Primary Pancreatic Lesions Research Articles

Interim analysis of feasibility, safety, and tumor control in two first-in-human trials of a novel alpha-emitting radionuclide for pancreatic adenocarcinoma.

741 Background: This study aims to report the initial feasibility, safety, and tumor response of delivering Diffusing Alpha-Emitter Radiation Therapy (Alpha DaRT) to the pancreas. This innovative approach involves the interstitial implantation of a novel alpha-emitting radiation source via endoscopic ultrasound (EUS) for the treatment of pancreatic cancer. Methods: The study enrolled patients treated with Alpha DaRT to the pancreas across two protocols (PANC and ALL). The primary objective was to assess the safety of Alpha DaRT delivery to the target lesion via EUS, while the secondary objective was to evaluate initial tumor response using the Response Evaluation Criteria in Solid Tumors version 1.1 at 1 and 3 months post-Alpha DaRT source insertion. Toxicity was evaluated according to the Common Terminology Criteria for Adverse Events version 4.03. The PANC protocol included patients with biopsy-proven adenocarcinoma, either unresectable, recurrent, or metastatic, who were unfit for standard treatment. The ALL protocol allowed for any malignancy with a targetable lesion and permitted concurrent systemic therapy. For this analysis, only patients from the ALL protocol with pancreatic adenocarcinoma treated to the primary tumor were included. Pre-procedure planning involved CT simulation and EUS, and EUS-guided Alpha DaRT placement was confirmed by CT. The median follow-up time was 91 days. Results: A total of 12 patients (9 male, 3 female) median age 73 (range: 59-85) were enrolled (4 in PANC, 8 in ALL). Four patients had localized, unresectable disease and eight had metastatic disease. Three patients had a history of prior radiotherapy. Successful placement of Alpha DaRT sources into the targetable pancreatic lesions was achieved in all cases (100%), as confirmed by post-treatment imaging. Grade 1-2 acute toxicities included fever in 2 of 12 patients (16.7%), fatigue/weakness in 2 of 12 patients (16.7%) and abdominal or back pain in 3 of 12 patients (25.0%). One patient was hospitalized for obstructive jaundice (Grade 3) possibly secondary to inflammation seven days post-implantation requiring percutaneous transhepatic cholangiography; all hepatic laboratory values returned back to normal post procedure. All adverse events resolved. No long-term toxicities ( > 3 months) have been seen to date. Tumor response data were available for 8 of 12 patients. Local control was 100% for all evaluable patients. Of these, 6 (75.0%) exhibited stable disease, while 2 (25.0%) showed a partial response ( > 30% tumor reduction). One patient had a complete metabolic response on PET-CT at both the primary pancreatic lesion and liver metastasis. Conclusions: Alpha DaRT delivered via endoscopy is feasible with a favorable safety profile and demonstrates promising tumor responses. Ongoing longer follow-up and larger studies are required to validate these findings. Clinical trial information: NCT05781555 and NCT05657743 .

Prospective Comparison of [18F]FDG and [18F]AIF-FAPI-74 PET/CT in the Evaluation of Potentially Resectable Pancreatic Ductal Adenocarcinoma

PurposeAccurate clinical staging of potentially resectable pancreatic ductal adenocarcinoma (PDAC) is critical for establishing optimal treatment strategies. While the efficacy of fluorine-18-fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) in clinical staging is unclear, PET/CT detecting fibroblast-activation protein (FAP) expression has recently received considerable attention for detecting various tumors, including PDAC, with high sensitivity. We explored the efficacy of [18F]FDG and [18F]AIF-FAPI-74 PET/CT in the initial evaluation of potentially resectable PDAC.ProceduresBetween 2021 and 2022, twenty participants with newly diagnosed potentially resectable PDAC were enrolled. After the initial evaluation with pancreatic CT, [18F]FDG PET/CT, and [18F]AIF-FAPI-74 PET/CT, treatment strategies were determined considering the participant’s general status, clinical staging, and resectability. Pathological information from the surgical specimens was only available in 17 participants who underwent curative-intent surgery. Head-to-head comparisons of quantitative radiotracer uptake and diagnostic performance were performed among imaging modalities.Results[18F]AIF-FAPI-74 PET/CT showed a significantly higher maximum standardized uptake value than [18F]FDG PET/CT did in evaluating primary pancreatic lesions (median [interquartile range]; 12.6 [10.7–13.7] vs. 6.3 [4.8–9.2]; P < 0.001). In contrast, [18F]AIF-FAPI-74 PET/CT showed a significantly lower mean standardized uptake value than [18F]FDG PET/CT did in evaluating background organ (median [interquartile range]) 0.8 [0.7–0.9] vs. 2.6 [2.3–2.7]; P < 0.001). In addition, the sensitivity of [18F]AIF-FAPI-74 PET/CT in detecting metastatic lymph nodes was higher than that of [18F]FDG PET/CT (50.0% vs. 0.0%; P = 0.026).ConclusionThis study demonstrated that [18F]AIF-FAPI-74 PET/CT could improve the clinical staging of potentially resectable PDAC.

Molecular mechanisms of pancreatic cancer liver metastasis: the role of PAK2.

