133 results on '"N. Joseph Espat"'
Search Results
2. Data from Phase I Hepatic Immunotherapy for Metastases Study of Intra-Arterial Chimeric Antigen Receptor–Modified T-cell Therapy for CEA+ Liver Metastases
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Richard P. Junghans, N. Joseph Espat, Robin Davies, Earle O. Assanah, Brian F. Stainken, Qiangzhong Ma, Mitchell Thorn, Pranay D. Khare, Gary R. Point, Wesley Mooring, Li Juan Wang, Elise McCormack, Rachel A. Burga, and Steven C. Katz
- Abstract
Purpose: Chimeric antigen receptor–modified T cells (CAR-T) have demonstrated encouraging results in early-phase clinical trials. Successful adaptation of CAR-T technology for CEA-expressing adenocarcinoma liver metastases, a major cause of death in patients with gastrointestinal cancers, has yet to be achieved. We sought to test intrahepatic delivery of anti-CEA CAR-T through percutaneous hepatic artery infusions (HAIs).Experimental Design: We conducted a phase I trial to test HAI of CAR-T in patients with CEA+ liver metastases. Six patients completed the protocol, and 3 received anti-CEA CAR-T HAIs alone in dose-escalation fashion (108, 109, and 1010 cells). We treated an additional 3 patients with the maximum planned CAR-T HAI dose (1010 cells × 3) along with systemic IL2 support.Results: Four patients had more than 10 liver metastases, and patients received a mean of 2.5 lines of conventional systemic therapy before enrollment. No patient suffered a grade 3 or 4 adverse event related to the CAR-T HAIs. One patient remains alive with stable disease at 23 months following CAR-T HAI, and 5 patients died of progressive disease. Among the patients in the cohort that received systemic IL2 support, CEA levels decreased 37% (range, 19%–48%) from baseline. Biopsies demonstrated an increase in liver metastasis necrosis or fibrosis in 4 of 6 patients. Elevated serum IFNγ levels correlated with IL2 administration and CEA decreases.Conclusions: We have demonstrated the safety of anti-CEA CAR-T HAIs with encouraging signals of clinical activity in a heavily pretreated population with large tumor burdens. Further clinical testing of CAR-T HAIs for liver metastases is warranted. Clin Cancer Res; 21(14); 3149–59. ©2015 AACR.
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- 2023
3. Supplemental Figure 4 from Phase I Hepatic Immunotherapy for Metastases Study of Intra-Arterial Chimeric Antigen Receptor–Modified T-cell Therapy for CEA+ Liver Metastases
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Richard P. Junghans, N. Joseph Espat, Robin Davies, Earle O. Assanah, Brian F. Stainken, Qiangzhong Ma, Mitchell Thorn, Pranay D. Khare, Gary R. Point, Wesley Mooring, Li Juan Wang, Elise McCormack, Rachel A. Burga, and Steven C. Katz
- Abstract
Supplemental Figure 4. Cytokine response to treatment
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- 2023
4. Supplemental Figure 3 from Phase I Hepatic Immunotherapy for Metastases Study of Intra-Arterial Chimeric Antigen Receptor–Modified T-cell Therapy for CEA+ Liver Metastases
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Richard P. Junghans, N. Joseph Espat, Robin Davies, Earle O. Assanah, Brian F. Stainken, Qiangzhong Ma, Mitchell Thorn, Pranay D. Khare, Gary R. Point, Wesley Mooring, Li Juan Wang, Elise McCormack, Rachel A. Burga, and Steven C. Katz
- Abstract
Supplemental Figure 3. Radiographic studies
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- 2023
5. Supplemental Figure 2 from Phase I Hepatic Immunotherapy for Metastases Study of Intra-Arterial Chimeric Antigen Receptor–Modified T-cell Therapy for CEA+ Liver Metastases
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Richard P. Junghans, N. Joseph Espat, Robin Davies, Earle O. Assanah, Brian F. Stainken, Qiangzhong Ma, Mitchell Thorn, Pranay D. Khare, Gary R. Point, Wesley Mooring, Li Juan Wang, Elise McCormack, Rachel A. Burga, and Steven C. Katz
- Abstract
Supplemental Figure 2. Flow cytometry gating
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- 2023
6. Role of yttrium-90 selective internal radiation therapy in the treatment of liver-dominant metastatic colorectal cancer: an evidence-based expert consensus algorithm
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D. Rohan Jeyarajah, Joseph Kim, David A. Iannitti, Paul D. Hansen, Thavam Thambi-Pillai, Brendan C. Visser, N. Joseph Espat, and Maria B. Doyle
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0301 basic medicine ,Chemotherapy ,Evidence-based practice ,Colorectal cancer ,business.industry ,medicine.medical_treatment ,Selective internal radiation therapy ,Gastroenterology ,Expert consensus ,Context (language use) ,Review Article ,Disease ,medicine.disease ,Palliative Therapy ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,medicine ,business ,Algorithm - Abstract
Surgical resection of colorectal liver metastases is associated with greater survival compared with non-surgical treatment, and a meaningful possibility of cure. However, the majority of patients are not eligible for resection and may require other non-surgical interventions, such as liver-directed therapies, to be converted to surgical eligibility. Given the number of available therapies, a general framework is needed that outlines the specific roles of chemotherapy, surgery, and locoregional treatments [including selective internal radiation therapy (SIRT) with Y-90 microspheres]. Using a data-driven, modified Delphi process, an expert panel of surgical oncologists, transplant surgeons, and hepatopancreatobiliary (HPB) surgeons convened to create a comprehensive, evidence-based treatment algorithm that includes appropriate treatment options for patients stratified by their eligibility for surgical treatment. The group coined a novel, more inclusive phrase for targeted locoregional tumor treatment (a blanket term for resection, ablation, and other emerging locoregional treatments): local parenchymal tumor destruction therapy. The expert panel proposed new nomenclature for 3 distinct disease categories of liver-dominant metastatic colorectal cancer that is consistent with other tumor types: (I) surgically treatable (resectable); (II) surgically untreatable (borderline resectable); (III) advanced surgically untreatable (unresectable) disease. Patients may present at any point in the algorithm and move between categories depending on their response to therapy. The broad intent of therapy is to transition patients toward individualized treatments where possible, given the survival advantage that resection offers in the context of a comprehensive treatment plan. This article reviews what is known about the role of SIRT with Y-90 as neoadjuvant, definitive, or palliative therapy in these different clinical situations and provides insight into when treatment with SIRT with Y-90 may be appropriate and useful, organized into distinct treatment algorithm steps.
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- 2020
7. Decreasing colorectal cancer screening disparities: A culturally tailored patient navigation program for Hispanic patients
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Carl S. Winkler, John C. Hardaway, M. Erkan Ceyhan, N. Joseph Espat, and Abdul Saied Calvino
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Male ,Cancer Research ,Oncology ,Humans ,Mass Screening ,Patient Navigation ,Female ,Colonoscopy ,Hispanic or Latino ,Colorectal Neoplasms ,Early Detection of Cancer - Abstract
Colorectal cancer (CRC) is the second leading cause of cancer-related death in Hispanic patients. Screening colonoscopy has been shown to reduce the incidence and mortality of CRC. However, utilization among Hispanic patients and other minority groups is low. The objective of this study was to evaluate colonoscopy utilization among Hispanic patients with a culturally tailored patient navigation program (CTPNP) in place.A CTPNP was designed to meet the needs of the authors' Hispanic patient population and their health care system characteristics. A CTPNP protocol was created, and a Spanish-speaking navigator/coordinator was hired. Enrolled patients received a Spanish-language introductory letter, an initial phone call for patient education, and follow-up calls to ensure that all potential barriers to colonoscopy were overcome. Colonoscopy completion (CC), colonoscopy cancellation (CN), and colonoscopy no-show (NS) rates were recorded and compared with historical rates in Rhode Island.Over a 28-month period, 773 patients were referred to the CTPNP, and 698 (53% female and 47% male) were enrolled in the program. The overall CC rate was 85% (n = 592) with no difference between males and females. The CN rate was 9% (n = 62), and the NS rate was 6% (n = 44). The most common reasons for CN and NS were cost and an inability to contact the patient after referral. Within the CC group, 43% (n = 254) of patients underwent polypectomy, and 1.3% (n = 8) required colectomy. Ninety percent (n = 530) of the CC group reported that they would not have completed colonoscopy without the CTPNP.Implementation of a CTPNP is an effective intervention to improve the CC rate and eliminate the historical gender gap in utilization among Hispanic patients.
- Published
- 2021
8. HITM-SIR: phase Ib trial of intraarterial chimeric antigen receptor T-cell therapy and selective internal radiation therapy for CEA+ liver metastases
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Vincent Armenio, Li Juan Wang, John C. Hardaway, Marissa Cunetta, Ethan A. Prince, Ashley E. Moody, Richard P. Junghans, Steven C. Katz, N. Joseph Espat, and Prajna Guha
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0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,business.industry ,Selective internal radiation therapy ,Neurotoxicity ,medicine.disease ,Systemic therapy ,Gastroenterology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Antigen ,030220 oncology & carcinogenesis ,Internal medicine ,Clinical endpoint ,Molecular Medicine ,Medicine ,Chimeric Antigen Receptor T-Cell Therapy ,business ,Molecular Biology ,Median survival ,Artery - Abstract
Effective chimeric antigen receptor-modified T-cell (CAR-T) therapy for liver metastases (LM) will require innovative solutions to ensure efficient delivery and minimization of systemic toxicity. We previously demonstrated the safety of CAR-T hepatic artery infusions (HAI). We subsequently conducted the phase 1b HITM-SIR trial, in which six patients (pts) with CEA+ LM received anti-CEA CAR-T HAIs and selective internal radiation therapy (SIRT). The primary endpoint was safety with secondary assessments of biologic activity. Enrolled pts had a mean LM size of 6.4 cm, 4 pts had >10 LM, and pts received an average of two lines of prior systemic therapy. No grade 4 or 5 toxicities were observed, and there were no instances of severe cytokine-release syndrome (CRS) or neurotoxicity. The mean transduction efficiency was 60.4%. Following CAR-T HAI, reduced levels of GM-CSF-R, IDO, and PD-L1 were detected in LM, and serum CEA levels were stable or decreased in all subjects. Median survival time was 8 months (mean 11, range 4–31). Anti-CEA CAR-T HAI with subsequent SIRT was well tolerated, and biologic responses were demonstrated following failure of conventional therapy. HAI of CAR-T was once again confirmed not to be associated with severe CRS or neurotoxicity.
