Staging Of Pancreatic Cancer Research Articles

Sa1459 COMPLIANCE WITH ASGE QUALITY INDICATORS FOR ENDOSCOPIC ULTRASOUND REPORTS IN THE EVALUATION OF PANCREATIC CANCER, COMPARISON OF COMMUNITY AND ACADEMIC PRACTICES

The American Society for Gastrointestinal Endoscopy (ASGE) has put forth a list of quality indicators for EUS which evaluate key steps that provide endoscopists targets to provide high quality care. Endoscopist compliance with the ASGE quality indicators has not been well studied in patients who have undergone EUS and subsequent resection for pancreatic cancer. The goal of this study is to evaluate the quality of EUS performed for pancreatic cancer diagnosis and staging in patients who had initial EUS performed at our institution or who had initial EUS performed at an outside institution and were referred to our institution and have subsequently undergone pancreatic cancer resection. Consecutive patients who had EUS for suspected pancreatic cancer and who had subsequently undergone Whipple at a single tertiary care center between 2013 and 2019 were identified by searching an IRB approved surgical database of patients with resected pancreatic cancer. Patients with incomplete documentation were excluded. Patient demographics, pancreatic lesion characteristics, surgical pathology and operative reports, as well as EUS report data were recorded. Comparative analysis of patients who had EUS performed at a single academic medical center (AMC) and referring institutions (OSH) was performed. 203 patients underwent surgical resection for pancreatic cancer between 2013-2019 and had an EUS report available for review. The mean patient age was 65.4±0.64* years, mean BMI 27.3±0.39, and 95 (46.8%) were female. EUS-FNA/B (fine needle aspiration/biopsy) revealed malignancy in 85.7% cases at the AMC and 80.4% at OSH (p=0.35). Significant differences between the AMC and OSH EUS reports were noted in terms of compliance with ASGE quality indicators. Specifically, the total number of ASGE quality indicators (6.6±0.1 vs 5.6±0.2, p= <0.001) included in the report, listing of an ASGE approved indication for EUS (99.3% vs 89.3%, p=0.002), use on an on-site cytopathologist (69.9% vs 51.8%, p= 0.02), TNM classification (56.3% vs 23.2%, p= <0.001) inclusion, and documentation of the presence or absence of an intraprocedural complication (100% vs 83.9%, p= <0.001) were significantly higher in the AMC EUS reports (Table 1). AMC EUS reports were more likely to describe the biliary tree (97.3% vs 67.9%, p= <0.001) though were less likely to describe the pancreatic duct (74.1% vs 89.3%, p=0.02). No other factors were statistically significant (Table 1). In our cohort of patients with resected pancreatic cancer who had previously undergone EUS, the quality of EUS reports from an AMC were superior to OSH EUS reports based on ASGE quality indicators for EUS. However, this did not translate into a statistically significant increase in the diagnostic yield of EUS-FNA/B. Further evaluation with a larger patient population will likely be beneficial.

A real-world comparison of efficacy and toxicity of FOLFIRINOX and gemcitabine to nab-paclitaxel in treatment of advanced stage pancreatic cancer.

e16728 Background: Pancreatic adenocarcinoma is a dreaded malignancy accounting for 7% of all cancer related deaths in the United States. The two most used chemotherapeutic regimens are a combination of 5- fluorouracil, leucovorin, oxaliplatin and irinotecan (FFX) and a combination of gemcitabine nab paclitaxel (GN). Both improve survival when compared to gemcitabine alone but have not been compared directly. Methods: Retrospective chart review of 83 chemotherapy naïve patients with metastatic cancer of exocrine pancreas who underwent chemotherapy between February 2011 and June 2017. Patients who completed at least one cycle of chemotherapy regimen were included. Characteristics, efficacy and adverse events between the two regimens were compared using appropriate statistical analyses. Results: 83 patients met selection criteria. 39 patients received FFX and 44 received GN. Mean age of FFX and GN patients was 69.7 (SD 8.7) (Median 66) and 72.3 (SD 8.8) (Median 69) yrs respectively (p = 0.100). The proportion of patients with ECOG performance scale ≤1 receiving FFX vs. GN was 50.8% vs. 49.2% and &gt; 2 receiving FFX vs. GN was 33.3% vs 66.7% (p = .286). Of the 23 patients &gt; 75 yrs., 7 received FFX and 16 received GN (p = .086). Median overall survival was 10.1 months (95% CI: 5.4-18.7) in FFX and 7.2 months in GN (95% CI: 5.4-11.3) [p = 0.037]. Median survival based on site of tumor was 10.2 months (95% CI: 6.7-13.8) in head and 10.1 months (95% CI: 4.3-14.7) in body and tail tumors [p = 0.776]. Incidence of vomiting in FFX / GN was 94.1% / 73.7% (p =.027), vomiting requiring hospital admission was 55.9% / 21.1% (p = 0.003). Other events requiring admission included: diarrhea 31.4% / 17.9%; anemia 5.7% / 10.3%; thrombocytopenia 11.4% / 7.7%; febrile neutropenia 28.6% / 12.8% and acute kidney injury 25.7% / 15.4%; no statistically significant differences between groups. Conclusions: Patients treated with FFX had a longer survival in this retrospective review. FFX is associated with an increased incidence of vomiting requiring hospitalization. FFX remains a preferred regimen in treating patients with good performance status regardless of age.

