726 results on '"William A. Burns"'
Search Results
2. Retrograde open celiac stenting for ischemic hepatitis after pancreaticoduodenectomy
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Roberto G. Aru, MD, Sarah E. Deery, MD, MPH, Yasaman Kavousi, MD, James H. Black, III, MD, FACS, William R. Burns, MD, and Caitlin W. Hicks, MD, MS, FACS
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Celiac artery revascularization ,Ischemic hepatitis ,Pancreaticoduodenectomy ,Retrograde open mesenteric stenting ,Whipple procedure ,Surgery ,RD1-811 ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
A 74-year-old man with pancreatic cancer had undergone pancreaticoduodenectomy and subsequently developed ischemic hepatitis secondary to high-grade celiac artery stenosis. Celiac antegrade stenting via brachial artery access was unsuccessful, and open antegrade bypass would have required takedown of the pancreatic and/or biliary anastomoses for adequate exposure. Retrograde open celiac stenting was, therefore, successfully performed via the gastroduodenal artery stump. His ischemic hepatitis resolved, and he was ultimately discharged with dual antiplatelet therapy. Computed tomography angiography at 6 months demonstrated a widely patent celiac stent. Retrograde open celiac stenting via the gastroduodenal artery stump is an alternative to open bypass for celiac revascularization not amenable to percutaneous antegrade stenting in patients who have undergone pancreaticoduodenectomy.
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- 2023
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3. Obstructive sleep apnea predicts pathologic response to neoadjuvant therapy in resected pancreatic ductal adenocarcinoma
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Sami Shoucair, Ning Pu, Joseph R. Habib, Elizabeth Thompson, Christopher Shubert, Richard A. Burkhart, William R. Burns, Jin He, Kelly J. Lafaro, and Jun Yu
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Medicine - Published
- 2022
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4. They Believed That?: A Cultural Encyclopedia of Superstitions and the Supernatural around the World
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William E. Burns and William E. Burns
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- 2022
5. Science and Technology in World History: [2 volumes]
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William E. Burns, William E. Burns and William E. Burns, William E. Burns
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- 2020
6. Rapidly progressive metastatic cholangiocarcinoma in a postpartum patient with cystic fibrosis: a case report
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Sara W. Carson, Kelly E. Craven, David Nauen, Kristina Montemayor, Mark Yarchoan, William R. Burns, Christian A. Merlo, and Natalie E. West
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Cholangiocarcinoma ,Gastrointestinal cancer ,Cystic fibrosis, pregnancy ,Case report ,Diseases of the respiratory system ,RC705-779 - Abstract
Abstract Background Cholangiocarcinoma is a rare gastrointestinal malignancy that arises within the intrahepatic, perihilar, and/or extrahepatic bile ducts. Individuals with cystic fibrosis are at increased risk for gastrointestinal malignancies. The most common gastrointestinal malignancy in cystic fibrosis is colon cancer, but other gastrointestinal malignancies also occur at greater rates than the general population. Case presentation We present a case of a rapidly progressive metastatic intrahepatic cholangiocarcinoma in an individual with cystic fibrosis who was 5 months postpartum, incidentally found while undergoing a lung transplantation evaluation. Conclusion A heightened clinical awareness of gastrointestinal malignancies, beyond colon cancer, in individuals with cystic fibrosis is warranted. It remains unclear if pregnancy is an additional risk factor for gastrointestinal malignancies in cystic fibrosis.
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- 2020
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7. Contributors
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Parul Agarwal, Vinod P. Balachandran, Challice L. Bonifant, Timothy N.J. Bullock, William R. Burns, Sophia Y. Chen, Daniel Delitto, Stephen Desiderio, Jad Farouqa, Maria J. Gutierrez, Thatcher R. Heumann, Hyun Min Jung, Silvia Manzanero, Jamileh Nabizadeh, John E. Niederhuber, Olamide Olayinka, Nadya Panagides, Luis A. Rojas, Barbara E. Rolfe, Melanie Rutkowski, Stefan E. Sonderegger, Brant M. Weinstein, Trent M. Woodruff, and Lei Zheng
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- 2024
8. The major clinical components of cancer immunotherapy (modulating cell-mediated immune mechanisms)
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Challice L. Bonifant and William R. Burns
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- 2024
9. Protein synthesis inhibitor omacetaxine is effective against hepatocellular carcinoma
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Ling Li, Gilad Halpert, Michael G. Lerner, Haijie Hu, Peter Dimitrion, Matthew J. Weiss, Jin He, Benjamin Philosophe, Richard Burkhart, William R. Burns, Russell N. Wesson, Andrew MacGregor Cameron, Christopher L. Wolfgang, Christos Georgiades, Satomi Kawamoto, Nilofer S. Azad, Mark Yarchoan, Stephen J. Meltzer, Kiyoko Oshima, Laura M. Ensign, Joel S. Bader, and Florin M. Selaru
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Hepatology ,Oncology ,Medicine - Abstract
Hepatocellular carcinoma (HCC) is the sixth most common and the fourth most deadly cancer worldwide. The development cost of new therapeutics is a major limitation in patient outcomes. Importantly, there is a paucity of preclinical HCC models in which to test new small molecules. Herein, we implemented potentially novel patient-derived organoid (PDO) and patient-derived xenografts (PDX) strategies for high-throughput drug screening. Omacetaxine, an FDA-approved drug for chronic myelogenous leukemia (CML), was found to be a top effective small molecule in HCC PDOs. Next, omacetaxine was tested against a larger cohort of 40 human HCC PDOs. Serial dilution experiments demonstrated that omacetaxine is effective at low (nanomolar) concentrations. Mechanistic studies established that omacetaxine inhibits global protein synthesis, with a disproportionate effect on short–half-life proteins. High-throughput expression screening identified molecular targets for omacetaxine, including key oncogenes, such as PLK1. In conclusion, by using an innovative strategy, we report — for the first time to our knowledge — the effectiveness of omacetaxine in HCC. In addition, we elucidate key mechanisms of omacetaxine action. Finally, we provide a proof-of-principle basis for future studies applying drug screening PDOs sequenced with candidate validation in PDX models. Clinical trials could be considered to evaluate omacetaxine in patients with HCC.
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- 2021
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10. Evaluation of the IgG antibody response to SARS CoV-2 infection and performance of a lateral flow immunoassay: cross-sectional and longitudinal analysis over 11 months
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David Hunter, Peter Sharpe, Louise J Robertson, Julie S Moore, Kevin Blighe, Kok Yew Ng, Nigel Quinn, Fergal Jennings, Gary Warnock, Mark Clarke, Kathryn Maguire, Sharon Rainey, Ruth K Price, William P Burns, Amanda M Kowalczyk, Agnes Awuah, Sara E McNamee, Gayle E Wallace, Steve Sager, Connie Chao Shern, M Andrew Nesbit, James A D McLaughlin, and Tara Moore
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Medicine - Abstract
Objective To evaluate the dynamics and longevity of the humoral immune response to SARS-CoV-2 infection and assess the performance of professional use of the UK-RTC AbC-19 Rapid Test lateral flow immunoassay (LFIA) for the target condition of SARS-CoV-2 spike protein IgG antibodies.Design Nationwide serological study.Setting Northern Ireland, UK, May 2020–February 2021.Participants Plasma samples were collected from a diverse cohort of individuals from the general public (n=279), Northern Ireland healthcare workers (n=195), pre-pandemic blood donations and research studies (n=223) and through a convalescent plasma programme (n=183). Plasma donors (n=101) were followed with sequential samples over 11 months post-symptom onset.Main outcome measures SARS-CoV-2 antibody levels in plasma samples using Roche Elecsys Anti-SARS-CoV-2 IgG/IgA/IgM, Abbott SARS-CoV-2 IgG and EuroImmun IgG SARS-CoV-2 ELISA immunoassays over time. UK-RTC AbC-19 LFIA sensitivity and specificity, estimated using a three-reference standard system to establish a characterised panel of 330 positive and 488 negative SARS-CoV-2 IgG samples.Results We detected persistence of SARS-CoV-2 IgG antibodies for up to 10 months post-infection, across a minimum of two laboratory immunoassays. On the known positive cohort, the UK-RTC AbC-19 LFIA showed a sensitivity of 97.58% (95.28% to 98.95%) and on known negatives, showed specificity of 99.59% (98.53 % to 99.95%).Conclusions Through comprehensive analysis of a cohort of pre-pandemic and pandemic individuals, we show detectable levels of IgG antibodies, lasting over 46 weeks when assessed by EuroImmun ELISA, providing insight to antibody levels at later time points post-infection. We show good laboratory validation performance metrics for the AbC-19 rapid test for SARS-CoV-2 spike protein IgG antibody detection in a laboratory-based setting.