Pancreatic cancer remains an extremely malignant digestive tract tumor, posing a significant global public health burden. Patients with pancreatic cancer, once metastasis occurs, lose all hope of cure, and prognosis is extremely poor. It is important to investigate liver metastasis of Pancreatic cancer in depth, not just because it is the most common form of metastasis in pancreatic cancer, but also because it is crucial for treatment planning and prognosis assessment. This study aims to delve into the mechanisms of pancreatic cancer liver metastasis, with the goal of providing crucial scientific groundwork for the development of future treatment methods and drugs. We explored the mechanisms of pancreatic cancer liver metastasis using single-cell sequencing data (GSE155698 and GSE154778) and bulk data (GSE71729, GSE19279, TCGA-PAAD). Initially, Seurat package was employed for single-cell data processing to obtain expression matrices for primary pancreatic cancer lesions and liver metastatic lesions. Subsequently, high-dimensional weighted gene co-expression network analysis (hdWGCNA) was used to identify genes associated with liver metastasis. Machine learning algorithms and COX regression models were employed to further screen genes related to patient prognosis. Informed by both biological understanding and the outcomes of algorithms, we meticulously identified the ultimate set of liver metastasis-related gene (LRG). In the study of LRG genes, various databases were utilized to validate their association with pancreatic cancer liver metastasis. In order to analyze the effects of these agents on tumor microenvironment, we conducted an in-depth analysis, including changes in signaling pathways (GSVA), cell differentiation (pseudo-temporal analysis), cell communication networks (cell communication analysis), and downstream transcription factors (transcription factor activity prediction). Additionally, drug sensitivity analysis and metabolic analysis were performed to reveal the effects of LRG on gemcitabine resistance and metabolic pathways. Finally, functional experiments were conducted by silencing the expression of LRG in PANC-1 and Bx-PC-3 cells to validate its influence to proliferation and invasiveness on PANC-1 and Bx-PC-3 cells. Through a series of algorithmic filters, we identified PAK2 as a key gene promoting pancreatic cancer liver metastasis. GSVA analysis elucidated the activation of the TGF-beta signaling pathway by PAK2 to promote the occurrence of liver metastasis. Pseudo-temporal analysis revealed a significant correlation between PAK2 expression and the lower differentiation status of pancreatic cancer cells. Cell communication analysis revealed that overexpression of PAK2 promotes communication between cancer cells and the tumor microenvironment. Transcription factor activity prediction displayed the transcription factor network regulated by PAK2. Drug sensitivity analysis and metabolic analysis revealed the impact of PAK2 on gemcitabine resistance and metabolic pathways. CCK8 experiments showed that silencing PAK2 led to a decrease in the proliferative capacity of pancreatic cancer cells and scratch experiments demonstrated that low expression of PAK2 decreased invasion capability in pancreatic cancer cells. Flow cytometry reveals that PAK2 significantly inhibited apoptosis in pancreatic cancer cell lines. Molecules related to the TGF-beta pathway decreased with the inhibition of PAK2, and there were corresponding significant changes in molecules associated with EMT. PAK2 facilitated the angiogenic potential of cancer cells and promotes the epithelial-mesenchymal transition process by activating the TGF-beta signaling pathway. Simultaneously, it decreased the differentiation level of cancer cells, consequently enhancing their malignancy. Additionally, PAK2 fostered communication between cancer cells and the tumor microenvironment, augments cancer cell chemoresistance, and modulates energy metabolism pathways. In summary, PAK2 emerged as a pivotal gene orchestrating pancreatic cancer liver metastasis. Intervening in the expression of PAK2 may offer a promising therapeutic strategy for preventing liver metastasis of pancreatic cancer and improving its prognosis.

Abstract 935: The real-world data of the cancer genome profiling testing for pancreatic ductal adenocarcinoma from a nationwide database in Japan

Abstract Background: In Japan, which has a universal health insurance system, cancer genomic profiling (CGP) testing was approved by the authority in June 2019. 99.7% of CGP data under insurance coverage have been registered with a nationwide database; C-CAT (Center for Cancer Genomics and Advanced Therapeutics). This study aims to clarify the real-world data of CGP for pancreatic ductal adenocarcinoma (PDAC) in Japan with particular attention to KRAS mutation and homologous recombination deficiency (HRD) status. Method: 2568 PDAC patients enrolled in C-CAT from June 2019 to January 2022 were analyzed retrospectively. The clinical background, treatment outcomes and the detection rate of gene alterations such as Big4 genes (KRAS, TP53, SMAD4, CDKN2A) or other druggable genes, especially HRD genes, were evaluated. We defined it significant when genetic alterations are described as oncogenic/pathogenic in C-CAT report. Results: 85.7% and 14.3% of patients underwent tissue DNA sequence (FoundationOne (F1) CDx 62.9%, NCC OncoPanel 22.8%) and ctDNA assays (F1 Liquid), respectively. 70.3% of the analyzed tissue were obtained from the primary pancreatic lesions. Big4 genes mutations were most frequently prevalent such as KRAS (85.1%), TP53 (69.1%) and CDKN2A (35.4%). Big4 genes mutations were detected significantly more frequently in the tissue samples than in the liquid: KRAS (92.2% vs 42.1%) and TP53 (73.0% vs 45.6%). 16.1% of enrolled patients carried pathogenic variants related to HRD, such as ARID1A, BRCA2, ATM, PALB2 and BRCA1. Therapeutic agents were proposed in 27.6% of cases, the proportion of successfully treated patients eligible for targeted therapy was 2.6%. The median OS of KRAS-wild patients was prolonged than KRAS-mutated patients (65.4 vs 27.1 months, p&amp;lt;0.001). The median TTF of BRCA1/2 mutated patients who received FOLFIRINOX as a first line treatment was better than BRCA1/2 wild patients (9.3 vs 5.6 months, p=0.025). Conversely, there was no difference between HRD and non-HRD (6.9 vs 6.5 months, p=0.25). Conclusion: Detection rates of gene alteration vary widely between tissue and liquid samples. KRAS mutation is confirmed as a poor prognostic factor for PDAC and patients with BRCA1/2 mutation are sensitive to FOLFIRINOX. Further accumulation of cases will help us to elucidate the more details of the relationship between gene alteration and therapeutic efficacy. Citation Format: Toshifumi Doi, Takeshi Ishikawa, Tomoki Sakakida, Ryuichi Morita, Daiki Sone, Junichiro Itani, Seita Kataoka, Hayato Miyake, Masahiro Iwasaku, Yoshio Sogame, Hideyuki Konishi, Koichi Takayama, Yoshito Itoh. The real-world data of the cancer genome profiling testing for pancreatic ductal adenocarcinoma from a nationwide database in Japan [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 935.