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- 2019
9. STAT3 inhibition induces Bax-dependent apoptosis in liver tumor myeloid-derived suppressor cells
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George Miller, Steven C. Katz, Prajna Guha, Marissa Cunetta, N. Joseph Espat, Josephine Darpolor, Jillian Gardell, Richard P. Junghans, and Matthew Lima
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0301 basic medicine ,Cancer Research ,biology ,p38 mitogen-activated protein kinases ,medicine.medical_treatment ,Immunotherapy ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Downregulation and upregulation ,Cell culture ,Apoptosis ,030220 oncology & carcinogenesis ,Genetics ,biology.protein ,medicine ,Cancer research ,Myeloid-derived Suppressor Cell ,Signal transduction ,STAT3 ,Molecular Biology - Abstract
Immunosuppressive myeloid-derived suppressor cells (MDSC) subvert antitumor immunity and limit the efficacy of chimeric antigen receptor T cells (CAR-T). Previously, we reported that the GM-CSF/JAK2/STAT3 axis drives liver-associated MDSC (L-MDSC) proliferation and blockade of this axis rescued antitumor immunity. We extended these findings in our murine liver metastasis (LM) model, by treating tumor-bearing mice with STAT3 inhibitors (STATTIC or BBI608) to further our understanding of how STAT3 drives L-MDSC suppressive function. STAT3 inhibition caused significant reduction of tumor burden as well as L-MDSC frequencies due to decrease in pSTAT3 levels. L-MDSC isolated from STATTIC or BBI608-treated mice had significantly reduced suppressive function. STAT3 inhibition of L-MDSC was associated with enhanced antitumor activity of CAR-T. Further investigation demonstrated activation of apoptotic signaling pathways in L-MDSC following STAT3 inhibition as evidenced by an upregulation of the pro-apoptotic proteins Bax, cleaved caspase-3, and downregulation of the anti-apoptotic protein Bcl-2. Accordingly, there was also a decrease of pro-survival markers, pErk and pAkt, and an increase in pro-death marker, Fas, with activation of downstream JNK and p38 MAPK. These findings represent a previously unrecognized link between STAT3 inhibition and Fas-induced apoptosis of MDSCs. Our findings suggest that inhibiting STAT3 has potential clinical application for enhancing the efficacy of CAR-T cells in LM through modulation of L-MDSC.
- Published
- 2018
10. Association of primary tumor lymph node ratio with burden of liver metastases and survival in stage IV colorectal cancer
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Jeffrey Reha, Ali Ahmad, Abdul Saied, Steven C. Katz, N. Joseph Espat, and Ponnandai Somasundar
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0301 basic medicine ,medicine.medical_specialty ,Multivariate analysis ,Proportional hazards model ,business.industry ,Odds ratio ,medicine.disease ,Gastroenterology ,Primary tumor ,Confidence interval ,Surgery ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Internal medicine ,Cohort ,medicine ,Chi-square test ,business ,Lymph node - Abstract
Background: The primary objective of our study was to assess the association of primary tumor lymph node ratio (LNR) in stage IV colorectal adenocarcinomas (CRC) with overall survival (OS) and the extent of metastatic disease in the liver. Methods: We analyzed data on 53 stage IV CRC patients who underwent surgical resection of the primary tumor. The median LNR of 0.25 was used to stratify patients into high LNR (H-LNR) and low LNR (L-LNR) groups. Statistical comparison was performed using chi square test and multiple regression models. OS was calculated using the Kaplan-Meier (KM) method while cox regression was used for multivariate analysis. Results: H-LNR status was associated with the presence of >3 liver metastases (LM) [odds ratio (OR): 2.43, P=0.047] and bilobar LM (OR: 3.94, P=0.039). The OS in H-LNR patients was significantly worse in the entire cohort compared to L-LNR (9% vs. 34% at 3 years, P=0.027). The 5-year OS in patients undergoing liver resection for LM was also significantly worse in the H-LNR group (0% vs. 37%, P=0.013). LNR was independently associated with survival on multivariate analysis [HR: 2.63; 95% confidence intervals (CI), 1.13–6.14; P=0.025]. Conclusions: In stage IV CRC, LNR is associated with the extent of hepatic tumor burden and was an independent predictor of survival in patients undergoing liver resection.
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- 2017
11. Frontline Science: Functionally impaired geriatric CAR-T cells rescued by increased α5β1 integrin expression
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Marissa Cunetta, Prajna Guha, Richard P. Junghans, Ponnandai Somasundar, Steven C. Katz, and N. Joseph Espat
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Adult ,Cytotoxicity, Immunologic ,Male ,0301 basic medicine ,Aging ,T-Lymphocytes ,medicine.medical_treatment ,Blotting, Western ,Immunology ,Integrin ,Receptors, Antigen, T-Cell ,Biology ,Lymphocyte Activation ,Young Adult ,03 medical and health sciences ,Transduction (genetics) ,Immune system ,medicine ,Humans ,Immunology and Allergy ,Aged ,Chimera ,Reverse Transcriptase Polymerase Chain Reaction ,Cell Biology ,Immunotherapy ,Flow Cytometry ,Chimeric antigen receptor ,Cell biology ,030104 developmental biology ,Perforin ,Granzyme ,biology.protein ,Female ,CD8 ,Integrin alpha5beta1 - Abstract
Chimeric antigen receptor expressing T cells (CAR-T) are a promising form of immunotherapy, but the influence of age-related immune changes on CAR-T production remains poorly understood. We showed that CAR-T cells from geriatric donors (gCAR-T) are functionally impaired relative to CAR-T from younger donors (yCAR-T). Higher transduction efficiencies and improved cell expansion were observed in yCAR-T cells compared with gCAR-T. yCAR-T demonstrated significantly increased levels of proliferation and signaling activation of phosphorylated (p)Erk, pAkt, pStat3, and pStat5. Furthermore, yCAR-T contained higher proportions of CD4 and CD8 effector memory (EM) cells, which are known to have enhanced cytolytic capabilities. Accordingly, yCAR-T demonstrated higher levels of tumor antigen-specific cytotoxicity compared with gCAR-T. Enhanced tumor killing by yCAR-T correlated with increased levels of perforin and granzyme B. yCAR-T had increased α5β1 integrin expression, a known mediator of retroviral transduction. We found that treatment with M-CSF or TGF-β1 rescued the impaired transduction efficiency of the gCAR-T by increasing the α5β1 integrin expression. Neutralization of α5β1 confirmed that this integrin was indispensable for CAR expression. Our study suggests that the increase of α5β1 integrin expression levels enhances CAR expression and thereby improves tumor killing by gCAR-T.
