scholarly journals A Functional Spatial Analysis Platform for Discovery of Immunological Interactions Predictive of Low-Grade to High-Grade Transition of Pancreatic Intraductal Papillary Mucinous Neoplasms

2018 ◽  
Vol 17 ◽  
pp. 117693511878288 ◽  
Author(s):  
Souptik Barua ◽  
Luisa Solis ◽  
Edwin Roger Parra ◽  
Naohiro Uraoka ◽  
Mei Jiang ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Subsequent Development ◽  
Ductal Adenocarcinoma ◽  
Low Grade ◽  
High Grade ◽  
Cellular Interactions ◽  
Spatial Interactions ◽  
Intraductal Papillary Mucinous Neoplasms ◽  
Remnant Pancreas ◽  
Mucinous Neoplasms

Intraductal papillary mucinous neoplasms (IPMNs), critical precursors of the devastating tumor pancreatic ductal adenocarcinoma (PDAC), are poorly understood in the pancreatic cancer community. Researchers have shown that IPMN patients with high-grade dysplasia have a greater risk of subsequent development of PDAC in the remnant pancreas than do patients with low-grade dysplasia. In this study, we built a computational prediction model that encapsulates the spatial cellular interactions in IPMNs that play key roles in the transformation of low-grade IPMN cysts to high-grade cysts en route to PDAC. Using multiplex immunofluorescent images of IPMN cysts, we adopted algorithms from spatial statistics and functional data analysis to create metrics that summarize the spatial interactions in IPMNs. We showed that an ensemble of models learned using these spatial metrics can robustly predict, with high accuracy, (1) the dysplasia grade (low vs high grade) and (2) the risk of a low-grade cyst progressing to a high-grade cyst. We obtained high classification accuracies on both tasks, with areas under the curve of 0.81 (95% confidence interval: 0.71-0.9) for task 1 and 0.81 (95% confidence interval: 0.7-0.94) for task 2. To the best of our knowledge, this is the first application of an ensemble machine learning approach for discovering critical cellular spatial interactions in IPMNs using imaging data. We envision that our work can be used as a risk assessment tool for patients diagnosed with IPMNs and facilitate greater understanding and investigation of the cellular interactions that cause transition of IPMNs to PDAC.

scholarly journals Surgical strategy for intraductal papillary mucinous neoplasms of the pancreas

Surgery Today ◽  
2019 ◽  
Vol 50 (1) ◽  
pp. 50-55 ◽  
Author(s):  
Seiko Hirono ◽  
Hiroki Yamaue
Keyword(s):  
Surgical Resection ◽  
Treatment Strategy ◽  
Mucinous Carcinoma ◽  
Current Treatment ◽  
Low Grade ◽  
Intraductal Papillary Mucinous Neoplasms ◽  
International Consensus ◽  
Branch Duct ◽  
Remnant Pancreas ◽  
Mucinous Neoplasms

AbstractThe current treatment strategy for intraductal papillary mucinous neoplasms (IPMNs), based on the international consensus guideline, has been accepted widely. However, reported outcomes after surgical resection for IPMN show that once the tumor progresses to invasive intraductal papillary mucinous carcinoma (IPMC), recurrence is not uncommon. The surgical treatment for IPMN is invasive and sometimes followed by complications. Therefore, the best timing for resection might be at the point when high-grade dysplasia (HGD) is evident. According to previous reports, main duct type IPMN has a high malignant potential and its surgical resection is universally accepted, whereas, the incidence of HGD/invasive IPMC in branch duct and mixed type IPMNs is thought to be lower. In addition to mural nodules and a dilated main pancreatic duct, cytology and measurement of the carcinoembryonic antigen level in the pancreatic juice might be useful to differentiate HGD/invasive IPMC from low-grade dysplasia. The nomogram proposed recently to predict the risk of HGD/invasive IPMC in IPMN patients might help surgeons decide on the best treatment strategy, depending on the patient’s age and general condition. Second resection for high-risk lesions in the remnant pancreas might improve the survival of IPMN patients.

scholarly journals Development of Pancreatic Ductal Adenocarcinoma Associated with Intraductal Papillary Mucinous Neoplasia

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Kazuo Inui ◽  
Junji Yoshino ◽  
Hironao Miyoshi ◽  
Takashi Kobayashi ◽  
Satoshi Yamamoto
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Magnetic Resonance Cholangiopancreatography ◽  
Ductal Adenocarcinoma ◽  
Intraductal Papillary Mucinous Neoplasms ◽  
Cancer Occurrence ◽  
Remnant Pancreas ◽  
Mucinous Neoplasms ◽  
Group 2 ◽  
Enhanced Computed Tomography ◽  
Periodic Evaluation

We retrospectively investigated the incidence of pancreatic ductal adenocarcinoma among patients with intraductal papillary mucinous neoplasms of the pancreas. Based on imaging in 195 such patients, we chose surgery as initial treatment for 54, and periodic evaluation over 6 to 192 months (mean, 52) for 141. In 6 of the 141 patients observed for intraductal papillary mucinous neoplasm (4.2%), pancreatic ductal adenocarcinoma developed. Further, careful monitoring for cancer occurrence in the remnant pancreas proved essential in the surgical resection group; 2 of 26 patients (7.7%) subsequently developed pancreatic ductal adenocarcinoma in the remnant pancreas, at 41 months and 137 months after surgery. Serial observation of patients with intraductal papillary mucinous neoplasms by contrast-enhanced computed tomography or magnetic resonance cholangiopancreatography therefore is critical, whether or not surgical treatment initially was performed.

