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Pancreatic cystic lesions (PCL) are increasingly diagnosed. Endoscopic ultrasound fine-needle aspiration (EUS-FNA) cytology is often used for diagnostic confirmation but can be inconclusive. In this study, the role of molecular analyses in the pre-operative diagnostics of PCL is evaluated. Targeted Next Generation Sequencing (NGS) applied on cytology smears was retrospectively evaluated in a cohort of 37 resected PCL. Usefulness of NGS on fresh cyst fluids was tested in a prospective cohort of patients with newly diagnosed PCL (n = 71). In the retrospective cohort, cytology plus NGS displayed higher sensitivity (94.1% vs. 87.1%) and specificity (100% vs. 50%) than cytology alone for the detection of mucinous neoplasms. In the prospective cohort, sensitivity and specificity of conventional cytology alone were 54.2% and 100% for the detection of mucinous neoplasia and 50.0% and 100% for the detection of high-grade dysplasia, respectively. Adding NGS, all lesions which underwent histopathologic verification (12/71, 17%) could be classified without false positive or false negative results regarding the detection of mucinous neoplasm so far. NGS analysis of cfDNA in PCL fluids is feasible and can increase diagnostic accuracy in the detection of mucinous neoplasms compared to cytology alone. However, algorithms for the detection of high-risk lesions need further improvement.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors with a poor prognosis. A characteristic of PDAC is the formation of an immunosuppressive tumor microenvironment (TME) that facilitates bypassing of the immune surveillance. The TME consists of a desmoplastic stroma, largely composed of cancer-associated fibroblasts (CAFs), immunosuppressive immune cells, immunoregulatory soluble factors, neural network cells, and endothelial cells with complex interactions. PDAC develops from various precursor lesions such as pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasms (IPMN), mucinous cystic neoplasms (MCN), and possibly, atypical flat lesions (AFL). In this review, we focus on the composition of the TME in PanINs to reveal detailed insights into the complex restructuring of the TME at early time points in PDAC progression and to explore ways of modifying the TME to slow or even halt tumor progression.

Currently available serum biomarkers for pancreatobiliary cancers lack sensitivity and specificity and ultimate diagnosis still requires invasive procedures for histological confirmation. The detection of tumor-specific genetic aberrations with utilization of cell free DNA (cfDNA) is a less invasive approach than traditional tissue biopsies; however, it has not been implemented into clinical routine. In this study, we investigated bile as a liquid biopsy source in pancreatobiliary cancers and compared its potential as cell-free DNA source to plasma. Blood (n = 37) and bile (n = 21) samples were collected from patients affected by pancreatic ductal adenocarcinoma (PDAC) and extrahepatic cholangiocarcinoma (CCA) or with non-malignant biliary obstructions (blood n = 16; bile n = 21). Panel-based next generation sequencing (NGS) and digital droplet PCR (ddPCR) were applied for tumor mutation profiling. NGS results from matched tumor tissues (n = 29) served as comparison. Sequencing of cfDNA from bile resulted in detection of 96.2% of the pathogenic tumor mutations found in matched tissue samples. On the other hand, only 31.6% of pathogenic tumor mutations found in tissue could be detected in plasma. In a direct comparison, only half of the mutations detected in bile cfDNA were concordantly detected in plasma from the same patients. Panel NGS and ddPCR displayed comparable sensitivity. In conclusion, bile is a suitable source of cfDNA for the diagnosis of pancreatobiliary cancer and performs more reliably than plasma. Although primary diagnosis still requires histologic confirmation, bile-derived cfDNA could offer an alternative if tissue sampling is not feasible and might allow less invasive disease monitoring.

Pancreatic cancer, ranking as the third factor in cancer‐related deaths, necessitates enhanced diagnostic measures through early detection. In response, SiMoT‐Single‐molecule with a large Transistor multiplexing array, achieving a Technology Readiness Level of 5, is proposed for a timely identification of pancreatic cancer precursor cysts and is benchmarked against the commercially available chemiluminescent immunoassay SIMOA (Single molecule array) SP‐X System. A cohort of 39 samples, comprising 33 cyst fluids and 6 blood plasma specimens, undergoes detailed examination with both technologies. The SiMoT array targets oncoproteins MUC1 and CD55, and oncogene KRAS, while the SIMOA SP‐X planar technology exclusively focuses on MUC1 and CD55. Employing Principal Component Analysis (PCA) for multivariate data processing, the SiMoT array demonstrates effective discrimination of malignant/pre‐invasive high‐grade or potentially malignant low‐grade pancreatic cysts from benign non‐mucinous cysts. Conversely, PCA analysis applied to SIMOA assay reveals less effective differentiation ability among the three cyst classes. Notably, SiMoT unique capability of concurrently analyzing protein and genetic markers with the threshold of one single molecule in 0.1 mL positions it as a comprehensive and reliable diagnostic tool. The electronic response generated by the SiMoT array facilitates direct digital data communication, suggesting potential applications in the development of field‐deployable liquid biopsy. SiMoT‐Single‐Molecule with Large Transistor technology simultaneously analyzes protein and genetic markers, achieving a one‐molecule threshold in 0.1 mL. Benchmarking against SIMOA chemiluminescent ultrasensitive assay, SiMoT outperforms SIMOA in speed and overall performance. Moreover, SiMoT provides an electronic response, enhancing its suitability for direct digital data communication.

