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%).

Impact of hemolysis on multi-OMIC pancreatic biomarker discovery to derisk biomarker development in precision medicine studies.

Cancer biomarker discovery is critically dependent on the integrity of biofluid and tissue samples acquired from study participants. Multi-omic profiling of candidate protein, lipid, and metabolite biomarkers is confounded by timing and fasting status of sample collection, participant demographics and treatment exposures of the study population. Contamination by hemoglobin, whether caused by hemolysis during sample preparation or underlying red cell fragility, contributes 0-10 g/L of extraneous protein to plasma, serum, and Buffy coat samples and may interfere with biomarker detection and validation. We analyzed 617 plasma, 701 serum, and 657 buffy coat samples from a 7-year longitudinal multi-omic biomarker discovery program evaluating 400+ participants with or at risk for pancreatic cancer, known as Project Survival. Hemolysis was undetectable in 93.1% of plasma and 95.0% of serum samples, whereas only 37.1% of buffy coat samples were free of contamination by hemoglobin. Regression analysis of multi-omic data demonstrated a statistically significant correlation between hemoglobin concentration and the resulting pattern of analyte detection and concentration. Although hemolysis had the greatest impact on identification and quantitation of the proteome, distinct differentials in metabolomics and lipidomics were also observed and correlated with severity. We conclude that quality control is vital to accurate detection of informative molecular differentials using OMIC technologies and that caution must be exercised to minimize the impact of hemolysis as a factor driving false discovery in large cancer biomarker studies.

Laparoscopic-assisted ERCP following RYGB: a 12-year assessment of outcomes and learning curve at a high-volume pancreatobiliary center.

INTRODUCTION: Treatment of pancreaticobiliary pathology following Roux-en-Y gastric bypass (RYGB) poses significant technical challenges. Laparoscopic-assisted endoscopic retrograde cholangiopancreatography (LA-ERCP) can overcome those anatomical hurdles, allowing access to the papilla. Our aims were to analyze our 12-year institutional outcomes and determine the learning curve for LA-ERCP. METHODS: A retrospective review of cases between 2007 and 2019 at a high-volume pancreatobiliary unit was performed. Logistic regression was used to identify predictors of specific outcomes. To identify the learning curve, CUSUM analyses and innovative methods for standardizing the surgeon's timelines were performed. RESULTS: 131 patients underwent LA-ERCP (median age 60, 81% females) by 17 surgeons and 10 gastroenterologists. Cannulation of the papilla was achieved in all cases. Indications were choledocholithiasis (78%), Sphincter of Oddi dysfunction/Papillary stenosis (18%), management of bile leak (2%) and stenting/biopsy of malignant strictures (2%). Median total, surgical and ERCP times were 180, 128 and 48 min, respectively, and 47% underwent concomitant cholecystectomy. Surgical site infection developed in 9.2% and post-ERCP pancreatitis in 3.8%. Logistic regression revealed multiple abdominal operations and magnitude of BMI decrease (between RYGB and LA-ERCP) to be predictive of conversion to open approach. CUSUM analysis of operative time demonstrated a learning curve at case 27 for the surgical team and case 9 for the gastroenterology team. On binary cut analysis, 3-5 cases per surgeon were needed to optimize operative metrics. CONCLUSION: LA-ERCP is associated with high success rates and low adverse events. We identify outcome benchmarks and a learning curve for new adopters of this increasingly performed procedure.

Treatment burden of robotic gastrectomy for locally advanced gastric cancer (LAGC): a single western experience.