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- 2021
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11. Cancer-cell-derived sialylated IgG as a novel biomarker for predicting poor pathological response to neoadjuvant therapy and prognosis in pancreatic cancer
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Ming Cui, Sami Shoucair, Quan Liao, Xiaoyan Qiu, Benedict Kinny-Köster, Joseph R. Habib, Elie M. Ghabi, Junke Wang, Eun Ji Shin, Sean X. Leng, Syed Z. Ali, Elizabeth D. Thompson, Jacquelyn W. Zimmerman, Christopher R. Shubert, Kelly J. Lafaro, Richard A. Burkhart, William R. Burns, Lei Zheng, Jin He, Yupei Zhao, Christopher L. Wolfgang, and Jun Yu
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Surgery ,General Medicine - Published
- 2023
12. Implantation of a neoantigen-targeted hydrogel vaccine prevents recurrence of pancreatic adenocarcinoma after incomplete resection
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Daniel Delitto, Daniel J. Zabransky, Fangluo Chen, Elizabeth D. Thompson, Jacquelyn W. Zimmerman, Todd D. Armstrong, James M. Leatherman, Reecha Suri, Tamara Y. Lopez-Vidal, Amanda L. Huff, Melissa R. Lyman, Samantha R. Guinn, Marina Baretti, Luciane T. Kagohara, Won Jin Ho, Nilofer S. Azad, William R. Burns, Jin He, Christopher L. Wolfgang, Richard A. Burkhart, Lei Zheng, Mark Yarchoan, Neeha Zaidi, and Elizabeth M. Jaffee
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pancreatic adenocarcinoma ,immunotherapy ,neoantigen ,vaccine ,hydrogel ,surgery ,Immunologic diseases. Allergy ,RC581-607 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Tumor involvement of major vascular structures limits surgical options in pancreatic adenocarcinoma (PDAC), which in turn limits opportunities for cure. Despite advances in locoregional approaches, there is currently no role for incomplete resection. This study evaluated a gelatinized neoantigen-targeted vaccine applied to a grossly positive resection margin in preventing local recurrence. Incomplete surgical resection was performed in mice bearing syngeneic flank Panc02 tumors, leaving a 1 mm rim adherent to the muscle bed. A previously validated vaccine consisting of neoantigen peptides, a stimulator of interferon genes (STING) agonist and AddaVaxTM (termed PancVax) was embedded in a hyaluronic acid hydrogel and applied to the tumor bed. Tumor remnants, regional lymph nodes, and spleens were analyzed using histology, flow cytometry, gene expression profiling, and ELISPOT assays. The immune microenvironment at the tumor margin after surgery alone was characterized by a transient influx of myeloid-derived suppressor cells (MDSCs), prolonged neutrophil influx, and near complete loss of cytotoxic T cells. Application of PancVax gel was associated with enhanced T cell activation in the draining lymph node and expansion of neoantigen-specific T cells in the spleen. Mice implanted with PancVax gel demonstrated no evidence of residual tumor at two weeks postoperatively and healed incisions at two months postoperatively without local recurrence. In summary, application of PancVax gel at a grossly positive tumor margin led to systemic expansion of neoantigen-specific T cells and effectively prevented local recurrence. These findings support further work into locoregional adjuncts to immune modulation in PDAC.
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- 2021
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13. Insights for Critical Alarm-Based Warning Systems from a Risk Analysis of Commercial Aviation Passenger Screening.
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Robin L. Dillon, William J. Burns, and Richard S. John
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- 2018
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14. Broad-spectrum suppression of bacterial pneumonia by aminoglycoside-propagated Acinetobacter baumannii.
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M Indriati Hood-Pishchany, Ly Pham, Christiaan D Wijers, William J Burns, Kelli L Boyd, Lauren D Palmer, Eric P Skaar, and Michael J Noto
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
Antimicrobial resistance is increasing in pathogenic bacteria. Yet, the effect of antibiotic exposure on resistant bacteria has been underexplored and may affect pathogenesis. Here we describe the discovery that propagation of the human pathogen Acinetobacter baumannii in an aminoglycoside antibiotic results in alterations to the bacterium that interact with lung innate immunity resulting in enhanced bacterial clearance. Co-inoculation of mice with A. baumannii grown in the presence and absence of the aminoglycoside, kanamycin, induces enhanced clearance of a non-kanamycin-propagated strain. This finding can be replicated when kanamycin-propagated A. baumannii is killed prior to co-inoculation of mice, indicating the enhanced bacterial clearance results from interactions with innate host defenses in the lung. Infection with kanamycin-propagated A. baumannii alters the kinetics of phagocyte recruitment to the lung and reduces pro- and anti-inflammatory cytokine and chemokine production in the lung and blood. This culminates in reduced histopathologic evidence of lung injury during infection despite enhanced bacterial clearance. Further, the antibacterial response induced by killed aminoglycoside-propagated A. baumannii enhances the clearance of multiple clinically relevant Gram-negative pathogens from the lungs of infected mice. Together, these findings exemplify cooperation between antibiotics and the host immune system that affords protection against multiple antibiotic-resistant bacterial pathogens. Further, these findings highlight the potential for the development of a broad-spectrum therapeutic that exploits a similar mechanism to that described here and acts as an innate immunity modulator.
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- 2020
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15. Critical Electrocardiogram Curriculum: Setting the Standard for Flipped-Classroom EKG Instruction
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William P. Burns, Nicholas D. Hartman, P. Logan Weygandt, Shanna C. Jones, Holly Caretta-Weyer, and Kristen Grabow Moore
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Medicine ,Medical emergencies. Critical care. Intensive care. First aid ,RC86-88.9 - Abstract
Introduction: Electrocardiogram (EKG) interpretation is integral to emergency medicine (EM). 1 In 2003 Ginde et al. found 48% of emergency medicine (EM) residency directors supported creating a national EKG curriculum. 2 No formal national curriculum exists, and it is unknown whether residents gain sufficient skill from clinical exposure alone. Methods: The authors sought to assess the value of this EKG curriculum, which provides exposure to critical EKG patterns, a framework for EKG interpretation when the diagnosis is not obvious, and implementation guidelines and open access to any interested residency. The Foundations of Emergency Medicine (FoEM) EKG I course launched in January 2016, followed by EKG II in July 2017; they are benchmarked to post-graduate year 1 (PGY) and PGY2 level learners, respectively. Selected topics included 15 published critical EKG diagnoses and 33 selected by the authors. 5 Cases included presenting symptoms, EKGs, and Free Open Access Medical Education (FOAM) links. Full EKG interpretations and question answers were provided. Results: Enrollment during 2017–2018 included 37 EM residencies with 663 learners in EKG I and 22 EM residencies with 438 learners in EKG II. Program leaders and learners were surveyed annually. Leaders indicated that content was appropriate for intended PGY levels. Leaders and learners indicated the curriculum improved the ability of learners to interpret EKGs while working in the emergency department (ED). Conclusion: There is an unmet need for standardization and improvement of EM resident EKG training. Leaders and learners exposed to FoEM EKG courses report improved ability of learners to interpret EKGs in the ED.