Magnetic resonance imaging for preoperative staging of pancreatic cancer based on the 8th edition of AJCC guidelines.

Preoperative staging of pancreatic cancer determines the choice of treatment. Magnetic resonance imaging (MRI) plays an important role in preoperative staging of pancreatic cancer. The American Joint Committee on Cancer (AJCC) TNM staging system was revised to its 8th version in 2016, there has been no report correlating the 8th edition of the AJCC TNM staging with preoperative MRI examinations and pathological findings. The purpose of our study is to determine the staging accuracy and evaluate the resectability by using MRI about pancreatic cancer compared with intraoperative or pathological findings according to the 8th edition of the AJCC TNM staging system. One hundred thirty-two patients with a pathological diagnosis of pancreatic cancer who underwent preoperative MRI were identified. The clinical data, MRI findings and pathological findings were analyzed. Preoperative MRI staging and resectability evaluation were compared with pathological findings. The accuracy of MRI for preoperative T and N staging was evaluated, and the sensitivity, specificity and accuracy of MRI in evaluating the resectability were assessed. All the staging and resectability assessments were according to the 8th edition of the AJCC TNM staging system. Analysis showed that the accuracy of MRI for evaluation of the T and N stages was 82.6% (109/132) and 74.2% (98/132), respectively. The sensitivity and specificity of MRI in assessing the resectability were 94.2% and 71.4%, respectively. Integrating the 8th edition of the AJCC TNM stage, no significant differences were identified between the preoperative MRI and pathological results for the staging of pancreatic cancer (P=0.805). MRI is highly accurate for T staging and moderately accurate for N staging. MRI provides important preoperative evaluation of the stage and resectability of pancreatic cancer based on the 8th edition of the AJCC TNM staging system.

Elevated CEA and CA19-9 serum levels independently predict advanced pancreatic cancer at diagnosis

Purpose: It is suggested that tumour markers carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) could be used to predict the stage of pancreatic cancer. However, optimal cut-off values for CEA and CA19-9 are disputable. This study aimed to assess the value of CEA and CA19-9 serum levels at diagnosis of pancreatic ductal adenocarcinoma (PDAC) as predictors for the advanced stage of PDAC in patients discussed at pancreatic multidisciplinary team (MDT) meetings.Methods: Patients with suspected PDAC discussed at MDT meetings from 2013 to 2017 were reviewed, in order to determine optimal cut-off values of both CEA and CA19-9.Results: In total, 375 patients were included. Optimal cut-off values for predicting advanced PDAC were 7.0 ng/ml for CEA and 305.0 U/ml for CA19-9, resulting in positive predictive values of 83.3%, 73.6%, and 91.4% for CEA, CA19-9 and combined, respectively. Both tumour markers were independent predictors of advanced PDAC, demonstrated by an odds ratio of 4.21 (95% CI:1.85–9.56; p = 0.001) for CEA and 2.58 for CA19-9 (95% CI:1.30–5.14; p = 0.007).Conclusions: CEA appears to be a more robust predictor of advanced PDAC than CA19-9. Implementing CEA and CA19-9 serum levels during MDT meetings as an additional tool for establishing tumour resectability is worthwhile for tailored diagnostics.

Impact of biliary metal and plastic stents on preoperative staging for pancreatic cancer.