BACKGROUND: This study compares standard of care (SOC) open and robotic D2-gastrectomy for locally advanced gastric cancer (LAGC) in the Western context of low disease prevalence, reduced surgical volume, and neoadjuvant chemotherapy (NAC). We hypothesized that robotic gastrectomy (RG) after NAC reduces treatment burden for LAGC across multiple outcome domains vs. SOC. METHODS: Single institution, interrupted time series comparing SOC (2008-2013) for LAGC (T2-4Nany/TanyN+) vs. NAC + RG (2013-2018). Treatment burden was a composite metric of narcotic consumption, oncologic efficacy, cumulative morbidity, and 90-day resource utilization. Predictors were evaluated via multivariate modeling. Learning curve analysis was done using CUSUM. RESULTS: After exclusions, 87 subjects with equivalent baseline characteristics, aside from male sex, were treated via SOC (n=55) or NAC + RG (n=32). All four domains of treatment burden were significantly reduced in the NAC + RG cohort compared to SOC (P=0.003). The odds ratio for excess treatment burden in the NAC/RG was 0.23 (95% CI: 0.07-0.72, P=0.0117) vs. SOC upon multivariable modeling, whereas the extent of resection (total/subtotal), tumor size, T-stage, sex, and early learning curve had no effect. Differences in treatment burden persisted in subgroup analysis for NAC (n=51). CONCLUSIONS: NAC + RG was associated with decreased treatment burden relative to SOC for LAGC. Frequencies of unfavorable hospitalization, adverse oncological outcomes, major morbidity, and narcotic consumption all decreased in this interrupted time series.

Minimally Invasive Techniques for Pancreatic Resection.

There is increasing interest in the role of minimally invasive surgery (MIS) for pancreatectomy. Prospective data indicate significant advantages for MIS when performed for left-sided pancreatic pathologies and may be deemed as the standard of care. However, there is reluctance in implementing this technique to pancreaticoduodenectomy because of the complexity of the operation and the mixed results from randomized trials. A detailed description of the technical aspects of robotic pancreaticoduodenectomy and distal pancreatectomy is presented in this article in addition to a summary of the most important prospective and cohort studies. We also provide insights into patient selection and the learning curve of MIS surgery for pancreatectomy.

Mentorship and formal robotic proficiency skills curriculum improve subsequent generations' learning curve for the robotic distal pancreatectomy.

BACKGROUND: Minimally invasive distal pancreatectomy is the accepted standard of care. The robotic distal (RDP) learning curve is 20-40 surgeries with operating time (ORT) as the most significant factor. This study evaluates how formal mentorship and a robotic skills curriculum impact the learning curve for subsequent generation surgeons. METHODS: Consecutive RDP from 2008 to 2017 were evaluated. First Generation was two surgeons who started program without training or mentorship. Second Generation was the two surgeons who joined the program with mentorship. Third Generation was fellows who benefited from both formal training and mentorship. Multivariable models (MVA) were performed for ORT, clinically relevant pancreatic fistula (CR-POPF), and major complications (Clavien≥3). RESULTS: A total of 296 RDP were performed of which 187 did not include other procedures: First Generation (n = 71), Second Generation (n = 50), and Third Generation (n = 66). ORT decreased by generation (p < 0.001) without any differences in CR-POPF or Clavien≥3. On MVA, earlier generation (p = 0.019), pre-operative albumin (p = 0.001) and pancreatic adenocarcinoma (p = 0.019) were predictive of ORT. Increased BMI (p = 0.049) and neoadjuvant therapy (p = 0.046) were predictive of CR-POPF. Fellow participation at the console increased over time. CONCLUSION: Formal mentorship and a skills curriculum decreased the learning curve and complications were largely dependent on patient factors.

Elevated levels of mitochondrial CoQ10 induce ROS-mediated apoptosis in pancreatic cancer.

