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ASO Visual Abstract: Predictors for Long-Term Survival After Resection of Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-Analysis
Javed, Ammar A; Mahmud, Omar; Fatimi, Asad Saulat; Habib, Alyssar; Grewal, Mahip; He, Jin; Wolfgang, Christopher L; Besselink, Marc G; ,
PMID: 38819749
ISSN: 1534-4681
CID: 5663962
ASO Author Reflections: The Role of Established Prognostic Factors in Long-Term Survival After Resection of Pancreatic Ductal Adenocarcinoma
Mahmud, Omar; Javed, Ammar A; Fatimi, Asad Saulat; Habib, Alyssar; Grewal, Mahip; He, Jin; Wolfgang, Christopher L; Besselink, Marc G; ,
PMID: 38767804
ISSN: 1534-4681
CID: 5654172
Progression of Site-specific Recurrence of Pancreatic Cancer and Implications for Treatment
Rompen, Ingmar F; Levine, Jonah; Habib, Joseph R; Sereni, Elisabetta; Mughal, Nabiha; Hewitt, Daniel Brock; Sacks, Greg D; Welling, Theodore H; Simeone, Diane M; Kaplan, Brian; Berman, Russell S; Cohen, Steven M; Wolfgang, Christopher L; Javed, Ammar A
OBJECTIVE:To analyze postrecurrence progression in the context of recurrence sites and assess implications for postrecurrence treatment. BACKGROUND:Most patients with resected pancreatic ductal adenocarcinoma (PDAC) recur within 2 years. Different survival outcomes for location-specific patterns of recurrence are reported, highlighting their prognostic value. However, a lack of understanding of postrecurrence progression and survival remains. METHODS:This retrospective analysis included surgically treated patients with PDAC at NYU Langone Health (2010-2021). Sites of recurrence were identified at the time of diagnosis and further follow-up. Kaplan-Meier curves, log-rank test, and Cox regression analyses were applied to assess survival outcomes. RESULTS:Recurrence occurred in 57.3% (196/342) patients with a median time to recurrence of 11.3 months (95% CI: 12.6-16.5). The first site of recurrence was local in 43.9% of patients, liver in 23.5%, peritoneal in 8.7%, lung in 3.6%, whereas 20.4% had multiple sites of recurrence. Progression to secondary sites was observed in 11.7%. Only lung involvement was associated with significantly longer survival after recurrence compared with other sites (16.9 vs 8.49 months, P = 0.003). In local recurrence, 21 (33.3%) patients were alive after 1 year without progression to secondary sites. This was associated with a CA19-9 of <100 U/mL at the time of primary diagnosis ( P = 0.039), nodal negative disease ( P = 0.023), and well-moderate differentiation ( P = 0.042) compared with patients with progression. CONCLUSION/CONCLUSIONS:Except for lung recurrence, postrecurrence survival after PDAC resection is associated with poor survival. A subset of patients with local-only recurrence do not quickly succumb to systemic spread. This is associated with markers for favorable tumor biology, making them candidates for potential curative re-resections when feasible.
PMCID:11259998
PMID: 37870253
ISSN: 1528-1140
CID: 5697432
What is the optimal surgical approach for ductal adenocarcinoma of the pancreatic neck? - a retrospective cohort study
Rompen, Ingmar F; Habib, Joseph R; Sereni, Elisabetta; Stoop, Thomas F; Musa, Julian; Cohen, Steven M; Berman, Russell S; Kaplan, Brian; Hewitt, D Brock; Sacks, Greg D; Wolfgang, Christopher L; Javed, Ammar A
BACKGROUND:The appropriate surgical approach for pancreatic ductal adenocarcinoma (PDAC) is determined by the tumor's relation to the porto-mesenteric axis. Although the extent and location of lymphadenectomy is dependent on the type of resection, a pancreatoduodenectomy (PD), distal pancreatectomy (DP), or total pancreatectomy (TP) are considered equivalent oncologic operations for pancreatic neck tumors. Therefore, we aimed to assess differences in histopathological and oncological outcomes for surgical approaches in the treatment of pancreatic neck tumors. METHODS:Patients with resected PDAC located in the pancreatic neck were identified from the National Cancer Database (2004-2020). Patients with metastatic disease were excluded. Furthermore, patients with 90-day mortality and R2-resections were excluded from the multivariable Cox-regression analysis. RESULTS:Among 846 patients, 58% underwent PD, 25% DP, and 17% TP with similar R0-resection rates (p = 0.722). Significant differences were observed in nodal positivity (PD:44%, DP:34%, TP:57%, p < 0.001) and mean-number of examined lymph nodes (PD:17.2 ± 10.4, DP:14.7 ± 10.5, TP:21.2 ± 11.0, p < 0.001). Furthermore, inadequate lymphadenectomy (< 12 nodes) was observed in 30%, 44%, and 19% of patients undergoing PD, DP, and TP, respectively (p < 0.001). Multivariable analysis yielded similar overall survival after DP (HR:0.83, 95%CI:0.63-1.11), while TP was associated with worse survival (HR:1.43, 95%CI:1.08-1.89) compared to PD. CONCLUSION/CONCLUSIONS:While R0-rates are similar amongst all approaches, DP is associated with inadequate lymphadenectomy which may result in understaging disease. However, this had no negative influence on survival. In the premise that an oncological resection of the pancreatic neck tumor is feasible with a partial pancreatectomy, no benefit is observed by performing a TP.