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- 2017
12. Fibrolamellar Carcinoma: Novel Insights into a Rare Subtype
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N. Joseph Espat, Ponnandai Somasundar, and Asish Patel
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Oncology ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,business.industry ,Prognosis ,Survival Rate ,Surgical oncology ,Internal medicine ,Biomarkers, Tumor ,medicine ,Hepatectomy ,Humans ,Surgery ,alpha-Fetoproteins ,business ,Fibrolamellar Carcinoma - Published
- 2020
13. HITM-SIR: phase Ib trial of intraarterial chimeric antigen receptor T-cell therapy and selective internal radiation therapy for CEA
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Steven C, Katz, John, Hardaway, Ethan, Prince, Prajna, Guha, Marissa, Cunetta, Ashley, Moody, Li Juan, Wang, Vincent, Armenio, N Joseph, Espat, and Richard P, Junghans
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Adult ,Male ,Receptors, Chimeric Antigen ,Rectal Neoplasms ,Brachytherapy ,Liver Neoplasms ,Middle Aged ,GPI-Linked Proteins ,Combined Modality Therapy ,Immunotherapy, Adoptive ,Carcinoembryonic Antigen ,Pancreatic Neoplasms ,Liver ,Colonic Neoplasms ,Humans ,Infusions, Intra-Arterial ,Female ,Response Evaluation Criteria in Solid Tumors ,Aged ,Follow-Up Studies - Abstract
Effective chimeric antigen receptor-modified T-cell (CAR-T) therapy for liver metastases (LM) will require innovative solutions to ensure efficient delivery and minimization of systemic toxicity. We previously demonstrated the safety of CAR-T hepatic artery infusions (HAI). We subsequently conducted the phase 1b HITM-SIR trial, in which six patients (pts) with CEA
- Published
- 2019
14. Efficacy and Tolerability of 5-Year Adjuvant Imatinib Treatment for Patients With Resected Intermediate- or High-Risk Primary Gastrointestinal Stromal Tumor: The PERSIST-5 Clinical Trial
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Dejka M. Araujo, Chandrajit P. Raut, Jonathan C. Trent, Toni Faith Williams, Robert G. Maki, Ronald P. DeMatteo, Das Purkayastha, and N. Joseph Espat
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Gastrointestinal Stromal Tumors ,Antineoplastic Agents ,Disease-Free Survival ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,medicine ,Clinical endpoint ,Humans ,Adverse effect ,Aged ,Gastrointestinal Neoplasms ,Neoplasm Staging ,Original Investigation ,Aged, 80 and over ,GiST ,Dose-Response Relationship, Drug ,business.industry ,Imatinib ,Middle Aged ,Combined Modality Therapy ,Discontinuation ,Clinical trial ,Imatinib mesylate ,Treatment Outcome ,Oncology ,Tolerability ,Chemotherapy, Adjuvant ,030220 oncology & carcinogenesis ,Imatinib Mesylate ,030211 gastroenterology & hepatology ,Female ,business ,medicine.drug - Abstract
Importance Three years of adjuvant imatinib mesylate therapy is associated with reduced recurrence rates and improved overall survival in patients with high-risk primary gastrointestinal stromal tumor (GIST) compared with patients who receive 1 year of treatment. The impact of a longer duration of therapy is unknown. Objective To determine whether adjuvant treatment for primary GIST with imatinib for 5 years is tolerable and efficacious. Design, Setting, and Participants This prospective, single-arm, phase 2 clinical trial (Postresection Evaluation of Recurrence-free Survival for Gastrointestinal Stromal Tumors With 5 Years of Adjuvant Imatinib [PERSIST-5]) included adult patients with primary GIST (expressing KIT) at 21 US institutions who underwent a macroscopically complete resection and were at intermediate or high risk of recurrence, defined as primary GIST at any site measuring 2 cm or larger with 5 or more mitoses per 50 high-power field or nongastric primary GIST measuring 5 cm or larger. Data were collected from August 5, 2009, through December 20, 2016. Interventions Imatinib, 400 mg once daily, orally for 5 years or until discontinuation of therapy because of progression or intolerance. Main Outcomes and Measures The primary end point was recurrence-free survival (RFS). The secondary end point was overall survival. Results Of the 91 patients enrolled, 48 (53%) were men with a median age of 60 years (range, 30-90 years). Median tumor size was 6.5 cm (range, 2.3-30.0 cm). Median treatment duration was 55.1 months (range, 0.5-60.6 months); 46 patients (51%) completed 5 years of imatinib therapy. Estimated 5-year RFS was 90% (95% CI, 80%-95%), and overall survival was 95% (95% CI, 86%-99%). Recurrence was noted in 7 patients: 1 had disease recur while receiving imatinib (PDGFRAD842V mutation) and died; 6 had disease recur after discontinuation of imatinib therapy. Two additional deaths were unrelated to treatment or tumor progression. Forty-five patients (49%) stopped treatment early because of patient choice (10 [21%]), adverse events (15 [16%]), or other (11 [12%]). All 91 patients experienced at least 1 adverse event, and 17 (19%) experienced grade 3 or 4 adverse events. Conclusions and Relevance In this first adjuvant trial, to our knowledge, of patients with resected primary GIST who received 5 years of imatinib therapy, no patient with imatinib-sensitive mutations had disease recur during therapy. For patients in whom disease recurred, recurrence was within 2 years of discontinuation of imatinib therapy. Approximately half of the patients discontinued treatment early, most commonly because of patient choice, thus emphasizing the importance of close clinical monitoring to continue imatinib treatment for patients at appropriate risk. Trial Registration ClinicalTrials.gov identifier:NCT00867113
- Published
- 2018
15. Predictors of surgical non-referral for colorectal liver metastases
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Ponnandai Somasundar, Jeffrey Reha, Ali Ahmad, Steven C. Katz, and N. Joseph Espat
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Male ,medicine.medical_specialty ,Multivariate analysis ,Referral ,Colorectal cancer ,Adenocarcinoma ,030230 surgery ,03 medical and health sciences ,0302 clinical medicine ,Quantitative assessment ,Overall survival ,Humans ,Medicine ,Referral and Consultation ,Aged ,Retrospective Studies ,Proportional hazards model ,business.industry ,Liver Neoplasms ,Rhode Island ,Odds ratio ,Middle Aged ,medicine.disease ,Confidence interval ,Surgery ,General Surgery ,030220 oncology & carcinogenesis ,Female ,Colorectal Neoplasms ,business - Abstract
Surgical resection is the only curative option for patients with colorectal liver metastases (CRLM). The objective of our study was to identify factors associated with failure to refer patients with CRLM to a surgeon with oncologic and hepatobiliary expertise.Data were retrospectively reviewed on 75 patients with CRLM treated at our institution. Patients were divided into referred and nonreferred groups for comparison. Quantitative assessment of association was tabulated using the odds ratio (OR). Statistical comparison was performed using the chi-square test and multiple regression models. Overall survival (OS) was calculated using the Kaplan-Meier method. Multivariate analysis was done using Cox regression.Factors independently associated with lower surgical referral rates included age ≥ 65 y (OR 0.29, 95% confidence interval [CI] 0.09-0.89, P = 0.032), bilobar CRLM (OR 0.35, 95% CI 0.09-0.97, P = 0.048), and presence of3 CRLM (OR 0.33, 95% CI 0.11-0.94, P = 0.044). The 5-y OS for referred patients was 33% compared with only 8% in patients who were not referred (P 0.001). Factors independently associated with worse OS included age ≥ 65 y (hazard ratio [HR] 2.01, 95% CI 1.12-3.59, P = 0.019), bilobar hepatic metastases (HR 3.04, 95% CI 1.62-5.70, P 0.001), and the presence of extrahepatic metastases (HR 2.11, 95% CI 1.02-4.16, P = 0.011). Referral to a surgeon was associated with improved OS (HR 0.42, 95% CI 0.24-0.74, P = 0.003).Failure to refer CRLM patients for surgical evaluation is associated with aggressive biologic features that do not necessarily preclude resection. Determination of resectability should be made with input from appropriately trained surgical experts.
- Published
- 2016
16. STAT3 inhibition induces Bax-dependent apoptosis in liver tumor myeloid-derived suppressor cells
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Prajna, Guha, Jillian, Gardell, Josephine, Darpolor, Marissa, Cunetta, Matthew, Lima, George, Miller, N Joseph, Espat, Richard P, Junghans, and Steven C, Katz
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Male ,STAT3 Transcription Factor ,Antineoplastic Agents ,Apoptosis ,Adenocarcinoma ,Mice ,Liver Neoplasms, Experimental ,Cell Line, Tumor ,Animals ,Molecular Targeted Therapy ,fas Receptor ,Benzofurans ,bcl-2-Associated X Protein ,Mice, Knockout ,Myeloid-Derived Suppressor Cells ,Cyclic S-Oxides ,Neoplasm Proteins ,Specific Pathogen-Free Organisms ,Tumor Burden ,Gene Expression Regulation, Neoplastic ,Mice, Inbred C57BL ,Tumor Escape ,Immunotherapy ,Drug Screening Assays, Antitumor ,Apoptosis Regulatory Proteins ,Colorectal Neoplasms ,Naphthoquinones ,Signal Transduction - Abstract
Immunosuppressive myeloid-derived suppressor cells (MDSC) subvert antitumor immunity and limit the efficacy of chimeric antigen receptor T cells (CAR-T). Previously, we reported that the GM-CSF/JAK2/STAT3 axis drives liver-associated MDSC (L-MDSC) proliferation and blockade of this axis rescued antitumor immunity. We extended these findings in our murine liver metastasis (LM) model, by treating tumor-bearing mice with STAT3 inhibitors (STATTIC or BBI608) to further our understanding of how STAT3 drives L-MDSC suppressive function. STAT3 inhibition caused significant reduction of tumor burden as well as L-MDSC frequencies due to decrease in pSTAT3 levels. L-MDSC isolated from STATTIC or BBI608-treated mice had significantly reduced suppressive function. STAT3 inhibition of L-MDSC was associated with enhanced antitumor activity of CAR-T. Further investigation demonstrated activation of apoptotic signaling pathways in L-MDSC following STAT3 inhibition as evidenced by an upregulation of the pro-apoptotic proteins Bax, cleaved caspase-3, and downregulation of the anti-apoptotic protein Bcl-2. Accordingly, there was also a decrease of pro-survival markers, pErk and pAkt, and an increase in pro-death marker, Fas, with activation of downstream JNK and p38 MAPK. These findings represent a previously unrecognized link between STAT3 inhibition and Fas-induced apoptosis of MDSCs. Our findings suggest that inhibiting STAT3 has potential clinical application for enhancing the efficacy of CAR-T cells in LM through modulation of L-MDSC.
- Published
- 2017
17. Population Health Initiatives Increase Patient Engagement and Satisfaction with Health Care Services
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John C. Hardaway, Ayana Allard-Picou, Abdul Saied Calvino, and N. Joseph Espat
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Nursing ,business.industry ,Health care ,Medicine ,Surgery ,Patient engagement ,Population health ,business - Published
- 2018
18. Liver myeloid-derived suppressor cells expand in response to liver metastases in mice and inhibit the anti-tumor efficacy of anti-CEA CAR-T
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Alfred Ayala, Prajna Guha, Cang T. Nguyen, Gary Point, Ronald P. DeMatteo, Richard P. Junghans, Mitchell Thorn, Rachel A. Burga, Lauren A. Licata, Steven C. Katz, and N. Joseph Espat
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Male ,STAT3 Transcription Factor ,Cancer Research ,Liver cytology ,Recombinant Fusion Proteins ,T cell ,Immunology ,Receptors, Antigen, T-Cell ,Mice, Transgenic ,CD8-Positive T-Lymphocytes ,Article ,B7-H1 Antigen ,Mice ,Antigen ,Cell Line, Tumor ,Animals ,Immunology and Allergy ,Medicine ,Myeloid Cells ,Receptor ,STAT3 ,biology ,business.industry ,Liver Neoplasms ,Granulocyte-Macrophage Colony-Stimulating Factor ,Carcinoembryonic Antigen ,Tumor Burden ,Blockade ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,Liver ,Oncology ,Cell culture ,Myeloid-derived Suppressor Cell ,biology.protein ,Cancer research ,business ,human activities - Abstract
Chimeric antigen receptor-modified T cell (CAR-T) technology, a promising immunotherapeutic tool, has not been applied specifically to treat liver metastases (LM). While CAR-T delivery to LM can be optimized by regional intrahepatic infusion, we propose that liver CD11b+Gr-1+ myeloid-derived suppressor cells (L-MDSC) will inhibit the efficacy of CAR-T in the intrahepatic space. We studied anti-CEA CAR-T in a murine model of CEA+ LM and identified mechanisms through which L-MDSC expand and inhibit CAR-T function. We established CEA+ LM in mice and studied purified L-MDSC and responses to treatment with intrahepatic anti-CEA CAR-T infusions. L-MDSC expanded threefold in response to LM, and their expansion was dependent on GM-CSF, which was produced by tumor cells. L-MDSC utilized PD-L1 to suppress anti-tumor responses through engagement of PD-1 on CAR-T. GM-CSF, in cooperation with STAT3, promoted L-MDSC PD-L1 expression. CAR-T efficacy was rescued when mice received CAR-T in combination with MDSC depletion, GM-CSF neutralization to prevent MDSC expansion, or PD-L1 blockade. As L-MDSC suppressed anti-CEA CAR-T, infusion of anti-CEA CAR-T in tandem with agents targeting L-MDSC is a rational strategy for future clinical trials.