Pancreatic cystic lesions are increasingly diagnosed. Among other criteria, they are often distinguished in mucinous versus nonmucinous cysts. Mucinous pancreatic cystic lesions have received increasing attention, especially those known as precursors of pancreatic ductal adenocarcinoma. However, the group of nonmucinous cystic lesions of the pancreas includes numerous entities that may pose a diagnostic challenge. Their accurate diagnosis and classification are crucial for adequate patient management. To review the spectrum of nonmucinous cystic lesions of the pancreas, taking into consideration their epidemiology and typical clinical context, their characteristic gross morphology and histomorphology, as well as their immunohistochemical and molecular profile. Literature was searched and reviewed with MEDLINE via PubMed. Macroscopic and microscopic images were obtained from the archives of the Institute of Pathology, Heinrich Heine University and University Hospital of Duesseldorf, Germany. Nonmucinous cysts of the pancreas comprise numerous, mostly rare entities displaying different biological behaviors. The most frequent are serous cystic neoplasms, solid-pseudopapillary neoplasms, cystic neuroendocrine tumors, and pancreatitis-associated pseudocysts. Accurate diagnosis can be achieved if characteristic clinical context, histomorphology, and immunoprofile are taken into account.

Background Myxofibrosarcoma is a common soft tissue sarcoma of the extremities, which occurs very rarely in the thyroid gland. Case presentation We report the case of a 61-year-old male who presented with a swelling of the left side of the neck and a newly emerged hoarseness. Ultrasound depicted a hypoechoic thyroid nodule with microcalcifications that was highly suspicious for malignancy. He underwent a left hemithyroidectomy. Histopathological examination and immunohistochemical studies revealed a myxofibrosarcoma of the thyroid gland. Conclusion Myxofibrosarcoma of the thyroid gland is extremely rare. The diagnosis is based on histopathological features. Radical surgery achieving tumor-free resection margins remains the only chance for cure. However, the role of radiotherapy and/or chemotherapy is still under debate. Due to their high tendency for locoregional recurrence, a close follow-up after surgery is mandatory.

Background Metastatic spread to the pancreas is a rare event. Renal cell carcinoma represents one possible site of origin of pancreatic metastases. Renal cell carcinoma often metastasizes late and exclusively to the pancreas, suggesting a special role of renal cell carcinoma among primaries metastasizing to the pancreas. Even rarer, renal cell carcinoma may occur simultaneously with pancreatic ductal adenocarcinoma. Case presentation We present the case of a 78-year-old male Caucasian patient with a history of clear-cell renal cell carcinoma treated with oncological left nephrectomy 20 years before. The patient was diagnosed with pancreatic ductal adenocarcinoma by fine-needle aspiration cytology. At our institution, he received neoadjuvant therapy with folic acid, fluorouracil, irinotecan, oxaliplatin for borderline-resectable pancreatic ductal adenocarcinoma, and subsequently underwent total pancreatectomy. Upon resection, pancreatic ductal adenocarcinoma as well as two metachronous metastases of clear-cell renal cell carcinoma occurring simultaneously and cospatially with pancreatic ductal adenocarcinoma were diagnosed in the pancreatic body. Conclusions Renal cell carcinoma metastases of the pancreas are rare and often occur decades after the initial diagnosis of renal cell carcinoma. The combination of renal cell carcinoma metastases and pancreatic ductal adenocarcinoma is even rarer. However, the possibility should be considered by clinicians, radiologists, and pathologists. The special role of renal cell carcinoma as a site of origin of pancreatic metastasis should be further elucidated.