Tumor-to-blood ratio for assessment of fibroblast activation protein receptor density in pancreatic cancer using [68Ga]Ga-FAPI-04.

[68Ga]Ga-FAPI PET/CT has been widely used in clinical diagnosis and radiopharmaceutical therapy. In this study, tumor-to-blood ratio (TBR) was evaluated as a powerful tool for semiquantitative assessment of [68Ga]Ga-FAPI-04 tumor uptake and as an effective index for tumors with high FAP expression in theranostics. Nine patients with pancreatic cancer underwent a 60-min dynamic PET/CT scan by total-body PET/CT (with a long AFOV of 194 cm) after injection of [68Ga]Ga-FAPI-04. After dynamic PET/CT scan, three patients received chemotherapy and underwent the second dynamic scan to evaluate treatment response. Time-activity curves (TACs) were obtained by drawing regions of interest for primary pancreatic lesions and metastatic lesions. The lesion TACs were fitted using four compartment models by the software PMOD PKIN kinetic modeling. The preferred pharmacokinetic model for [68Ga]Ga-FAPI-04 was evaluated based on the Akaike information criterion. The correlations between simplified methods for quantification of [68Ga]Ga-FAPI-04 (SUVs; tumor-to-blood ratios [TBRs]) and the total distribution volume (Vt) estimates obtained from pharmacokinetic analysis were calculated. In total, 9 primary lesions and 25 metastatic lesions were evaluated. The reversible two-tissue compartment model (2TCM) was the most appropriate model among the four compartment models. The total distribution volume Vt values derived from 2TCM varied significantly in pathological lesions and background regions. A strong positive correlation was observed between TBRmean and Vt from the 2TCM model in pathological lesions (R2=0.92, P<0.001). The relative difference range for TBRmean was 2.1% compared to the reduction rate of Vt in the patients who were treated with chemotherapy. A strong positive correlation was observed between TBRmean and Vt for [68Ga]Ga-FAPI-04. TBRmean reflects FAP receptor density better than SUVmean and SUVmax, and would be the preferred measurement tool for semiquantitative assessment of [68Ga]Ga-FAPI-04 tumor uptake and as a means for evaluating treatment response.

The Significance of FDG PET/CT-Derived Parameters in Determining Prognosis of Cases with Pancreatic Adenocarcinoma: A Prospective Study.

Background and objectives: Pancreatic adenocarcinoma represents one of the common malignancies with a relatively poor prognosis. However, early detection of this type of cancer may prove to be curable. Recent advancements in the radiological techniques might represent a hope for the early diagnosis and prediction of prognosis of pancreatic adenocarcinoma. This study aimed to assess the prognostic value of the primary tumor volumetric parameters obtained from FDG PET/CT first stage for the overall survival (OS) and progression-free survival (PFS) of patients with pancreatic adenocarcinoma and to explore the possible correlation between serum matrix metalloproteinase-2 (MMP-2) and the patients’ characteristics. Methods: Fifty patients with pancreatic adenocarcinoma were subjected to FDG PET/CT scan. The SUVpeak, SUVmax, and the metabolic tumor volume (MTV) were determined, as well as the SUVmean of the liver. Moreover, serum levels of MMP-2 were assessed. Follow-up of the patients was carried out for sixty months with determination of PFS and OS. Results: Peak SUV ≥ 3.9 was significantly correlated with the primary pancreatic lesions’ mean total glycolytic activity of >92 g, and MTV and was directly correlated with mortality. There was a positive correlation between peak SUV ≥ 3.9 and 50% SUVmax threshold > 82. Moreover, there was significant correlation between the total glycolytic activity and the studied clinicopathologic factors, except the age and sex of the patients and ECOG performance status. In addition, FDG uptake and the tumor glycolytic activity were substantially linked with a shorter PFS. Similarly, a strong correlation was found between MTV and PFS. Serum MMP-2 levels showed a significant relationship with the performance status, tumor stage, SUVmax threshold, and the glycolytic activity. Conclusions: Peak SUV, main lesion SUVmax, serum MMP-2, and the tumor glycolytic activity are good predictors of PFS of patients with pancreatic adenocarcinoma.

