Short-term and Long-term Outcomes of Robotic Enucleation of Tumors Located in the Pancreatic Head and Uncinate Process.

OBJECTIVE: To assess short-term and long-term outcomes following robotic enucleation (REn) of tumors in the proximal pancreas. BACKGROUND: Despite the advantages of preserving function via pancreatic enucleation, controversies persist, since this can be associated with severe complications, such as clinically relevant postoperative pancreatic fistula, especially when performed near the main pancreatic duct. The safety and efficacy of REn in this context remain largely unknown. METHODS: A retrospective analysis was performed of all patients who underwent REn for benign and low-grade malignant neoplasms in the pancreatic head and uncinate process between January 2005 and December 2021. Clinicopathologic, perioperative, and long-term outcomes were compared with a similar open enucleation (OEn) group. RESULTS: Of 146 patients, 92 underwent REn with a zero conversion-to-open rate. REn was superior to OEn in terms of shorter operative time (90.0 minutes vs 120.0 minutes, P<0.001), decreased blood loss (20.0 mL vs 100.0 min, P=0.001), and lower clinically relevant postoperative pancreatic fistula rate (43.5% vs 61.1%, P=0.040). Bile leakage rate, major morbidity, 90-day mortality, and length of hospital stay were comparable between groups. No post-REn grade C POPF or grade IV/V complication was identified. Subgroup analyses for uncinate process tumors and proximity to the main pancreatic duct did not demonstrate inferior postoperative outcomes. In a median follow-up period of 50 months, REn outcomes were comparable to OEn regarding recurrence rate and pancreatic endocrine or exocrine function. CONCLUSIONS: REn for pancreatic head and uncinate process tumors improved clinically relevant outcomes without increased major complications compared to OEn, while demonstrating comparable long-term oncological and functional outcomes.

The Impact of Molecular Subtyping on Pathological Staging of Pancreatic Cancer.

BACKGROUND: The long-term outcomes following surgical resection for pancreatic ductal adenocarcinoma (PDAC) remains poor, with only 20% of patients surviving 5 years after pancreatectomy. Patient selection for surgery remains suboptimal largely due to the absence of consideration of aggressive tumor biology. OBJECTIVE: The aim of this study was to evaluate traditional staging criteria for PDAC in the setting of molecular subtypes. METHODS: Clinicopathological data were obtained for 5 independent cohorts of consecutive unselected patients, totaling n = 1298, including n = 442 that underwent molecular subtyping. The main outcome measure was disease-specific survival following surgical resection for PDAC stratified according to the American Joint Commission for Cancer (TNM) staging criteria, margin status, and molecular subtype. RESULTS: TNM staging criteria and margin status confers prognostic value only in tumors with classical pancreatic subtype. Patients with tumors that are of squamous subtype, have a poor outcome irrespective of favorable traditional pathological staging [hazard ratio (HR) 1.54, 95% confidence interval (CI) 1.04-2.28, P = 0.032]. Margin status has no impact on survival in the squamous subtype (16.0 vs 12.1 months, P = 0.374). There were no differences in molecular subtype or gene expression of tumors with positive resection margin status. CONCLUSIONS: Aggressive tumor biology as measured by molecular subtype predicts poor outcome following pancreatectomy for PDAC and should be utilized to inform patient selection for surgery.

A Delay in Adjuvant Therapy Is Associated With Worse Prognosis Only in Patients With Transitional Circulating Tumor Cells After Resection of Pancreatic Ductal Adenocarcinoma.

