- Browse by Author
Browsing by Author "Yip-Schneider, Michele"
Now showing 1 - 8 of 8
Results Per Page
Sort Options
Item Diminished Immune Surveillance during Histologic Progression of Intraductal Papillary Mucinous Neoplasms Offers a Therapeutic Opportunity for Cancer Interception(American Association for Cancer Research, 2022) Hernandez, Sharia; Parra, Edwin Roger; Uraoka, Naohiro; Tang, Ximing; Shen, Yu; Qiao, Wei; Jiang, Mei; Zhang, Shanyu; Mino, Barbara; Lu, Wei; Pandurengan, Renganayaki; Haymaker, Cara; Affolter, Kajsa; Scaife, Courtney L.; Yip-Schneider, Michele; Schmidt, C. Max; Firpo, Matthew A.; Mulvihill, Sean J.; Koay, Eugene J.; Wang, Huamin; Wistuba, Ignacio I.; Maitra, Anirban; Solis, Luisa M.; Sen, Subrata; Surgery, School of MedicinePurpose: Intraductal papillary mucinous neoplasms (IPMN) are bona fide precursors to pancreatic ductal adenocarcinoma (PDAC). While genomic alterations during multistep IPMN progression have been well cataloged, the accompanying changes within the tumor immune microenvironment (TIME) have not been comprehensively studied. Herein, we investigated TIME-related alterations during IPMN progression, using multiplex immunofluorescence (mIF) coupled with high-resolution image analyses. Experimental design: Two sets of formalin-fixed, paraffin-embedded tissue samples from surgically resected IPMNs were analyzed. The training set of 30 samples consisted of 11 low-grade IPMN (LG-IPMN), 17 high-grade IPMN (HG-IPMN), and 2 IPMN with PDAC, while a validation set of 93 samples comprised of 55 LG-IPMN and 38 HG-IPMN. The training set was analyzed with two panels of immuno-oncology-related biomarkers, while the validation set was analyzed with a subset of markers found significantly altered in the training set. Results: Cell types indicative of enhanced immune surveillance, including cytotoxic and memory T cells, and antigen-experienced T cells and B cells, were all found at higher densities within isolated LG-IPMNs compared with HG-IPMNs. Notably, the TIME of LG-IPMNs that had progressed at the time of surgical resection (progressor LGD) resembled that of the synchronous HG-IPMNs, underscoring that attenuated immune surveillance occurs even in LG-IPMNs destined for progression. Conclusions: Our findings provide a basis for interception of cystic neoplasia to PDAC, through maintenance of sustained immune surveillance using vaccines and other prevention approaches.Item Integrated Molecular Characterization of Intraductal Papillary Mucinous Neoplasms: An NCI Cancer Moonshot Precancer Atlas Pilot Project(American Association for Cancer Research, 2023) Semaan, Alexander; Bernard, Vincent; Wong, Justin; Makino, Yuki; Swartzlander, Daniel B.; Rajapakshe, Kimal I.; Lee, Jaewon J.; Officer, Adam; Schmidt, Christian Max; Wu, Howard H.; Scaife, Courtney L.; Affolter, Kajsa E.; Nachmanson, Daniela; Firpo, Matthew A.; Yip-Schneider, Michele; Lowy, Andrew M.; Harismendy, Olivier; Sen, Subrata; Maitra, Anirban; Jakubek, Yasminka A.; Guerrero, Paola A.; Surgery, School of MedicineIntraductal papillary mucinous neoplasms (IPMN) are cystic precursor lesions to pancreatic ductal adenocarcinoma (PDAC). IPMNs undergo multistep progression from low-grade (LG) to high-grade (HG) dysplasia, culminating in invasive neoplasia. While patterns of IPMN progression have been analyzed using multiregion sequencing for somatic mutations, there is no integrated assessment of molecular events, including copy-number alterations (CNA) and transcriptional changes that accompany IPMN progression. We performed laser capture microdissection on surgically resected IPMNs of varying grades of histologic dysplasia obtained from 23 patients, followed by whole-exome and whole-transcriptome sequencing. Overall, HG IPMNs displayed a significantly greater aneuploidy score than LG lesions, with chromosome 1q amplification being associated with HG progression and with cases that harbored co-occurring PDAC. Furthermore, the combined assessment of single-nucleotide variants (SNV) and CNAs identified both linear