PMID: 39028426
ISSN: 1435-2451
CID: 5699472
REDISCOVER International Guidelines on the Perioperative Care of Surgical Patients With Borderline-resectable and Locally Advanced Pancreatic Cancer
Boggi, Ugo; Kauffmann, Emanuele; Napoli, Niccolò; Barreto, S George; Besselink, Marc G; Fusai, Giuseppe K; Hackert, Thilo; Abu Hilal, Mohammad; Marchegiani, Giovanni; Salvia, Roberto; Shrikhande, Shailesh V; Truty, Mark; Werner, Jens; Wolfgang, Christopher L; Bannone, Elisa; Capretti, Giovanni; Cattelani, Alice; Coppola, Alessandro; Cucchetti, Alessandro; De Sio, Davide; Di Dato, Armando; Di Meo, Giovanna; Fiorillo, Claudio; Gianfaldoni, Cesare; Ginesini, Michael; Hidalgo Salinas, Camila; Lai, Quirino; Miccoli, Mario; Montorsi, Roberto; Pagnanelli, Michele; Poli, Andrea; Ricci, Claudio; Sucameli, Francesco; Tamburrino, Domenico; Viti, Virginia; Addeo, Pietro F; Alfieri, Sergio; Bachellier, Philippe; Baiocchi, Gian Luca; Balzano, Gianpaolo; Barbarello, Linda; Brolese, Alberto; Busquets, Juli; Butturini, Giovanni; Caniglia, Fabio; Caputo, Damiano; Casadei, Riccardo; Chunhua, Xi; Colangelo, Ettore; Coratti, Andrea; Costa, Francesca; Crafa, Francesco; Dalla Valle, Raffaele; De Carlis, Luciano; de Wilde, Roeland F; Del Chiaro, Marco; Di Benedetto, Fabrizio; Di Sebastiano, Pierluigi; Dokmak, Safi; Hogg, Melissa; Egorov, Vyacheslav I; Ercolani, Giorgio; Ettorre, Giuseppe Maria; Falconi, Massimo; Ferrari, Giovanni; Ferrero, Alessandro; Filauro, Marco; Giardino, Alessandro; Grazi, Gian Luca; Gruttadauria, Salvatore; Izbicki, Jakob R; Jovine, Elio; Katz, Matthew; Keck, Tobias; Khatkov, Igor; Kiguchi, Gozo; Kooby, David; Lang, Hauke; Lombardo, Carlo; Malleo, Giuseppe; Massani, Marco; Mazzaferro, Vincenzo; Memeo, Riccardo; Miao, Yi; Mishima, Kohei; Molino, Carlo; Nagakawa, Yuichi; Nakamura, Masafumi; Nardo, Bruno; Panaro, Fabrizio; Pasquali, Claudio; Perrone, Vittorio; Rangelova, Elena; Liu, Rong; Romagnoli, Renato; Romito, Raffaele; Rosso, Edoardo; Schulick, Richard; Siriwardena, Ajith; Spampinato, Marcello Giuseppe; Strobel, Oliver; Testini, Mario; Troisi, Roberto Ivan; Uzunoglo, Faik G; Valente, Roberto; Veneroni, Luigi; Zerbi, Alessandro; Vicente, Emilio; Vistoli, Fabio; Vivarelli, Marco; Wakabayashi, Go; Zanus, Giacomo; Zureikat, Amer; Zyromski, Nicholas J; Coppola, Roberto; D'Andrea, Vito; Davide, José; Dervenis, Christos; Frigerio, Isabella; Konlon, Kevin C; Michelassi, Fabrizio; Montorsi, Marco; Nealon, William; Portolani, Nazario; Sousa Silva, DonzÃlia; Bozzi, Giuseppe; Ferrari, Viviana; Trivella, Maria G; Cameron, John; Clavien, Pierre-Alain; Asbun, Horacio J; ,
OBJECTIVE:The REDISCOVER consensus conference aimed at developing and validating guidelines on the perioperative care of patients with borderline-resectable (BR-) and locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC). BACKGROUND:Coupled with improvements in chemotherapy and radiation, the contemporary approach to pancreatic surgery supports the resection of BR-PDAC and, to a lesser extent, LA-PDAC. Guidelines outlining the selection and perioperative care for these patients are lacking. METHODS:The Scottish Intercollegiate Guidelines Network (SIGN) methodology was used to develop the REDISCOVER guidelines and create recommendations. The Delphi approach was used to reach a consensus (agreement ≥80%) among experts. Recommendations were approved