OBJECTIVES: The aim of the study was to assess the association of circulating tumor cells (CTCs) with survival as a biomarker in pancreatic ductal adenocarcinoma (PDAC) within the context of a delay in the initiation of adjuvant therapy. BACKGROUND: Outcomes in patients with PDAC remain poor and are driven by aggressive systemic disease. Although systemic therapies improve survival in resected patients, factors such as a delay in the initiation of adjuvant therapy are associated with worse outcomes. CTCs have previously been shown to be predictive of survival. METHODS: A retrospective study was performed on PDAC patients enrolled in the prospective CircuLating tUmor cellS in pancreaTic cancER trial (NCT02974764) on CTC-dynamics at the Johns Hopkins Hospital. CTCs were isolated based on size (isolation by size of epithelial tumor cells; Rarecells) and counted and characterized by subtype using immunofluorescence. The preoperative and postoperative blood samples were used to identify 2 CTC types: epithelial CTCs (eCTCs), expressing pancytokeratin, and transitional CTCs (trCTCs), expressing both pancytokeratin and vimentin. Patients who received adjuvant therapy were compared with those who did not. A delay in the receipt of adjuvant therapy was defined as the initiation of therapy ≥8 weeks after surgical resection. Clinicopathologic features, CTCs characteristics, and outcomes were analyzed. RESULTS: Of 101 patients included in the study, 43 (42.5%) experienced a delay in initiation and 20 (19.8%) did not receive adjuvant therapy. On multivariable analysis, the presence of trCTCs ( P =0.002) and the absence of adjuvant therapy ( P =0.032) were associated with worse recurrence-free survival (RFS). Postoperative trCTC were associated with poorer RFS, both in patients with a delay in initiation (12.4 vs 17.9 mo, P =0.004) or no administration of adjuvant chemotherapy (3.4 vs NR, P =0.016). However, it was not associated with RFS in patients with timely initiation of adjuvant chemotherapy ( P =0.293). CONCLUSIONS: Postoperative trCTCs positivity is associated with poorer RFS only in patients who either experience a delay in initiation or no receipt of adjuvant therapy. This study suggests that a delay in the initiation of adjuvant therapy could potentially provide residual systemic disease (trCTCs) a window of opportunity to recover from the surgical insult. Future studies are required to validate these findings and explore the underlying mechanisms involved.

Geographic variation in attitudes regarding management of locally advanced pancreatic cancer.

Background: Recent literature suggests wide variations exist in the international management of locally advanced pancreatic cancer. This study sought to evaluate how geography contributes to variations in management of locally advanced pancreatic cancer. Methods: An electronic survey investigating preferences for the evaluation and management of locally advanced pancreatic cancer was distributed to an international cohort of pancreatic surgeons. Surgeons were classified according to geographic location of practice, and survey responses were compared across locations. Results: A total of 153 eligible responses were received from 4 continents: North and South America (n = 94, 61.4%), Europe (n = 25, 16.3%), and Asia (n = 34, 22.2%). Preferences for the use and duration of neoadjuvant chemotherapy and radiotherapy varied widely. For example, participants in Asia commonly preferred 2 months of neoadjuvant chemotherapy (61.8%), whereas North and South American participants preferred 4 months (52.1%), and responses in Europe were mixed (P = .006). Participants in Asia were less likely to consider isolated liver or lung metastases contraindications to exploration and consequently had a greater propensity to consider exploration in a vignette of oligometastatic disease (56.7% vs North and South America: 25.6%, Europe: 43.5%; P = .007). Conclusion: In an international survey of pancreatic surgeons, attitudes regarding locally advanced pancreatic cancer and metastatic disease management varied widely across geographic locations. Better evidence is needed to define optimal management of locally advanced pancreatic cancer.

Oncological outcomes of robotic pancreatectomy in patients with pancreatic cancer who receive adjuvant chemotherapy: A propensity score-matched retrospective cohort study.

BACKGROUND: Limited data are available regarding long-term oncological outcomes in patients with pancreatic ductal adenocarcinoma (PDAC) who undergo robotic pancreatectomy (RP). METHOD: All patients who underwent RP and open pancreatectomy (OP) for resectable PDAC between January 2011 and December 2019 were included. The RP group was matched 1:1 with OP group by propensity score matching (PSM). The oncological outcomes were collected and analyzed. RESULTS: Overall, 1606 patients were included in this study. After PSM, a well-balanced cohort of 335 patients in each group was selected for further analysis. The RP group had shorter operative time (210 min vs. 240 min, P < 0.001), lower estimated blood loss (200 ml vs. 300 ml, P = 0.011), lower wound infection rates (4.5% vs. 10.1%, P = 0.005) and shorter length of postoperative hospital stay (15 days vs. 17 days, P = 0.001) compared to the OP group, with no significant differences in other perioperative outcomes. OS was comparable between the two groups (31 months vs. 28 months, P = 0.077); however, RFS was improved in the RP group (17 months vs. 14 months, P = 0.015). Subgroup analysis showed that patients who received adjuvant chemotherapy (AC) in the RP group had better RFS than the similar patient cohort in the OP group (17 months vs. 14 months, P = 0.024). CONCLUSION: Robotic pancreatectomy is safe and oncologically effective for resectable PDAC. OS was comparable between RP and OP, and RFS was improved in the RP group, especially in patients who receive AC.