Background Pancreatic ductal adenocarcinoma (PDAC) is known to develop through a stepwise progression from precursor lesions, such as pancreatic intraepithelial neoplasias (PanIN). An alternative carcinogenic pathway has been proposed via transformation of acinar cells, with development of acinar-ductal metaplasia (ADM) and atypical flat lesions (AFL). Defining the characteristics of PDAC precursors is crucial to better understand PDAC carcinogenesis. Methods 15 KC ( Ptf1a Cre/+ , Kras LSLG12D/+ ) and 15 KPC-like mice ( Ptf1a Cre/+ , Kras LSLG12D/+ , Trp53 LoxP/LoxP , referred as fKPC hereafter) were sacrificed at different time points. A meticulous morphological evaluation was performed to define different lesion types. Multiplex immunofluorescence staining was applied to define the characteristics of the immune and stromal microenvironment of the lesions. To investigate the association between the genetic alterations and the components of the microenvironment, all lesion types were subjected to next-generation sequencing (NGS) using a 20 genes-panel. Results AFL showed a trend towards a more intense immune cell infiltration compared to PanIN and ADM. AFL had higher number of CD4 + helper T cells, FOXP3 + regulatory T cells, and CD19 + B cells than all other analyzed lesions. They displayed more CD8 + cytotoxic T cells and FOXP3 + cells than PDAC, while peripheral and central PDAC tissues tended to be infiltrated by macrophages in higher frequency. In addition, αSMA-expressing myofibroblastic cancer-associated fibroblasts were tendentially more frequent in AFL than other lesions. PDAC appeared to have higher CXCL12 expression and more common CD109 + cells than other lesions. In NGS analysis, none of the lesions in fKPC mice revealed additional coding mutations, while the preneoplastic lesions in 7 KC mice showed variable coding alterations in 16 different genes. The most frequently affected genes were Arid1a , Rnf43 , and Pik3ca . PDAC precursors in KC mice showed more dense infiltration of adaptive immune cells than in fKPC mice, supporting the immunosuppressive role of Trp53 alterations. Conclusions Our study highlights the unique immunological and stromal features of AFL. Moreover, reinforcing their potential as precursor lesions, ADM and AFL exhibit variable alterations in the genes that have a critical role in PDAC carcinogenesis. Graphical Abstract

Purpose To compare CT, MRI, and [ 18 F]-fluorodeoxyglucose positron emission tomography ([ 18 F]-FDG PET/MRI) for nodal status, regarding quantity and location of metastatic locoregional lymph nodes in patients with newly diagnosed breast cancer. Materials and methods One hundred eighty-two patients (mean age 52.7 ± 11.9 years) were included in this prospective double-center study. Patients underwent dedicated contrast-enhanced chest/abdomen/pelvis computed tomography (CT) and whole-body ([ 18 F]-FDG PET/) magnet resonance imaging (MRI). Thoracal datasets were evaluated separately regarding quantity, lymph node station (axillary levels I–III, supraclavicular, internal mammary chain), and lesion character (benign vs. malign). Histopathology served as reference standard for patient-based analysis. Patient-based and lesion-based analyses were compared by a McNemar test. Sensitivity, specificity, positive and negative predictive values, and accuracy were assessed for all three imaging modalities. Results On a patient-based analysis, PET/MRI correctly detected significantly more nodal positive patients than MRI ( p  < 0.0001) and CT ( p  < 0.0001). No statistically significant difference was seen between CT and MRI. PET/MRI detected 193 lesions in 75 patients (41.2%), while MRI detected 123 lesions in 56 patients (30.8%) and CT detected 104 lesions in 50 patients, respectively. Differences were statistically significant on a lesion-based analysis (PET/MRI vs. MRI, p  < 0.0001; PET/MRI vs. CT, p  < 0.0001; MRI vs. CT, p  = 0.015). Subgroup analysis for different lymph node stations showed that PET/MRI detected significantly more lymph node metastases than MRI and CT in each location (axillary levels I–III, supraclavicular, mammary internal chain). MRI was superior to CT only in axillary level I ( p  = 0.0291). Conclusion [ 18 F]-FDG PET/MRI outperforms CT or MRI in detecting nodal involvement on a patient-based analysis and on a lesion-based analysis. Furthermore, PET/MRI was superior to CT or MRI in detecting lymph node metastases in all lymph node stations. Of all the tested imaging modalities, PET/MRI showed the highest sensitivity, whereas CT showed the lowest sensitivity, but was most specific.

ObjectiveDue to the limited number of modifiable risk factors, secondary prevention strategies based on early diagnosis represent the preferred route to improve the prognosis of pancreatic ductal adenocarcinoma (PDAC). Here, we provide a comparative morphogenetic analysis of PDAC precursors aiming at dissecting the process of carcinogenesis and tackling the heterogeneity of preinvasive lesions.DesignTargeted and whole-genome low-coverage sequencing, genome-wide methylation and transcriptome analyses were applied on a final collective of 122 morphologically well-characterised low-grade and high-grade PDAC precursors, including intestinal and gastric intraductal papillary mucinous neoplasms (IPMN) and pancreatic intraepithelial neoplasias (PanIN).ResultsEpigenetic regulation of mucin genes determines the phenotype of PDAC precursors. PanIN and gastric IPMN display a ductal molecular profile and numerous similarly regulated pathways, including the Notch pathway, but can be distinguished by recurrent deletions and differential methylation and, in part, by the expression of mucin-like 3. Intestinal IPMN are clearly distinct lesions at the molecular level with a more instable genotype and are possibly related to a different ductal cell compartment.ConclusionsPDAC precursors with gastric and intestinal phenotype are heterogeneous in terms of morphology, genetic and epigenetic profile. This heterogeneity is related to a different cell identity and, possibly, to a different aetiology.