Multiregion whole-exome sequencing of intraductal papillary mucinous neoplasms reveals frequent somatic KLF4 mutations predominantly in low-grade regions

Gut ◽  
2020 ◽  
pp. gutjnl-2020-321217
Author(s):  
Kohei Fujikura ◽  
Waki Hosoda ◽  
Matthäus Felsenstein ◽  
Qianqian Song ◽  
Johannes G Reiter ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
High Grade Dysplasia ◽  
Low Grade ◽  
High Grade ◽  
Intraductal Papillary Mucinous Neoplasms ◽  
Whole Exome ◽  
Mucinous Neoplasms ◽  
Hotspot Mutations ◽  
Independent Cohort

ObjectiveIntraductal papillary mucinous neoplasms (IPMNs) are non-invasive precursor lesions that can progress to invasive pancreatic cancer and are classified as low-grade or high-grade based on the morphology of the neoplastic epithelium. We aimed to compare genetic alterations in low-grade and high-grade regions of the same IPMN in order to identify molecular alterations underlying neoplastic progression.DesignWe performed multiregion whole exome sequencing on tissue samples from 17 IPMNs with both low-grade and high-grade dysplasia (76 IPMN regions, including 49 from low-grade dysplasia and 27 from high-grade dysplasia). We reconstructed the phylogeny for each case, and we assessed mutations in a novel driver gene in an independent cohort of 63 IPMN cyst fluid samples.ResultsOur multiregion whole exome sequencing identified KLF4, a previously unreported genetic driver of IPMN tumorigenesis, with hotspot mutations in one of two codons identified in >50% of the analyzed IPMNs. Mutations in KLF4 were significantly more prevalent in low-grade regions in our sequenced cases. Phylogenetic analyses of whole exome sequencing data demonstrated diverse patterns of IPMN initiation and progression. Hotspot mutations in KLF4 were also identified in an independent cohort of IPMN cyst fluid samples, again with a significantly higher prevalence in low-grade IPMNs.ConclusionHotspot mutations in KLF4 occur at high prevalence in IPMNs. Unique among pancreatic driver genes, KLF4 mutations are enriched in low-grade IPMNs. These data highlight distinct molecular features of low-grade and high-grade dysplasia and suggest diverse pathways to high-grade dysplasia via the IPMN pathway.

scholarly journals Pancreatic Cancers with High Grade Tumor Budding Exhibit Hallmarks of Diminished Anti-Tumor Immunity

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1090
Author(s):  
Hassan Sadozai ◽  
Animesh Acharjee ◽  
Thomas Gruber ◽  
Beat Gloor ◽  
Eva Karamitopoulou
Keyword(s):  
Gene Expression ◽  
Pancreatic Cancer ◽  
Disease Progression ◽  
Immune Escape ◽  
Epithelial Mesenchymal Transition ◽  
Tumor Budding ◽  
Ductal Adenocarcinoma ◽  
Low Grade ◽  
High Grade ◽  
Mesenchymal Transition

Tumor budding is associated with epithelial-mesenchymal transition and diminished survival in a number of cancer types including pancreatic ductal adenocarcinoma (PDAC). In this study, we dissect the immune landscapes of patients with high grade versus low grade tumor budding to determine the features associated with immune escape and disease progression in pancreatic cancer. We performed immunohistochemistry-based quantification of tumor-infiltrating leukocytes and tumor bud assessment in a cohort of n = 111 PDAC patients in a tissue microarray (TMA) format. Patients were divided based on the ITBCC categories of tumor budding as Low Grade (LG: categories 1 and 2) and High Grade (HG: category 3). Tumor budding numbers and tumor budding grade demonstrated a significant association with diminished overall survival (OS). HG cases exhibit notably reduced densities of stromal (S) and intratumoral (IT) T cells. HG cases also display lower M1 macrophages (S) and increased M2 macrophages (IT). These findings were validated using gene expression data from TCGA. A published tumor budding gene signature demonstrated a significant association with diminished survival in PDAC patients in TCGA. Immune-related gene expression revealed an immunosuppressive TME in PDAC cases with high expression of the budding signature. Our findings highlight a number of immune features that permit an improved understanding of disease progression and EMT in pancreatic cancer.

scholarly journals Radiomic nomogram based on MRI to predict grade of branching type intraductal papillary mucinous neoplasms of the pancreas: a multicenter study