and branched evolutionary trajectories, underscoring the heterogeneity in the progression of LG lesions to HG and PDAC. At the transcriptome level, upregulation of MYC-regulated targets and downregulation of transcripts associated with the MHC class I antigen presentation machinery as well as pathways related to glycosylation were a common feature of progression to HG. In addition, the established PDAC transcriptional subtypes (basal-like and classical) were readily apparent within IPMNs. Taken together, this work emphasizes the role of 1q copy-number amplification as a putative biomarker of high-risk IPMNs, underscores the importance of immune evasion even in noninvasive precursor lesions, and reinforces that evolutionary pathways in IPMNs are heterogenous, comprised of both SNV and CNA-driven events. Significance: Integrated molecular analysis of genomic and transcriptomic alterations in the multistep progression of IPMNs, which are bona fide precursors of pancreatic cancer, identifies features associated with progression of low-risk lesions to high-risk lesions and cancer, which might enable patient stratification and cancer interception strategies.Item A multimodality test to guide the management of patients with a pancreatic cyst(American Association for the Advancement of Science, 2019-07-17) Springer, Simeon; Masica, David L.; Dal Molin, Marco; Douville, Christopher; Thoburn, Christopher J.; Afsari, Bahman; Li, Lu; Cohen, Joshua D.; Thompson, Elizabeth; Allen, Peter J.; Klimstra, David S.; Schattner, Mark A.; Schmidt, C. Max; Yip-Schneider, Michele; Simpson, Rachel E.; Castillo, Carlos Fernandez-Del; Mino-Kenudson, Mari; Brugge, William; Brand, Randall E.; Singhi, Aatur D.; Scarpa, Aldo; Lawlor, Rita; Salvia, Roberto; Zamboni, Giuseppe; Hong, Seung-Mo; Hwang, Dae Wook; Jang, Jin-Young; Kwon, Wooil; Swan, Niall; Geoghegan, Justin; Falconi, Massimo; Crippa, Stefano; Doglioni, Claudio; Paulino, Jorge; Schulick, Richard D.; Edil, Barish H.; Park, Walter; Yachida, Shinichi; Hijioka, Susumu; van Hooft, Jeanin; He, Jin; Weiss, Matthew J.; Burkhart, Richard; Makary, Martin; Canto, Marcia I.; Goggins, Michael G.; Ptak, Janine; Dobbyn, Lisa; Schaefer, Joy; Sillman, Natalie; Popoli, Maria; Klein, Alison P.; Tomasetti, Cristian; Karchin, Rachel; Papadopoulos, Nickolas; Kinzler, Kenneth W.; Vogelstein, Bert; Wolfgang, Christopher L.; Hruban, Ralph H.; Lennon, Anne Marie; Surgery, School of MedicinePancreatic cysts are common and often pose a management dilemma, because some cysts are precancerous, whereas others have little risk of developing into invasive cancers. We used supervised machine learning techniques to develop a comprehensive test, CompCyst, to guide the management of patients with pancreatic cysts. The test is based on selected clinical features, imaging characteristics, and cyst fluid genetic and biochemical markers. Using data from 436 patients with pancreatic cysts, we trained CompCyst to classify patients as those who required surgery, those who should be routinely monitored, and those who did not require further surveillance. We then tested CompCyst in an independent cohort of 426 patients, with histopathology used as the gold standard. We found that clinical management informed by the CompCyst test was more accurate than the management dictated by conventional clinical and imaging criteria alone. Application of the CompCyst test would have spared surgery in more than half of the patients who underwent unnecessary resection of their cysts. CompCyst therefore has the potential to reduce the patient morbidity and economic costs associated with current standard-of-care pancreatic cyst management practices.Item A Plasma-Derived Protein-Metabolite Multiplexed Panel for Early-Stage Pancreatic Cancer(Oxford University Press, 2019-04-01) Fahrmann, Johannes F.; Bantis, Leonidas E.; Capello, Michela; Scelo, Ghislaine; Dennison, Jennifer B.; Patel, Nikul; Murage, Eunice; Vykoukal, Jody; Kundnani, Deepali