646 Background: Multiple studies have shown the superiority of biliary metal compared with plastic stents for pre-operative (preop) biliary drainage in pancreatic cancer (PDAC). Despite the importance of preop cross-sectional imaging, particularly in the era of neoadjuvant treatment, there is no data on the impact of such stents on the quality of preop cross-sectional imaging. We hypothesis, that biliary metal stents negatively impact the accuracy of preop cross-sectional imaging in pancreatic cancer, with unknown impact for the adequacy of surgical candidacy. Methods: Data of all patients undergoing pancreatic resection for PDAC between 1/1/2012 and 1/1/2018 was retrospectively abstracted. Clinical staging based on preop cross-sectional imaging following biliary stent placement (within 2 months prior surgical resection) was compared with the surgical pathology (staging gold standard). Accuracy of clinical and surgical pathology staging was compared. Logistic regression was performed to control for biliary stent type, neoadjuvant treatment and patient baseline characteristics including BMI and type of imaging. Results: 312 patients underwent pancreatic resections. 118 patients required preop biliary drainage in setting of PDAC, including 92 ERCPs of which 83 were successful (46 plastic and 37 metal stents). 76 patients underwent neoadjuvant chemoradiation therapy. Surgical pathology revealed following stages: 0 n = 4, 1A n = 5, 1B n = 8, 2A n = 20, 2B n = 24, 3 n = 1, 4 n = 14. 96% underwent preop CT and 4% MRI pancreas protocol imaging. Exact correlation between clinical and surgical pathology was present in only 48% of cases (57% plastic, 46% metal stent), with 28% of clinical T overstaging, 4% clinical T understaging, 16% clinical N understaging and 4% unable to stage due to artefacts. More importantly, 8% patients were incorrectly staged to be surgical candidates (14% plastic, 6% metal). Controlling for stent type, neoadjuvant treatment and BMI did not impact preop cross-sectional imaging accuracy. Conclusions: Despite their impact on preop cross-imaging biliary metal stents did not negatively impact the accuracy and patient selection for surgical candidacy compared with biliary plastic stents in PDAC.

Older Patients with Pancreatic Cancer Stage I-II in Belgium, Norway and the Netherlands from the EURECCA Pancreas Consortium

Background: There is lack of evidence on treatment and survival of older patients with pancreatic cancer. This is relevant since the population of older patients with pancreatic cancer is increasing and these patients are underrepresented in clinical trials. The aim of this study was to compare treatment strategies and survival outcomes of patients aged 70 years and older with pancreatic cancer stage I & II in three national cancer registries from the EURECCA Pancreas Consortium.

Correlation between solute carrier transporter 22A3 gene rs7758229 polymorphism and prognosis of pancreatic cancer

Objective To investigate the relationship between solute carrier transporter 22A3 (SLC22A3) gene rs7758229 polymorphism and prognosis of pancreatic cancer. Methods One hundred patients with resectable pancreatic cancer who underwent surgery were admitted to our hospital from March 30, 2014 to March 30, 2016 were selected. There were were 61 male and 39 female patients, aging from 35 to 79 years with a median age of (49.1±5.7) years. The location included head and neck of the pancreas (n=66), body and tail of pancreas (n=34). According to the 7th American Joint Committee on Cancer (AJCC) Pancreatic Cancer Staging System, 19 cases were in stage I, 56 cases were in stage Ⅱ and 25 cases in stage Ⅲ. On the 2nd day after admission, 5 ml of fasting venous blood was taken, and the polymorphism of SLC22A3 gene rs7758229 was detected by DNA extraction kit and sequencing method. The patients were followed up and the end point was all-cause death. The correlation between polymorphism of rs7758229 and the prognosis of pancreatic cancer, and the factors affecting the overall survival (OS) of the patients were analyzed. The date analysis was conducted by SPSS 25.0; the gene type distribution deviation was tested by Hardy-Weinberg equilibrium, the correlation analysis of clinical date was analyzed by χ2 test analysis. The correlation between polymorphism of rs7758229 and the prognosis of pancreatic cancer, and the factors affecting the OS of the patients were analyzed by by Kaplan- Meier method and Cox model respectively. Results There were 28 cases (28.0%) of GG type, 51 cases (51.0%) of GT type, and 21 cases (21.0%) of TT type. The rs7758229 mononucleic acid polymorphism was significantly correlated with the degree of tumor differentiation and clinical stage (χ2=10.209, 10.826, P<0.05). Six patients were lost to follow-up (2 patients with GG, 3 patients with GT, and 1 patient with TT) with a median follow-up of 46 months. There were 73 deaths. Kaplan-Meier analysis and Log-rank test showed that overall survival (OS) was significantly shortened in patients with rs7758229 TT as compared with that in those with rs7758229 GG (Log-rank: χ2=11.254, P<0.05). Cox proportional hazard model results showed that rs7758229 mononuclear acid polymorphism [TT type/GG type, P<0.05, odds ratio (OR): 2.357, 95% confidence interval (CI): 1.524-6.317], TNM stage (P<0.05, OR: 1.194, 95%CI: 0.031-3.491), age (P<0.05, OR: 1.354, 95%CI: 1.067-4.357), degree of tumor differentiation (P<0.05, OR: 1.687, 95%CI: 1.108-4.217), and margin situation (P<0.05, OR: 1.947, 95%CI: 1.354-5.218) were independent prognostic factors influencing OS in patients with pancreatic cancer (P<0.05). Conclusion The rs7758229 polymorphism of SLC22A3 gene is associated with the survival rate of pancreatic cancer. The OS of TT patients is shorter. Key words: Solute carrier transporter 22A3 gene; Mononucleotide polymorphism; Pancreatic cancer; Overall survival