Reactive oxygen species (ROS) are implicated in triggering cell signalling events and pathways to promote and maintain tumorigenicity. Chemotherapy and radiation can induce ROS to elicit cell death allows for targeting ROS pathways for effective anti-cancer therapeutics. Coenzyme Q10 is a critical cofactor in the electron transport chain with complex biological functions that extend beyond mitochondrial respiration. This study demonstrates that delivery of oxidized Coenzyme Q10 (ubidecarenone) to increase mitochondrial Q-pool is associated with an increase in ROS generation, effectuating anti-cancer effects in a pancreatic cancer model. Consequent activation of cell death was observed in vitro in pancreatic cancer cells, and both human patient-derived organoids and tumour xenografts. The study is a first to demonstrate the effectiveness of oxidized ubidecarenone in targeting mitochondrial function resulting in an anti-cancer effect. Furthermore, these findings support the clinical development of proprietary formulation, BPM31510, for treatment of cancers with high ROS burden with potential sensitivity to ubidecarenone.

500 Minimally Invasive Robotic Pancreatoduodenectomies: One Decade of Optimizing Performance.

OBJECTIVES: This study aims to present the outcomes of our decade-long experience of robotic pancreatoduodenectomy and provide insights into successful program implementation. BACKGROUND: Despite significant improvement in mortality over the past 30 years, morbidity following open pancreatoduodenectomy remains high. We implemented a minimally invasive pancreatic surgery program based on the robotic platform as one potential method of improving outcomes for this operation. METHODS: A retrospective review of a prospectively maintained institutional database was performed to identify patients who underwent robotic pancreatoduodenectomy (RPD) between 2008 and 2017 at the University of Pittsburgh. RESULTS: In total, 500 consecutive RPDs were included. Operative time, conversion to open, blood loss, and clinically relevant postoperative pancreatic fistula improved early in the experience and have remained low despite increasing complexity of case selection as reflected by increasing number of patients with pancreatic cancer, vascular resections, and higher Charlson Comorbidity scores (all P<0.05). Operating room time plateaued after 240 cases at a median time of 391 minutes (interquartile rang 340-477). Major complications (Clavien >2) occurred in less than 24%, clinically relevant postoperative pancreatic fistula in 7.8%, 30- and 90-day mortality were 1.4% and 3.1% respectively, and median length of stay was 8 days. Outcomes were not impacted by integration of trainees or expansion of selection criteria. CONCLUSIONS: Structured implementation of robotic pancreatoduodenectomy can be associated with excellent outcomes. In the largest series of RPD, we establish benchmarks for the surgical community to consider when adopting this approach.

International Validation of Reduced Major Morbidity After Minimally Invasive Distal Pancreatectomy Compared With Open Pancreatectomy.

OBJECTIVE: To quantify the nationwide impact of minimally invasive distal pancreatectomy (MIDP) on major morbidity as compared with open distal pancreatectomy (ODP). BACKGROUND: A recent randomized controlled trial (RCT) demonstrated significant reduction in time to functional recovery after MIDP compared with ODP, but was not powered to assess potential risk reductions in major morbidity. METHODS: International cohort study using the American College of Surgeons' National Quality Improvement Program (ACS-NSQIP) (88 centers; 2014-2016) to evaluate the association between surgical approach (MIDP vs ODP) and 30-day composite major morbidity (CMM; death or severe complications) with external model validation using Dutch Pancreatic Cancer Group data (17 centers; 2005-2016). Multivariable logistic regression assessed the impact of nationwide MIDP rates between 0% and 100% on postoperative CMM at conversion rates between 0% and 25%, using estimated marginal effects. A sensitivity analysis tested the impact at various scenarios and patient populations. RESULTS: Of 2921 ACS-NSQIP patients, 1562 (53%) underwent MIDP with 18% conversion, and 1359 (47%) underwent ODP. MIDP was independently associated with reduced CMM [odds ratio (OR) 0.50, 95% confidence interval (CI) 0.42-0.60, P < 0.001], confirmed by external model validation (n = 637, P < 0.003). The association between rising MIDP implementation rates and falling postoperative morbidity was linear between 0% (all ODP) and 100% (all MIDP). The absolute risk reduction for CMM was 11% (95% CI 7.3%-15%) at observed conversion rates and improved to 14% (95% CI 11%-18%) as conversion approached 0%. Similar effects were seen across subgroups. CONCLUSION: This international study predicted a nationwide 11% risk reduction for CMM after MIDP versus ODP, which is likely to improve as conversion rates decrease. These findings confirm secondary outcomes of the recent LEOPARD RCT.