after a debate and vote among international experts in pancreatic surgery and pancreatic cancer management. A Validation Committee used the AGREE II-GRS tool to assess the methodological quality of the guidelines. Moreover, an independent multidisciplinary advisory group revised the statements to ensure adherence to nonsurgical guidelines. RESULTS:Overall, 34 recommendations were created targeting centralization, training, staging, patient selection for surgery, possibility of surgery in uncommon scenarios, timing of surgery, avoidance of vascular reconstruction, details of vascular resection/reconstruction, arterial divestment, frozen section histology of perivascular tissue, extent of lymphadenectomy, anticoagulation prophylaxis, and role of minimally invasive surgery. The level of evidence was however low for 29 of 34 clinical questions. Participants agreed that the most conducive means to promptly advance our understanding in this field is to establish an international registry addressing this patient population ( https://rediscover.unipi.it/ ). CONCLUSIONS:The REDISCOVER guidelines provide clinical recommendations pertaining to pancreatectomy with vascular resection for patients with BR-PDAC and LA-PDAC, and serve as the basis of a new international registry for this patient population.
PMCID:11161250
PMID: 38407228
ISSN: 1528-1140
CID: 5664592
Predictors for Long-Term Survival After Resection of Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-Analysis
Javed, Ammar A; Mahmud, Omar; Fatimi, Asad Saulat; Habib, Alyssar; Grewal, Mahip; He, Jin; Wolfgang, Christopher L; Besselink, Marc G; ,
BACKGROUND:Improved systemic therapy has made long term (≥ 5 years) overall survival (LTS) after resection of pancreatic ductal adenocarcinoma (PDAC) increasingly common. However, a systematic review on predictors of LTS following resection of PDAC is lacking. METHODS:The PubMed, Embase, Scopus, and Cochrane CENTRAL databases were systematically searched from inception until March 2023. Studies reporting actual survival data (based on follow-up and not survival analysis estimates) on factors associated with LTS were included. Meta-analyses were conducted by using a random effects model, and study quality was gauged by using the Newcastle-Ottawa Scale (NOS). RESULTS:Twenty-five studies with 27,091 patients (LTS: 2,132, non-LTS: 24,959) who underwent surgical resection for PDAC were meta-analyzed. The median proportion of LTS patients was 18.32% (IQR 12.97-21.18%) based on 20 studies. Predictors for LTS included sex, body mass index (BMI), preoperative levels of CA19-9, CEA, and albumin, neutrophil-lymphocyte ratio, tumor grade, AJCC stage, lymphovascular and perineural invasion, pathologic T-stage, nodal disease, metastatic disease, margin status, adjuvant therapy, vascular resection, operative time, operative blood loss, and perioperative blood transfusion. Most articles received a "good" NOS assessment, indicating an acceptable risk of bias. CONCLUSIONS:Our meta-analysis pools all true follow up data in the literature to quantify associations between prognostic factors and LTS after resection of PDAC. While there appears to be evidence of a complex interplay between risk, tumor biology, patient characteristics, and management related factors, no single parameter can predict LTS after the resection of PDAC.