- Published
- 2015
19. Contributors
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Ghassan K. Abou-Alfa, Jad Abou Khalil, Pietro Addeo, N. Volkan Adsay, Anil Kumar Agarwal, Farzad Alemi, Peter J. Allen, Ahmed Al-Mukhtar, Thomas A. Aloia, Jesper B. Andersen, Christopher D. Anderson, Vittoria Arslan-Carlon, Horacio J. Asbun, Béatrice Aussilhou, Joseph Awad, Daniel Azoulay, Philippe Bachellier, Talia B. Baker, Zubin M. Bamboat, Jeffrey Stewart Barkun, Claudio Bassi, Olca Basturk, Rachel E. Beard, Pierre Bedossa, Jacques Belghiti, Omar Bellorin-Marin, Marc G.H. Besselink, Anton J. Bilchik, Leslie H. Blumgart, Franz Edward Boas, Lynn A. Brody, Karen T. Brown, Jordi Bruix, David A. Bruno, Elizabeth M. Brunt, Justin M. Burns, Giovanni Butturini, Juan Carlos Caicedo, Mark P. Callery, Abdul Saied Calvino, Danielle H. Carpenter, C. Ross Carter, François Cauchy, Chung Yip Chan, See Ching Chan, William C. Chapman, Daniel Cherqui, Clifford S. Cho, Jin Wook Chung, Jesse Clanton, Bryan Marshall Clary, Sean Patrick Cleary, Kelly M. Collins, John Barry Conneely, Louise C. Connell, Carlos U. Corvera, Guido Costa, Anne M. Covey, Jeffrey S. Crippin, Kristopher P. Croome, Hany Dabbous, Michael I. D'Angelica, Michael D. Darcy, Jeremy L. Davis, Jeroen de Jonge, Ronald P. DeMatteo, Danielle K. DePeralta, Niraj M. Desai, Eduardo de Santibañes, Martin de Santibañes, Euan J. Dickson, Christopher John DiMaio, Richard Kinh Gian Do, Safi Dokmak, Marcello Donati, M.B. Majella Doyle, Vikas Dudeja, Mark Dunphy, Truman M. Earl, Tomoki Ebata, Imane El Dika, Yousef El-Gohary, Itaru Endo, C. Kristian Enestvedt, N. Joseph Espat, Cecilia G. Ethun, Sheung Tat Fan, Paul T. Fanta, Olivier Farges, Cristina R. Ferrone, Ryan C. Fields, Mary Fischer, Sarah B. Fisher, Devin C. Flaherty, Yuman Fong, Scott L. Friedman, Ahmed Gabr, John R. Galloway, David A. Geller, Hans Gerdes, Scott R. Gerst, George K. Gittes, Jaime Glorioso, Jill S. Gluskin, Brian K.P. Goh, Stevan A. Gonzalez, Karyn A. Goodman, Gregory J. Gores, Eduardo H. Gotuzzo, Dirk J. Gouma, Paul D. Greig, James F. Griffin, Christopher M. Halloran, Neil A. Halpern, Chet W. Hammill, Paul D. Hansen, James J. Harding, Ewen M. Harrison, Werner Hartwig, Kiyoshi Hasegawa, Jaclyn F. Hechtman, Julie K. Heimbach, William S. Helton, Alan W. Hemming, J. Michael Henderson, Asher Hirshberg, James R. Howe, Christopher B. Hughes, Christine Iacobuzio-Donahue, William R. Jarnagin, Roger L. Jenkins, Zeljka Jutric, Christoph Kahlert, Joseph Ralph Kallini, Ivan Kangrga, Paul J. Karanicolas, Seth S. Katz, Steven C. Katz, Kaitlyn J. Kelly, Nancy E. Kemeny, Eugene P. Kennedy, Korosh Khalili, Adeel S. Khan, Saboor Khan, Heung Bae Kim, T. Peter Kingham, Allan D. Kirk, David S. Klimstra, Michael Kluger, Stuart J. Knechtle, Jonathan B. Koea, Norihiro Kokudo, Dionysios Koliogiannis, David A. Kooby, Kevin Korenblat, Simone Krebs, Michael J. LaQuaglia, Michael P. LaQuaglia, Nicholas F. LaRusso, Alexis Laurent, Konstantinos N. Lazaridis, Julie N. Leal, Eliza J. Lee, Major Kenneth Lee, Ser Yee Lee, Riccardo Lencioni, Alexandre Liccioni, Michael E. Lidsky, Chung-Wei Lin, David C. Linehan, Roberto Carlos Lopez-Solis, Jeffrey A. Lowell, David C. Madoff, Jason Maggi, Shishir K. Maithel, Ali W. Majeed, Peter Malfertheiner, Giuseppe Malleo, Shennen A. Mao, Giovanni Marchegiani, Luis A. Marcos, James F. Markmann, J. Wallis Marsh, Robert C.G. Martin, Ryusei Matsuyama, Matthias S. Matter, Francisco Juan Mattera, Jessica E. Maxwell, Oscar M. Mazza, Ian D. McGilvray, Colin J. McKay, Doireann M. McWeeney, Jose Melendez, Robin B. Mendelsohn, George Miller, Klaus E. Mönkemüller, Ryutaro Mori, Vitor Moutinho, Masato Nagino, David M. Nagorney, Satish Nagula, Attila Nakeeb, Geir I. Nedredal, John P. Neoptolemos, James Neuberger, Scott L. Nyberg, Rachel O'Connor, John G. O'Grady, Frances E. Oldfield, Karl J. Oldhafer, Kim M. Olthoff, Susan L. Orloff, Alessandro Paniccia, Valérie Paradis, Rowan W. Parks, Gérard Pascal, Stephen M. Pastores, Timothy M. Pawlik, Venu G. Pillarisetty, James Francis Pingpank, C. Wright Pinson, Henry Anthony Pitt, James J. Pomposelli, Fabio Procopio, Michael J. Pucci, Motaz Qadan, Kheman Rajkomar, Srinevas K. Reddy, Maria E. Reig, Joseph Arturo Reza, John Paul Roberts, Piera Marie Cote Robson, Flavio G. Rocha, Garrett Richard Roll, Sean M. Ronnekleiv-Kelly, Alexander S. Rosemurgy, Charles B. Rosen, Pierre F. Saldinger, Riad Salem, Suhail Bakr Salem, Roberto Salvia, Charbel Sandroussi, Dominic E. Sanford, Olivier Scatton, Mark Andrew Schattner, William Palmer Schecter, Hans Francis Schoellhammer, Richard D. Schulick, Lawrence H. Schwartz, Kevin N. Shah, Ross W. Shepherd, Hiroshi Shimada, Masafumi Shimoda, Junichi Shindoh, Hosein Shokouh-Amiri, Jason K. Sicklick, Robert H. Siegelbaum, Gagandeep Singh, Rory L. Smoot, Stephen B. Solomon, Olivier Soubrane, Nicholas Spinelli, John A. Stauffer, Lygia Stewart, Matthew S. Strand, James H. Tabibian, Guido Torzilli, James F. Trotter, Simon Turcotte, Yumirle P. Turmelle, Demetrios J. Tzimas, Thomas Van Gulik, Andrea Vannucci, Jean-Nicolas Vauthey, Diana Vetter, Valérie Vilgrain, Alejandra Maria Villamil, Louis P. Voigt, Charles M. Vollmer, Jack R. Wands, Julia Wattacheril, Sharon Marie Weber, Matthew J. Weiss, Jürgen Weitz, Jens Werner, Megan Winner, John Wong, Dennis Yang, Hooman Yarmohammadi, Charles J. Yeo, Theresa Pluth Yeo, Chang Jin Yoon, Adam Yopp, D. Owen Young, Kai Zhao, Gazi B. Zibari, and George Zogopoulos
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- 2017
20. Cholangitis
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N. Joseph Espat and Abdul Saied Calvino
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business.industry ,Medicine ,business - Published
- 2017
21. Liver metastases induce reversible hepatic B cell dysfunction mediated by Gr-1+CD11b+ myeloid cells
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Rachel A. Burga, Mitchell Thorn, Gary Point, Steven C. Katz, N. Joseph Espat, and Cang T. Nguyen
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Male ,Adoptive cell transfer ,viruses ,T cell ,Immunology ,B-Lymphocyte Subsets ,Down-Regulation ,chemical and pharmacologic phenomena ,Receptors, Cell Surface ,Lymphocyte Activation ,Immunoglobulin D ,CD19 ,Mice ,T-Lymphocyte Subsets ,Cell Line, Tumor ,parasitic diseases ,medicine ,Animals ,Immunology and Allergy ,Myeloid Cells ,Neoplasm Metastasis ,B cell ,CD11b Antigen ,biology ,business.industry ,Inflammation, Extracellular Mediators, & Effector Molecules ,Liver Neoplasms ,virus diseases ,hemic and immune systems ,Cell Biology ,Adoptive Transfer ,digestive system diseases ,Molecular Imaging ,Tumor Burden ,Disease Models, Animal ,medicine.anatomical_structure ,Tumor progression ,Luminescent Measurements ,B7-1 Antigen ,biology.protein ,Cancer research ,B7-2 Antigen ,business ,Ex vivo ,CD80 - Abstract
LM escape immune surveillance, in part, as a result of the expansion of CD11b+MC, which alter the intrahepatic microenvironment to promote tumor tolerance. HBC make up a significant proportion of liver lymphocytes and appear to delay tumor progression; however, their significance in the setting of LM is poorly defined. Therefore, we characterized HBC and HBC/CD11b+MC interactions using a murine model of LM. Tumor-bearing livers showed a trend toward elevated absolute numbers of CD19+ HBC. A significant increase in the frequency of IgMloIgDhi mature HBC was observed in mice with LM compared with normal mice. HBC derived from tumor-bearing mice demonstrated increased proliferation in response to TLR and BCR stimulation ex vivo compared with HBC from normal livers. HBC from tumor-bearing livers exhibited significant down-regulation of CD80 and were impaired in inducing CD4+ T cell proliferation ex vivo. We implicated hepatic CD11b+MC as mediators of CD80 down-modulation on HBC ex vivo via a CD11b-dependent mechanism that required cell-to-cell contact and STAT3 activity. Therefore, CD11b+MC may compromise the ability of HBC to promote T cell activation in the setting of LM as a result of diminished expression of CD80. Cross-talk between CD11b+MC and HBC may be an important component of LM-induced immunosuppression.