Procedure-specific Training for Robot-assisted Distal Pancreatectomy.

OBJECTIVE: To train practicing surgeons in robot-assisted distal pancreatectomy (RADP) and assess the impact on 5 domains of healthcare quality. BACKGROUND: RADP may reduce the treatment burden compared with open distal pancreatectomy (ODP), but studies on institutional training and implementation programs are scarce. METHODS: A retrospective, single-center, cohort study evaluating surgical performance during a procedure-specific training program for RADP (January 2006 to September 2017). Baseline and unadjusted outcomes were compared "before training" (ODP only; June 2012). Exclusion criteria were neoadjuvant therapy, vascular- and unrelated organ resection. Run charts evaluated index length of stay (LOS) and 90-day comprehensive complication index. Cumulative sum charts of operating time (OT) assessed institutional learning. Adjusted outcomes after RADP versus ODP were compared using a secondary propensity-score-matched (1:1) analysis to determine clinical efficacy. RESULTS: After screening, 237 patients were included in the before-training (133 ODP) and after-training (24 ODP, 80 RADP) groups. After initiation of training, mean perioperative blood loss decreased (-255 mL, P<0.001), OT increased (+65 min, P < 0.001), and median LOS decreased (-1 day, P < 0.001). All other outcomes remained similar (P>0.05). Over time, there were nonrandom (P < 0.05) downward shifts in LOS, while comprehensive complication index was unaffected. We observed 3 learning curve phases in OT: accumulation (<31 cases), optimization (case 31-65), and a steady-state (>65 cases). Propensity-score-matching confirmed reductions in index and 90-day LOS and blood loss with similar morbidity between RADP and ODP. CONCLUSION: Supervised procedure-specific training enabled successful implementation of RADP by practicing surgeons with immediate improvements in length of stay, without adverse effects on safety.

Current Status of Metabolomic Biomarker Discovery: Impact of Study Design and Demographic Characteristics.

Widespread application of omic technologies is evolving our understanding of population health and holds promise in providing precise guidance for selection of therapeutic interventions based on patient biology. The opportunity to use hundreds of analytes for diagnostic assessment of human health compared to the current use of 10-20 analytes will provide greater accuracy in deconstructing the complexity of human biology in disease states. Conventional biochemical measurements like cholesterol, creatinine, and urea nitrogen are currently used to assess health status; however, metabolomics captures a comprehensive set of analytes characterizing the human phenotype and its complex metabolic processes in real-time. Unlike conventional clinical analytes, metabolomic profiles are dramatically influenced by demographic and environmental factors that affect the range of normal values and increase the risk of false biomarker discovery. This review addresses the challenges and opportunities created by the evolving field of clinical metabolomics and highlights features of study design and bioinformatics necessary to maximize the utility of metabolomics data across demographic groups.

Association of Mentorship and a Formal Robotic Proficiency Skills Curriculum With Subsequent Generations' Learning Curve and Safety for Robotic Pancreaticoduodenectomy.