Robotic versus open pancreaticoduodenectomy with vascular resection for pancreatic ductal adenocarcinoma: surgical and oncological outcomes from pilot experience.

PURPOSE: Venous resection and reconstruction (VR) is a feasible surgical technique to achieve optimal outcomes in selected patients with pancreatic ductal adenocarcinoma (PDAC) who undergo open pancreaticoduodenectomy (OPD). However, data regarding patient outcomes in patients who undergo VR in robotic-assisted pancreaticoduodenectomy (RPD) are scarce. METHODS: All patients with a diagnosis of PDAC who underwent upfront open or robotic pancreatoduodenectomy with VR in a high-volume institution for pancreatic surgery between 2011 and 2019 were retrospectively reviewed. Perioperative and long-term outcomes were compared between the RPD and OPD cohorts. RESULTS: A total of 84 patients were included in the final analysis, 14 patients underwent RPD with VR and 70 who had OPD with VR. Reconstructed venous patency, postoperative 30-day morbidity, and 90-day mortality were comparable; however, lymph node resection rates were lower in the RPC cohort (p = 0.029). No difference was identified in 3-year survival rates between the two groups (34.0% versus 25.7% respectively, p = 0.667). CONCLUSION: RPD with VR is a feasible approach for patients with PDAC and venous invasion. Further studies are needed to assess long-term outcomes compared to the open approach.

Severity of Pancreatic Leak in Relation to Gut Restoration After Pancreaticoduodenectomy: The Role of the Roux-en-Y Configuration.

Background: Pancreatic leak after pancreaticoduodenectomy and gut restoration via a single jejunal loop remains the crucial predictor of patients' outcome. Our reasoning that active pancreatic enzymes may be more disruptive to the pancreatojejunostomy prompted us to explore a Roux-en-Y configuration for the gut restoration, anticipating diversion of bile salts away from the pancreatic stump. Our study aims at comparing two techniques regarding the severity of postoperative pancreatic fistula (POPF) and patients' outcome. Methods: The files of 415 pancreaticoduodenectomy patients were retrospectively reviewed. Based on gut restoration, the patients were divided into: cohort A (n = 105), with gut restoration via a single jejunal loop, cohort B (n = 140) via a Roux-en-Y technique assigning the draining of pancreatic stump to the short limb and gastrojejunostomy and bile (hepaticojejunostomy) flow to long limb, and cohort C (n = 170) granting the short limb to the gastric and pancreatic anastomosis, whereas hepaticojejunostomy was performed to the long limp. The POPF-related morbidity and mortality were analyzed. Results: Overall POPF in cohort A versus cohorts B and C was 19% versus 12.1% and 9.4%, respectively (P = 0.01 A vs B + C). POPF-related morbidity in cohort A versus cohorts B and C was 10.5% versus 7.3% and 6.3%, respectively (P = 0.03 A vs B+C). POPF-related total hospital mortality in cohorts A versus B and C was 1.9% versus 0.8% and 0.59%, respectively (P = 0.02 A vs B+C). Conclusion: Roux-en-Y configuration showed lower incidence and severity of POPF. Irrespective of technical skill, creating a gastrojejunostomy close to pancreatojejunostomy renders the pancreatic enzymes less active by leaping the bile salts away from the pancreatic duct and providing a lower pH.

Anatomic Criteria Determine Resectability in Locally Advanced Pancreatic Cancer.

