9% for cross-sectional imaging ( p  = 0.03). Overall, EUS-FNA-CEA provided a correct diagnosis in more patients with PCLs than cross-sectional imaging (72% vs. 50%, p  = 0.01). Conclusions EUS-FNA-CEA is accurate and should be considered a complementary test in the diagnosis of PCLs. However, the detection of PCLs with high-grade dysplasia or adenocarcinoma needs to be improved. Cyst size does not seem to be a reliable predictor of high-grade dysplasia or adenocarcinoma