Importance: Learning curves are unavoidable for practicing surgeons when adopting new technologies. However, patient outcomes are worse in the early stages of a learning curve vs after mastery. Therefore, it is critical to find a way to decrease these learning curves without compromising patient safety. Objective: To evaluate the association of mentorship and a formal proficiency-based skills curriculum with the learning curves of 3 generations of surgeons and to determine the association with increased patient safety. Design, Setting, and Participants: All consecutive robotic pancreaticoduodenectomies (RPDs) performed at the University of Pittsburgh Medical Center between 2008 and 2017 were included in this study. Surgeons were split into generations based on their access to mentorship and a proficiency-based skills curriculum. The generations are (1) no mentorship or curriculum, (2) mentorship but no curriculum, and (3) mentorship and curriculum. Univariable and multivariable analyses were used to create risk-adjusted learning curves by surgical generation and to analyze factors associated with operating room time, complications, and fellows completing the full resection. The participants include surgical oncology attending surgeons and fellows who participated in an RPD at University of Pittsburgh Medical Center between 2008 and 2017. Main Outcomes and Measures: The primary outcome was operating room time (ORT). Secondary outcomes were postoperative pancreatic fistula and Clavien-Dindo classification higher than grade 2. Results: We identified 514 RPDs completed between 2008 and 2017, of which 258 (50.2%) were completed by first-generation surgeons, 151 (29.3%) were completed by the second generation, and 82 (15.9%) were completed by the third generation. There was no statistically significant difference between groups with respect to age (66.3-67.3 years; P = .52) or female sex (n = 34 [41.5%] vs n = 121 [46.9%]; P = .60). There was a significant decrease in ORT (P < .001), from 450.8 minutes for the first-generation surgeons to 348.6 minutes for the third generation. Additionally, across generations, Clavien-Dindo classification higher than grade 2 (n = 74 [28.7%] vs n = 30 [9.9%] vs n = 12 [14.6%]; P = .01), conversion rates (n = 18 [7.0%] vs n = 7 [4.6%] vs n = 0; P = .006), and estimated blood loss (426 mL vs 288.6 mL vs 254.7 mL; P < .001) decreased significantly with subsequent generations. There were no significant differences in postoperative pancreatic fistula. Conclusions and Relevance: In this study, ORT, conversion rates, and estimated blood loss decreased across generations without a concomitant rise in adverse patient outcomes. These findings suggest that a proficiency-based curriculum coupled with mentorship allows for the safe introduction of less experienced surgeons to RPD without compromising patient safety.

Biliary palliation for unresectable pancreatic adenocarcinoma: surgical bypass or self-expanding metal stent?

BACKGROUND: Standard of care guidelines endorse self-expanding metal stents (SEMS) rather than open surgical biliary bypass (OSBB) for biliary palliation in the setting of unresectable pancreatic ductal adenocarcinoma (PDAC). This study used competing risk analysis to compare short- and long-term morbidity and overall survival among patients undergoing SEMS or OSBB after unresectable or metastatic disease is identified at the time of exploration. METHODS: Single institution retrospective cohort study (n = 127) evaluating outcomes after OSBB and SEMS for biliary palliation in patients found to have unresectable PDAC at exploration. Short-term, long-term, and lifetime risk of biliary occlusion and survival were compared after adjustment for stage and comprehensive complication index (CCI). RESULTS: Baseline demographics and tumor characteristics were equivalent between cohorts. Short-term complications were more frequent after OSBB, whereas late complications were greater after SEMS. The cumulative incidence of recurrent biliary obstruction was greater after SEMS, but lifetime complication burden and median survival were equivalent. CONCLUSION: OSBB was associated with longer hospital stays and more short-term complications, and SEMS was associated with a higher risk of recurrent biliary obstruction among surgical patients with unresectable PDAC. Patient preference should be defined pre-operatively in the case the unresectable disease is encountered during attempted resection.

Incidental pulmonary embolism in pancreatic ductal adenocarcinoma: Impact of tumor and AJCC stages at initial staging CT.