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- 2019
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16. Tailoring Adjuvant Chemotherapy to Biologic Response Following Neoadjuvant Chemotherapy Impacts Overall Survival in Pancreatic Cancer
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Elie M. Ghabi, Sami Shoucair, Ding Ding, Ammar A. Javed, Elizabeth D. Thompson, Lei Zheng, John L. Cameron, Christopher L. Wolfgang, Christopher R. Shubert, Kelly J. Lafaro, Richard A. Burkhart, William R. Burns, and Jin He
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Gastroenterology ,Surgery ,Article - Abstract
BACKGROUND: The role of postoperative chemotherapy in patients with resected pancreatic cancer who receive neoadjuvant treatment is unknown. Clinicians use changes in CA19-9 and histopathologic scores to assess treatment response. We sought to investigate if CA19-9 normalization in response to NAT can help guide the need for postoperative treatment. METHODS: Patients with elevated baseline CA19-9 (CA19-9 > 37U/mL) who received NAT followed by surgery between 2011 and 2019 were retrospectively reviewed. Treatment response was determined by CA19-9 normalization following NAT and histopathologic scoring. The role of postoperative chemotherapy was analyzed in light of CA19-9 normalization and histopathologic response. RESULTS: We identified and included 345 patients. Following NAT, CA19-9 normalization was observed in 125 patients (36.2%). CA19-9 normalization was associated with a favorable histopathologic response (41.6% vs 23.2%, p < 0.001) and a lower ypT (p < 0.001) and ypN stage (p = 0.003). Receipt of adjuvant chemotherapy was associated with improved overall survival in patients in whom CA19-9 did not normalize following NAT (26.8 vs 16.4 months, p = 0.008). In patients who received 5FU-based NAT and in whom CA19-9 did not normalize, receipt of 5FU-based adjuvant chemotherapy was associated with improved OS (p = 0.014). CONCLUSION: CA19-9 normalization in response to NAT was associated with favorable outcomes and can serve as a biomarker for treatment response. In patients where CA19-9 did not normalize, receipt of postoperative chemotherapy was associated with improved OS. These patients also benefited from additional 5FU-based postoperative chemotherapy following 5FU-based NAT.
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- 2022
17. A Delay in Adjuvant Therapy Is Associated With Worse Prognosis Only in Patients With Transitional Circulating Tumor Cells After Resection of Pancreatic Ductal Adenocarcinoma
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Ammar A, Javed, A, Floortje van Oosten, Joseph R, Habib, Alina, Hasanain, Benedict, Kinny-Köster, Georgios, Gemenetzis, Vincent, Groot, Ding, Ding, John L, Cameron, Kelly J, Lafaro, William R, Burns, Richard A, Burkhart, Jun, Yu, Jin, He, and Christopher L, Wolfgang
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Surgery - Abstract
The aim of the study was to assess the association of circulating tumor cells (CTCs) with survival as a biomarker in pancreatic ductal adenocarcinoma (PDAC) within the context of a delay in initiation of adjuvant therapy.Outcomes in patients with PDAC remain poor and are driven by aggressive systemic disease. While systemic therapies improve survival in resected patients, factors such as a delay in initiation of adjuvant therapy are associated with worse outcomes. CTCs have previously been shown to be predictive of survival.A retrospective study was performed on PDAC patients enrolled in the prospective CLUSTER trial (NCT02974764) on CTC-dynamics at the Johns Hopkins Hospital. CTCs were isolated based on size (ISET; Rarecells) and counted and characterized by subtype using immunofluorescence. The preoperative and postoperative blood samples were used to identify two CTC types: epithelial CTCs (eCTCs), expressing pan-cytokeratin, and transitional CTCs (trCTCs), expressing both pan-cytokeratin and vimentin. Patients who received adjuvant therapy were compared with those who did not. A delay in receipt of adjuvant therapy was defined as initiation of therapy ≥8 weeks after surgical resection. Clinicopathological features, CTCs characteristics, and outcomes were analyzed.Of 101 patients included in the study, 43 (42.5%) experienced a delay in initiation and 20 (19.8%) did not receive adjuvant therapy. On multivariable analysis, presence of transitional CTCs (trCTCs, P=0.002) and absence of adjuvant therapy (P=0.032) were associated with worse recurrence-free survival (RFS). Postoperative trCTC were associated with poorer RFS, both in patients with a delay in initiation (12.4 vs. 17.9 mo, P=0.004) or no administration of adjuvant chemotherapy (3.4 vs. NR, P=0.016). However, it was not associated with RFS in patients with timely initiation of adjuvant chemotherapy (P=0.293).Postoperative trCTCs positivity is associated with poorer RFS only in patients who either experience a delay in initiation or no receipt of adjuvant therapy. This study suggests that a delay in initiation of adjuvant therapy could potentially provide residual systemic disease (trCTCs) a window of opportunity to recover from the surgical insult. Future studies are required to validate these findings and explore the underlying mechanisms involved.
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- 2022
18. Landslides Across the USA: Occurrence, Susceptibility, and Data Limitations
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Benjamin B. Mirus, Eric S. Jones, Rex L. Baum, Jonathan W. Godt, Stephen Slaughter, Matthew M. Crawford, Jeremy Lancaster, Thomas Stanley, Dalia B. Kirschbaum, William J. Burns, Robert G. Schmitt, Kassandra O. Lindsey, and Kevin M. McCoy
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Geosciences (General) - Abstract
Detailed information about landslide occurrence is the foundation for advancing process understanding, susceptibility mapping, and risk reduction. Despite the recent revolution in digital elevation data and remote sensing technologies, landslide mapping remains resource intensive. Consequently, a modern, comprehensive map of landslide occurrence across the United States (USA) has not been compiled. As a first step toward this goal, we present a national-scale compilation of existing, publicly available landslide inventories. This geodatabase can be downloaded in its entirety or viewed through an online, searchable map, with parsimonious attributes and direct links to the contributing sources with additional details. The mapped spatial pattern and concentration of landslides are consistent with prior characterization of susceptibility within the conterminous USA, with some notable exceptions on the West Coast. Although the database is evolving and known to be incomplete in many regions, it confirms that landslides do occur across the country, thus highlighting the importance of our national-scale assessment. The map illustrates regions where high-quality mapping has occurred and, in contrast, where additional resources could improve confidence in landslide characterization. For example, borders between states and other jurisdictions are quite apparent, indicating the variation in approaches to data collection by different agencies and disparity between the resources dedicated to landslide characterization. Further investigations are needed to better assess susceptibility and to determine whether regions with high relief and steep topography, but without mapped landslides, require further landslide inventory mapping. Overall, this map provides a new resource for accessing information about known landslides across the USA.
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- 2020
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19. Postoperative Chemotherapy is Associated with Improved Survival in Patients with Node-Positive Pancreatic Ductal Adenocarcinoma After Neoadjuvant Therapy
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Gabriel D. Ivey, Sami Shoucair, Daniel J. Delitto, Joseph R. Habib, Benedict Kinny-Köster, Christopher R. Shubert, Kelly J. Lafaro, John L. Cameron, William R. Burns, Richard A. Burkhart, Elizabeth L. Thompson, Amol Narang, Lei Zheng, Christopher L. Wolfgang, and Jin He