Manifestation of Pathological States of Numerous Diseases in the Largest Organ of the Human Body: (II) From Pancreatitis to Pancreatic Cancer Invasion, Formation of Stroma around the Primary Tumor in the Fascia, to Early Detection of Non-Coding microRNAs in Body Fluids and Development of Drugs to Treat Different Stages of Pancreatic Cancer

Patients suffering from pancreatic ductal adenocarcinoma (PDAC) have an average survival time of 4 - 6 months after confirmed diagnosis. The primary tumor is surrounded by a thick interstitial fluid with high pressure and dense distribution of collagen, forming a huge stroma, rendering the tumor resistant to chemo- and radiotherapy. From the genetic point of view, pancreatic carcinogenesis is driven by mutations, resulting in common activation of the oncogene KRAS, and/or inactivation of one or more of the tumor suppressor genes CDKN2A, TP53, SMAD4 [1]. The pancreas is a mixed exocrine and autocrine organ, with different cell types building up the organ. The pathogenesis involves more than 13 signaling pathways at different stages. Off-balance of the function of the proteins in these pathways due to the stated 4 plus other mutations could readily lead to carcinogenesis. We first present the basic mechanism of these 13 relevant pathways. We then provide a detailed analysis of the progression of this disease, from pancreatitis to tumor formation and metastasis, with special attention on the roles played by the newly discover calcium channel Piezo, stellate cells, stem-cell-like cells, and the concept invadopodium. Thirty potential drugs, based on in vitro and xenograft experiments from different groups, are discussed, including vitamins A, Tocotrienols-E, and D, chemical compounds, non-coding micro RNAs, circular RNA, piwi-interacting RNAs. The recent detection of exosomes enclosing many of these RNAs in body fluids gives us hope of developing early detection methodology because these RNAs carry messages for cell-cell communication at a distance. Delivery of potent drugs by nanoparticles gives us chance to send drugs through the stroma to target the tumor. Since body fluids form a circulating system, together with the connective tissues (where the tumor is associated) form the largest organ—the fascia, we conclude that manifestation of successive pathological states of pancreatic carcinogenesis can be found in compartments of the fascia. We present 17 figures, hoping to ease off the complexity of the pathogenesis of this most lethal cancer disease.

Impact of concurrent acute pancreatitis on pancreatic cancer stage, treatment, and prognosis: a study of two cohorts

Impact of concurrent acute pancreatitis on pancreatic cancer stage, treatment, and prognosis: a study of two cohorts

Computer-Aided Diagnosis and Staging of Pancreatic Cancer Based on CT Images

Pancreatic cancer (PC) is a malignant tumor that seriously threatens the survival of patients. Artificial classification has practical difficulties, such as unstable classification accuracy, a heavy workload, and the classification results depend on the subjective judgment of the clinician during the diagnosis and staging of PC. In addition, accurate PC staging could better help clinicians deliver the optimal therapeutic schedule for PC patients of different stages. Therefore, this study proposes a comprehensive medical computer-aided method for preoperative diagnosis and staging of PC based on an ensemble learning-support vector machine (EL-SVM) and computed tomography (CT) images. The least absolute shrinkage and selection operator (LASSO) algorithm was chosen for feature selection. In contrast to no feature selection, the model optimization time decreased by 19.94 seconds while maintaining precision. The EL-SVM learner was used to classify 168 CT images of normal pancreas and different stages of PC. The experimental results demonstrated that the normal pancreas (normal)-pancreatic cancer early stage (early stage) classification accuracy was 86.61%, the normal-pancreatic cancer stage III (stage III) classification accuracy was 87.04%, the normal-pancreatic cancer stage IV (stage IV) classification accuracy was 91.63%, the normal-PC classification accuracy was 87.89%, the early stage-stage III classification accuracy was 75.03%, and the early stage-stage IV classification accuracy was 81.22%, and the stage III-stage IV classification accuracy was 82.48%. Our experimental results prove that our proposed method is feasible and promising for clinical applications for the preoperative diagnosis and staging of PC via CT images.