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- 2014
22. Pressure enabled drug delivery of anti-CEA CAR-T cells increases intra-hepatic CAR-T tumor penetration and therapeutic index in a murine model of liver metastasis
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John C Hardaway, Louis F. Chai, Mikayla Lopes, Benjamin Rabinowitz, Prajna Guha, David Jaroch, Bryan Cox, Robert Knight, Jerome Zeldis, N. Joseph Espat, and Steven C Katz
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Immunology ,Immunology and Allergy - Abstract
Introduction We have demonstrated safety and clinical activity with anti-CEA CAR-T (Sorrento/TNK Therapeutics, Inc.) regional infusions for treatment of liver metastases (LM) using a pressure-enabled drug delivery device (PEDD™, TriSalus™ Life Sciences, Inc.) to increase CAR-T penetration. To further explore the potential benefit of PEDD, we developed a pre-clinical murine LM model that enables correlation of infusion pressure with response. Methodology Mice with CEA+ LM were infused with anti-CEA CAR-T into the portal vein with specified rate and pressure levels. Flow cytometry (FC), bioluminescence imaging (BLI), and serum liver function tests (LFTs) were conducted at multiple time points. Results Flow-pressure relationship was established with ΔP of 7.23 mmHg vs 2.33 mmHg (p=0.01) in high-pressure (10 mL/min, HP) and low-pressure (1 mL/min, LP) cohorts. FC assessment of hepatic non-parenchymal cells 1d after infusion demonstrated 15.9% CD3+CAR+ in HP, compared to 5.1% in LP (p=0.0004). Tumor BLI at day 3 (geometric mean relative to baseline) showed significantly enhanced therapeutic effect in HP, −18% relative signal intensity (RSI), compared to +148% RSI in LP (p=0.05) or +178% RSI in controls (p=0.04). LFTs were similar in LP and HP groups with AST 302 vs 437 U/L (p=0.60) and total bilirubin 0.25 vs 0.7 mg/dL (p=0.33), respectively. Conclusions HP delivery correlated with enhanced CAR-T delivery and control of tumor growth, without an increase in liver toxicity. Follow up to this proof of concept study will investigate multiple infusions with combinatorial approaches with the goal of durable tumor eradication. An ongoing clinical study will further explore CAR-T PEDD in patients.
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- 2019
23. Regional pressure-enabled drug delivery of anti-PD-1 agent for colorectal liver metastases improves anti-tumor activity without increased hepatic toxicity
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Louis F. Chai, John C. Hardaway, Mikayla C. Lopes, Benjamin A. Rabinowitz, Prajna Guha, David Jaroch, Bryan Cox, N. Joseph Espat, and Steven C. Katz
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Immunology ,Immunology and Allergy - Abstract
Introduction Checkpoint inhibitors (CI) have greatly impacted the treatment of solid tumors. Success in the liver has been more limited. When intravenously infused, the CI is delivered predominantly to extrahepatic sites, which results in systemic side effects. Previously, we reported on regional delivery of cellular immunotherapy for liver tumors using pressure-enabled drug delivery (PEDD™, TriSalus™ Life Sciences, Inc.). We hypothesized that PEDD of CI would improve the therapeutic index (TI). Methods In a murine model of colorectal liver metastases (CRLM), we infused high (HP) or low pressure (LP) anti-PD-1 antibodies (RMP1-14) via the portal vein and compared to systemic tail vein delivery (SD) at 0, 0.3, 1.0 and 3.0 mg/kg. Tumor bioluminescence (TB), histopathology, and serologic analysis informed treatment effects and toxicity. Results At a dose of 3mg/kg, LP resulted in similar IVIS TB growth kinetics compared to SD 3 mg/kg at 7 days post-treatment (geometric mean, p = 0.94). In animals treated with a 10-fold lower dose (0.3 mg/kg), tumor growth was significantly lower with HP vs. LP (7.5-fold improvement, p = 0.04). Circulating serum anti-PD-1 levels were similar when we compared SD and LP at 1 and 3 mg/kg (Mean 2512.0 vs. 2250.2 ng/mL, p = 0.25). Comparatively, systemic exposure was significantly lower at 0.3 mg/kg LP (Mean 508.1 ng/mL, p < 0.0001). No increases in hepatotoxicity were seen with PEDD (AST p = 0.57, ALT p = 0.43). Conclusion PEDD of anti-PD-1 CI improved liver tumor control while also limiting systemic exposure. These findings support PEDD for anti-PD-1 therapy to improve TI. Phase 1 exploration of anti-PD-1 PEDD for patients with hepatic malignancy is thus warranted.
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- 2019
24. The effects of sorafenib on liver regeneration in a model of partial hepatectomy
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Ponnandai Somasundar, Vincent Falanga, Xiaofei Wang, Steven C. Katz, N. Joseph Espat, Li Juan Wang, Peter C. Kurniali, and Katie O'Gara
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Liver Cirrhosis ,Male ,Niacinamide ,Sorafenib ,Carcinoma, Hepatocellular ,Pyridines ,medicine.medical_treatment ,Partial hepatectomy ,urologic and male genital diseases ,Article ,Resection ,Mice ,medicine ,Carcinoma ,Animals ,Hepatectomy ,heterocyclic compounds ,Protein Kinase Inhibitors ,neoplasms ,Cell Proliferation ,Dose-Response Relationship, Drug ,business.industry ,Phenylurea Compounds ,Benzenesulfonates ,Liver Neoplasms ,medicine.disease ,female genital diseases and pregnancy complications ,digestive system diseases ,Liver regeneration ,Liver Regeneration ,Mice, Inbred C57BL ,Hepatocellular carcinoma ,Models, Animal ,Hepatocytes ,Cancer research ,Surgery ,business ,Adjuvant ,medicine.drug - Abstract
Sorafenib is currently approved for advanced hepatocellular carcinoma (HCC) and is presently being studied as an adjuvant treatment for HCC following resection. The effects of sorafenib on liver regeneration have not been clearly defined. Our objective was to identify the effects of sorafenib on liver regeneration in a murine partial hepatectomy (PH) model.We performed PH in C57Bl/6 mice treated with a range of sorafenib doses with assessments at several time points. Liver sinusoidal endothelial cells (LSEC) and hepatocyte DNA synthesis and proliferation were assessed with 5-bromo-2'-deoxyuridine (BrdU) and Ki67 by flow cytometry and immunohistochemistry.Treatment with sorafenib did not result in any deaths following PH. When we measured BrdU uptake to assess DNA synthesis, there was a statistically significant increase at 48 h post-PH for nonfibrotic LSEC following treatment with 60 mg/kg of sorafenib. However, BrdU and Ki67 staining among LSEC and hepatocytes was not significantly affected by sorafenib at any of the other doses or time points. BrdU and Ki67 flow cytometry data correlated with immunohistochemistry findings and postoperative liver weights.In a murine PH model, sorafenib did not alter the repair response of normal or fibrotic livers following PH as measured by changes in liver weight, DNA synthesis, and cellular proliferation. These findings suggest sorafenib administered following hepatic resection does not impair liver regeneration.