Can Surgical Resection of Metastatic Lesions Be Beneficial to Pancreatic Ductal Adenocarcinoma Patients with Isolated Lung Metastasis?

Simple SummaryWith the development of chemotherapy, studies have been conducted on the possibility of conversion surgery in metastatic pancreatic ductal adenocarcinoma (PDAC) patients. In addition, studies with large-scale public data have reported that patients with isolated lung metastasis have a good prognosis and can benefit from survival through surgical treatment. Our study aims to evaluate the effect of metastatectomy and prognostic factors in PDAC patients with isolated lung metastasis by analyzing the data from 1342 patients in our institution. We showed that PDAC patients with isolated lung metastasis who underwent metastatectomy seemed to have better survival when compared with patients who underwent only chemotherapy or supportive care. In addition, we performed the analysis using the National Cancer Database for external validation purposes and found consistent results compared to our analysis. Our findings suggest that PDAC patients with isolated lung metastasis should be considered for multimodal therapy with chemotherapy and surgical treatment.In the era of effective chemotherapy on pancreatic ductal adenocarcinoma (PDAC) with distant metastasis, data on the effects of metastatectomy are lacking. So, we investigated the effect of metastatectomy on survival after metastasis in PDAC patients with isolated lung metastasis. This retrospective study analyzed 1342 patients who were histologically diagnosed with PDAC with distant metastasis from January 2007 to December 2018, of which 83 patients had isolated pulmonary metastasis. Additionally, 4263 patients were extracted from the National Cancer Database (NCDB) and analyzed. Log-rank test and Kaplan−Meier survival analysis were used to analyze survival after metastasis. The five-year survival rate was significantly higher in patients who underwent pulmonary metastatectomy than in those who received only chemotherapy or supportive treatment (60.6% vs. 6.2% vs. 0.0%, p < 0.001). A similar trend was observed in the NCDB (two-year survival rate, 27.4% vs. 15.8% vs. 4.7%, p < 0.001). In the multivariate analysis, lung lesion multiplicity (hazard ratio (HR) = 2.004, p = 0.017), metastatectomy (HR = 0.278, p = 0.036), chemotherapy (HR = 0.434, p = 0.024), and chemotherapy cycles (HR = 0.300, p < 0.001) had significant effects on survival. Metastatectomy with primary pancreatic lesions is recommended with effective chemotherapy in PDAC patients with isolated lung metastasis.

Using PET to Image the Tumour Micro-Environment of Pancreatic Cancer: Applications to Improve Early Diagnosis, Staging and Therapy

Introduction: Fibroblast activating protein inhibitor (FAPI) is a novel targeting agent used with positron emission tomography (PET) to detect cancer associated fibroblasts (CAFs) in the tumour micro-environment. FAPI has been shown to outperform 18-fluorodeoxyglucose (FDG) in detecting primary and secondary deposits of invasive carcinoma. Our aim was to establish the role of FAPI-PET/CT in pancreatic cancer; specifically, its ability to diagnose early primary lesions, detect occult distant metastases and be used as a theranostic (i.e., targeted radiotherapeutic) agent. Methods: Patients with either a suspicious pancreatic lesion or confirmed pancreatic cancer at any stage were eligible for inclusion. All participants underwent pre-treatment FAPI-PET/CT. We determined maximum standardized uptake value (SUVmax) at multiple time points following injection of tracer for all primary pancreatic lesions. We determined SUVmax at a single time point for all secondary deposits of pancreatic cancer, as well as detection rate for previously occult distant metastases. All primary lesions underwent pathological assessment using biopsy or surgical specimens. The malignant nature of distant lesions was confirmed with biopsy or other established imaging in all cases. Results: We present findings from a world first study to prospectively compare FAPI uptake in benign and malignant primary pancreatic lesions, determine detection rate and accuracy for occult metastases among all potentially resectable disease, and measure SUVmax at all malignant sites to determine applicability for theranostics. Conclusion: Through improved detection of malignant deposits and re-purposing as a theranostic agent, FAPI could solve the problem of delayed diagnosis, under-staging, and treatment resistance for this poor-outcome disease.

P-P46 The use of FDG-PET/CT in the pre-operative staging of pancreatic ductal adenocarcinoma