Pancreatic Cancer Imaging: What the Surgeon Wants to Know?

AbstractPancreatic cancer is rare but is one of the deadliest cancers. Complete surgical removal of the cancer with negative margins is the only potentially curative treatment. However, majority of the cases present with distant metastases and/or locally advanced disease, and only a limited subset (up to 20%) of patients are surgical candidates. Therefore, accurate staging of pancreatic cancer is very important for treatment planning. It is very important to distinguish between patients who are surgical candidates and those who would need palliative treatment. Imaging plays a crucial role in the detection of the primary tumor, vascular involvement and variants, metastasis, prediction of resectability, and monitoring treatment response. High-resolution multidetector computed tomography (CT) is the primary imaging modality of choice for diagnosing and staging pancreatic cancers. Nevertheless, integration of ultrasound, CT, and magnetic resonance imaging (MRI) may be needed for accurate determination of the tumor extent and optimal management. Herein, we aim to provide a radiological review for “what the surgeon wants to know about pancreatic cancer?” In this review, we highlight the main types of invasive pancreatic cancers and discuss the role of imaging in determining the resectability of pancreatic tumors and the role of neoadjuvant treatment in downstaging borderline or unresectable cases in addition to featuring significant postsurgical complications.

In vivo multiplex gene targeting with Streptococcus pyogens and Campylobacter jejuni Cas9 for pancreatic cancer modeling in wild-type animal.

Pancreatic ductal adenocarcinoma is a lethal cancer type that is associated with multiple gene mutations in somatic cells. Genetically engineered mouse is hardly applicable for developing a pancreatic cancer model, and the xenograft model poses a limitation in the reflection of early stage pancreatic cancer. Thus, in vivo somatic cell gene engineering with clustered regularly interspaced short palindromic repeats is drawing increasing attention for generating an animal model of pancreatic cancer. In this study, we selected Kras, Trp53, Ink4a, Smad4, and Brca2 as target genes, and applied Campylobacter jejuni Cas9 (CjCas9) and Streptococcus pyogens Cas9 (SpCas9) for developing pancreatic cancer using adeno associated virus (AAV) transduction. After confirming multifocal and diffuse transduction of AAV2, we generated SpCas9 overexpression mice, which exhibited high double-strand DNA breakage (DSB) in target genes and pancreatic intraepithelial neoplasia (PanIN) lesions with two AAV transductions; however, wild-type (WT) mice with three AAV transductions did not develop PanIN. Furthermore, small-sized Cjcas9 was applied to WT mice with two AAV system, which, in addition, developed high extensive DSB and PanIN lesions. Histological changes and expression of cancer markers such as Ki67, cytokeratin, Mucin5a, alpha smooth muscle actin in duct and islet cells were observed. In addition, the study revealed several findings such as 1) multiple DSB potential of AAV-CjCas9, 2) peri-ductal lymphocyte infiltration, 3) multi-focal cancer marker expression, and 4) requirement of > 12 months for initiation of PanIN in AAV mediated targeting. In this study, we present a useful tool for in vivo cancer modeling that would be applicable for other disease models as well.

Pre-operative timeline of resectable pancreatic cancer in a community setting

Presenter: Navid Ajabshir MD | Mount Sinai Medical Center of Florida Background: Early stage pancreatic cancer is currently best-managed by surgical resection, with 5-year survival rates approaching 30% when amenable to resection and carried out in a timely fashion. Delays from symptom onset to surgical intervention can be due to a number of factors. A handful of studies have aimed to determine the maximum allowable window of time from diagnosis to treatment. Methods: This retrospective cohort reviewed the practice patterns in a community-based, tertiary care hospital, in patients who underwent pancreatic tumor resection from 2009 to 2018. Parameters investigated were time from radiographic image acquisition to surgical consultation, time from surgical consultation to resection, presenting symptomatology, and number and type of preoperative images performed. Results: In total, 135 patients were seen, evaluated, and treated with surgery at our institution. Of these, 35 patients were excluded for insufficient data. The medial number of days from diagnosis to surgical consultation was eleven days and from consult to surgical resection was also eleven days. On average, 48 days passed before a patient was initially imaged until they underwent surgical resection. The majority of patients presented with pain as one of their initial symptoms (n=58). When stratified for a presenting symptom of jaundice, patients were seen in surgical consultation six days earlier and operated on four days sooner. Patients received, on average, three imaging studies prior to resection. Of these, computed tomography was performed at least once in 89 percent of patients. Conclusion: In this study, we report the real-world time course and pre-operative expectations for patients with pancreatic cancer. Future studies should aim to highlight areas where efficiency may be improved upon.