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Surgery - Published
- 2022
20. Should non-invasive diffuse main-duct intraductal papillary mucinous neoplasms be treated with total pancreatectomy?
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William H. Burns, Kelly J. Lafaro, Jin He, Richard A. Burkhart, Matthew J. Weiss, John L. Cameron, Christopher L. Wolfgang, James F. Griffin, Joseph R. Habib, Ross M. Beckman, and Alex B. Blair
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medicine.medical_specialty ,endocrine system diseases ,Total pancreatectomy ,medicine.medical_treatment ,Pancreatic Intraductal Neoplasms ,Malignancy ,Main duct ,Article ,Pancreatectomy ,Humans ,Medicine ,Retrospective Studies ,Hepatology ,Intraductal papillary mucinous neoplasm ,business.industry ,Gastroenterology ,medicine.disease ,Pancreaticoduodenectomy ,Adenocarcinoma, Mucinous ,Pancreatic Neoplasms ,Partial Pancreatectomy ,medicine.anatomical_structure ,Dysplasia ,Radiology ,business ,Pancreas ,Carcinoma, Pancreatic Ductal ,Dilatation, Pathologic - Abstract
BACKGROUND: Main-duct (MD) intraductal papillary mucinous neoplasm (IPMN) is associated with malignancy risk. There is a lack of consensus on treatment (partial or total pancreatectomy) when the MD is diffusely involved. We sought to characterize the pancreatic remnant fate after partial pancreatectomy for non-invasive diffuse MD-IPMN. METHODS: Consecutive patients with partial pancreatectomy for non-invasive MD-IPMN from 2004 to 2016 were analyzed. Diffuse MD-IPMN was defined by preoperative imaging as dilation of the MD in the head of the pancreas more than 5mm and involving the whole gland. RESULTS: Of 127 patients with resected non-invasive MD-IPMN, 47 (37%) had diffuse MD involvement. Eleven of 47(23%) patients developed imaging evidence of progression or new cystic disease in the pancreatic remnant. Patients with diffuse MD-IPMN were older (73yrs vs 67yrs, p=0.009), more likely to receive a pancreaticoduodenectomy (96% vs 56%, p
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- 2022
21. Data from Precision Medicine in Pancreatic Cancer: Patient-Derived Organoid Pharmacotyping Is a Predictive Biomarker of Clinical Treatment Response
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Richard A. Burkhart, Elizabeth M. Jaffee, David T. Ting, Theodore S. Hong, Alec C. Kimmelman, David P. Ryan, James R. Eshlemann, David A. Tuveson, Lei Zheng, Ying S. Zou, Christopher L. Wolfgang, Jin He, Kelly J. Lafaro, William R. Burns, John L. Cameron, Christopher R. Shubert, Annamaria Szabolcs, Gabriel D. Ivey, Haley Zlomke, Reecha Suri, Jacquelyn W. Zimmerman, and Toni T. Seppälä
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Purpose:Patient-derived organoids (PDO) are a promising technology to support precision medicine initiatives for patients with pancreatic ductal adenocarcinoma (PDAC). PDOs may improve clinical next-generation sequencing (NGS) and enable rapid ex vivo chemotherapeutic screening (pharmacotyping).Experimental Design:PDOs were derived from tissues obtained during surgical resection and endoscopic biopsies and studied with NGS and pharmacotyping. PDO-specific pharmacotype is assessed prospectively as a predictive biomarker of clinical therapeutic response by leveraging data from a randomized controlled clinical trial.Results:Clinical sequencing pipelines often fail to detect PDAC-associated somatic mutations in surgical specimens that demonstrate a good pathologic response to previously administered chemotherapy. Sequencing the PDOs derived from these surgical specimens, after biomass expansion, improves the detection of somatic mutations and enables quantification of copy number variants. The detection of clinically relevant mutations and structural variants is improved following PDO biomass expansion. On clinical trial, PDOs were derived from biopsies of treatment-naïve patients prior to treatment with FOLFIRINOX (FFX). Ex vivo PDO pharmacotyping with FFX components predicted clinical therapeutic response in these patients with borderline resectable or locally advanced PDAC treated in a neoadjuvant or induction paradigm. PDO pharmacotypes suggesting sensitivity to FFX components were associated with longitudinal declines of tumor marker, carbohydrate-antigen 19–9 (CA-19–9), and favorable RECIST imaging response.Conclusions:PDOs established from tissues obtained from patients previously receiving cytotoxic chemotherapies can be accomplished in a clinically certified laboratory. Sequencing PDOs following biomass expansion improves clinical sequencing quality. High in vitro sensitivity to standard-of-care chemotherapeutics predicts good clinical response to systemic chemotherapy in PDAC.See related commentary by Zhang et al., p. 3176
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- 2023
22. Supplementary Figure from Precision Medicine in Pancreatic Cancer: Patient-Derived Organoid Pharmacotyping Is a Predictive Biomarker of Clinical Treatment Response
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Richard A. Burkhart, Elizabeth M. Jaffee, David T. Ting, Theodore S. Hong, Alec C. Kimmelman, David P. Ryan, James R. Eshlemann, David A. Tuveson, Lei Zheng, Ying S. Zou, Christopher L. Wolfgang, Jin He, Kelly J. Lafaro, William R. Burns, John L. Cameron, Christopher R. Shubert, Annamaria Szabolcs, Gabriel D. Ivey, Haley Zlomke, Reecha Suri, Jacquelyn W. Zimmerman, and Toni T. Seppälä
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Supplementary Figure from Precision Medicine in Pancreatic Cancer: Patient-Derived Organoid Pharmacotyping Is a Predictive Biomarker of Clinical Treatment Response
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- 2023
23. Supplementary Table from Precision Medicine in Pancreatic Cancer: Patient-Derived Organoid Pharmacotyping Is a Predictive Biomarker of Clinical Treatment Response
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Richard A. Burkhart, Elizabeth M. Jaffee, David T. Ting, Theodore S. Hong, Alec C. Kimmelman, David P. Ryan, James R. Eshlemann, David A. Tuveson, Lei Zheng, Ying S. Zou, Christopher L. Wolfgang, Jin He, Kelly J. Lafaro, William R. Burns, John L. Cameron, Christopher R. Shubert, Annamaria Szabolcs, Gabriel D. Ivey, Haley Zlomke, Reecha Suri, Jacquelyn W. Zimmerman, and Toni T. Seppälä
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Supplementary Table from Precision Medicine in Pancreatic Cancer: Patient-Derived Organoid Pharmacotyping Is a Predictive Biomarker of Clinical Treatment Response
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- 2023
24. Supplementary Data from Precision Medicine in Pancreatic Cancer: Patient-Derived Organoid Pharmacotyping Is a Predictive Biomarker of Clinical Treatment Response
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Richard A. Burkhart, Elizabeth M. Jaffee, David T. Ting, Theodore S. Hong, Alec C. Kimmelman, David P. Ryan, James R. Eshlemann, David A. Tuveson, Lei Zheng, Ying S. Zou, Christopher L. Wolfgang, Jin He, Kelly J. Lafaro, William R. Burns, John L. Cameron, Christopher R. Shubert, Annamaria Szabolcs, Gabriel D. Ivey, Haley Zlomke, Reecha Suri, Jacquelyn W. Zimmerman, and Toni T. Seppälä
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Supplementary Data from Precision Medicine in Pancreatic Cancer: Patient-Derived Organoid Pharmacotyping Is a Predictive Biomarker of Clinical Treatment Response
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- 2023
25. Supplementary Figure 1 from A High Molecular Weight Melanoma-Associated Antigen–Specific Chimeric Antigen Receptor Redirects Lymphocytes to Target Human Melanomas
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Richard A. Morgan, Steven A. Rosenberg, Soldano Ferrone, Steven A. Feldman, Hui Xu, Zhili Zheng, Christian S. Hinrichs, Timothy L. Frankel, Yangbing Zhao, and William R. Burns
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Supplementary Figure 1 from A High Molecular Weight Melanoma-Associated Antigen–Specific Chimeric Antigen Receptor Redirects Lymphocytes to Target Human Melanomas
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- 2023
26. Supplementary Figure 3 from A High Molecular Weight Melanoma-Associated Antigen–Specific Chimeric Antigen Receptor Redirects Lymphocytes to Target Human Melanomas
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Richard A. Morgan, Steven A. Rosenberg, Soldano Ferrone, Steven A. Feldman, Hui Xu, Zhili Zheng, Christian S. Hinrichs, Timothy L. Frankel, Yangbing Zhao, and William R. Burns
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Supplementary Figure 3 from A High Molecular Weight Melanoma-Associated Antigen–Specific Chimeric Antigen Receptor Redirects Lymphocytes to Target Human Melanomas
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- 2023
27. Supplementary Figure 5 from A High Molecular Weight Melanoma-Associated Antigen–Specific Chimeric Antigen Receptor Redirects Lymphocytes to Target Human Melanomas
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Richard A. Morgan, Steven A. Rosenberg, Soldano Ferrone, Steven A. Feldman, Hui Xu, Zhili Zheng, Christian S. Hinrichs, Timothy L. Frankel, Yangbing Zhao, and William R. Burns
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Supplementary Figure 5 from A High Molecular Weight Melanoma-Associated Antigen–Specific Chimeric Antigen Receptor Redirects Lymphocytes to Target Human Melanomas
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- 2023
28. pplementary Figure 1, Table 1 from Cell Surface Lactate Receptor GPR81 Is Crucial for Cancer Cell Survival
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Craig D. Logsdon, Zobeida Cruz-Monserrate, Huamin Wang, Vijaya Ramachandran, William R. Burns, Sobeyda Gomez, Bincy Philip, Shi He Liu, Defeng Deng, Thiruvengadam Arumugam, and Christina L. Roland
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PDF file - 163K, Supplementary Figure 1: Lentiviral shRNA mediated knockdown or ectopic expression of GPR81. Supplementary Figure 2: Lentiviral shRNA mediated knockdown of GPR81 is associated with reduced levels of MCT1. Supplemental Table 1: Primer sequences for quantitative RT-PCR.