Abstract Background The NICE Quality Standard for Pancreatic Cancer (December 2018) recommends that ‘adults with localised pancreatic cancer on CT(should) have staging using fluorodeoxyglucose positron emission tomography/CT(FDG-PET/CT) before they have surgery, radiotherapy or systemic therapy’. Such FDG-PET/CT staging aims to provide additional information to conventional cross-sectional imaging, thus presenting the most accurate staging of disease. However, the sensitivity and specificity of FDG-PET/CT to deliver relevant additional clinical information must be balanced with potential delays to treatment, and additional cost associated with its use, in the management of a time-critical pathology. Methods Consecutive pancreatic ductal adenocarcinoma(PDAC) patients deemed resectable on conventional imaging, and therefore referred for FDG-PET/CT assessment, were included for analysis. Data were derived from a single tertiary Hepatopancreaticobiliary(HPB) centre between May 2018 and June 2021. Data were collected and analysed from a combination of prospectively-collated electronic databases and paper patient records. Results Of 89 patients analysed, 55(61.7%) patients were male. Primary pancreatic lesions were PET avid in 81 cases(91%). Median time from request to FDG-PET/CT performance was 11 days(Range 1-35). Additional clinical information from FDG-PET/CT was provided in 61(68.5%) patients. Further investigations to assess FDG-PET/CT findings were arranged in 23 patients(25.8%; including liver MRI and EUS), demonstrating that FDG-PET/CT findings were true-positive in 6(26.1%), false-positive in 15(65.2%) and equivocal in 2(8.7%). There was a median delay of 60.5 days(Range 26 to 256) from FDG-PET/CT to surgery in those undergoing additional investigation. In total, a new diagnosis of metastatic/non-resectable disease was made in 14(15.7%) patients, preventing progression to planned operative intervention. Conclusions FDG-PET/CT provided additional information to conventional imaging that led to cancellation of planned operative resection in 14(15.7%) PDAC patients-8 directly and 6 following further investigation. However, there was a median delay of 11 days to FDG-PET/CT and 60.5 days from FDG-PET/CT to surgery in those undergoing additional investigation. Whilst FDG-PET/CT can lead to avoidance of unnecessary surgical intervention in PDAC patients with unsuspected metastatic/non-resectable disease, it can lead to delay, over-investigation, excess cost and anxiety in resectable patients. HPB units should audit their own findings to assess whether the use of FDG-PET/CT should be considered on a standard or selected basis.

Fluorine‐18 fluorodeoxyglucose positron emission tomography‐computed tomography for staging of canine insulinoma: 3 cases (2019–2020)

Canine insulinomas are uncommon malignant functional pancreatic neuroendocrine tumours with a high metastatic rate. Diagnostic imaging aids with staging and surgical planning of these tumours; however, identification is unpredictable across modalities. High-grade human pancreatic neuroendocrine tumours display increased avidity on 18 F-fluorodeoxyglucose positron emission tomography-CT. Dogs with clinicopathologic findings consistent with pancreatic insulinoma were prospectively enrolled. Patients underwent 18 F-fluorodeoxyglucose positron emission tomography-CT and CT angiography, followed by exploratory laparotomy. Three patients met the inclusion criteria and had histologically confirmed insulinomas. Both metastatic lesions in patient 1 were mildly avid (SUVmax 2.79 and 3.01). In patient 2, the primary pancreatic insulinoma was minimally avid (SUVmax 2.16). The primary pancreatic lesion in patient 3 had similar avidity to normal pancreatic parenchyma (SUVmax 1.54) and was undetected on 18 F-fluorodeoxyglucose positron emission tomography-CT. Insulinomas demonstrated variable attenuation and contrast enhancement patterns on CT angiography and certain lesions were more conspicuous than on 18 F-fluorodeoxyglucose positron emission tomography-CT. Two metastatic lesions not visible on either imaging modality were discovered in patient 2 at surgery. Canine insulinomas were inconsistently avid on 18 F-fluorodeoxyglucose positron emission tomography-CT. This finding is likely attributable to the confounding clinicopathological features and multifaceted transformation of these tumours, in addition to the influence of variable tumour size, composition and vascularity. Unpredictable tumoural avidity limits the value of 18 F-fluorodeoxyglucose positron emission tomography-CT for staging canine insulinomas.

Positron emission tomography and computed tomography with [68Ga]Ga-fibroblast activation protein inhibitors improves tumor detection and staging in patients with pancreatic cancer.

This study aimed to investigate the diagnostic performance of [68Ga]Ga-FAPI PET/CT for primary and metastatic pancreatic carcinoma lesions and compare the results with those of [18F]-fluorodeoxyglucose ([18F]FDG) PET/CT. Patients with suspected or diagnosed pancreatic malignancy, who underwent contemporaneous [18F]FDG and [68Ga]Ga-FAPI PET/CT between June 2020 and January 2021, were retrospectively analyzed. Routine contrast-enhanced CT (CE-CT) is performed in all patients as standardized care. Findings were confirmed by histopathology or radiographic follow-up. We compared radiotracer uptake, diagnostic performance, and TNM (tumor-node-metastasis) classifications. We evaluated 36 participants (25/36 men; median age, 60years), including 26 patients with pancreatic malignancies and ten patients with pancreatic benign lesions. [68Ga]Ga-FAPI PET/CT showed higher radiotracer uptake and higher sensitivity than [18F]FDG PET/CT in evaluating primary tumors (SUVmax, 21.4 vs. 4.8; sensitivity, 100% vs. 73.1%), involved lymph nodes (SUVmax, 8.6 vs. 2.7; sensitivity, 81.8% vs. 59.1%), and metastases (SUVmax, 7.9 vs. 3.5; sensitivity, 91.5% vs. 44.0%); Compared with [18F]FDG, [68Ga]Ga-FAPI PET/CT upstaged six patients' TNM staging (6/23, 26.1%) and changed two patients' clinical management (2/23, 8.7%). Compared with CE-CT, [68Ga]Ga-FAPI PET/CT upgraded TNM staging in five patients (5/23, 21.7%) and changed the therapeutic regimen in only one patient (1/23, 4.3%). Intense [68Ga]Ga-FAPI uptake was observed throughout the pancreas in 12/26 pancreatic malignancies; dual-time point [68Ga]Ga-FAPI PET/CT may differentiate pancreatitis from malignancy. Compared with [18F]FDG PET/CT, [68Ga]Ga-FAPI PET/CT shows higher sensitivity in detecting primary pancreatic tumors, involved lymph nodes, and metastases and is superior in terms of TNM staging. Prospective trials with larger patient population are needed to evaluate whether [68Ga]Ga-FAPI PET/CT could elicit treatment modification in pancreatic cancer when compared with standard of care imaging.