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- 2012
25. Laparoscopic spleen-preserving distal pancreatectomy in elderly subjects: splenic vessel sacrifice may be associated with a higher rate of splenic infarction
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Keith Baldwin, Ponnandai Somasundar, Steven C. Katz, and N. Joseph Espat
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Reoperation ,medicine.medical_specialty ,Time Factors ,medicine.medical_treatment ,Splenectomy ,Spleen ,Splenic artery ,Risk Assessment ,elderly ,Pancreatectomy ,Risk Factors ,medicine.artery ,medicine ,Humans ,Splenic Infarction ,splenic preservation ,Laparoscopy ,Aged ,Aged, 80 and over ,Chi-Square Distribution ,medicine.diagnostic_test ,Hepatology ,business.industry ,Age Factors ,Gastroenterology ,Rhode Island ,Original Articles ,medicine.disease ,Surgery ,medicine.anatomical_structure ,Treatment Outcome ,Splenic vein ,Splenic Vein ,Splenic infarction ,laparoscopic distal pancreatectomy ,Feasibility Studies ,Distal pancreatectomy ,business ,Splenic Artery - Abstract
BackgroundLaparoscopic spleen-preserving distal pancreatectomy has gained popularity in recent years. Splenic preservation can be achieved with or without splenic vessel preservation (SVP). The potential morbidity of this approach in patients aged >70 years has not been well defined.MethodsTen patients aged >70 years underwent attempted laparoscopic spleen-preserving distal pancreatectomy within a 2-year period. Multiple patient parameters were examined and chi-squared analysis was used to evaluate the association between the operative technique (SVP or splenic vessel division [SVD]) and splenic infarction. The Mann–Whitney test was used to compare the SVP and SVD groups with regard to age, estimated blood loss (EBL), operating time, splenic volume and length of stay (LoS).ResultsMedian age was 81 years (range: 71–92 years). Operating room time, LoS, EBL and complication rates were similar to those reported in published series of younger patients. In four patients, the splenic vessels were divided in a manner relying on short gastric collateral flow; SVP was achieved in all other patients. All four patients who underwent SVD developed splenic infarcts and three required splenectomy to manage this (P= 0.002). Median LoS was increased in the SVD group (9.3 days vs. 4.3 days; P= 0.053). Estimated blood loss was higher in the SVP group (200ml vs. 100ml; P= 0.091). One pancreatic leak occurred. There were no mortalities.ConclusionsSpleen-preserving laparoscopic distal pancreatectomy can be performed safely in elderly patients, with results comparable with those achieved in younger subjects. However, elderly patients undergoing division of the splenic artery and vein may be at higher risk for splenic infarct and the aetiology of this is unclear.
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- 2011
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26. Who Should Receive Neoadjuvant Chemotherapy Prior to Liver Resection for Colorectal Carcinoma Liver Metastases?
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Keith Baldwin, N. Joseph Espat, and Ponnandai Somasundar
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Oncology ,medicine.medical_specialty ,Chemotherapy ,Hepatology ,business.industry ,Colorectal cancer ,medicine.medical_treatment ,Gastroenterology ,Cancer ,medicine.disease ,Colorectal surgery ,Resection ,law.invention ,Randomized controlled trial ,law ,Internal medicine ,medicine ,Metastasectomy ,Hepatectomy ,business - Abstract
The role for neoadjuvant chemotherapy in patients with colorectal cancer liver metastases has expanded over the last 10 years. Evolution of various therapeutic modalities has occurred in the setting of an evolving and more frequent use of hepatic metastasectomy. It is clear that achieving a state of potential “resectability” is the only opportunity to obtain a cure and/or significantly extend life. Compelling evidence now exists that a neoadjuvant approach should be standard for select patients with so-called “borderline resectable” lesions. In addition, patients with initially resectable liver metastases may achieve further survival benefit from the addition of neoadjuvant treatment, with the subset of patients that obtain a complete pathologic response benefitting the most. Future neoadjuvant randomized controlled trials may further elucidate patients that will benefit from these therapeutic strategies.
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- 2011
27. Management of an Incidental Liver Mass
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Cherif Boutros, Steven C. Katz, and N. Joseph Espat
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Diagnostic Imaging ,medicine.medical_specialty ,genetic structures ,Biopsy ,Risk of malignancy ,Context (language use) ,Malignancy ,Liver mass ,Diagnosis, Differential ,Course of action ,Risk Factors ,Patient age ,Intervention (counseling) ,medicine ,Humans ,Intensive care medicine ,Incidental Findings ,business.industry ,Incidence ,Liver Neoplasms ,medicine.disease ,eye diseases ,Surgery ,sense organs ,Radiology ,business ,Risk assessment - Abstract
The wide availability and use of advanced imaging modalities, including ultrasonography (US), CT, MRI, and positron emission tomography (PET), have led to increased identification of incidental liver masses (ILMs). The discovery of an ILM typically occurs during the course of an evaluation for an unrelated suspected or existing clinical problem. ILMs have also been detected during whole-body cross-sectional imaging offered on a proprietary basis for screening purposes. 1 On detection of ILM, it is incumbent on caring physicians to balance the potential risks posed by a lesion with the costs of further evaluation or treatment. Real harm can result from failure to diagnose a malignancy or inappropriate work-up of a harmless lesion. Through careful consideration of patient factors and imaging characteristics of ILMs, clinicians can recommend a safe, effective, and efficient course of action. This article begins by considering the clinical factors that should be incorporated into the risk assessment of ILMs. Subsequently, the radiologic features of ILMs are reviewed, which are used in conjunction with clinical circumstances to define the risk of malignancy and the need for further evaluation and management. Specific indications for biopsy or therapeutic intervention are discussed. The article concludes with consideration of the specific pathologic entities accounting for the majority of ILMs. An algorithmic approach is outlined as a conceptual framework to assist with the development of an individualized assessment and management strategy for each patient confronted with an ILM (Fig. 1). CLINICAL FACTORS RELATED TO INCIDENTAL LIVER MASS RISK Although most of this discussion focuses on the radiographic or physical characteristics of ILMs, placing incidental imaging findings in the appropriate clinical context is of the utmost importance. Factors, including patient age, gender, history of malignancy
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- 2010
28. Liver-specific programming of myeloid cells promotes intrahepatic immunosuppression
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Prajna Guha, Jillian Gardell, Mikayla Lopes, N. Joseph Espat, and Steven C. Katz
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Immunology ,Immunology and Allergy - Abstract
Liver is a tolerogenic organ and has variety of immune cells resulting in a profoundly immunosuppressive space. We recently reported that GM-CSF/JAK2/STAT3 axis drives liver myeloid suppressor cell (L-MDSC) proliferation and STAT3 inhibition causes activation of apoptosis signaling via Bax up-regulation. Herein, we explore liver specific programming events that promote L-MDSC suppressive conditioning. Bone marrow derived MDSC (BM-MDSC) were expanded in CD45.1+ mice in response to intraperitoneal MC38 tumors. CD45.1+ BM-MDSC were adoptively transferred into CD45.2+ recipient mice via tail vein (TV) or portal vein (PV). CD11b+ cells were harvested 48 hrs later from recipient liver and lungs. Liver from PV and lung from TV CD45.1+ MDSC recipients were compared. There was increased expansion of CD45.1+ MDSC (CD11b+Gr1+) in PV-liver as compared to TV-lung group (Liver-PV 45±3% vs. Lung-TV 15±2% vs. Tumor 43±3, p
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- 2018
29. Extrahepatic Cholangiocarcinoma: Current Surgical Strategy
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Cherif Boutros, Ponnandai Somasundar, and N. Joseph Espat
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medicine.medical_specialty ,Surgical strategy ,business.industry ,Disease ,digestive system ,Hepatobiliary cancer ,Gastroenterology ,Rare cancer ,digestive system diseases ,Cholangiocarcinoma ,Extrahepatic Cholangiocarcinoma ,Bile Ducts, Intrahepatic ,Bile Duct Neoplasms ,Oncology ,Bile Ducts, Extrahepatic ,Internal medicine ,Humans ,Medicine ,Surgery ,business ,neoplasms - Abstract
Cholangiocarcinoma is a rare cancer. Although rare, it remains the second most common hepatobiliary cancer and its incidence is increasing worldwide. Extrahepatic cholangiocarcinoma can occur anywhere along the biliary tree and prognosis varies according to the location of disease.
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- 2009
30. Evaluation of a bipolar radiofrequency device for laparoscopic hepatic resection: technique and clinical experience in 18 patients
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Cherif Boutros, N. Joseph Espat, W. Scott Helton, and Ponnandai Somasundar
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medicine.medical_specialty ,Hepatology ,medicine.diagnostic_test ,business.industry ,Hepatic resection ,laparoscopy ,Gastroenterology ,bipolar RFA ,Original Articles ,medicine.disease ,Energy device ,Benign tumours ,Surgery ,Safety profile ,Blood loss ,Hepatocellular carcinoma ,liver resection ,medicine ,Bipolar radiofrequency ,Laparoscopy ,business - Abstract
BackgroundThe increased frequency of laparoscopic hepatic resection as a principal or adjunct component of patient care has driven the need for and development of efficient and safe hepatic parenchymal transection technologies. At present, various devices are available for pre-coagulation transection (PCT) of hepatic parenchyma with the intent of minimizing procedure-associated postoperative haemorrhage and bile leak. This report presents the evaluation of a novel bipolar radiofrequency (RF) energy device for PCT used for laparoscopic hepatic resection.MethodsPatients undergoing laparoscopic hepatic resection using the Enseal™ device (SurgRx Inc.) were identified from the prospectively maintained hepatobiliary database. Information on patient demographics, procedures and postoperative complications was collected and analysed; complications were grouped into early (at
- Published
- 2009
31. Lipopolysaccharide-Stimulated RAW 264.7 Macrophage Inducible Nitric Oxide Synthase and Nitric Oxide Production Is Decreased by an Omega-3 Fatty Acid Lipid Emulsion
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Tricia A. Babcock, Anthony Razzak, Christopher Aldridge, N. Joseph Espat, and W. Scott Helton
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Lipopolysaccharide ,biology ,Chemistry ,Leukotriene B4 ,Nitric oxide ,Nitric oxide synthase ,chemistry.chemical_compound ,Biochemistry ,medicine ,biology.protein ,Surgery ,Arachidonic acid ,Tumor necrosis factor alpha ,Prostaglandin E2 ,Omega 3 fatty acid ,medicine.drug - Abstract
Background Omega-3 fatty acids (ω-3 FA) have been demonstrated to have anti-inflammatory properties, postulated to occur through several principal mechanisms, including (1) displacement of arachidonic acid from the cellular membrane; (2) shifting of prostaglandin E2 and leukotriene B4 production; and (3) molecular level alterations including decreased activation of nuclear factor kappa B and activator protein-1. An additional regulator that is likely associated is the production of nitric oxide (NO) by nitric oxide synthetase. NO is a short-lived free radical involved in many biological functions. However, excessive NO production can lead to complications, suggesting that decreased NO production is a potential target for some inflammatory diseases. We hypothesized that pretreating with an ω-3 FA lipid emulsion would decrease the production of NO in macrophages and that this effect would occur through alterations in inducible nitric oxide synthetase (iNOS). Materials and methods Greiss reagent was used to assess NO production in RAW 264.7 macrophages following ω-3 or ω-6 FA treatment alone or in combination with lipopolysaccharide (LPS) stimulation for 12 h/24 h. iNOS levels were determined by Western blot. Tumor necrosis factor-alpha levels were determined by enzyme-linked immunosorbent assay. Results Following LPS-stimulation, ω-3 FA pretreatment at 12 and 24 h produced significantly less NO (P Conclusion These experiments demonstrate that, in addition to other anti-inflammatory effects, ω-3 FA lipid emulsions also significantly lower NO production in LPS-stimulated macrophages through altered iNOS protein expression.