Circulating natural antibodies against 3'-sialyllactose complement the diagnostic performance of CA19-9 for the early detection of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma is a devastating malignancy with an extremely poor prognosis. Although the most widely used biomarker for pancreatic cancer is carbohydrate antigen CA19-9, it is elevated mainly in the late stage of pancreatic cancer. Some serum natural antibodies against carbohydrates have been shown to be possible diagnostic markers for cancer. This study was conducted to determine whether the level of natural antibodies against carbohydrates fluctuates in pancreatic ductal adenocarcinoma. Serum from pancreatic cancer subjects (n= 55) and 43 subjects free of malignant disease were studied. The contents of natural antibodies against sialyl glycans and CA19-9 in serum were determined by enzyme-linked immunosorbent assay. The level of serum anti-3'-sialyllactose antibodies in pancreatic cancer subjects was significantly lower than that in healthy controls. In contrast, the amounts of serum antibodies against other sialyl glycans were comparable between the two groups. Concentration of serum anti-3'-sialyllactose IgG provided excellent AUC of 0.86, with sensitivity 82%, specificity 81%, and accuracy 82%. The combination of serum anti-3'-sialyllactose IgG with CA19-9 improved the sensitivity of pancreatic cancer detection at an early stage. Natural antibodies against 3'-sialyllactose constitute a promising biomarker for pancreatic cancer detection. The measurement of serum anti-3'-sialyllactose antibodies could play a supportive role in diagnostics and complement the performance of CA19-9 for the early detection of pancreatic ductal adenocarcinoma.

Early Detection in a Mouse Model of Pancreatic Cancer by Imaging DNA Damage Response Signaling

Despite its widespread use in oncology, the PET radiotracer 18F-FDG is ineffective for improving early detection of pancreatic ductal adenocarcinoma (PDAC). An alternative strategy for early detection of pancreatic cancer involves visualization of high-grade pancreatic intraepithelial neoplasias (PanIN-3s), generally regarded as the noninvasive precursors of PDAC. The DNA damage response is known to be hyperactivated in late-stage PanINs. Therefore, we investigated whether the SPECT imaging agent 111In-anti-γH2AX-TAT allows visualization of the DNA damage repair marker γH2AX in PanIN-3s in an engineered mouse model of PDAC, to facilitate early detection of PDAC. Methods: Genetically engineered KPC (KRasLSL.G12D/+; p53LSL.R172H/+; PdxCre) mice were imaged with 18F-FDG and 111In-anti-γH2AX-TAT. The presence of PanIN/PDAC as visualized by histologic examination was compared with autoradiography and immunofluorescence. Separately, the survival of KPC mice imaged with 111In-anti-γH2AX-TAT was evaluated. Results: In KPC mouse pancreata, γH2AX expression was increased in high-grade PanINs but not in PDAC, corroborating earlier results obtained from human pancreas sections. Uptake of 111In-anti-γH2AX-TAT, but not 111In-IgG-TAT or 18F-FDG, within the pancreas correlated positively with the age of KPC mice, which correlated with the number of high-grade PanINs. 111In-anti-γH2AX-TAT localizes preferentially in high-grade PanIN lesions but not in established PDAC. Younger, non–tumor-bearing KPC mice that show uptake of 111In-anti-γH2AX-TAT in the pancreas survive for a significantly shorter time than mice with physiologic 111In-anti-γH2AX-TAT uptake. Conclusion: 111In-anti-γH2AX-TAT imaging allows noninvasive detection of DNA damage repair signaling upregulation in preinvasive PanIN lesions and is a promising new tool to aid in the early detection and staging of pancreatic cancer.