BACKGROUND: The introduction of multi-agent chemotherapy and radiation therapy has facilitated potential resection with curative intent in selected locally advanced pancreatic cancer (LAPC) patients with excellent outcomes. Nevertheless, there remains a remarkable lack of consensus on the management of LAPC. We sought to describe the outcomes of patients with LAPC and objectively define the multidisciplinary selection process for operative exploration based on anatomical factors. METHODS: Consecutive patients with LAPC were evaluated for pancreatic surgery in the multidisciplinary clinic of a high-volume institution, between 2013 and 2018. Prospective stratification (LAPC-1, LAPC-2, and LAPC-3), based on the involvement of regional anatomical structures, was performed at the time of presentation prior to the initiation of treatment. Resection rates and patient outcomes were evaluated and correlated with the initial anatomic stratification system. RESULTS: Overall, 415 patients with LAPC were included in the study, of whom 84 (20%) were successfully resected, with a median overall survival of 35.3 months. The likelihood of operative exploration was associated with the pretreatment anatomic LAPC score, with a resection rate of 49% in patients classified as LAPC-1, 32% in LAPC-2, and 11% in LAPC-3 (p < 0.001). Resected patients with improvement of the LAPC score at the time of exploration had significantly longer median overall survival compared with those with no change or progression of LAPC score (60.7 vs. 29.8 months, p = 0.006). CONCLUSIONS: Selected patients with LAPC can undergo curative-intent surgery with excellent outcomes. The proposed Johns Hopkins anatomic LAPC score provides an objective system to anticipate the probability of eventual surgical resection after induction therapy.

Robotic versus Open Pancreatoduodenectomy for Pancreatic and Periampullary Tumors (PORTAL): a study protocol for a multicenter phase III non-inferiority randomized controlled trial.

BACKGROUND: Pancreatoduodenectomy is a complex and challenging procedure that requires meticulous tissue dissection and proficient suturing skills. Minimally invasive surgery with the utilization of robotic platforms has demonstrated advantages in perioperative patient outcomes in retrospective studies. The development of robotic pancreatoduodenectomy (RPD) in specific has progressed significantly, since first reported in 2003, and high-volume centers in pancreatic surgery are reporting large patient series with improved pain management and reduced length of stay. However, prospective studies to assess objectively the feasibility and safety of RPD compared to open pancreatoduodenectomy (OPD) are currently lacking. METHODS/DESIGN: The PORTAL trial is a multicenter randomized controlled, patient-blinded, parallel-group, phase III non-inferiority trial performed in seven high-volume centers for pancreatic and robotic surgery in China (> 20 RPD and > 100 OPD annually in each participating center). The trial is designed to enroll and randomly assign 244 patients with an indication for elective pancreatoduodenectomy for malignant periampullary and pancreatic lesions, as well as premalignant and symptomatic benign periampullary and pancreatic disease. The primary outcome is time to functional recovery postoperatively, measured in days. Secondary outcomes include postoperative morbidity and mortality, as well as perioperative costs. A sub-cohort of 128 patients with pancreatic adenocarcinoma (PDAC) will also be compared to assess the percentage of patients who undergo postoperative adjuvant chemotherapy within 8 weeks, in each arm. Secondary outcomes in this cohort will include patterns of disease recurrence, recurrence-free survival, and overall survival. DISCUSSION: The PORTAL trial is designed to assess the feasibility and safety of RPD compared to OPD, in terms of functional recovery as described previously. Additionally, this trial will explore whether RPD allows increased access to postoperative adjuvant chemotherapy, in a sub-cohort of patients with PDAC. TRIAL REGISTRATION: ClinicalTrials.gov NCT04400357 . Registered on May 22, 2020.

Proclivity to Explore Locally Advanced Pancreas Cancer Is Not Associated with Surgeon Volume.