Primary pancreatic Ewing’s sarcoma: Dreadful yet treatable alien

Ewing's sarcoma is a highly aggressive malignant tumour most commonly affecting long bones in children and adolescents. Primary presentation in Pancreas is considered to be an extremely rare and only a handful of cases have been published to date. Our case intensifies the importance to recognize this rare type of tumor in young adults with a primary pancreatic lesion as there is a broad spectrum of tumours with a similar morphological and radiological presentation. A 26-year-old man was evaluated for upper abdominal pain with cross sectional imaging studies which revealed 3 × 3.3 cm complex cystic lesion in head of pancreas. Serum tumor markers and other blood investigations were within normal limits. We conducted tumour board meeting and proceeded for laparoscopic pancreaticoduodenectomy. Post-operative whipples specimen was subjected for histopathological analysis and Immunohistochemistry which confirmed the diagnosis of Ewing's sarcoma of pancreas. Currently, the patient is receiving regular follow-up care and received 3 cycles of adjuvant chemotherapy till now and has no evidence of cancer at six months post-surgery. Primary pancreatic Ewing sarcoma is a very rare highly aggressive malignant tumour that should be considered in differential diagnosis of an unusual pancreatic tumour especially in young adults. Being rare, we only have 32 reported cases up-to-date. Establishing the correct diagnosis requires a multidisciplinary approach involving close cooperation between clinical, radiological and pathological teams with accurate application of immunohistochemistry or cytogenetic analysis. Complete surgical excision with adjuvant chemotherapy and with or without radiation therapy is the standard of care.

Sa1441 ENDOSCOPIC ULTRASOUND-GUIDED RADIOFREQUENCY ABLATION OF PANCREATIC METASTASES FROM RENAL CELL CANCER: FEASIBILITY AND SAFETY

Renal cell carcinoma (RCC) is the most common renal cancer in adults, characterised by high 5-year survival rates (up to 95%) when tumour is limited to the kidney. Up to 50% of patients will develop widespread metastatic disease after nephrectomy with worsening of the 5-year survival rate to 10%-15%. Pancreas is an elective site for RCC metastases. Surgery is the first choice for the treatment of pancreatic metastases. For not-resectable pancreatic metastases therapeutical options are limited. Radiofrequency ablation (RFA) is a local ablative method that destroys the tumour by thermal coagulation. RFA has been successfully performed in the treatment of not-resectable solid tumours of liver, lung and prostate. Recent studies have shown that endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is a feasible and safe technique for the treatment of primary pancreatic lesions. However, there are no data regarding its use in the treatment of pancreatic metastases from RCC. The aim of the present study is to evaluate the feasibility and safety of EUS-RFA in the treatment of pancreatic metastases from RCC. This is a single centre prospective study. Patients affected by pancreatic metastases from RCC with non-resectable lesions or not amenable to surgery were enrolled. Patients and tumour features were recorded. All patients underwent EUS-RFA with a monopolar, 19 G RFA needle (Endoscopic UltraSound guided Radio-frequency Ablation electrode; EUSRA) directly introduced in the endoscope’s operative channel, with a RF power of 30W. All patients underwent CT/MRI scan after 24 hours from the procedure. Feasibility was defined as the possibility of inserting the needle in the lesion and applying the radiofrequency. Safety was defined by collecting data of any complication occurred within 3 months of follow-up. From January to August 2019, three patients were enrolled (2 women; mean age 64 ±19 years). Overall, four lesions were treated (Mean size 26±17 mm). 3 out of 4 lesions were located in pancreatic head. The procedure resulted feasible in 100% of cases. No complications occurred after the treatment. The post-procedural imaging showed in all cases the presence of a necrotic area in the site of treatment. EUS-RFA seems to be a feasible and safe technique for the treatment of not surgical pancreatic metastases from RCC. Further studies are necessary to determine the efficacy of this treatment.

Simultaneous resection of the primary tumour and liver metastases after conversion chemotherapy versus standard therapy in pancreatic cancer with liver oligometastasis: protocol of a multicentre, prospective, randomised phase III control trial (CSPAC-1)

IntroductionApproximately 50% of pancreatic ductal adenocarcinoma (PDAC) patients are diagnosed with distant metastasis, especially liver metastasis. The current standard treatment for these stage IV patients is palliative chemotherapy. There is...

Incidental splenic findings in pancreatosplenectomy specimens resected for primary pancreatic lesions.

