Dynamics of Serum CA19-9 in Patients Undergoing Pancreatic Cancer Resection.

BACKGROUND: Carbohydrate antigen (CA) 19-9 is an established perioperative prognostic biomarker for pancreatic ductal adenocarcinoma (PDAC). However, it is unclear how CA19-9 monitoring should be used during postoperative surveillance to detect recurrence and to guide the initiation of recurrence-focused therapy. OBJECTIVE: This study aimed to elucidate the value of CA19-9 as a diagnostic biomarker for disease recurrence in patients who underwent PDAC resection. METHODS: Serum CA19-9 levels at diagnosis, after surgery, and during postoperative follow-up were analyzed in patients who underwent PDAC resection. All patients with at least two postoperative follow-up CA19-9 measurements before recurrence were included. Patients deemed to be nonsecretors of CA19-9 were excluded. The relative increase in postoperative CA19-9 was calculated for each patient by dividing the maximum postoperative CA19-9 value by the first postoperative value. Receiver operating characteristic analysis was performed to identify the optimal threshold for the relative increase in CA19-9 levels to identify recurrence in the training set using Youden's index. The performance of this cutoff was validated in a test set by calculating the area under the curve (AUC) and was compared to the performance of the optimal cutoff for postoperative CA19-9 measurements as a continuous value. In addition, sensitivity, specificity, and predictive values were assessed. RESULTS: In total, 271 patients were included, of whom 208 (77%) developed recurrence. Receiver operating characteristic analysis demonstrated that a relative increase in postoperative serum CA19-9 of 2.6× was predictive of recurrence, with 58% sensitivity, 83% specificity, 95% positive predictive value, and 28% negative predictive value. The AUC for a 2.6× relative increase in the CA19-9 level was 0.719 in the training set and 0.663 in the test set. The AUC of postoperative CA19-9 as a continuous value (optimal threshold, 52) was 0.671 in the training set. In the training set, the detection of a 2.6-fold increase in CA19-9 preceded the detection of recurrence by a mean difference of 7 months ( P <0.001) and in the test set by 10 months ( P <0.001). CONCLUSIONS: A relative increase in the postoperative serum CA19-9 level of 2.6-fold is a stronger predictive marker for recurrence than a continuous CA19-9 cutoff. A relative CA19-9 increase can precede the detection of recurrence on imaging for up to 7 to 10 months. Therefore, CA19-9 dynamics can be used as a biomarker to guide the initiation of recurrence-focused treatment.

Predicting post-recurrence survival for patients with pancreatic cancer recurrence after primary resection: A Bi-institutional validated risk classification.

BACKGROUND: Over 80% of patients will develop disease recurrence after radical resection of pancreatic ductal adenocarcinoma (PDAC). This study aims to develop and validate a clinical risk score predicting post-recurrence survival (PRS) at time of recurrence. METHODS: All patients who had recurrence after undergoing pancreatectomy for PDAC at the Johns Hopkins Hospital or at the Regional Academic Cancer Center Utrecht during the study period were included. Cox proportional hazard model was used to develop the risk model. Performance of the final model was assessed in a test set after internal validation. RESULTS: Of 718 resected PDAC patients, 72% had recurrence after a median follow-up of 32 months. The median overall survival was 21 months and the median PRS was 9 months. Prognostic factors associated with shorter PRS were age (hazard ratio [HR] 1.02; 95% confidence interval [95%CI] 1.00-1.04), multiple-site recurrence (HR 1.57; 95%CI 1.08-2.28), and symptoms at time of recurrence (HR 2.33; 95%CI 1.59-3.41). Recurrence-free survival longer than 12 months (HR 0.55; 95%CI 0.36-0.83), FOLFIRINOX and gemcitabine-based adjuvant chemotherapy (HR 0.45; 95%CI 0.25-0.81; HR 0.58; 95%CI 0.26-0.93, respectively) were associated with a longer PRS. The resulting risk score had a good predictive accuracy (C-index: 0.73). CONCLUSION: This study developed a clinical risk score based on an international cohort that predicts PRS in patients who underwent surgical resection for PDAC. This risk score will become available on www.evidencio.com and can help clinicians with patient counseling on prognosis.

Association of Matrix Metalloproteinase 7 Expression With Pathologic Response After Neoadjuvant Treatment in Patients With Resected Pancreatic Ductal Adenocarcinoma.