Abstract A62: Regulatory T-cell depletion promotes oncogenic Kras-driven pancreatic carcinogenesis

Abstract Objective: Pancreatic cancer is a deadly malignancy, and little progress has been made in the survival of patients during the past 40 years. Harnessing the immune system to elicit anticancer response is an attractive therapeutic option, alone or in combination with antitumor agents. Targeting regulatory T cell (Treg), which acts to suppress immune responses, holds promise as one potential approach to relieve the immune suppression of pancreatic cancer, but functional studies investigating whether Treg depletion at different stages of pancreatic cancer has therapeutic benefit are needed. Methods: We are using KC; Foxp3DTR mice generated by crossing KC (p48-Cre; LSL-KrasG12D) with Foxp3DTR (B6.129(Cg)-Foxp3tm3(DTR/GFP)Ayr/J, Jackson Laboratory) to determine the requirement of Tregs during oncogenic Kras-induced pancreatic cancer precursor lesion formation and progression. We depleted Foxp3-expressing Tregs by Diphtheria Toxin (DT) injection at different time points—either before or after PanIN formation. Multiplex immunohistochemistry and Cytometry by Time-of-Flight (CyTOF) were performed for tumor immunophenotyping; RNA sequencing was used for transcriptomic analysis of the tumor epithelial cells, fibroblasts, and myeloid cells. Results: Surprisingly, instead of blocking tumorigenesis, depletion of Tregs during these early stages led to accelerated tumor progression. We show that Tregs are a key source of TGFb, and accordingly their depletion alters fibroblast population, exemplified by loss of Smooth Muscle Actin expression. Treg depletion further resulted in a compensatory influx of suppressive myeloid cells, thereby preventing an antitumor immune response. Mechanistically, we show that this myeloid recruitment was driven through the CCR1 axis, with the receptor expressed on tumor-associated myeloid cells and several ligands upregulated in epithelial cells and fibroblasts upon Treg depletion. Finally, blockade of CCR1 signaling successfully inhibits tumor progression upon Treg-depletion. Conclusion: Our study revealed an immunosuppressive network of interactions between different components within the pancreatic tumor microenvironment, including Tregs, fibroblasts, tumor cells, and macrophages. Depleting one component (Tregs) can lead to the compensation of immunosuppression from the rest of components within the network. Thus, a thorough understanding of the immunosuppressive network in pancreatic neoplasia is necessary to optimize our approaches to treatment and identify opportunities for combination therapy and prevent potential feedback mechanisms resulting in tumor resistance and relapse. Citation Format: Yaqing Zhang, Jenny Lazarus, Nina Steele, Wei Yan, Ho-Joon Lee, Christopher J. Halbrook, Rosa Menjivar, Samantha B. Kemp, Veerin Sirihorachai, Eileen S. Carpenter, Anna C. Nevison, Alekya Vinta, Michelle A. Anderson, Howard C. Crawford, Costas A. Lyssiotis, Timothy L. Frankel, Filip Bednar, Marina Pasca di Magliano. Regulatory T-cell depletion promotes oncogenic Kras-driven pancreatic carcinogenesis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A62.

Abstract I18: Retooling a blood-based biomarker into a theranostic agent

Abstract Over the past 30 years, our ability to noninvasively diagnose, localize, and treat many forms of cancer has grown significantly. However, the biomolecular basis of many malignancies—most notably pancreatic cancer—remains convoluted, and technical advances have not translated to significantly improved survival rates. This is reflected in 1- and 5-year survival rates of 27% and 6%, respectively, for pancreatic cancer diagnoses. Given the tremendous current focus on the creation of new therapeutics for treating pancreatic cancer, the development of companion technologies that can safely, accurately, and unambiguously aid in the early diagnosis, staging, and treatment monitoring of pancreatic cancer is a vitally important—yet unmet—clinical need. The remarkable specificity and selectivity of antibodies for cancer biomarkers have made immunoglobulins some of the most flexible and adaptable tools in modern medicine. For therapeutic purposes, a wide range of nonlabeled antibodies has now entered the clinic. Antibody-based PET and SPECT imaging agents are not far behind. For example, an array of 89Zr-labeled radioimmunoconjugates has shown significant promise in both preclinical and clinical studies. CA19-9 levels in the serum are routinely used for diagnosis, risk stratification, and follow-up of PDAC. While CA19-9 is a shed antigen entering the circulation, the concentration is much higher in the tumor tissue, making it a potential target for in vivo imaging with radiolabeled antibodies. Our studies show that a tumor antigen secreted to the circulation can be used for sensitive detection of primary tumors and metastatic disease by immuno-PET. For example, in proof-of-concept preclinical studies, we were able to visualize pancreatic cancer xenograft and orthotopic models of early- and late-stage disease with excellent tumoral uptake and target-to-non-target ratios using the 89Zr-labeled human monoclonal antibody [89Zr]Zr-DFO-HuMab-5B1 (MVT-2163, NCT02687230). This 5B1 radioimmunoconjugate scaffold has also been deployed with therapeutic beta- and alpha-emitting radionuclides, creating an effective radiotherapeutic paradigm for the imaging and therapy of PDAC. In conclusion, our study shows that a tumor antigen secreted by PDAC to the circulation can be used for sensitive detection of primary tumors and metastatic disease by immuno-PET. This significantly broadens the number of molecular targets that can be used for PET imaging and provides new opportunities for noninvasive characterization of tumors in pancreatic cancer patients. Citation Format: Jason S. Lewis. Retooling a blood-based biomarker into a theranostic agent [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I18.