Little has been written on the frequency and nature of incidental splenic lesions diagnosed on histopathological examination of pancreatosplenectomy specimens. For 191 such specimens, incidental histological findings after haematopathologist re-review were tabulated. Cases suspicious for lymphoid malignancy underwent molecular analysis for immunoglobulin heavy and kappa light chain rearrangement. Follow-up was obtained on selected cases. In five cases (3%), the spleen was sampled but not mentioned in the original microscopic report; all were normal on re-review. Otherwise, most (171 of 186, 92%) were initially diagnosed as normal, with 160 (94%) remaining so on re-review. Findings on re-review not initially described (n=11, 6%) included four cases with splenic morphology suspicious for possible leukaemia/lymphoma involvement. Additional findings included abscess formation, foamy macrophages, necrotising granulomas and simple cysts. Fifteen spleens were initially diagnosed as abnormal; the histopathological process was confirmed in all, including non-necrotising granulomas, cysts, Gamna-Gandy bodies, foamy macrophages, involvement by pancreatic neoplasm and involvement by known chronic lymphocytic leukaemia (CLL). Molecular analysis was performed on the five cases of known/suspected lymphoma and two were positive for monoclonal gene rearrangement, including the known CLL and a previously undiagnosed case with similar immunophenotype. Incidental splenic findings are not uncommon in pancreatosplenectomy specimens. While most are of limited clinical significance, low-grade lymphoproliferative disorders may go undetected if the spleen is overlooked. We recommend careful observation of splenic findings in these specimens, with a low threshold for haematopathological consultation when in doubt.

An Analysis of Patients with DNA Repair Pathway Mutations Treated with a PARP Inhibitor.

Molecular analysis has revealed four subtypes of pancreatic ductal adenocarcinoma (PDAC). One subtype identified for the presence of DNA damage repair deficiency can be targeted therapeutically with the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib. We performed a single institution retrospective analysis of treatment response in patients with PDAC treated with olaparib who have DNA damage repair deficiency mutations. Patients with germline or somatic mutations involving the DNA repair pathway were identified and treated with olaparib. The primary objective was to examine the objective response rate (ORR). The secondary objectives were assessing tolerability, overall survival, and change in cancer antigen 19-9. Quantitative texture analysis (QTA) was evaluated from CT scans to explore imaging biomarkers. Thirteen individuals with metastatic PDAC were treated with Olaparib. The ORR to Olaparib was 23%. Median overall survival (OS) was 16.47 months. Four of seven patients with BRCA mutations had an effect on RAD51 binding, with a median OS of 24.60 months. Exploratory analysis of index lesions using QTA revealed correlations between lesion texture and OS (hepatic lesion tumor texture correlation coefficient [CC], 0.683, p = .042) and time on olaparib (primary pancreatic lesion tumor texture CC, 0.778, p = .023). In individuals with metastatic PDAC who have mutations involved in DNA repair, Olaparib may provide clinical benefit. BRCA mutations affecting RAD51 binding domains translated to improved median OS. QTA of individual tumors may allow for additional information that predicts outcomes to treatment with PARP inhibitors. Pursuing germline and somatic DNA sequencing in individuals with pancreatic ductal adenocarcinoma may yield abnormalities in DNA repair pathways. These individuals may receive benefit with poly (ADP-ribose) polymerase (PARP) inhibition. Radiomics and deep sequencing analysis may yet uncover additional information that may predict outcome to treatment with PARP inhibitors.

Thrombin Signaling Promotes Pancreatic Adenocarcinoma through PAR-1-Dependent Immune Evasion.

Pancreatic ductal adenocarcinoma (PDAC) is associated with robust activity of the coagulation system. To determine mechanisms by which clotting factors influence PDAC tumor progression, we generated and characterized C57Bl/6-derived KPC (KRasG12D, TRP53R172H ) cell lines. Tissue factor (TF) and protease-activated receptor-1 (PAR-1) were highly expressed in primary KPC pancreatic lesions and KPC cell lines similar to expression profiles observed in biopsies of patients with PDAC. In allograft studies, tumor growth and metastatic potential were significantly diminished by depletion of TF or Par-1 in cancer cells or by genetic or pharmacologic reduction of the coagulation zymogen prothrombin in mice. Notably, PAR-1-deleted KPC cells (KPC-Par-1KO) failed to generate sizable tumors, a phenotype completely rescued by restoration of Par-1 expression. Expression profiling of KPC and KPC-Par-1KO cells indicated that thrombin-PAR-1 signaling significantly altered immune regulation pathways. Accordingly, KPC-Par-1KO cells failed to form tumors in immune-competent mice but displayed robust tumor growth comparable to that observed with control KPC cells in immune-compromised NSG mice. Immune cell depletion studies indicated that CD8 T cells, but not CD4 cells or natural killer cells, mediated elimination of KPC-Par-1KO tumor cells in C57Bl/6 mice. These results demonstrate that PDAC is driven by activation of the coagulation system through tumor cell-derived TF, circulating prothrombin, and tumor cell-derived PAR-1 and further indicate that one key mechanism of thrombin/PAR-1-mediated tumor growth is suppression of antitumor immunity in the tumor microenvironment. SIGNIFICANCE: The tissue factor-thrombin-PAR-1 signaling axis in tumor cells promotes PDAC growth and disease progression with one key mechanism being suppression of antitumor immunity in the microenvironment.