Importance: The use of neoadjuvant therapy (NAT) in resectable pancreatic ductal adenocarcinoma (PDAC) remains controversial. A favorable pathologic response (complete or marked tumor regression) to NAT is associated with better outcomes in patients with resected PDAC. The role of NAT for early systemic control compared with immediate surgical resection for PDAC is under investigation. In the era of precision medicine, biomarkers for patient selection and prediction of therapy response are crucial. Objective: To evaluate the use of assessment for protein expression on fine-needle aspiration (FNA) biopsy specimens in predicting pathologic response to NAT in treatment-naive patients. Design, Setting, and Participants: This was a single-institution prognostic study from a high-volume center for pancreatic cancer. All specimens were obtained between January 1, 2009, and December 31, 2018, with a median (SE) follow-up of 20.2 (1.4) months. Analysis of the data was performed from October 1, 2019, to April 30, 2021. Targeted RNA sequencing of frozen FNA biopsy specimens from a discovery cohort of 23 patients was performed to identify genes with aberrant expression that was associated with patients' pathologic response to NAT. Immunohistochemical staining was performed on an additional 80 FNA biopsy specimens to assess expression of matrix metalloproteinase 7 (MMP-7) and its association with pathologic response. Receiver operating characteristic curves for prediction of favorable pathologic response were determined. Results: In the discovery cohort (12 [52.1%] male; 3 [13.0%] Black and 20 [86.9%] White), RNA sequencing showed that lower MMP-7 expression was associated with favorable pathologic response (College of American Pathologists system scores of 0 [complete response] and 1 [marked response]). In the validation cohort (40 [50.0%] female; 9 [11.3%] Black and 71 [88.7%] White), patients with negative MMP-7 expression were significantly more likely to have a favorable pathologic response (odds ratio, 21.25; 95% CI, 6.19-72.95; P = .001). Receiver operating characteristic curves for prediction of favorable pathologic response from multivariable Cox proportional hazards regression modeling showed that MMP-7 expression increased the area under the curve from 0.726 to 0.906 (P < .001) even after stratifying by resectability status. The positive predictive value and negative predictive value of MMP-7 protein expression on FNA biopsy specimens in predicting unfavorable pathologic response (scores of 2 [partial response] or 3 [poor or no response]) were 88.2% and 73.9%, respectively. Conclusions and Relevance: Assessment of MMP-7 expression on FNA biopsy specimens at the time of diagnosis may help identify patients who would benefit the most from NAT.

Preoperative predictors for early and very early disease recurrence in patients undergoing resection of pancreatic ductal adenocarcinoma.

BACKGROUND: This study aimed to identify predictors for early and very early disease recurrence in patients undergoing resection of pancreatic ductal adenocarcinoma (PDAC) resection with and without neoadjuvant therapy. METHODS: Included were patients who underwent PDAC resection (2014-2016). Multivariable multinomial regression was performed to identify preoperative predictors for manifestation of recurrence within 3, 6 and 12 months after PDAC resection. RESULTS: 836 patients with a median follow-up of 37 (interquartile range [IQR] 30-48) months and overall survival of 18 (IQR 10-32) months were analyzed. 670 patients (80%) developed recurrence: 82 patients (10%) <3 months, 96 patients (11%) within 3-6 months and 226 patients (27%) within 6-12 months. LogCA 19-9 (OR 1.25 [95% CI 1.10-1.41]; P < 0.001) and neoadjuvant treatment (OR 0.09 [95% CI 0.01-0.68]; P = 0.02) were associated with recurrence <3 months. LogCA 19-9 (OR 1.23 [95% CI 1.10-1.38]; P < 0.001) and 0-90° venous involvement on CT imaging (OR 2.93 [95% CI 1.60-5.37]; P < 0.001) were associated with recurrence within 3-6 months. A Charlson Age Comorbidity Index ≥4 (OR 1.53 [95% CI 1.09-2.16]; P = 0.02) and logCA 19-9 (OR 1.24 [95% CI 1.14-1.35]; P < 0.001) were related to recurrence within 6-12 months. CONCLUSION: This study demonstrates preoperative predictors that are associated with the manifestation of early and very early recurrence after PDAC resection. Knowledge of these predictors can be used to guide individualized surveillance and treatment strategies.

Technical progress in robotic pancreatoduodenectomy: TRIANGLE and periadventitial dissection for retropancreatic nerve plexus resection.