Is the New T1 Category as Defined in the Eighth Edition of the AJCC Pancreatic Cancer Staging System an Improvement?

BackgroundThe new T1 pancreatic cancer by the eighth edition of the AJCC staging system discards the concept of “extension beyond the pancreas” and focuses on size only. Furthermore, the new T1 is divided into T1a, T1b, and T1c based on size. The evidence pertaining to these changes has not been evaluated. This is to evaluate the feasibility of the new T1 definition in the pancreas head cancer cohort. MethodsData from 540 patients with T1 pancreatic ductal adenocarcinoma as defined by the eighth edition were collected from Korea, Japan, and the USA. Invasive IPMNs were excluded. Survival analyses were performed. ResultsOf the 540 patients, 181 patients were T1 according to the seventh edition and 359 were down-staged to T1 from the former T3 because the concept of “extension beyond the pancreas” was discarded. The 5-year survival rate and the median survival of T1 patients were 30.6% and 27 months, respectively. Comparing tumors that extend beyond the pancreas (new T1) and those confined within the pancreas (original T1), the latter showed significantly longer median survival (43 vs. 24 months, p < 0.001). In terms of T1a/b/c, there were no significant differences in survival. Using MaxStat, subdividing into two groups using 1.1 cm as the cut-off value, yielded significantly discrete prognostic groups (p < 0.001). ConclusionThe new T1 definition may be more practical, but the implications of the concept of “extension beyond the pancreas” should be re-investigated. Further, the subcategorization of T1a/b/c may not be adequate and may require revision or deletion.

Imaging and Management of Pancreatic Cancer

Pancreatic cancer is an aggressive disease with rising incidence and high mortality despite advances in imaging and therapeutic options. Surgical resection is currently the only curative treatment, with expanding roles for adjuvant and neoadjuvant chemoradiation. Accurate detection, staging, and post-treatment monitoring of pancreatic cancer are critical to improving survival and imaging plays a central role in the multidisciplinary approach to this disease. This article will provide a broad overview of the imaging and management of pancreatic cancer with a focus on diagnosis and staging, operative and nonoperative treatments, and post-therapeutic appearances after surgery and chemoradiation therapy.

Acute pancreatitis as an early marker of pancreatic cancer and cancer stage, treatment, and prognosis

BackgroundWe aimed to examine the association between acute pancreatitis, a potential early symptom of pancreatic cancer, and pancreatic cancer stage, treatment, and prognosis. MethodsWe conducted a cohort study of patients diagnosed with pancreatic cancer during 2004–2017 using population-based registry data from Denmark and Surveillance, Epidemiology, and End Results (SEER) data linked with Medicare claims from the United States (US), which include individuals aged 65 + . We ascertained information on acute pancreatitis diagnoses up to 90 days before pancreatic cancer and followed them for a maximum of five years. We assessed overall survival difference at 30 days, six months, and one, three and five years, comparing patients with and without coexistence of acute pancreatitis. Secondary outcomes were cancer stage and treatment. ResultsWe identified 12,522 Danish and 37,552 US patients with pancreatic cancer (median age 71 and 78 years, respectively). In the Danish cohort, 1.4 % had acute pancreatitis before pancreatic cancer vs. 5.9 % in the US cohort. After five years of follow-up, the survival difference was 6.1 % (95 % CI: [-0.4 %, 12.6 %]) in Danish and 1.7 % (95 % CI: [0.8 %, 2.7 %]) in US patients, comparing patients with and without acute pancreatitis. Patients with acute pancreatitis had lower prevalence of metastatic tumors at diagnosis (Denmark: 42.5 % vs. 48.7 %; US: 34.4 % vs. 45.9 %) and higher resection frequencies (Denmark: 20.1 % vs. 12.1 %; US: 16.1 % vs.11.3 %) than patients without acute pancreatitis. ConclusionsPancreatic cancer patients with acute pancreatitis diagnosed up to 90 days before cancer diagnosis had earlier stage at diagnosis and better survival than patients without acute pancreatitis.