L.; Foretova, Lenka; Fabianova, Eleonora; Holcatova, Ivana; Janout, Vladimir; Feng, Ziding; Yip-Schneider, Michele; Zhang, Jianjun; Brand, Randall; Taguchi, Ayumu; Maitra, Anirban; Brennan, Paul; Max Schmidt, C.; Hanash, Samir; Surgery, School of MedicineBACKGROUND: We applied a training and testing approach to develop and validate a plasma metabolite panel for the detection of early-stage pancreatic ductal adenocarcinoma (PDAC) alone and in combination with a previously validated protein panel for early-stage PDAC. METHODS: A comprehensive metabolomics platform was initially applied to plasmas collected from 20 PDAC cases and 80 controls. Candidate markers were filtered based on a second independent cohort that included nine invasive intraductal papillary mucinous neoplasm cases and 51 benign pancreatic cysts. Blinded validation of the resulting metabolite panel was performed in an independent test cohort consisting of 39 resectable PDAC cases and 82 matched healthy controls. The additive value of combining the metabolite panel with a previously validated protein panel was evaluated. RESULTS: Five metabolites (acetylspermidine, diacetylspermine, an indole-derivative, and two lysophosphatidylcholines) were selected as a panel based on filtering criteria. A combination rule was developed for distinguishing between PDAC and healthy controls using the Training Set. In the blinded validation study with early-stage PDAC samples and controls, the five metabolites yielded areas under the curve (AUCs) ranging from 0.726 to 0.842, and the combined metabolite model yielded an AUC of 0.892 (95% confidence interval [CI] = 0.828 to 0.956). Performance was further statistically significantly improved by combining the metabolite panel with a previously validated protein marker panel consisting of CA 19-9, LRG1, and TIMP1 (AUC = 0.924, 95% CI = 0.864 to 0.983, comparison DeLong test one-sided P= .02). CONCLUSIONS: A metabolite panel in combination with CA19-9, TIMP1, and LRG1 exhibited substantially improved performance in the detection of early-stage PDAC compared with a protein panel alone.Item Proinsulin Secretion Is a Persistent Feature of Type 1 Diabetes(American Diabetes Association, 2019-02) Sims, Emily K.; Bahnson, Henry T.; Nyalwidhe, Julius; Haataja, Leena; Davis, Asa K.; Speake, Cate; DiMeglio, Linda A.; Blum, Janice; Morris, Margaret A.; Mirmira, Raghavendra G.; Nadler, Jerry; Mastracci, Teresa L.; Marcovina, Santica; Qian, Wei-Jun; Yi, Lian; Swensen, Adam C.; Yip-Schneider, Michele; Schmidt, C. Max; Considine, Robert V.; Arvan, Peter; Greenbaum, Carla J.; Evans-Molina, Carmella; T1D Exchange Residual C-peptide Study Group; Pediatrics, School of MedicineOBJECTIVE: Abnormally elevated proinsulin secretion has been reported in type 2 and early type 1 diabetes when significant C-peptide is present. We questioned whether individuals with long-standing type 1 diabetes and low or absent C-peptide secretory capacity retained the ability to make proinsulin. RESEARCH DESIGN AND METHODS: C-peptide and proinsulin were measured in fasting and stimulated sera from 319 subjects with long-standing type 1 diabetes (≥3 years) and 12 control subjects without diabetes. We considered three categories of stimulated C-peptide: 1) C-peptide positive, with high stimulated values ≥0.2 nmol/L; 2) C-peptide positive, with low stimulated values ≥0.017 but <0.2 nmol/L; and 3) C-peptide <0.017 nmol/L. Longitudinal samples were analyzed from C-peptide-positive subjects with diabetes after 1, 2, and 4 years. RESULTS: Of individuals with long-standing type 1 diabetes, 95.9% had detectable serum proinsulin (>3.1 pmol/L), while 89.9% of participants with stimulated C-peptide values below the limit of detection (<0.017 nmol/L; n = 99) had measurable proinsulin. Proinsulin levels remained stable over 4 years of follow-up, while C-peptide decreased slowly during longitudinal analysis. Correlations between proinsulin with C-peptide and mixed-meal stimulation of proinsulin were found only in subjects with high stimulated C-peptide values (≥0.2 nmol/L). Specifically, increases in proinsulin with mixed-meal