PURPOSE: The resection of retropancreatic nerve plexuses for pancreatic head cancer became standard of care during open pancreatoduodenectomy to minimize local recurrences. Since more surgical centers are progressing on the learning curve, robotically-assisted pancreatoduodenectomy is now increasingly performed with decreasing anatomic exclusion criteria. To achieve comparable and favorable oncologic outcomes, advanced surgical techniques should be transferred and implemented when performing robotic resections. METHODS: The nomenclature and anatomic principles of retropancreatic nerve plexuses and three different levels of dissections are utilized based on established definitions. RESULTS: The en bloc dissection in the "TRIANGLE" area (triangular-shaped retropancreatic space enclosed by the common hepatic artery, superior mesenteric artery, and superior mesenteric vein/portal vein) and the periadventitial dissection of arteries for non-tunica media-invading tumors were executed robotically. Both can be utilized to achieve a radical dorsal and medial margin. Video recordings are provided to illustrate varying TRIANGLE dissections. CONCLUSION: To accomplish oncologic non-inferiority, established principles from open pancreatic resections can be incorporated precisely and safely, overcoming the lack of haptic feedback while exploiting the technological advantages of the robotically-assisted platform.

Perioperative Outcomes of Robotic Pancreaticoduodenectomy: a Propensity-Matched Analysis to Open and Laparoscopic Pancreaticoduodenectomy.

INTRODUCTION: Robotic pancreaticoduodenectomy is slowly gaining acceptance within pancreatic surgery. Advantages have been demonstrated for robotic surgery in other fields, but robust data for pancreaticoduodenectomy is limited. The aim of this study was to compare the short-term outcomes of robotic pancreaticoduodenectomy (RPD) to open pancreaticoduodenectomy (OPD) and laparoscopic pancreaticoduodenectomy (LPD). METHODS: Patients who underwent a pancreaticoduodenectomy between January 2011 and July 2019 at the Johns Hopkins Hospital were included in this retrospective propensity-matched analysis. The RPD cohort was matched to patients who underwent OPD in a 1:2 fashion and LPD in a 1:1 fashion. Short-term outcomes were analyzed for all three cohorts. RESULTS: In total, 1644 patients were included, of which 96 (5.8%) underwent RPD, 131 (8.0%) LPD, and 1417 (86.2%) OPD. RPD was associated with a decreased incidence of delayed gastric emptying (9.4%) compared to OPD (23.5%; P = 0.006). The median estimated blood loss was significantly less in the RPD cohort (RPD vs OPD, 150 vs 487 mL; P < 0.001, RPD vs LPD, 125 vs 300 mL; P < 0.001). Compared to OPD, the robotic approach was associated with a shorter median length of stay (median 8 vs 9 days; P = 0.014) and a decrease in wound complications (4.2% vs 16.7%; P = 0.002). The incidence of other postoperative complications was comparable between RPD and OPD, and RPD and LPD. CONCLUSION: In the hands of experienced surgeons, RPD may have a modest yet statistically significant reduction in estimated blood loss, postoperative length of stay, wound complications, and delayed gastric emptying comparing to OPD in similar patients.

Pattern of Invasion in Human Pancreatic Cancer Organoids Is Associated with Loss of SMAD4 and Clinical Outcome.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by extensive local invasion and systemic spread. In this study, we employed a three-dimensional organoid model of human pancreatic cancer to characterize the molecular alterations critical for invasion. Time-lapse microscopy was used to observe invasion in organoids from 25 surgically resected human PDAC samples in collagen I. Subsequent lentiviral modification and small-molecule inhibitors were used to investigate the molecular programs underlying invasion in PDAC organoids. When cultured in collagen I, PDAC organoids exhibited two distinct, morphologically defined invasive phenotypes, mesenchymal and collective. Each individual PDAC gave rise to organoids with a predominant phenotype, and PDAC that generated organoids with predominantly mesenchymal invasion showed a worse prognosis. Collective invasion predominated in organoids from cancers with somatic mutations in the driver gene SMAD4 (or its signaling partner TGFBR2). Reexpression of SMAD4 abrogated the collective invasion phenotype in SMAD4-mutant PDAC organoids, indicating that SMAD4 loss is required for collective invasion in PDAC organoids. Surprisingly, invasion in passaged SMAD4-mutant PDAC organoids required exogenous TGFß, suggesting that invasion in SMAD4-mutant organoids is mediated through noncanonical TGFß signaling. The Rho-like GTPases RAC1 and CDC42 acted as potential mediators of TGFß-stimulated invasion in SMAD4-mutant PDAC organoids, as inhibition of these GTPases suppressed collective invasion in our model. These data suggest that PDAC utilizes different invasion programs depending on SMAD4 status, with collective invasion uniquely present in PDAC with SMAD4 loss. SIGNIFICANCE: Organoid models of PDAC highlight the importance of SMAD4 loss in invasion, demonstrating that invasion programs in SMAD4-mutant and SMAD4 wild-type tumors are different in both morphology and molecular mechanism.

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.