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- 2023
29. Supplementary Figure 4 from A High Molecular Weight Melanoma-Associated Antigen–Specific Chimeric Antigen Receptor Redirects Lymphocytes to Target Human Melanomas
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Richard A. Morgan, Steven A. Rosenberg, Soldano Ferrone, Steven A. Feldman, Hui Xu, Zhili Zheng, Christian S. Hinrichs, Timothy L. Frankel, Yangbing Zhao, and William R. Burns
- Abstract
Supplementary Figure 4 from A High Molecular Weight Melanoma-Associated Antigen–Specific Chimeric Antigen Receptor Redirects Lymphocytes to Target Human Melanomas
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- 2023
30. Supplementary Figure 6 from A High Molecular Weight Melanoma-Associated Antigen–Specific Chimeric Antigen Receptor Redirects Lymphocytes to Target Human Melanomas
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Richard A. Morgan, Steven A. Rosenberg, Soldano Ferrone, Steven A. Feldman, Hui Xu, Zhili Zheng, Christian S. Hinrichs, Timothy L. Frankel, Yangbing Zhao, and William R. Burns
- Abstract
Supplementary Figure 6 from A High Molecular Weight Melanoma-Associated Antigen–Specific Chimeric Antigen Receptor Redirects Lymphocytes to Target Human Melanomas
- Published
- 2023
31. Oncologic resection of pancreatic cancer with isolated liver metastasis: Favorable outcomes in select patients
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Minako Nagai, Michael J. Wright, Ding Ding, Elizabeth D. Thompson, Ammar A. Javed, Matthew J. Weiss, Ralph H. Hruban, Jun Yu, Richard A. Burkhart, Jin He, John L. Cameron, Christopher L. Wolfgang, and William R. Burns
- Subjects
Hepatology ,Surgery - Published
- 2023
32. Accurate Nodal Staging in Pancreatic Cancer in the Era of Neoadjuvant Therapy
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Ammar A. Javed, Ding Ding, Erum Baig, Michael J. Wright, Jonathan A. Teinor, Daniyal Mansoor, Elizabeth Thompson, Ralph H. Hruban, Amol Narang, William R. Burns, Richard A. Burkhart, Kelly Lafaro, Matthew J. Weiss, John L. Cameron, Christopher L. Wolfgang, and Jin He
- Subjects
Surgery - Published
- 2022
33. Notch signaling regulates immunosuppressive tumor-associated macrophage function in pancreatic cancer
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Wei Yan, Nina G. Steele, Samantha B. Kemp, Rosa E. Menjivar, Wenting Du, Eileen S. Carpenter, Katelyn L. Donahue, Kristee L. Brown, Valerie Irizarry-Negron, Sion Yang, William R. Burns, Yaqing Zhang, Marina Pasca di Magliano, and Filip Bednar
- Abstract
Pancreatic ductal adenocarcinoma (PDA) continues to have a dismal prognosis. The poor survival of patients with PDA has been attributed to a high rate of early metastasis and low efficacy of current therapies, which partly result from its complex immunosuppressive tumor microenvironment. Previous studies from our group and others have shown that tumor-associated macrophages (TAMs) are instrumental in maintaining immunosuppression in PDA. Here, we explored the role of Notch signaling, a key regulator of immune response, within the PDA microenvironment. We identified Notch pathway components in multiple immune cell types within human and mouse pancreatic cancer. TAMs, the most abundant immune cell population in the tumor microenvironment, express high levels of Notch receptors with cognate ligands such asJAG1expressed on tumor epithelial cells, endothelial cells and fibroblasts. TAMs with activated Notch signaling expressed higher levels of immunosuppressive mediators including arginase 1 (Arg1) suggesting that Notch signaling plays a role in macrophage polarization within the PDA microenvironment. Combination of Notch inhibition with PD-1 blockade resulted in increased cytotoxic T cell infiltration, tumor cell apoptosis, and smaller tumor size. Our work implicates macrophage Notch signaling in the establishment of immunosuppression and indicates that targeting the Notch pathway may improve the efficacy of immune-based therapies in PDA patients.
- Published
- 2023
34. Multi-institutional Validation Study of Cyst Fluid Protein Biomarkers in Patients With Cystic Lesions of the Pancreas
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Michael I. D’Angelica, Mark A. Schattner, Peter J. Allen, William R. Brugge, Carlos Fernandez-del Castillo, Matthew J. Weiss, Keith D. Lillemoe, Nan Pang, William H. Burns, Mohammad Al Efishat, Clifton Rodrigues, Christopher L. Wolfgang, William R. Jarnagin, Jin He, Ammar A. Javed, Brenna Casey, Debra A. Goldman, Aadhi Vaithiya Santharaman, Jeffrey A. Drebin, Mithat Gonen, Vinod P. Balachandran, T. Peter Kingham, Richard A. Burkhart, Caitlin A. McIntyre, Debora Ciprani, Anne Marie Lennon, and Anna Lokshin
- Subjects
Endoscopic ultrasound ,medicine.medical_specialty ,Radiography ,Humans ,Medicine ,Cyst ,Prospective Studies ,Prospective cohort study ,Pancreas ,medicine.diagnostic_test ,Cysts ,business.industry ,Cyst Fluid ,Cancer ,Nomogram ,medicine.disease ,Pancreatic Neoplasms ,medicine.anatomical_structure ,Dysplasia ,Surgery ,Radiology ,Pancreatic Cyst ,business ,Biomarkers ,Carcinoma, Pancreatic Ductal - Abstract
Objective Prospective evaluation of 2 clinical-molecular models in patients with unknown pathology who underwent endoscopic ultrasound with fine-needle aspiration (EUS-FNA) for a cystic lesion of the pancreas. Summary of background data Preoperative prediction of histologic subtype (mucinous vs nonmucinous) and grade of dysplasia in patients with pancreatic cystic neoplasms is challenging. Our group has previously published 2 clinical-molecular nomograms for intraductal papillary mucinous neoplasms (IPMN) that incorporated both clinical/radiographic features and cyst fluid protein markers (sFASL, CA72-4, MMP9, IL-4). Methods This multiinstitutional study enrolled patients who underwent EUS-FNA for a cystic lesion of the pancreas. Treatment recommendations regarding resection were based on standard clinical, radiographic, and endoscopic features. Predicted probabilities of high-risk IPMN (high-grade dysplasia/invasive cancer) were calculated using the previously developed clinical-molecular nomograms. Results Cyst fluid was obtained from 100 patients who underwent diagnostic EUS-FNA. Within this group there were 35 patients who underwent resection, and 65 were monitored radiographically. Within the group that underwent resection, 26 had low-risk IPMN or benign non-IPMN lesions, and 9 had high-risk IPMN. Within the surveillance group, no patient progressed to resection or developed cancer after a median follow-up of 12 months (range: 0.5-38). Using the clinical/radiographic nomogram alone, 2 out of 9 patients with high-risk IPMN had a predicted probability >0.5. In the clinical-molecular models, 6 of 9 patients in model 1, and 6 of 9 in model 2, had scores >0.5. Conclusions This prospective study of patients with unknown cyst pathology further demonstrates the importance of cyst fluid protein analysis in the preoperative identification of patients with high-risk IPMN. Longer follow-up is necessary to determine if this model will be useful in clinical practice.
- Published
- 2021
35. Evaluation of a technology enabled garment for older walkers.
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William P. Burns, Chris D. Nugent, Paul J. McCullagh, Dewar D. Finlay, Ian Cleland, Bryan W. Scotney, Sally I. McClean, Jane McCann, and Daniel Gueldenring
- Published
- 2012
- Full Text
- View/download PDF
36. A Smart Garment for Older Walkers.
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William P. Burns, Chris D. Nugent, Paul J. McCullagh, Dewar D. Finlay, Ian Cleland, Sally I. McClean, Bryan W. Scotney, and Jane McCann