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- 2008
32. Attenuation of iNOS in an LPS-Stimulated Macrophage Model by Omega-3 Fatty Acids is Independent of COX-2 Derived PGE2
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Anthony Razzak, Abdul Saied, Chris Aldrich, N. Joseph Espat, and Tricia A. Babcock
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Lipopolysaccharides ,medicine.medical_specialty ,Lipopolysaccharide ,medicine.medical_treatment ,Nitric Oxide Synthase Type II ,Nitric Oxide ,Dinoprostone ,Cell Line ,Nitric oxide ,Mice ,chemistry.chemical_compound ,Internal medicine ,Fatty Acids, Omega-3 ,medicine ,Animals ,Cyclooxygenase Inhibitors ,Drug Interactions ,Prostaglandin E2 ,biology ,Macrophages ,Nitric oxide synthase ,Blot ,Endocrinology ,Biochemistry ,chemistry ,Cyclooxygenase 2 ,Cell culture ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Surgery ,Arachidonic acid ,medicine.drug ,Prostaglandin E - Abstract
Background Omega-3 fatty acids (n-3 FA) demonstrate significant anti-inflammatory properties thought to occur through three principal mechanisms; (1) displacement of arachidonic acid from the cellular membrane, (2) differential prostaglandin E 2 (PGE 2 ) and LTB 4 production, and (3) molecular level alterations such as diminished nuclear factor kappa B and AP-1 activation. Recently, n-3 FA have been demonstrated to significantly decrease nitric oxide (NO) production in a lipopolysaccharide (LPS)-stimulated MΦ model. We hypothesized that decreased NO production by n-3 FA occurs through inhibition of cyclooxygenase-2 (COX-2) derived PGE 2 and that repletion of the system with PGE 2 would obliterate these effects. Selective COX-2 inhibitor (L-748,731) experiments and separate PGE 2 repletion studies were used to test this hypothesis. Methods NO production was assessed following 24 h with or without LPS/PGE 2 in the presence of n-3 FA, L-748,731 (a selective COX-2 inhibitor), or combination (n-3 FA + L-748,731) treatment. Western blots were used to assess inducible NO synthase protein expression. Results Independently or in the presence of LPS, treatment with a COX-2 inhibitor significantly increased NO production compared with control, n-3 FA, and combination treatment. NO production in combination treatment is slightly increased compared to n-3 FA treatment. In control cells treated with LPS, PGE 2 repletion resulted in a significant decrease in NO. All other treatment groups repleted with PGE 2 demonstrated no significant alterations in NO production. Inducible NO synthase protein expression levels were similar to NO production across all treatments. Conclusion These experiments disproved our original hypothesis that the decrease in NO production associated with n-3 FA treatment occurs through a COX-2 derived PGE 2 dependent mechanism. Eliminating COX-2 derived PGE 2 by a selective inhibitor actually increased NO production. Exogenous PGE 2 repletion did not restore the system. Therefore, mechanisms other than n-3 FA associated alterations in COX-2 derived PGE 2 are likely involved in decreasing NO production in LPS stimulated MΦ.
- Published
- 2008
33. Gastric Adenocarcinoma Arising from Fundic Gland Polyps in a Patient with Familial Adenomatous Polyposis Syndrome
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Sean Garrean, Justin Hering, Jigna C. Jani, Abdul Saied, and N. Joseph Espat
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Male ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Pathology ,Colorectal cancer ,Population ,Adenocarcinoma ,digestive system ,Gastroenterology ,Familial adenomatous polyposis ,Gastric adenocarcinoma ,Stomach Neoplasms ,Internal medicine ,Humans ,Medicine ,Gastric Fundus ,Stomach cancer ,education ,neoplasms ,education.field_of_study ,business.industry ,Stomach ,Cancer ,General Medicine ,Middle Aged ,medicine.disease ,digestive system diseases ,Fundic Gland Polyp ,medicine.anatomical_structure ,Adenomatous Polyposis Coli ,business - Abstract
Familial adenomatous polyposis (FAP) is a rare hereditary syndrome characterized by multiple colorectal polyps and early development of colorectal cancer. Although FAP uniformly involves the large bowel, it may also produce lesions in the stomach and upper intestinal tract. Fundic gland polyps are the most common gastric lesion in FAP. In the general population, these polyps are considered benign and have no malignant potential. However, in FAP patients, fundic gland polyps have been occasionally recognized as precursor lesions from which invasive cancer may develop. Herein, we present a case of gastric adenocarcinoma arising from fundic gland polyps in an FAP patient. We also review reported cases of gastric cancer in FAP and FAP variant patients in an effort to better understand the pathology, clinical course, and optimal screening and treatment strategies for this disease manifestation.
- Published
- 2008
34. G2/M Cell-Cycle Arrest and Apoptosis by n-3 Fatty Acids in a Pancreatic Cancer Model
- Author
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Thomas Dekoj, Sang Lee, W. Scott Helton, Jose G. Trevino, Tricia A. Babcock, Sagun Desai, and N. Joseph Espat
- Subjects
G2 Phase ,medicine.medical_specialty ,Programmed cell death ,medicine.medical_treatment ,Blotting, Western ,Apoptosis ,Biology ,Flow cytometry ,Membrane Lipids ,chemistry.chemical_compound ,Annexin ,Cell Line, Tumor ,Internal medicine ,CDC2 Protein Kinase ,Fatty Acids, Omega-3 ,medicine ,Humans ,Propidium iodide ,Annexin A5 ,Chromatography, High Pressure Liquid ,Cell Proliferation ,Dose-Response Relationship, Drug ,medicine.diagnostic_test ,Cell cycle ,Flow Cytometry ,Molecular biology ,Pancreatic Neoplasms ,Endocrinology ,Cytokine ,Proto-Oncogene Proteins c-bcl-2 ,chemistry ,Cell culture ,Surgery ,Poly(ADP-ribose) Polymerases ,Cell Division - Abstract
Background n-3 fatty acids (n-3FA) have anti-inflammatory and anti-proliferative effects including modulation of pro-inflammatory cascade mediators and cytokine elaboration (i.e., TNF-α, IL-10 and PGE2) in many cell lines. However, mechanisms of anti-proliferative effects have not been clearly defined. Materials and methods MIA PaCa-2 pancreatic cancer cells were treated either with n-3FA (treatment), media (control), or n-6FA (control) for all experiments. Cellular proliferation was evaluated with WST-1 reagent. Cells were stained with propidium iodide and analyzed by flow cytometry for cell-cycle arrest, which was further analyzed by cdc2 expression. Membrane and media lipid concentrations were analyzed by high-performance liquid chromatography. Apoptosis was evaluated by AnnexinV-FITC flow cytometry and reconfirmed by poly (ADP-ribose) polymerase (PARP) cleavage and Bcl-2 expression. Results Propidium iodide flow cytometry of MIA PaCa-2 dosed with n-3FA showed a decrease in cells in G1 phase (11–17%) and an increase cells in G2 phase (7–13%) from controls. cdc2 expression was also decreased at 24 h compared to controls. Annexin-V staining of n-3FA-treated cells demonstrated time-dependent increased apoptosis and PARP cleavage was present only in the n-3FA treatment group. Phospho-Bcl-2 was also decreased in the n-3FA-treated cells compared to controls. Conclusions Co-incubation of MIA PaCa-2 cells with n-3FA results in both dose- and time-dependent cell-cycle arrest. Cells also progress to cell death via apoptosis. These data support the potential applicability for n-3FA as an antiproliferative and pro-apoptotic strategy.
- Published
- 2007
35. Intraductal papillary mucinous neoplasms of the pancreas
- Author
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Jose G. Trevino, N. Joseph Espat, and W. Scott Helton
- Subjects
medicine.medical_specialty ,Invasive carcinoma ,business.industry ,General surgery ,Gastroenterology ,Psychological intervention ,Disease ,Malignancy ,medicine.disease ,Malignant disease ,Natural history ,medicine.anatomical_structure ,Medicine ,business ,Pancreas ,Survival rate - Abstract
Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are rare tumors with different characteristics than conventional ductal pancreatic adenocarcinomas. Although they are commonly classified as cystic neoplasms of the pancreas, within their own subgroup of pancreatic cystic tumors, they are unique in their presentation, histologic characteristics, treatment, and survival rates. Currently, strategies are being implemented to better characterize these tumors preoperatively. Once IPMN is diagnosed, treatment strategies are based upon multiple factors, including patient condition, symptoms, and type and extent of disease. Although these factors may determine different treatment strategies, surgery remains the mainstay of therapy due to the favorable survival rate if the disease is diagnosed and treated prior to the development of invasive carcinoma. The goal of treatment is to alleviate symptoms and to extirpate disease prior to its transition to malignancy, invasion, and metastases. Although some experts advocate a nonoperative approach to patients with suspected benign disease, the risk of progression to malignancy can present a dilemma for the treating physician and patient. Unfortunately, differentiation of benign from malignant disease can only be determined conclusively following complete review of the entire surgical specimen. To further complicate treatment strategies, IPMN is a multifocal disease, and additional lesions can develop in the remnant pancreas. This fact has compelled most physicians familiar with the disease to institute lifelong surveillance for patients with the disease. Although our understanding of IPMN has increased greatly since its initial description in 1982, the natural history of the disease is poorly defined, and there is no consensus among experts on standards of practice. Although additional long-term follow-up of greater numbers of patients and their response to various interventions are necessary to develop consensus-based practice guidelines, this review will discuss our treatment recommendations based upon a review of the literature.