BACKGROUND AND PURPOSE: There is limited high-level evidence to guide locally advanced pancreas cancer (LAPC) management. Recent work shows that surgeons' preferences in LAPC management vary broadly. We sought to examine whether surgeon volume was associated with attitudes regarding LAPC management. METHODS: An electronic survey was distributed by email to an international cohort of pancreas surgeons to evaluate practice patterns regarding LAPC management. Clinical vignette-based questions evaluated surgeons' attitudes regarding patient eligibility and the proclivity to offer exploration. Surgeons were classified into "low-" or "high-volume" categories according to thresholds of self-reported annual pancreatectomy volume. Surgeon's attitudes regarding LAPC management and inclination to consider exploration were compared across annual volume categories. RESULTS: A total of 153 eligible responses were received from 4 continents, for an estimated response rate of 10.6%. Median duration of practice was 12 years (IQR 6-20). Most respondents reported >25 cases/year (89, 58.2%), of which 34 (22.2%) reported >50. Compared to surgeons with <25 cases/year, surgeons with >25 cases/year practiced longer (median 15 vs. 7.5 years, P<0.001) and were more likely to "always" recommend neoadjuvant chemotherapy (83.2% vs. 56.3%, P=0.001). Surgeons performing >50 cases/year were more likely to offer arterial resection (70.6% vs. 43.7%, P=0.006). The willingness to offer (or defer) exploration did not differ across any categories of surgeons' annual case volume. CONCLUSIONS: In an international survey of pancreas surgeons, the proclivity to consider exploration for LAPC was not associated with multiple categories of surgeon volume. Better evidence is needed to define the optimal management approach to LAPC.

Surgical Management of Non-Metastatic Pancreatic Cancer in the United Kingdom: Results of a Nationwide Survey on Current Practice.

BACKGROUND: It is presently unclear what clinical pathways are followed for patients with non-metastatic PDAC in specialised centres for pancreatic surgery across the United Kingdom (UK). METHODS: Between August 2019 and August 2020 an electronic survey was conducted aiming at a national cohort of pancreatic surgeons in the UK. Participants replied to a list of standardised questions and clinical vignettes, and data were collected and analysed focusing on management preferences, resectability criteria, and contraindications to surgery. RESULTS: Within the study period, 65 pancreatic surgeons from 27 specialist centres in the UK (96%) completed the survey. Multidisciplinary team meetings are utilised universally for the management of patients with PDAC, however, different staging systems for resectability classification are being applied. In borderline resectable PDAC, most surgeons were keen to proceed with surgical exploration post NAT, but differences were noted in preferred chemotherapy regimens. Surgeons from standard volume institutions performed fewer vein resections annually and were more likely to deem patients with locally advanced PDAC as unresectable. Intra-institutional variability in patient management was also present and ranging between 20-80%. CONCLUSIONS: Significant variability in the surgical management of non-metastatic PDAC was identified both on inter- and intra-institutional level.

Management of Locally Advanced Pancreatic Cancer: Results of an International Survey of Current Practice.

OBJECTIVE: The aim of this study was to investigate surgeon preferences for the management of patients with locally advanced pancreatic cancer (LAPC). BACKGROUND: Select patients with LAPC may become candidates for curative resection following neoadjuvant therapy, and recent reports of survival are encouraging. Yet the optimal management approach remains unclear. METHODS: An extensive electronic survey was systematically distributed by email to an international cohort of pancreas surgeons. Data collected included practice characteristics, management preferences, attitudes regarding contraindications to surgery, and 6 clinical vignettes of patients that ultimately received a margin negative resection (with detailed videos of post-neoadjuvant imaging) to assess propensity for surgical exploration if resection status is not known. RESULTS: A total of 153 eligible responses were received from 4 continents. Median duration of practice is 12 years (interquartile range 6-20) and 77% work in a university setting. Most surgeons (86%) are considered high volume (>10 resections/yr), 33% offer a minimally-invasive approach, and 50% offer arterial resections in select patients. Most (72%) always recommend neoadjuvant chemotherapy, and 65% prefer FOLFIRINOX. Preferences for the duration of chemotherapy varied widely: 39% prefer ≥2 months, 43% prefer ≥4 months, and 11% prefer ≥6 months. Forty-one percent frequently recommend neoadjuvant radiotherapy, and 53% prefer 5 to 6 weeks of chemoradiation. The proportion of surgeons favoring exploration following neoadjuvant varied extensively across 5 vignettes of LAPC, from 14% to 53%. In a vignette of oligometastatic liver metastases, 31% would offer exploration if a favorable therapy response is observed. CONCLUSIONS: In an international cohort of pancreas surgeons, there is substantial variation in management preferences, perceived contraindications to surgery, and the propensity to consider exploration in LAPC. These results emphasize the importance of a robust and nuanced multidisciplinary discussion for each patient, and suggest an evolving concept of "resectability."