BACKGROUND/OBJECTIVES: To determine the prevalence of incidental pulmonary embolism (PE) detected during initial staging CT among patients with newly diagnosed pancreatic ductal adenocarcinoma (PDAC) and assess their association with underlying tumor burden. MATERIALS AND METHODS: This retrospective cohort study evaluated staging chest CT scans (2013-2017) to identify PE among patients with treatment naïve, biopsy-proven PDAC. Data included age, sex, T stage, AJCC stage, presence/absence of metastases and their location at diagnosis. The association of PE with tumor (T1-T4) and AJCC stage were assessed using Pearson Chi-square and Fischer's exact test. A threshold p-value of <0.05 indicated statistical significance. RESULTS: A total of 174 patients (90 female, mean age, 68 years; range: 34-93) were identified, of which 10 patients harbored incidental PE (prevalence, 5.7%). In the PE group, two patients presented with distant metastasis (liver, 20%), while eight patients had T4 tumors (80%). No statistical association was detected between PE and age, sex, and the presence/absence or location of distant metastasis (p = 0.065, p = 0.59, p = 0.687 and p = 0.933, respectively). Patients with T4 tumors and higher AJCC stages (stage III/IV) were significantly more likely to present with PE than those with lower T stage (p = 0.045) and AJCC stage (stage I/II; p = 0.017). CONCLUSION: The prevalence of incidental PE among PDAC patients undergoing initial CT staging is 5.7%. Patients with T4 and AJCC stages III/IV are at higher risk of PE. Caution should be exercised during radiographic interpretation of initial staging chest CTs, as incidental PE may be lurking and require treatment.

Does surgical approach affect outcomes of enucleation for benign and low-grade pancreatic tumors? An ACS-NSQIP evaluation.

BACKGROUND: Enucleation of low-grade pancreatic tumors achieves oncological outcomes equivalent to resection but conserves parenchyma. Given strict selection criteria, we hypothesized that minimally-invasive (MI) enucleation is associated with decreased composite major morbidity (CMM) compared to open. METHODS: Pancreas-targeted ACS NSQIP (2014 -2016) was queried for enucleation (CPT code: 48120) and analyzed by intended surgical approach regardless of conversion. The primary outcome was CMM, a validated 30-day composite metric of adverse events. RESULTS: Enucleation was performed using an open (n = 71; 62.3%) or MI (n = 43; 37.7%) approach with 7 conversions (16.2%). Both cohorts had interchangeable baseline characteristics. No selection factors governing MI were identified. MI-enucleation reduced median length of stay (4 vs. 5 days; p = 0.003), whereas rates of CMM after open (24; 34%) and MIenucleation (12; 28%) were equivalent (p = 0.541). Multivariable analysis demonstrated an association between CMM and prolonged operative time (OR 2.7, 95% CI 1.14 -6.74), female sex (OR 0.38, 95% CI 0.16 -0.94), and ASA score <3 (OR 0.39, 95% CI 0.16 -0.96) but not surgical approach. CONCLUSION: MI-enucleation was not associated with reduced 30-day CMM compared to open, whereas prolonged operating time and unmodifiable patient factors were correlated with adverse outcomes.

Outcomes and Risk Score for Distal Pancreatectomy with Celiac Axis Resection (DP-CAR): An International Multicenter Analysis.

BACKGROUND: Distal pancreatectomy with celiac axis resection (DP-CAR) is a treatment option for selected patients with pancreatic cancer involving the celiac axis. A recent multicenter European study reported a 90-day mortality rate of 16%, highlighting the importance of patient selection. The authors constructed a risk score to predict 90-day mortality and assessed oncologic outcomes. METHODS: This multicenter retrospective cohort study investigated patients undergoing DP-CAR at 20 European centers from 12 countries (model design 2000-2016) and three very-high-volume international centers in the United States and Japan (model validation 2004-2017). The area under receiver operator curve (AUC) and calibration plots were used for validation of the 90-day mortality risk model. Secondary outcomes included resection margin status, adjuvant therapy, and survival. RESULTS: For 191 DP-CAR patients, the 90-day mortality rate was 5.5% (95 confidence interval [CI], 2.2-11%) at 5 high-volume (≥ 1 DP-CAR/year) and 18% (95 CI, 9-30%) at 18 low-volume DP-CAR centers (P = 0.015). A risk score with age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) score, multivisceral resection, open versus minimally invasive surgery, and low- versus high-volume center performed well in both the design and validation cohorts (AUC, 0.79 vs 0.74; P = 0.642). For 174 patients with pancreatic ductal adenocarcinoma, the R0 resection rate was 60%, neoadjuvant and adjuvant therapies were applied for respectively 69% and 67% of the patients, and the median overall survival period was 19 months (95 CI, 15-25 months). CONCLUSIONS: When performed for selected patients at high-volume centers, DP-CAR is associated with acceptable 90-day mortality and overall survival. The authors propose a 90-day mortality risk score to improve patient selection and outcomes, with DP-CAR volume as the dominant predictor.

