Faculty Bibliography
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686
Predictors for Long-Term Survival After Resection of Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-Analysis
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
REDISCOVER International Guidelines on the Perioperative Care of Surgical Patients With Borderline-resectable and Locally Advanced Pancreatic Cancer
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
Transfer Learning Reveals Cancer-Associated Fibroblasts Are Associated with Epithelial-Mesenchymal Transition and Inflammation in Cancer Cells in Pancreatic Ductal Adenocarcinoma
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
ASO Visual Abstract: Predictors for Long-Term Survival After Resection of Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-Analysis
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
PMID: 38767804
ISSN: 1534-4681
CID: 5654172
Factors associated with radiological misstaging of pancreatic ductal adenocarcinoma: A retrospective observational study
PURPOSE/OBJECTIVE:Accurate staging of disease is vital in determining appropriate care for patients with pancreatic ductal adenocarcinoma (PDAC). It has been shown that the quality of scans and the experience of a radiologist can impact computed tomography (CT) based assessment of disease. The aim of the current study was to evaluate the impact of the rereading of outside hospital (OH) CT by an expert radiologist and a repeat pancreatic protocol CT (PPCT) on staging of disease. METHODS:Patients evaluated at the our institute's pancreatic multidisciplinary clinic (2006 to 2014) with OH scan and repeat PPCT performed within 30 days were included. In-house radiologists staged disease using OH scans and repeat PPCT, and factors associated with misstaging were determined. RESULTS:The study included 100 patients, with a median time between OH scan and PPCT of 19 days (IQR: 13-23 days.) Stage migration was mostly accounted for by upstaging of disease (58.8 % to 83.3 %) in all comparison groups. When OH scans were rereviewed, 21.5 % of the misstaging was due to missed metastases, however, when rereads were compared to the PPCT, occult metastases accounted for the majority of misstaged patients (62.5 %). Potential factors associated with misstaging were primarily related to imaging technique. CONCLUSION/CONCLUSIONS:A repeat PPCT results in increased detection of metastatic disease that rereviews of OH scans may otherwise miss. Accessible insurance coverage for repeat PPCT imaging even within 30 days of an OH scan could help optimize delivery of care and alleviate burdens associated with misstaging.
PMID: 38522966
ISSN: 1535-6302
CID: 5644372
Anatomical and Biological Considerations to Determine Resectability in Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDAC) remains associated with poor outcomes with a 5-year survival of 12% across all stages of the disease. These poor outcomes are driven by a delay in diagnosis and an early propensity for systemic dissemination of the disease. Recently, aggressive surgical approaches involving complex vascular resections and reconstructions have become more common, thus allowing more locally advanced tumors to be resected. Unfortunately, however, even after the completion of surgery and systemic therapy, approximately 40% of patients experience early recurrence of disease. To determine resectability, many institutions utilize anatomical staging systems based on the presence and extent of vascular involvement of major abdominal vessels around the pancreas. However, these classification systems are based on anatomical considerations only and do not factor in the burden of systemic disease. By integrating the biological criteria, we possibly could avoid futile resections often associated with significant morbidity. Especially patients with anatomically resectable disease who have a heavy burden of radiologically undetected systemic disease most likely do not derive a survival benefit from resection. On the contrary, we could offer complex resections to those who have locally advanced or oligometastatic disease but have favorable systemic biology and are most likely to benefit from resection. This review summarizes the current literature on defining anatomical and biological resectability in patients with pancreatic cancer.