stimulation were present only in the group with high stimulated C-peptide values, with no increases observed among subjects with low or undetectable (<0.017 nmol/L) residual C-peptide. CONCLUSIONS: In individuals with long-duration type 1 diabetes, the ability to secrete proinsulin persists, even in those with undetectable serum C-peptide.Item Response to Comment on Sims et al. Proinsulin Secretion Is a Persistent Feature of Type 1 Diabetes. Diabetes Care 2019;42:258–264(American Diabetes Association, 2019-05) Sims, Emily K.; Bahnson, Henry T.; Nyalwidhe, Julius; Haataja, Leena; Davis, Asa K.; Speake, Cate; DiMeglio, Linda A.; Blum, Janice; Morris, Margaret A.; Mirmira, Raghavendra G.; Nadler, Jerry; Mastracci, Teresa L.; Marcovina, Santica; Qian, Wei-Jun; Yi, Lian; Swensen, Adam C.; Yip-Schneider, Michele; Schmidt, C. Max; Considine, Robert V.; Arvan, Peter; Greenbaum, Carla J.; Evans-Molina, Carmella; Pediatrics, School of MedicineItem Secretin-induced Duodenal Aspirate of Pancreatic Juice (SIDA): Utility of Commercial Genetic Analysis(International Institute of Anticancer Research, 2020) Simpson, Rachel E.; Yip-Schneider, Michele; Flick, Katelyn F.; Soufi, Mazhar; Ceppa, Eugene P.; Al-Haddad, Mohammad A.; Easler, Jeffrey J.; Sherman, Stuart; Dewitt, John M.; Schmidt, C. Max; Surgery, School of MedicineBackground: Secretin-induced duodenal aspiration (SIDA) of pancreatic duct fluid has been proposed for pancreatic neoplasm screening in very high-risk patients. We sought to determine the clinical yield and safety of commercially-analyzed SIDA samples in patients at moderately elevated risk. Patients and Methods: A prospectively maintained institutional database of pancreatic fluid DNA profiles was retrospectively reviewed. Results: Fifty-seven patients underwent SIDA testing, most commonly for intraductal papillary mucinous neoplasms (n=43) and not otherwise specified solitary cysts (n=9). SIDA mutation yield was low compared to 37 concomitant endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) samples of pancreatic fluid: KRAS (2.5% vs. 40.0%), GNAS (2.6% vs. 11.1%) and allelic loss of heterozygosity (3.1% vs. 0%). Patients undergoing SIDA alone experienced no complications while 3 patients with concomitant EUS-FNA had post-procedural pancreatitis. Conclusion: The genetic yield of commercially-analyzed SIDA samples was relatively low in a moderately elevated risk cohort. SIDA testing may have a better safety profile than EUS-FNA.Item Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of The Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential(American Association for Cancer Research, 2023) Sans, Marta; Makino, Yuki; Min, Jimin; Rajapakshe, Kimal I.; Yip-Schneider, Michele; Schmidt, C. Max; Hurd, Mark W.; Burks, Jared K.; Gomez, Javier A.; Thege, Fredrik I.; Fahrmann, Johannes F.; Wolff, Robert A.; Kim, Michael P.; Guerrero, Paola A.; Maitra, Anirban; Surgery, School of MedicineIntraductal papillary mucinous neoplasms (IPMN) of the pancreas are bona fide precursor lesions of pancreatic ductal adenocarcinoma (PDAC). The most common subtype of IPMNs harbors a gastric foveolar-type epithelium, and these low-grade mucinous neoplasms are harbingers of IPMNs with high-grade dysplasia and cancer. The molecular underpinning of gastric differentiation in IPMNs is unknown, although identifying drivers of this indolent phenotype might enable opportunities for intercepting progression to high-grade IPMN and cancer. We conducted spatial transcriptomics on a cohort of IPMNs, followed by orthogonal and cross-species validation studies, which established the transcription factor NKX6-2 as a key determinant of gastric cell identity in low-grade IPMNs. Loss of NKX6-2 expression is a consistent feature of IPMN progression, while reexpression of Nkx6-2 in murine IPMN lines recapitulates the aforementioned gastric transcriptional program and glandular morphology. Our study identifies NKX6-2 as a previously unknown transcription factor driving indolent gastric differentiation in IPMN pathogenesis.