Main driver genes and BRCA mutation in Chinese patients with pancreatic adenocarcinoma.

e15741 Background: Data on pathogenic genetic alterations in Chinese patients with pancreatic adenocarcinoma (PAC) are limited. Especially, as BRCA mutations may become potential biomarkers guiding therapy for PAC patients, the prevalence of BRCA mutations in Chinese patients remains largely unknown.We performed the study to analyze genes mutational landscape and determine the prevalence of BRCA mutations in Chinese PAC patients. Methods: We reviewed clinical characteristics and genes mutations of 134 patients with a pathologically confirmed PAC from West China Hospital of Sichuan University between May 2016 and November 2018. All of them underwent gene-testing and genes variant evaluation with a panel of 381 genes by next-generation sequencing (NGS). The test samples were mainly from primary pancreatic lesions, other were from peripheral blood and metastatic sites. All main driver gene mutations and clinical stages were measured to determine associations of driver gene mutations, the number of altered genes, the level of CA199 with clinical stage. Results: Of the 134 patients, 73 (54.5%) were men with a median age of 58 (range from 34 to 82) years. The major driver mutations were KRAS (89.6%), TP53 (71.6%), CDKN2A (26.9%), SMAD4 (18.7%) and ARID1A (10.4%). The majority of patients (76.9%) had 2 genes or more genes mutations, KRAS/TP53 and KRAS/TP53/CDKN2A were the most frequently combinate types. Stages of PAC was relevant to numbers of altered genes (p = 0.040) and the level of CA199 (p = 0.002). Five (3.7%) patients with BRCA mutations were identified, two patients had somatic BRCA2 variants, one patient had somatic BRCA1 mutation and the other two patients had germline BRCA2 mutation. Two patients with germline BRCA2 mutations received olaparib and keep stable disease for 4 months and more than 8 months. Our finding revealed patients with PAC had a low TMB (median 3.81 per Mb (range 0.81-9 per Mb)) and PD-L1 expression (16/36, 44.4%), nearly all of them were MSS (50/51,98.0%), just three patients with dMMR (3/134,2.2%). Conclusions: The PAC patient commonly harbored two or more number of five major driver mutations including KRAS, TP53, CDKN2A, SMAD4 and ARID1A. The frequency of BRCA1/2 mutations in Chinese patients with PAC was 3.7%. Olaparib may be effective for PAC patients with BRCA mutations. The PAC may be poor response to immunotherapy.

Laparoscopic Approach of the Left Side of the Pancreas

IntroductionLaparoscopic left-sided pancreatectomy (LLP) is an increasingly used surgical technique for the treatment of benign and malignant lesions of the left side of the pancreas. The results of LLP as a treatment for primary pancreatic lesions of the head and tail of the pancreas were evaluated. MethodsFrom November 2011 to November 2017, 18 patients underwent surgery for primary lesions of the pancreas by means of a laparoscopic distal pancreatectomy. An intra-abdominal drain tube was used in all cases, and the recommendations of the International Study Group for Pancreatic Fistula (ISGPF) were followed. ResultsThe mean age was 66.5 years (IQR 46–74). Among the 18 left pancreatectomies performed, four were with splenic preservation, and one was a central pancreatectomy. There were two conversions. The median surgical time was 247.5 minutes (IQR 242–275). The median postoperative hospital stay was 7 days (IQR 6–8). After 90 days, complications were detected in five patients: three grade II, one grade III and one grade V according to the modified Clavien-Dindo classification. There was one grade B pancreatic fistula, and four patients had to be readmitted to hospital because of peripancreatic collections. The anatomic pathology diagnosis was malignant neoplasm in 38.9% of cases, all of them with negative resection margins. ConclusionsLLP can be considered the technique of choice in the treatment of primary benign pancreatic lesions and an alternative to the open approach in selected patients diagnosed with malignant pancreatic lesions.

Abordaje laparoscópico del páncreas izquierdo

IntroductionLaparoscopic left-sided pancreatectomy (LLP) is an increasingly used surgical technique for the treatment of benign and malignant lesions of the left side of the pancreas. The results of LLP as a treatment for primary pancreatic lesions of the head and tail of the pancreas were evaluated. MethodsFrom November 2011 to November 2017, 18 patients underwent surgery for primary lesions of the pancreas by means of a laparoscopic distal pancreatectomy. An intra-abdominal drain tube was used in all cases, and the recommendations of the International Study Group for Pancreatic Fistula (ISGPF) were followed. ResultsThe mean age was 66.5years (IQR 46-74). Among the 18 left pancreatectomies performed, four were with splenic preservation, and one was a central pancreatectomy. There were two conversions. The median surgical time was 247.5minutes (IQR 242-275). The median postoperative hospital stay was 7days (IQR 6-8). After 90days, complications were detected in five patients: three gradeII, one gradeIII and one gradeV according to the modified Clavien-Dindo classification. There was one gradeB pancreatic fistula, and four patients had to be readmitted to hospital because of peripancreatic collections. The anatomic pathology diagnosis was malignant neoplasm in 38.9% of cases, all of them with negative resection margins. ConclusionsLLP can be considered the technique of choice in the treatment of primary benign pancreatic lesions and an alternative to the open approach in selected patients diagnosed with malignant pancreatic lesions.