PMCID:11164751
PMID: 38710910
ISSN: 1534-4681
CID: 5668592
Quantifying Patient Risk Threshold in Managing Pancreatic Intraductal Papillary Mucinous Neoplasms
Kaslow, Sarah R; Sharma, Acacia R; Hewitt, D Brock; Bridges, John F P; Javed, Ammar A; Wolfgang, Christopher L; Braithwaite, Scott; Sacks, Greg D
OBJECTIVE:We aimed to better understand patients' treatment preferences and quantify the level of cancer risk at which treatment preferences change (risk threshold) to inform better counseling of patients with intraductal papillary mucinous neoplasms (IPMNs). SUMMARY BACKGROUND DATA/BACKGROUND:The complexity of IPMN management provides an opportunity to align treatment with individual preference. METHODS:We surveyed a sample of healthy volunteers simulating a common scenario: undergoing an imaging study that incidentally identifies an IPMN. In the scenario, the estimated risk of cancer in the IPMN was 5%. Patients were asked their treatment preference (surgery or surveillance), to quantify the level of cancer risk in the IPMN at which their treatment preference would change (i.e. risk threshold), and their level of cancer anxiety as measured on a 5-point Likert scale. We examined associations between participant characteristics, treatment preferences, and risk threshold using multivariable linear regression. RESULTS:The median risk threshold among the 520 participants was 25% (IQR 2.3-50%). The risk threshold had a bimodal distribution: 40% of participants had a risk threshold between 0-10% and 47% had a risk threshold above 30%. When informed that the risk of cancer was 5%, 62% of participants (n=323) preferred surveillance, and the remaining 38% (n=197) preferred surgery. After adjusting for potential confounders, participants who expressed "worry" or "extreme worry" about the malignancy risk of IPMN had significantly lower risk thresholds than participants who were "not at all worried" (Coefficient -12, 95%CI -21 to -2, P=0.015 and Coefficient -18, 95%CI -29 to -8, P<0.001, respectively). CONCLUSIONS:Participants varied in treatment preference and risk threshold of incidentally identified IPMNs. Given the uncertainty in estimating the true malignant potential of IPMNs, a better understanding of a patient's risk threshold, as influenced by patient concern about malignancy, will help inform the shared decision-making process.
PMID: 38810270
ISSN: 1528-1140
CID: 5663642
Transfer Learning Reveals Cancer-Associated Fibroblasts Are Associated with Epithelial-Mesenchymal Transition and Inflammation in Cancer Cells in Pancreatic Ductal Adenocarcinoma
Guinn, Samantha; Kinny-Köster, Benedict; Tandurella, Joseph A; Mitchell, Jacob T; Sidiropoulos, Dimitrios N; Loth, Melanie; Lyman, Melissa R; Pucsek, Alexandra B; Zabransky, Daniel J; Lee, Jae W; Kartalia, Emma; Ramani, Mili; Seppälä, Toni T; Cherry, Christopher; Suri, Reecha; Zlomke, Haley; Patel, Jignasha; He, Jin; Wolfgang, Christopher L; Yu, Jun; Zheng, Lei; Ryan, David P; Ting, David T; Kimmelman, Alec; Gupta, Anuj; Danilova, Ludmila; Elisseeff, Jennifer H; Wood, Laura D; Stein-O'Brien, Genevieve; Kagohara, Luciane T; Jaffee, Elizabeth M; Burkhart, Richard A; Fertig, Elana J; Zimmerman, Jacquelyn W
UNLABELLED:Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by an immunosuppressive tumor microenvironment enriched with cancer-associated fibroblasts (CAF). This study used a convergence approach to identify tumor cell and CAF interactions through the integration of single-cell data from human tumors with human organoid coculture experiments. Analysis of a comprehensive atlas of PDAC single-cell RNA sequencing data indicated that CAF density is associated with increased inflammation and epithelial-mesenchymal transition (EMT) in epithelial cells. Transfer learning using transcriptional data from patient-derived organoid and CAF cocultures provided in silico validation of CAF induction of inflammatory and EMT epithelial cell states. Further experimental validation in cocultures demonstrated integrin beta 1 (ITGB1) and vascular endothelial factor A (VEGFA) interactions with neuropilin-1 mediating CAF-epithelial cell cross-talk. Together, this study introduces transfer learning from human single-cell data to organoid coculture analyses for experimental validation of discoveries of cell-cell cross-talk and identifies fibroblast-mediated regulation of EMT and inflammation. SIGNIFICANCE/UNASSIGNED:Adaptation of transfer learning to relate human single-cell RNA sequencing data to organoid-CAF cocultures facilitates discovery of human pancreatic cancer intercellular interactions and uncovers cross-talk between CAFs and tumor cells through VEGFA and ITGB1.