- Published
- 2012
- Full Text
- View/download PDF
37. Assessment of Custom Fitted Heart Rate Sensing Garments whilst undertaking Everyday Activities.
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Ian Cleland, Chris D. Nugent, Dewar D. Finlay, William P. Burns, Jennifer Bougourd, and Roger Armitage
- Published
- 2012
- Full Text
- View/download PDF
38. Precision medicine in pancreatic cancer: Patient derived organoid pharmacotyping is a predictive biomarker of clinical treatment response
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Toni T. Seppälä, Jacquelyn W. Zimmerman, Reecha Suri, Haley Zlomke, Gabriel D. Ivey, Annamaria Szabolcs, Christopher R. Shubert, John L. Cameron, William R. Burns, Kelly J. Lafaro, Jin He, Christopher L. Wolfgang, Ying S. Zou, Lei Zheng, David A. Tuveson, James R. Eshlemann, David P. Ryan, Alec C. Kimmelman, Theodore S. Hong, David T. Ting, Elizabeth M. Jaffee, Richard A. Burkhart, ATG - Applied Tumor Genomics, and HUS Abdominal Center
- Subjects
Cancer Research ,3122 Cancers ,THERAPY ,Article ,Organoids ,Pancreatic Neoplasms ,Oncology ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,SURVIVAL ,Humans ,Precision Medicine ,Biomarkers ,Carcinoma, Pancreatic Ductal - Abstract
Purpose: Patient-derived organoids (PDO) are a promising technology to support precision medicine initiatives for patients with pancreatic ductal adenocarcinoma (PDAC). PDOs may improve clinical next-generation sequencing (NGS) and enable rapid ex vivo chemotherapeutic screening (pharmacotyping). Experimental Design: PDOs were derived from tissues obtained during surgical resection and endoscopic biopsies and studied with NGS and pharmacotyping. PDO-specific pharmacotype is assessed prospectively as a predictive biomarker of clinical therapeutic response by leveraging data from a randomized controlled clinical trial. Results: Clinical sequencing pipelines often fail to detect PDAC-associated somatic mutations in surgical specimens that demonstrate a good pathologic response to previously administered chemotherapy. Sequencing the PDOs derived from these surgical specimens, after biomass expansion, improves the detection of somatic mutations and enables quantification of copy number variants. The detection of clinically relevant mutations and structural variants is improved following PDO biomass expansion. On clinical trial, PDOs were derived from biopsies of treatment-naïve patients prior to treatment with FOLFIRINOX (FFX). Ex vivo PDO pharmacotyping with FFX components predicted clinical therapeutic response in these patients with borderline resectable or locally advanced PDAC treated in a neoadjuvant or induction paradigm. PDO pharmacotypes suggesting sensitivity to FFX components were associated with longitudinal declines of tumor marker, carbohydrate-antigen 19–9 (CA-19–9), and favorable RECIST imaging response. Conclusions: PDOs established from tissues obtained from patients previously receiving cytotoxic chemotherapies can be accomplished in a clinically certified laboratory. Sequencing PDOs following biomass expansion improves clinical sequencing quality. High in vitro sensitivity to standard-of-care chemotherapeutics predicts good clinical response to systemic chemotherapy in PDAC. See related commentary by Zhang et al., p. 3176
- Published
- 2022
39. Evolving Risk Perceptions About Near-Miss Terrorist Events.
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Robin L. Dillon, Catherine H. Tinsley, and William J. Burns
- Published
- 2014
- Full Text
- View/download PDF
40. Ovarian Metastasis from Pancreatic Ductal Adenocarcinoma
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Jun Yu, Joseph R. Habib, Elliot K. Fishman, Elizabeth D. Thompson, Sami Shoucair, Ammar A. Javed, William R. Burns, Shamsher Pasha, Subhan Khan, Jin He, Kelly J. Lafaro, Benedict Kinny-Köster, Brigitte M. Ronnett, Richard A. Burkhart, Ralph H. Hruban, and Christopher L. Wolfgang
- Subjects
Oncology ,medicine.medical_specialty ,endocrine system diseases ,business.industry ,medicine.medical_treatment ,Retrospective cohort study ,Vascular surgery ,medicine.disease ,Cardiac surgery ,Ovarian disease ,Cardiothoracic surgery ,Internal medicine ,Pancreatectomy ,medicine ,Carcinoma ,Surgery ,business ,Abdominal surgery - Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a high propensity for systemic dissemination. Ovarian metastases are rare and poorly described. We identified PDAC cases with ovarian metastasis from a prospectively maintained registry. We reported on the association between outcomes and clinicopathologic factors. Recurrence-free (RFS) and overall survival (OS) were calculated using Kaplan–Meier analysis. Twelve patients with PDAC and synchronous or metachronous ovarian metastases were identified. Nine patients (75%) underwent pancreatectomy for localized PDAC and developed metachronous ovarian recurrence. The median OS for all patients was 25.4 (IQR:15.4–82.9) months. For the nine patients with metachronous ovarian metastasis, the median RFS and OS were 14.2 (IQR:7.2–58.3) and 44.6 (IQR:18.6–82.9) months, respectively. Nodal disease, poor grade, vascular invasion in the pancreatic primary, and bilateral ovarian disease tended to confer worse outcomes. Patients with resected PDAC and ovarian recurrence tend to have a comparable disease course to more common patterns of recurrence. Primaries with nodal disease, poorer grade, vascular invasion, and bilateral ovarian disease were indicative of more aggressive disease biology. The ideal management remains largely unknown, and future collaborative efforts should optimize therapeutic strategies.
- Published
- 2021
41. Periadventitial dissection of the superior mesenteric artery for locally advanced pancreatic cancer: Surgical planning with the 'halo sign' and 'string sign'
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Richard A. Burkhart, Jin He, Christopher L. Wolfgang, Elliot K. Fishman, Kelly J. Lafaro, John L. Cameron, Joseph R. Habib, Benedict Kinny-Köster, Ammar A. Javed, William R. Burns, Floortje van Oosten, and Elizabeth D. Thompson
- Subjects
medicine.medical_specialty ,business.industry ,Dissection (medical) ,medicine.disease ,SMA ,Surgical planning ,medicine.anatomical_structure ,medicine.artery ,Pancreatic cancer ,medicine ,Surgery ,Superior mesenteric artery ,Radiology ,medicine.symptom ,Stage (cooking) ,business ,Halo sign ,Artery - Abstract
Most patients diagnosed with pancreatic cancer are classified as nonoperative candidates based on the contemporary guidelines of resectability. The advent of more potent control of systemic disease using neoadjuvant chemotherapy has enabled more aggressive operative interventions. In our multidisciplinary practice, patients with Stage III, locally advanced pancreatic cancer and superior mesenteric artery (SMA) encasement are now carefully triaged with high quality, preoperative imaging to determine if they can be considered candidates for operative resection with periadventitial dissection of the SMA. Patients displaying a "halo sign," where the encased SMA remains fully patent and free from arterial invasion, are now candidates for SMA periadventitial dissection. This procedure involves the surgical stripping of the infiltrated neurolymphatic tissue off the SMA leaving behind a bare "skeletonized artery." Alternatively, the "string sign" involving the SMA confers a more likely case of arterial invasion, where a complete oncologic resection cannot be achieved successfully. This method of patient selection in case of SMA involvement abandons the traditional metrics of circumferential degrees of the arterial encasement to guide surgical decisions. Our institutional approach has allowed us to meaningfully expand our operative methods of resection with the potential for improved longitudinal outcomes to pancreatic cancer patients who were deprived historically from the more effective and possibly curative treatment.
- Published
- 2021
42. The Enlightenment: History, Documents, and Key Questions
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William E. Burns and William E. Burns
- Published
- 2015
43. Conduits in Vascular Pancreatic Surgery: Analysis of Clinical Outcomes, Operative Techniques and Graft Performance
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Benedict Kinny-Köster, Joseph R. Habib, A. Floortje van Oosten, Ammar A. Javed, John L. Cameron, Richard A. Burkhart, William R. Burns, Jin He, and Christopher L. Wolfgang
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Surgery - Abstract
We analyze successes and failures of pushing the boundary in vascular pancreatic surgery to establish safety of conduit reconstructions.Improved systemic control from chemotherapy in pancreatic cancer is increasing the demand for surgical solutions of extensive local vessel involvement, but conduit-specific data are scarce.We identified 63 implanted conduits (41% autologous vessels, 37% allografts, 18% PTFE) in 56 pancreatic resections of highly selected cancer patients between October 2013 and July 2020 from our prospectively maintained database. Assessed parameters were survival, perioperative complications, operative techniques (anatomic and extra-anatomic routes) and conduit patency.For vascular reconstruction, 25 arterial and 38 venous conduits were utilized during 39 pancreatoduodenectomies, 14 distal pancreatectomies and 3 total pancreatectomies. The median postoperative survival was 2 years. A Clavien-Dindo grade ≥IIIa complication was apparent in 50% of the patients with a median Comprehensive Complication Index of 29.6. The 90-day mortality in this highly selected cohort was 9%. Causes of mortality were conduit-related in 3 patients, late postpancreatectomy hemorrhage in 1 patient and early liver metastasis in 1 patient. Image-based patency rates of conduits were 66% and 45% at postoperative days 30 and 90, respectively.Our perioperative mortality of vascular pancreatic surgery with conduits in the arterial or venous system is 9%. Reconstructions are technically feasible with different anatomic and extra-anatomic strategies, while identifying predictors of early conduit occlusion remains challenging. Optimizing reconstructed arterial and venous hemodynamics in the context of pancreatic malignancy will enable long-term survival in more patients responsive to chemotherapies.