DWI of Pancreatic Ductal Adenocarcinoma: A Pilot Study to Estimate the Correlation With Metastatic Disease Potential and Overall Survival.

OBJECTIVE: The purpose of this study is to analyze the relationship between the apparent diffusion coefficient (ADC) of pancreatic ductal adenocarcinoma (PDAC) and the presence or development of metastasis and overall survival (OS). MATERIALS AND METHODS: Of 290 consecutive patients with histopathologically proven PDAC from January 2013 to December 2014, staging DWI was performed for 124 patients. Image quality was adequate in 112 studies. Sixty-five patients were treatment naïve, but 17 of the 65 were excluded because of the presence of other associated pancreatic pathologic abnormalities. Data for the remaining 48 patients (24 men and 24 women; median age, 65.5 years; interquartile range, 56-77 years) were obtained during a 4-year follow-up period (mean [± SD], 397 ± 415.1 days). The correlation between ADC and the presence or development of metastasis was assessed using descriptive statistics. OS was determined and mortality analysis was performed using Pearson correlation and Kaplan-Meier curves. RESULTS: Of 48 patients, 10 had metastases at staging MRI, and 12 later developed metastatic disease. Among the latter, the mean time from staging MRI to metastasis was 258 ± 274.1 days. Most (86%) metastases were hepatic (n = 19). During the follow-up period, the remaining 26 patients (54%) never developed metastases. Patients with metastatic disease (n = 22) had significantly lower mean ADCs than did those without metastases (1.27 × 10-3 vs 1.43 × 10-3 mm2/s; p = 0.047). The ADC of PDAC had a positive correlation with survival: patients with PDAC with lower ADCs (< 1.36 × 10-3 mm2/s) had significantly worse 4-year OS rates than did patients with higher ADC values (p = 0.036). CONCLUSION: Pretreatment ADC values of PDAC may be significantly lower in patients who have or will develop metastatic disease and may correlate with worse OS.

Prospective study of germline genetic testing in incident cases of pancreatic adenocarcinoma.

BACKGROUND: The objective of this study was to investigate the prevalence of pathogenic germline variants (PGVs) in 32 cancer susceptibility genes in individuals with newly diagnosed pancreatic ductal adenocarcinoma (PDAC). A key secondary objective was to evaluate how often PGVs would have been undetected with existing genetic testing criteria. METHODS: From May 2016 through May 2017, this multicenter cohort study enrolled consecutive patients aged 18 to 89 years with histologically confirmed PDAC diagnosed within the previous 12 weeks. Demographics, medical histories, and 3-generation pedigrees were collected from participants who provided samples for germline DNA analysis. RESULTS: Four hundred nineteen patients were deemed eligible, 302 were enrolled, and 298 were included in the final cohort. Clinically actionable variants were reported in 29 PDAC patients (9.7%), with 23 (7.7%) having a PGV associated with an increased risk for PDAC. Six of 23 individuals (26%) with PDAC-associated gene mutations did not meet currently established genetic testing criteria. According to guideline-based genetic testing, only 11 of the 23 PGVs (48%) in known PDAC genes would have been detected. Six additional patients (2%) had PGVs associated with an increased risk for other cancers. CONCLUSIONS: These findings support the significant prevalence of PGVs associated with PDAC and the limitations of current paradigms for selecting patients for genetic testing, and they thereby lend support for universal germline multigene genetic testing in this population.