PMCID:11065624
PMID: 38587552
ISSN: 1538-7445
CID: 5657242
Defining the Minimal and Optimal Thresholds for Lymph Node Resection and Examination for Intraductal Papillary Mucinous Neoplasm Derived Pancreatic Cancer: A Multicenter Retrospective Analysis
Habib, Joseph R; Rompen, Ingmar F; Kaslow, Sarah R; Grewal, Mahip; Andel, Paul C M; Zhang, Shuang; Hewitt, D Brock; Cohen, Steven M; van Santvoort, Hjalmar C; Besselink, Marc G; Molenaar, I Quintus; He, Jin; Wolfgang, Christopher L; Javed, Ammar A; Daamen, Lois A
OBJECTIVE:To establish minimal and optimal lymphadenectomy thresholds for intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic ductal adenocarcinoma (PDAC) and evaluate their prognostic value. BACKGROUND:Current guidelines recommend a minimum of 12-15 lymph nodes (LNs) in PDAC. This is largely based on pancreatic intraepithelial neoplasia (PanIN)-derived PDAC, a biologically distinct entity from IPMN-derived PDAC. METHODS:Multicenter retrospective study including consecutive patients undergoing upfront surgery for IPMN-derived PDAC was conducted. The minimum cut-off for lymphadenectomy was defined as the maximum number of LNs where a significant node positivity difference was observed. Maximally selected log-rank statistic was used to derive the optimal lymphadenectomy cut-off (maximize survival). Kaplan-Meier curves and log-rank tests were used to analyze overall survival (OS) and recurrence-free survival (RFS). Multivariable Cox-regression was used to determine hazard ratios (HR) with 95% confidence intervals (95%CI). RESULTS:In 341 patients with resected IPMN-derived PDAC, the minimum number of LNs needed to ensure accurate nodal staging was 10 (P=0.040), whereas ≥20 LNs was the optimal number associated with improved OS (80.3 vs. 37.2 mo, P<0.001). Optimal lymphadenectomy was associated with improved OS [HR:0.57 (95%CI 0.39-0.83)] and RFS [HR:0.70 (95%CI 0.51-0.97)] on multivariable Cox-regression. On sub-analysis the optimal lymphadenectomy cut-offs for pancreatoduodenectomy, distal pancreatectomy, and total pancreatectomy were 20 (P<0.001), 23 (P=0.160), and 25 (P=0.008). CONCLUSION/CONCLUSIONS:In IPMN-derived PDAC, lymphadenectomy with at least 10 lymph nodes mitigates under-staging, and at least 20 lymph nodes is associated with the improved survival. Specifically, for pancreatoduodenectomy and total pancreatectomy, 20 and 25 lymph nodes were the optimal cut-offs.
PMCID:11470133
PMID: 38606874
ISSN: 1528-1140
CID: 5725942
Dynamics of Serum CA19-9 in Patients Undergoing Pancreatic Cancer Resection
van Oosten, A F; Groot, V P; Dorland, G; Burkhart, Richard A; Wolfgang, C L; van Santvoort, H C; He, J; Molenaar, I Q; Daamen, L A
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 prior to recurrence were included. Patients deemed to be non-secretors 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 (ROC) 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. ROC analysis demonstrated that a relative increase in postoperative serum CA19-9 of 2.6x was predictive of recurrence, with 58% sensitivity, 83% specificity, 95% positive predictive value, and 28% negative predictive value. The AUC for a 2.6x relative increase in 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). CONCLUSION/CONCLUSIONS:A relative increase in 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 7-10 months. Therefore, CA19-9 dynamics can be used as a biomarker to guide the initiation of recurrence-focused treatment.
PMID: 37389896
ISSN: 1528-1140
CID: 5540592