Challenges of the current precision medicine approach for pancreatic cancer: A single institution experience between 2013 and 2017.

Recent research on genomic profiling of pancreatic ductal adenocarcinoma (PDAC) has identified many potentially actionable alterations. However, the feasibility of using genomic profiling to guide routine clinical decision making for PDAC patients remains unclear. We retrospectively reviewed PDAC patients between October 2013 and December 2017, who underwent treatment at the Johns Hopkins Hospital and had clinical tumor next-generation sequencing (NGS) through commercial resources. Ninety-two patients with 93 tumors tested were included. Forty-eight (52%) patients had potentially curative surgeries. The median time from the tissue available to the NGS testing ordered was 229 days (interquartile range 62-415). A total of three (3%) patients had matched targeted therapies based on genomic profiling results. Genomic profiling guided personalized treatment for PDAC patients is feasible, but the percentage of patients who receive targeted therapy is low. The main challenges are ordering NGS testing early in the clinical course of the disease and the limited evidence of using a targeted approach in these patients. A real-time department level genomic testing ordering system in combination with an evidence-based flagging system for potentially actionable alterations could help address these shortcomings.

Robotic-assisted versus open total pancreatectomy: a propensity score-matched study.

BACKGROUND: Total pancreatectomy (TP) is a complex surgical procedure with significant postoperative morbidity. Despite the narrowed range of indications for TP, the introduction of neoadjuvant chemotherapy and the increasing complexity of surgical resections performed in high-volume centers has increased the number of annually performed TPs, especially regarding malignant disease. The introduction of robotic-assisted pancreatic surgery has provided a novel and minimally invasive approach for TP, yet the feasibility of this technique is still unknown. This study assessed the safety and efficacy of robotic-assisted total pancreatectomy (RTP) compared to conventional open total pancreatectomy (OTP). METHODS: All patients who underwent TP between March 2015 and July 2019 in a high-volume institution for pancreatic surgery were included in this retrospective study. Clinical data and perioperative outcomes were derived from the prospectively maintained institutional database. A 1:1 propensity score matching (PSM) method was utilized to compare the RTP and OTP cohorts to minimize bias. RESULTS: A standardized surgical protocol was utilized for RTP following a learning curve of RPD and RDP. The median operative time for patients who underwent RTP was significantly decreased compared to those who underwent OTP [300 (IQR, 250-360) vs. 360 min (IQR, 300-525), P=0.031]. Additionally, en bloc resection and spleen-preserving rates were also higher in the RTP cohort. Major 30-day morbidity (Clavien-Dindo > IIIa) and 90-day mortality were similar between the two cohorts. After a median follow-up time of 15 (IQR, 8-24) months, both the RTP and OTP cohorts had a comparable quality of life regarding exocrine and endocrine insufficiency. CONCLUSIONS: RTP appears to be safe and feasible when utilized in high-volume centers for the indicated management of benign and highly selected malignant pancreatic disease. However, further prospective randomized studies are needed to assess the feasibility of this approach.

Pancreatic circulating tumor cell detection by targeted single-cell next-generation sequencing.