PMCID:10854859
PMID: 38339242
ISSN: 2072-6694
CID: 5632152
Outcomes after distal pancreatectomy with or without splenectomy for intraductal papillary mucinous neoplasm: international multicentre cohort study
BACKGROUND:International guidelines on intraductal papillary mucinous neoplasm (IPMN) recommend a formal oncological resection including splenectomy when distal pancreatectomy is indicated. This study aimed to compare oncological and surgical outcomes after distal pancreatectomy with or without splenectomy in patients with presumed IPMN. METHODS:An international, retrospective cohort study was undertaken in 14 high-volume centres from 7 countries including consecutive patients after distal pancreatectomy for IPMN (2005-2019). Patients were divided into spleen-preserving distal pancreatectomy (SPDP) and distal pancreatectomy with splenectomy (DPS). The primary outcome was lymph node metastasis (LNM). Secondary outcomes were overall survival, duration of operation, blood loss, and secondary splenectomy. RESULTS:Overall, 700 patients were included after distal pancreatectomy for IPMN; 123 underwent SPDP (17.6%) and 577 DPS (82.4%). The rate of malignancy was 29.6% (137 patients) and the overall rate of LNM 6.7% (47 patients). Patients with preoperative suspicion of malignancy had a LNM rate of 17.2% (23 of 134) versus 4.3% (23 of 539) among patients without suspected malignancy (P < 0.001). Overall, SPDP was associated with a shorter operating time (median 180 versus 226 min; P = 0.001), less blood loss (100 versus 336 ml; P = 0.001), and shorter hospital stay (5 versus 8 days; P < 0.001). No significant difference in overall survival was observed between SPDP and DPS for IPMN after correction for prognostic factors (HR 0.50, 95% c.i. 0.22 to 1.18; P = 0.504). CONCLUSION/CONCLUSIONS:This international cohort study found LNM in 6.7% of patients undergoing distal pancreatectomy for IPMN. In patients without preoperative suspicion of malignancy, SPDP seemed oncologically safe and was associated with improved short-term outcomes compared with DPS.
PMCID:10776207
PMID: 38195084
ISSN: 1365-2168
CID: 5628612
International evidence-based Kyoto guidelines for the management of intraductal papillary mucinous neoplasm of the pancreas
This study group aimed to revise the 2017 international consensus guidelines for the management of intraductal papillary mucinous neoplasm (IPMN) of the pancreas, and mainly focused on five topics; the revision of high-risk stigmata (HRS) and worrisome features (WF), surveillance of non-resected IPMN, surveillance after resection of IPMN, revision of pathological aspects, and investigation of molecular markers in cyst fluid. A new development from the prior guidelines is that systematic reviews were performed for each one of these topics, and published separately to provide evidence-based recommendations. One of the highlights of these new "evidence-based guidelines" is to propose a new management algorithm, and one major revision is to include into the assessment of HRS and WF the imaging findings from endoscopic ultrasound (EUS) and the results of cytological analysis from EUS-guided fine needle aspiration technique, when this is performed. Another key element of the current guidelines is to clarify whether lifetime surveillance for small IPMNs is required, and recommends two options, "stop surveillance" or "continue surveillance for possible development of concomitant pancreatic ductal adenocarcinoma", for small unchanged BD-IPMN after 5 years surveillance. Several other points are also discussed, including identifying high-risk features for recurrence in patients who underwent resection of non-invasive IPMN with negative surgical margin, summaries of the recent observations in the pathology of IPMN. In addition, the emerging role of cyst fluid markers that can aid in distinguishing IPMN from other pancreatic cysts and identify those IPMNs that harbor high-grade dysplasia or invasive carcinoma is discussed.
PMID: 38182527
ISSN: 1424-3911
CID: 5628492
Machine learning to detect the SINEs of cancer
We previously described an approach called RealSeqS to evaluate aneuploidy in plasma cell-free DNA through the amplification of ~350,000 repeated elements with a single primer. We hypothesized that an unbiased evaluation of the large amount of sequencing data obtained with RealSeqS might reveal other differences between plasma samples from patients with and without cancer. This hypothesis was tested through the development of a machine learning approach called Alu Profile Learning Using Sequencing (A-PLUS) and its application to 7615 samples from 5178 individuals, 2073 with solid cancer and the remainder without cancer. Samples from patients with cancer and controls were prespecified into four cohorts used for model training, analyte integration, and threshold determination, validation, and reproducibility. A-PLUS alone provided a sensitivity of 40.5% across 11 different cancer types in the validation cohort, at a specificity of 98.5%. Combining A-PLUS with aneuploidy and eight common protein biomarkers detected 51% of the cancers at 98.9% specificity. We found that part of the power of A-PLUS could be ascribed to a single feature-the global reduction of AluS subfamily elements in the circulating DNA of patients with solid cancer. We confirmed this reduction through the analysis of another independent dataset obtained with a different approach (whole-genome sequencing). The evaluation of Alu elements may therefore have the potential to enhance the performance of several methods designed for the earlier detection of cancer.
PMID: 38266106
ISSN: 1946-6242
CID: 5624972