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Sijia Cui ◽  
Tianyu Tang ◽  
Qiuming Su ◽  
Yajie Wang ◽  
Zhenyu Shu ◽  
...  
Keyword(s):  
Calibration Curve ◽  
Main Pancreatic Duct ◽  
Validation Cohort ◽  
External Validation ◽  
High Grade ◽  
Intraductal Papillary Mucinous Neoplasms ◽  
Training Cohort ◽  
Independent Validation ◽  
Medical Centers ◽  
Mucinous Neoplasms

Abstract Background Accurate diagnosis of high-grade branching type intraductal papillary mucinous neoplasms (BD-IPMNs) is challenging in clinical setting. We aimed to construct and validate a nomogram combining clinical characteristics and radiomic features for the preoperative prediction of low and high-grade in BD-IPMNs. Methods Two hundred and two patients from three medical centers were enrolled. The high-grade BD-IPMN group comprised patients with high-grade dysplasia and invasive carcinoma in BD-IPMN (n = 50). The training cohort comprised patients from the first medical center (n = 103), and the external independent validation cohorts comprised patients from the second and third medical centers (n = 48 and 51). Within 3 months prior to surgery, all patients were subjected to magnetic resonance examination. The volume of interest was delineated on T1-weighted (T1-w) imaging, T2-weighted (T2-w) imaging, and contrast-enhanced T1-weighted (CET1-w) imaging, respectively, on each tumor slice. Quantitative image features were extracted using MITK software (G.E.). The Mann-Whitney U test or independent-sample t-test, and LASSO regression, were applied for data dimension reduction, after which a radiomic signature was constructed for grade assessment. Based on the training cohort, we developed a combined nomogram model incorporating clinical variables and the radiomic signature. Decision curve analysis (DCA), a receiver operating characteristic curve (ROC), a calibration curve, and the area under the ROC curve (AUC) were used to evaluate the utility of the constructed model based on the external independent validation cohorts. Results To predict tumor grade, we developed a nine-feature-combined radiomic signature. For the radiomic signature, the AUC values of high-grade disease were 0.836 in the training cohort, 0.811 in external validation cohort 1, and 0.822 in external validation cohort 2. The CA19–9 level and main pancreatic duct size were identified as independent parameters of high-grade of BD-IPMNs using multivariate logistic regression analysis. The CA19–9 level and main pancreatic duct size were then used to construct the radiomic nomogram. Using the radiomic nomogram, the high-grade disease-associated AUC values were 0.903 (training cohort), 0.884 (external validation cohort 1), and 0.876 (external validation cohort 2). The clinical utility of the developed nomogram was verified using the calibration curve and DCA. Conclusions The developed radiomic nomogram model could effectively distinguish high-grade patients with BD-IPMNs preoperatively. This preoperative identification might improve treatment methods and promote personalized therapy in patients with BD-IPMNs.

scholarly journals Aboriginal women have a higher risk of cervical abnormalities at screening; South Australia, 1993–2016

2018 ◽  
Vol 26 (2) ◽  
pp. 104-112
Author(s):  
Ming Li ◽  
David Roder ◽  
Lisa J Whop ◽  
Abbey Diaz ◽  
Peter D Baade ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Relative Risk ◽  
Confidence Interval ◽  
Cervical Screening ◽  
South Australia ◽  
Low Grade ◽  
High Grade ◽  
Mixed Effect ◽  
Aboriginal Women ◽  
Cytological Abnormality

Objective Cervical cancer mortality has halved in Australia since the national cervical screening program began in 1991, but elevated mortality rates persist for Aboriginal and Torres Strait Islander women (referred to as Aboriginal women in this report). We investigated differences by Aboriginal status in abnormality rates predicted by cervical cytology and confirmed by histological diagnoses among screened women. Methods Using record linkage between cervical screening registry and public hospital records in South Australia, we obtained Aboriginal status of women aged 20–69 for 1993–2016 (this was not recorded by the registry). Differences in cytological abnormalities were investigated by Aboriginal status, using relative risk ratios from mixed effect multinomial logistic regression modelling. Odds ratios were calculated for histological high grade results for Aboriginal compared with non-Aboriginal women. Results Of 1,676,141 linkable cytology tests, 5.8% were abnormal. Abnormal results were more common for women who were younger, never married, and living in a major city or socioeconomically disadvantaged area. After adjusting for these factors and numbers of screening episodes, the relative risk of a low grade cytological abnormality compared with a normal test was 14% (95% confidence interval 5–24%) higher, and the relative risk of a high grade cytological abnormality was 61% (95% confidence interval 44–79%) higher, for Aboriginal women. The adjusted odds ratio of a histological high grade was 76% (95% confidence interval 46–113%) higher. Conclusions Ensuring that screen-detected abnormalities are followed up in a timely way by culturally acceptable services is important for reducing differences in cervical cancer rates between Aboriginal and non-Aboriginal women.

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