BACKGROUND AND AIMS: Single-cell next-generation sequencing (scNGS) technology has been widely used in genomic profiling, which relies on whole-genome amplification (WGA). However, WGA introduces errors and is especially less accurate when applied to single nucleotide variant (SNV) analysis. Targeted scNGS for SNV without WGA has not been described. We aimed to develop a method to detect circulating tumor cells (CTCs) with DNA SNVs. METHODS: We tested this targeted scNGS method with three driver mutant genes (KRAS/TP53/SMAD4) on one pancreatic cancer cell line AsPC-1 and then applied it to patients with metastatic PDAC for the validation. RESULTS: All single-cell of AsPC-1 and spiked-in AsPC-1 cells in healthy donor blood, which were isolated by the filtration with size or by flow cytometry, were detected by targeted scNGS method. All blood samples from six patients with metastatic PDAC, for the validation of target scNGS method, showed CTCs with SNVs of KRAS/TP53/SMAD4 and the positive confirmation of immunofluorescent stainings with Pan-CK/Vimentin/CD45. Four patients with early stage disease, one patient with benign pancreatic cyst and a healthy control sample all showed concordant results between targeted scNGS and CTC enumeration. CONCLUSIONS: The novel technique of targeted scNGS for SNV analysis, without pre-amplification, is a promising method for identifying and characterizing circulating tumor cells.

Circulating Tumor DNA as a Clinical Test in Resected Pancreatic Cancer.

PURPOSE: In research settings, circulating tumor DNA (ctDNA) shows promise as a tumor-specific biomarker for pancreatic ductal adenocarcinoma (PDAC). This study aims to perform analytical and clinical validation of a KRAS ctDNA assay in a Clinical Laboratory Improvement Amendments (CLIA) and College of American Pathology-certified clinical laboratory. EXPERIMENTAL DESIGN: Digital-droplet PCR was used to detect the major PDAC-associated somatic KRAS mutations (G12D, G12V, G12R, and Q61H) in liquid biopsies. For clinical validation, 290 preoperative and longitudinal postoperative plasma samples were collected from 59 patients with PDAC. The utility of ctDNA status to predict PDAC recurrence during follow-up was assessed. RESULTS: ctDNA was detected preoperatively in 29 (49%) patients and was an independent predictor of decreased recurrence-free survival (RFS) and overall survival (OS). Patients who had neoadjuvant chemotherapy were less likely to have preoperative ctDNA than were chemo-naïve patients (21% vs. 69%; P < 0.001). ctDNA levels dropped significantly after tumor resection. Persistence of ctDNA in the immediate postoperative period was associated with a high rate of recurrence and poor median RFS (5 months). ctDNA detected during follow-up predicted clinical recurrence [sensitivity 90% (95% confidence interval (CI), 74%-98%), specificity 88% (95% CI, 62%-98%)] with a median lead time of 84 days (interquartile range, 25-146). Detection of ctDNA during postpancreatectomy follow-up was associated with a median OS of 17 months, while median OS was not yet reached at 30 months for patients without ctDNA (P = 0.011). CONCLUSIONS: Measurement of KRAS ctDNA in a CLIA laboratory setting can be used to predict recurrence and survival in patients with PDAC.

Defining and Predicting Early Recurrence in 957 Patients With Resected Pancreatic Ductal Adenocarcinoma.

OBJECTIVES: To establish an evidence-based cut-off to differentiate between early and late recurrence and to compare clinicopathologic risk factors between the two groups. SUMMARY BACKGROUND DATA: A clear definition of "early recurrence" after pancreatic ductal adenocarcinoma resection is currently lacking. METHODS: Patients undergoing pancreatectomy for pancreatic ductal adenocarcinoma between 2000 and 2013 were included. Exclusion criteria were neoadjuvant therapy and incomplete follow-up. A minimum P-value approach was used to evaluate the optimal cut-off value of recurrence-free survival to divide the patients into early and late recurrence cohorts based on subsequent prognosis. Potential risk factors for early recurrence were assessed with logistic regression models. RESULTS: Of 957 included patients, 204 (21.3%) were recurrence-free at last follow-up. The optimal length of recurrence-free survival to distinguish between early (n = 388, 51.5%) and late recurrence (n = 365, 48.5%) was 12 months (P < 0.001). Patients with early recurrence had 1-, and 2-year post-recurrence survival rates of 20 and 6% compared with 45 and 22% for the late recurrence group (both P < 0.001). Preoperative risk factors for early recurrence included a Charlson age-comorbidity index ≥4 (OR 1.65), tumor size > 3.0 cm on computed tomography (OR 1.53) and CA 19-9 > 210 U/mL (OR 2.30). Postoperative risk factors consisted of poor tumor differentiation grade (OR 1.66), microscopic lymphovascular invasion (OR 1.70), a lymph node ratio > 0.2 (OR 2.49), and CA 19-9 > 37 U/mL (OR 3.38). Adjuvant chemotherapy (OR 0.28) and chemoradiotherapy (OR 0.29) were associated with a reduced likelihood of early recurrence. CONCLUSION: A recurrence-free interval of 12 months is the optimal threshold for differentiating between early and late recurrence, based on subsequent prognosis.