- Published
- 2022
44. RAD51B Harbors Germline Mutations Associated With Pancreatic Ductal Adenocarcinoma
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Fanfan Xie, Ding Ding, Cong Lin, Dea Cunningham, Michael Wright, Ammar A. Javed, Nilo Azad, Valerie Lee, Ross Donehower, Ana De Jesus-Acosta, Dung T. Le, Michael Pishvaian, Eun Ji Shin, Anne Marie Lennon, Mouen Khashab, Vikesh Singh, Alison P. Klein, Nicholas J. Roberts, Amy Hacker-Prietz, Thomas McPhaul, Richard A. Burkhart, William R. Burns, Amol Narang, Atif Zaheer, Elliot K. Fishman, Elizabeth D. Thompson, Robert Anders, Jun Yu, Jin He, Christopher L. Wolfgang, Lei Zheng, Dongbing Liu, Kui Wu, and Daniel A. Laheru
- Subjects
DNA-Binding Proteins ,Pancreatic Neoplasms ,Cancer Research ,Oncology ,Genes, BRCA2 ,Original Reports ,Humans ,Germ-Line Mutation ,Carcinoma, Pancreatic Ductal - Abstract
PURPOSE Genetic alterations in many components of the homologous recombination, DNA damage response, and repair (HR-DDR) pathway are involved in the hereditary cancer syndromes, including familial pancreatic cancer. HR-DDR genes beyond BRCA1, BRCA2, ATM, and PALB2 may also mutate and confer the HR-DDR deficiency in pancreatic ductal adenocarcinoma (PDAC). METHODS We conducted a study to examine the genetic alterations using a companion diagnostic 15-gene HR-DDR panel in PDACs. HR-DDR gene mutations were identified and characterized by whole-exome sequencing and whole-genome sequencing. Different HR-DDR gene mutations are associated with variable homologous recombination deficiency (HRD) scores. RESULTS Eight of 50 PDACs with at least one HR-DDR gene mutation were identified. One tumor with BRCA2 mutations is associated with a high HRD score. However, another tumor with a CHEK2 mutation is associated with a zero HRD score. Notably, four of eight PDACs in this study harbor a RAD51B gene mutation. All four RAD51B gene mutations were germline mutations. However, currently, RAD51B is not the gene panel for germline tests. CONCLUSION The finding in this study thus supports including RAD51B in the germline test of HR-DDR pathway genes.
- Published
- 2022
45. Impact of Margin Status on Survival in Patients with Pancreatic Ductal Adenocarcinoma Receiving Neoadjuvant Chemotherapy
- Author
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Christopher L. Wolfgang, Michael J. Wright, Daniel Delitto, William R. Burns, Richard A. Burkhart, John L. Cameron, Ding Ding, Ryan K. Schmocker, Kelly J. Lafaro, and Jin He
- Subjects
Male ,medicine.medical_specialty ,Surgical margin ,FOLFIRINOX ,medicine.medical_treatment ,Leucovorin ,030230 surgery ,Irinotecan ,Gastroenterology ,Disease-Free Survival ,Pancreaticoduodenectomy ,03 medical and health sciences ,0302 clinical medicine ,Interquartile range ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Adjuvant therapy ,Humans ,Prospective Studies ,Pancreas ,Aged ,Neoplasm Staging ,Retrospective Studies ,business.industry ,Hazard ratio ,Margins of Excision ,Middle Aged ,Neoadjuvant Therapy ,Oxaliplatin ,Pancreatic Neoplasms ,Radiation therapy ,Chemotherapy, Adjuvant ,030220 oncology & carcinogenesis ,Pancreatectomy ,Female ,Surgery ,CA19-9 ,Fluorouracil ,Neoplasm Recurrence, Local ,business ,Carcinoma, Pancreatic Ductal ,Follow-Up Studies - Abstract
Background Historically, a positive margin after pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) was associated with decreased survival. In an era when neoadjuvant chemotherapy (NAC) is being used frequently, the prognostic significance of margin status is unclear. Study Design Patients with localized PDAC who received NAC and underwent pancreatectomy from 2011 to 2018 were identified from a single-institution database. Patients with fewer than 2 months of NAC, R2 resection, or fewer than 90 days of follow-up were excluded. A positive margin included tumors within 1 mm of the surgical margin. Results Four hundred and sixty-eight patients met inclusion criteria. Median age was 65 years and 53% were female. Preoperative clinical staging demonstrated that most had locally advanced (n = 222 [47%]) or borderline resectable (n = 172 [37%]) disease. Median follow-up was 18.5 months (interquartile range 10.6 to 30.0 months). Median duration of NAC was 119 days (interquartile range 87 to 168 days). FOLFIRINOX was first-line therapy for 67%, and 73% received neoadjuvant radiotherapy. Most underwent pancreaticoduodenectomy (69%). Forty percent were node-positive and 80% had an R0 resection. Fifty-six percent received at least 1 cycle of adjuvant therapy. Median overall survival and recurrence-free survival were 22.0 months (95% CI, 19.4 to 25.1 months) and 11.0 months (95% CI, 10.0 to 12.1 months). On multivariate analysis, margin status was not a significant predictor of overall survival or recurrence-free survival. Factors associated with overall survival included clinical stage, duration of NAC, nodal status, histopathologic treatment response score, and receipt of adjuvant chemotherapy. Conclusions Microscopic margin positivity is not associated with recurrence and survival in localized PDAC patients resected after treatment with NAC. Aggressive surgical extirpation in high-volume centers should be considered in selected patients after extensive NAC.
- Published
- 2021
46. Defining a minimum number of examined lymph nodes improves the prognostic value of lymphadenectomy in pancreas ductal adenocarcinoma
- Author
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Ralph H. Hruban, Zhiyao Chen, William R. Burns, Ding Ding, Elizabeth D. Thompson, Shanshan Gao, Kelly J. Lafaro, Michael Beckman, John L. Cameron, Lingdi Yin, Haijie Hu, Jin He, Richard A. Burkhart, Michele M. Gage, Jun Yu, Yayun Zhu, Ross Beckman, Ning Pu, Michael J. Wright, and Christopher L. Wolfgang
- Subjects
Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,030230 surgery ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Stage (cooking) ,Pancreas ,Lymph node ,Neoplasm Staging ,Hepatology ,business.industry ,Gastroenterology ,Cancer ,Prognosis ,medicine.disease ,Pancreatic Neoplasms ,Survival Rate ,Binomial distribution ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Pancreatectomy ,Lymph Node Excision ,Lymphadenectomy ,Lymph Nodes ,Lymph ,business ,Carcinoma, Pancreatic Ductal - Abstract
Background Lymph node (LN) metastasis is associated with decreased survival following resection for pancreatic ductal adenocarcinoma (PDAC). In N0 disease, increasing total evaluated LN (ELN) correlates with improved outcomes suggesting patients may be understaged when LNs are undersampled. We aim to assess the optimal number of examined lymph nodes (ELN) following pancreatectomy. Methods Data from 1837 patients undergoing surgery were prospectively collected. The binomial probability law was utilized to analyze the minimum number of examined LNs (minELN) and accurately characterize each histopathologic stage. LN ratio (LNR) was compared to American Joint Committee on Cancer (AJCC) guidelines. Results As ELN total increased, the likelihood of finding node positive disease increased. An evaluation based upon the binomial probability law suggested an optimal minELN of 12 for accurate AJCC N staging. As the number of ELNs increased, the discriminatory capacity of alternative strategies to characterize LN disease exceeded that offered by AJCC N stage. Conclusion This is the first study dedicated to optimizing histopathologic staging in PDAC using models of minELN informed by the binomial probability law. This study highlights two separate cutoffs for ELNs depending upon prognostic goal and validates that 12 LNs are adequate to determine AJCC N stage for the majority of patients.
- Published
- 2021
47. Minimal main pancreatic duct dilatation in small branch duct intraductal papillary mucinous neoplasms associated with high-grade dysplasia or invasive carcinoma
- Author
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Joseph R. Habib, Richard A. Burkhart, Lindsey Manos, Matthew J. Weiss, Ross Beckman, Atif Zaheer, Neda Rezaee, William R. Burns, Alex B. Blair, Ralph H. Hruban, Christopher L. Wolfgang, John L. Cameron, Neda Amini, Kelly J. Lafaro, Jin He, Anne Marie Lennon, and Elliot K. Fishman
- Subjects
medicine.medical_specialty ,Disease ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Aged ,Retrospective Studies ,Pancreatic duct ,Invasive carcinoma ,Hepatology ,business.industry ,Pancreatic Ducts ,Small branch ,Jaundice ,medicine.disease ,Adenocarcinoma, Mucinous ,Dilatation ,Pancreatic Neoplasms ,medicine.anatomical_structure ,Dysplasia ,030220 oncology & carcinogenesis ,Pancreatitis ,030211 gastroenterology & hepatology ,medicine.symptom ,business ,Duct (anatomy) ,Carcinoma, Pancreatic Ductal - Abstract
The aim of this study was to determine the incidence of high-grade dysplasia (HGD) or invasive carcinoma in patients with small branch duct intraductal papillary mucinous neoplasms (BD-IPMNs).923 patients who underwent surgical resection for an IPMN were identified. Sendai-negative patients were identified as those without history of pancreatitis or jaundice, main pancreatic duct size (MPD)5 mm, cyst size3 cm, no mural nodules, negative cyst fluid cytology for adenocarcinoma, or serum carbohydrate antigen 19-9 (CA 19-9)37 U/L.BD-IPMN was identified in 388 (46.4%) patients and 89 (22.9%) were categorized as Sendai-negative. Overall, 68 (17.5%) of BD-IPMN had HGD and 62 (16.0%) had an associated invasive-carcinoma. Among the 89 Sendai-negative patients, 12 (13.5%) had IPMNs with HGD and only one patient (1.1%) had invasive-carcinoma. Of note, older age (OR 1.13, 95% CI 1.03-1.23; P = 0.008) and minimal dilation of MPD (OR 11.3, 95% CI 2.40-53.65; P = 0.002) were associated with high-risk disease in Sendai-negative patients after multivariable risk adjustment.The risk of harboring a high-risk disease remains low in small BD-IPMNs. However, Sendai-negative patients who are older than 65 years old and those with minimal dilation of MPD (3-5 mm) are at greater risk of high-risk lesions and should be given consideration to be included as a "worrisome feature" in a future guidelines update.
- Published
- 2021
48. 3D Virtual worlds and the metaverse: Current status and future possibilities.
- Author
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John David N. Dionisio, William G. Burns III, and Richard Gilbert
- Published
- 2013
- Full Text
- View/download PDF
49. Topical lipoic acid choline ester eye drop for improvement of near visual acuity in subjects with presbyopia: a safety and preliminary efficacy trial
- Author
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Michael S Korenfeld, David G Evans, Stella M Robertson, Steven H Rauchman, Bee-Lian Chen, William H. Burns, Jerry M. Stein, Subha Venkataraman, Mark Wuttke, and Kenneth N Sall
- Subjects
Intraocular pressure ,genetic structures ,medicine.medical_treatment ,Visual Acuity ,Placebo ,Article ,Choline ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Prospective Studies ,Dosing ,Adverse effect ,030304 developmental biology ,0303 health sciences ,Thioctic Acid ,business.industry ,Esters ,Eye drop ,Presbyopia ,Prognosis ,medicine.disease ,Clinical trial ,Ophthalmology ,Tolerability ,Outcomes research ,Anesthesia ,030221 ophthalmology & optometry ,Ophthalmic Solutions ,business ,Follow-Up Studies - Abstract
Objectives This study evaluated the safety of topical lipoic acid choline ester (UNR844, 1.5%) ophthalmic solution and its efficacy in improving distance-corrected near visual acuity (DCNVA) in subjects with presbyopia. Subjects and methods This was a prospective, randomized, double-masked, and multicentre clinical trial. Subjects with a diagnosis of presbyopia (n = 75) were randomized 2:1 to UNR844 or placebo. On days 1–7, all subjects were dosed unilaterally (twice a day, b.i.d.) in their non-dominant eye to ensure safety and tolerability prior to days 8–91 when dosing was changed to bilateral (b.i.d.). Clinical assessments, including DCNVA and adverse events (AEs), were recorded at each study visit. Patients who completed the study were recruited into a non-interventional follow-up study that monitored them until 7 months after their final UNR844 exposure. The primary endpoints were safety and the mean change in DCNVA from baseline in the study eye. Results UNR844 administration (n = 50) produced no safety concerns and was well-tolerated, with no clinically-relevant changes in best-corrected distance visual acuity, pupil size, intraocular pressure, or discontinuations due to adverse events. DCNVA improved in the study eye in the UNR844 group compared to placebo during the 91 days of treatment [UNR844 vs. placebo, mean change in LogMAR (SD); −0.159 (0.120) vs. −0.079 (0.116)]. Bilateral DCNVA improved, with 53.1% UNR844 vs. 21.7% placebo subjects gaining ≥10 letters. Improvements in DCNVA were sustained at 5 and 7 months after UNR844 dosing ceased. Conclusions These results support further development of UNR844 ophthalmic solution for the treatment of presbyopia.
- Published
- 2021
50. Challenges of the current precision medicine approach for pancreatic cancer: A single institution experience between 2013 and 2017
- Author
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Cara Wilt, Jin He, Amy Ryan, Lei Zheng, Christi Walsh, Georgios Gemenetzis, Anne Marie Lennon, Dung T. Le, Vikesh K. Singh, Valerie Lee, Mouen A. Khashab, Eun Ji Shin, Lindsay Parish, Ding Ding, Chunhui Yuan, Daniel A. Laheru, Lindsey Manos, Elizabeth D. Thompson, Lara Groshek, Keith McIntyre, Dea Cunningham, Ross C. Donehower, Ana De Jesus-Acosta, Rachel Klein, John L. Cameron, Nilo Azad, Mary Hodgin, Alex B. Blair, Robert A. Anders, Elliot K. Fishman, Carol Judkins, Ammar A. Javed, William R. Burns, Jonathan Teinor, Amol Narang, Zunaira N. Javed, Richard A. Burkhart, Alison P. Klein, Adrian Murphy, Nicholas J. Roberts, Michael J. Wright, Christopher L. Wolfgang, Matthew J. Weiss, Elizabeth M. Jaffee, Amy Hacker-Prietz, Jun Yu, Atif Zaheer, Caitlin Brown, Ralph H. Hruban, and Vincent P. Groot
- Subjects
Male ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Time Factors ,Pancreatic ductal adenocarcinoma ,medicine.medical_treatment ,Disease ,Article ,Pancreaticoduodenectomy ,Targeted therapy ,03 medical and health sciences ,0302 clinical medicine ,Interquartile range ,Pancreatic cancer ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,medicine ,Humans ,Clinical genomic testing ,Molecular Targeted Therapy ,Precision Medicine ,Single institution ,Aged ,Retrospective Studies ,business.industry ,High-Throughput Nucleotide Sequencing ,Middle Aged ,Prognosis ,medicine.disease ,Precision medicine ,Combined Modality Therapy ,Pancreatic Neoplasms ,Actionable alteration ,030104 developmental biology ,Lymphatic Metastasis ,030220 oncology & carcinogenesis ,Mutation ,Feasibility Studies ,Female ,Matched therapy ,Personalized medicine ,business ,Carcinoma, Pancreatic Ductal ,Follow-Up Studies - Abstract
Recent research on genomic profiling of pancreatic ductal adenocarcinoma (PDAC) has identified many potentially actionable alterations. However, the feasibility of using genomic profiling to guide routine clinical decision making for PDAC patients remains unclear. We retrospectively reviewed PDAC patients between October 2013 and December 2017, who underwent treatment at the Johns Hopkins Hospital and had clinical tumor next-generation sequencing (NGS) through commercial resources. Ninety-two patients with 93 tumors tested were included. Forty-eight (52%) patients had potentially curative surgeries. The median time from the tissue available to the NGS testing ordered was 229 days (interquartile range 62–415). A total of three (3%) patients had matched targeted therapies based on genomic profiling results. Genomic profiling guided personalized treatment for PDAC patients is feasible, but the percentage of patients who receive targeted therapy is low. The main challenges are ordering NGS testing early in the clinical course of the disease and the limited evidence of using a targeted approach in these patients. A real-time department level genomic testing ordering system in combination with an evidence-based flagging system for potentially actionable alterations could help address these shortcomings.
- Published
- 2021
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