Recurrence after neoadjuvant therapy and resection of borderline resectable and locally advanced pancreatic cancer.

INTRODUCTION: The incidence, timing, and implications of recurrence in patients who underwent neoadjuvant treatment and surgical resection of borderline resectable (BRPC) or locally advanced (LAPC) pancreatic cancer are not well established. MATERIALS AND METHODS: Patients with BRPC/LAPC who underwent post-neoadjuvant resection between 2007 and 2015 were included. Associations between clinicopathologic characteristics and specific recurrence locations, recurrence-free survival (RFS), and overall survival from resection (OS) were assessed using Cox regression analyses. RESULTS: For 231 included patients, median survival from diagnosis and resection were 28.0 and 19.8 months, respectively. After a median RFS of 7.9 months, 189 (81.8%) patients had recurred. Multiple-site (n = 87, 46.0%) and liver-only recurrence (n = 28, 14.8%) generally occurred earlier and resulted in significantly worse OS when compared to local-only (n = 52, 27.5%) or lung-only recurrence (n = 18, 9.5%). Microscopic perineural invasion, yN1-yN2 status and elevated pre-surgery CA 19-9 >100 U/mL were associated with both local-only and multiple-site/liver-only recurrence. R1-margin was associated with local-only recurrence (HR 2.03). yN1-yN2 status and microscopic perineural invasion were independent predictors for both poor RFS and OS, while yT3-yT4 tumor stage (HR 1.39) and poor tumor differentiation (HR 1.60) were only predictive of poor OS. Adjuvant therapy was independently associated with both prolonged RFS (HR 0.73; median 7.0 vs. 10.9 months) and OS (HR 0.69; median 15.4 vs. 22.7 months). CONCLUSION: Despite neoadjuvant therapy leading to resection and relatively favorable pathologic tumor characteristics in BRPC/LAPC patients, more than 80% of patients experienced disease recurrence, 72.5% of which occurred at distant sites.

Isolated pulmonary recurrence after resection of pancreatic cancer: the effect of patient factors and treatment modalities on survival.

BACKGROUND: The literature suggests favorable survival for patients with isolated pulmonary recurrence after resection of pancreatic ductal adenocarcinoma (PDAC) as compared to other recurrence patterns. Within this cohort, it remains unclear what factors are associated with improved survival. METHODS: Patients who developed pulmonary recurrence after pancreatectomy were selected from a prospective database. Predictors for post-recurrence survival (PRS) were analyzed using a multivariable Cox regression model. RESULTS: Ninety-six patients were included. Median recurrence-free survival (RFS), PRS and overall survival (OS) were 16.3, 18.8 and 39.6 months, respectively. Further systemic treatment and/or metastasectomy (n = 64, 67%) was associated with significantly improved PRS and OS when compared to best supportive care (n = 35, 22%) (26.3 vs. 5.3 and 48.1 vs. 18.4, respectively; both P < 0.001). Patients who were able to undergo metastasectomy (n = 19) achieved a PRS and OS of 35.0 and 68.9 months, respectively. More than 5 pulmonary lesions, symptoms and CA 19-9 ≥100 U/mL at time of recurrence were predictive of decreased PRS. A recurrence-free interval of >16 months and treatment for recurrence were independently associated with improved PRS. CONCLUSIONS: Isolated pulmonary recurrence occurs in 13% of patients with recurrent PDAC and is associated with a median OS of 40 months. Aggressive treatment in highly selected patients was correlated with improved survival.