- Published
- 2006
36. Reported Outcome Factors for Hepatic Metastasectomy
- Author
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N. Joseph Espat
- Subjects
Ovarian Neoplasms ,medicine.medical_specialty ,Gastrointestinal Stromal Tumors ,business.industry ,Patient Selection ,General surgery ,Liver Neoplasms ,Gastroenterology ,Breast Neoplasms ,Sarcoma ,Outcome (game theory) ,Surgery ,Survival Rate ,Neuroendocrine Tumors ,Treatment Outcome ,medicine ,Hepatectomy ,Humans ,Female ,Metastasectomy ,business ,Melanoma - Abstract
The following SSAT/AHAPBA symposium summary is based on a more comprehensive review of the topic by Alseidi A, Helton WS, Espat NJ. Does the literature support an indication for hepatic metastasectomy other than for colorectal primary? J Gastrointest Surg in press.
- Published
- 2006
37. Hepatic Intra-Arterial Chemotherapy
- Author
-
Evan S. Ong, Madeleine Poirier, and N. Joseph Espat
- Subjects
Oncology ,medicine.medical_specialty ,Palliative care ,medicine.medical_treatment ,Treatment outcome ,Intra arterial chemotherapy ,Antineoplastic Agents ,Hepatic arterial infusion ,Quality of life ,Surgical oncology ,Internal medicine ,medicine ,Humans ,Infusions, Intra-Arterial ,Chemotherapy ,business.industry ,Patient Selection ,Liver Neoplasms ,Palliative Care ,Surgery ,Treatment Outcome ,Chemotherapy, Adjuvant ,Quality of Life ,Colorectal Neoplasms ,Colorectal metastasis ,business - Published
- 2006
38. Minimally Invasive Treatment of Esophageal Cancer
- Author
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N. Joseph Espat, Santiago Horgan, Phillip Donahue, and Garth R. Jacobsen
- Subjects
Cancer Research ,medicine.medical_specialty ,Esophageal Neoplasms ,business.industry ,Thoracoscopy ,General surgery ,medicine.medical_treatment ,Robotics ,Esophageal cancer ,medicine.disease ,Robotic esophagectomy ,Laparoscopic staging ,Esophagectomy ,medicine.anatomical_structure ,Oncology ,Invasive esophagectomy ,Invasive surgery ,medicine ,Humans ,Laparoscopy ,Robotic surgery ,Esophagus ,business ,Neoplasm Staging - Abstract
Minimally invasive surgical (MIS) procedures have become commonplace in modern surgical practice. The term minimally invasive surgery has been and continues to be interchangeably applied to describe laparoscopic, laparoscopic-assisted, thoracoscopic, and telesurgical (robotic) procedures. Minimally invasive surgical procedures for the treatment of benign and malignant disorders of the esophagus are being developed, refined, and clinically applied in parallel with the exponential availability of novel technologies and instrumentation. Herein, we review the progression from laparoscopic/thoracoscopic esophagectomy to telesurgical esophagectomy, presently termed minimally invasive esophagectomy, and describe the telesurgical procedure as well as early the clinical outcome experience.
- Published
- 2005
39. 1990–2001 U.S. general surgery chief resident gastric surgery operative experience: analysis of paradigm shift
- Author
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Evan S. Ong, W. Scott Helton, N. Joseph Espat, and Lloyd M. Nyhus
- Subjects
medicine.medical_specialty ,business.industry ,General surgery ,medicine.medical_treatment ,Stomach ,Gastroenterology ,Internship and Residency ,Vagotomy ,United States ,Surgery ,Benign gastric ulcer ,General Surgery ,medicine ,Humans ,Gastrectomy ,Surgical education ,Surgery operative ,Gastric resection ,business ,Digestive System Surgical Procedures - Abstract
The almost complete disappearance of benign gastric ulcer disease has led to the perception that there may be an insufficient gastric surgery experience for surgery residents. This study analyzed resident-reported gastric procedure experience by chief residents from U.S. programs. The Resident Statistic Summaries (Report C) for 1990-2001 were compiled and analyzed. Results are expressed as the average number of operations performed per resident, standard deviation (SD), and the percentage (%) of total gastric operative cases. For all gastric-related surgery, the average reported cases per chief resident ranged from 9.8-12.4 with a peak in 1990 and a nadir in 1999; in 2001 the reported case average was 11.3 (SD ranged from 6-8). Over the same interval, vagotomy decreased from 24% in 1990 to 7% in 2001, whereas gastric-reduction operations increased from 5%-34%. Total gastrectomy remained a constant less than 1.0 per chief resident (range 0.6-0.8), whereas partial gastric resection (PGR) was unchanged. The percentage of all types of gastric resections slightly diminished from 34% in 1990 to 29% in 2001. U.S. surgical chief residents report a widely variable experience in gastric surgery over the period analyzed. However, their overall experience has not significantly diminished since 1990 although specific procedural volume has varied.
- Published
- 2004
40. A potential role for perioperative hepatic arterial infusion chemotherapy?
- Author
-
M.S. N. Joseph Espat
- Subjects
Cancer Research ,Oncology ,business.industry ,Anesthesia ,Hepatic arterial infusion chemotherapy ,Medicine ,Perioperative ,business - Published
- 2004
41. Simplified Surgical Placement and Stabilization Methods for Intracerebroventricular Cannulas in Rat Lateral Ventricles
- Author
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David H. Jho, Altair Juarez, Herbert H. Engelhard, and N. Joseph Espat
- Subjects
Male ,medicine.medical_specialty ,Rat model ,Catheterization ,Cerebral Ventricles ,law.invention ,Lateral ventricles ,Stabilization methods ,law ,medicine ,Animals ,General Veterinary ,business.industry ,digestive, oral, and skin physiology ,equipment and supplies ,Cannula ,Rats, Inbred F344 ,Rats ,Surgery ,Bone screws ,surgical procedures, operative ,medicine.anatomical_structure ,Cyanoacrylate ,Ventricle ,Surgical Procedures, Operative ,Cerebral ventricle ,Animal Science and Zoology ,business - Abstract
Intracerebroventricular cannulation in rat models is an efficient tool for exploring the effects of substances directly injected into the CNS, bypassing the blood-brain barrier. Techniques for surgically securing the ICV cannula require a balance between ease of application and adequate stability. The authors tested several methods of lateral ventricle cannula stabilization, especially focusing on a comparison of cyanoacrylate gel to cranioplastic cement with an anchoring bone screw.
- Published
- 2003
42. Early experience employing a linear hepatic parenchyma coagulation device
- Author
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Cord Sturgeon, W. Scott Helton, Amit Lamba, N. Joseph Espat, and Gregorio Chejfec
- Subjects
Male ,medicine.medical_specialty ,Colorectal cancer ,Light Coagulation ,Surgical oncology ,Internal medicine ,Parenchyma ,medicine ,Hepatectomy ,Humans ,Aged ,Hepatology ,business.industry ,Liver Neoplasms ,medicine.disease ,Surgery ,Liver ,Coagulation ,Hepatocellular carcinoma ,Anesthetic ,Colorectal Neoplasms ,business ,Abdominal surgery ,medicine.drug - Abstract
Background. In recent years, hepatic resection for primary and metastatic disease has been facilitated by improved anesthetic and surgical techniques, as well as by the application of new technologies. Historically, the major complications associated with hepatic resection have been postoperative bleeding, bile leak, and liver failure. Resection techniques and devices that minimize hemorrhage and bile leak, and enable the preservation of functional hepatic parenchyma, have been useful in the surgical management of liver tumors. Methods. Herein, the use of a radiofrequency powered device for the pretransection coagulation of hepatic tissue that simultaneously seals blood vessels and bile ducts 3 mm in diameter or smaller is described. Results. Early results from our single-center experience with the use of this linear radiofrequency device are reported. Seven patients underwent liver resection for either hepatocellular carcinoma or colorectal cancer metastases. There were no postoperative bile leaks, hemorrhage, or hepatic insufficiency. No transfusions were required, and the mean estimated blood loss for the parenchymal transection phase was less than 165 cc. Conclusions. The linear radiofrequency device is expedient for the pretransection coagulation of hepatic tissue and, thus, facilitates liver resection.
- Published
- 2003
43. Omega-3 Fatty Acids: Implications for the Treatment of Tumor-Associated Inflammation
- Author
-
David Jho, Tricia A. Babcock, W. Scott Helton, and N. Joseph Espat
- Subjects
General Medicine - Abstract
Our in vivo and in vitro studies using ω-3 fatty acids (FA) have provided insight into the biological effects and mechanisms of their anti-inflammatory action(s). The implications for this research are profound because there are few nutritional therapies available that have the potential to be clinically effective in malignancies and other chronic inflammatory conditions as ω-3 FA. In this summary of experiments the biological effects of ω-3 FA are discussed and the potential mechanisms of action presented.
- Published
- 2003
44. NF-κB inhibition by ω-3 fatty acids modulates LPS-stimulated macrophage TNF-α transcription
- Author
-
N. Joseph Espat, Tricia A. Babcock, W. Scott Helton, David H. Jho, and Todd E. Novak
- Subjects
Pulmonary and Respiratory Medicine ,chemistry.chemical_classification ,Lipopolysaccharide ,Physiology ,medicine.medical_treatment ,Monocyte ,Fatty acid ,Cell Biology ,Biology ,Eicosapentaenoic acid ,Molecular biology ,chemistry.chemical_compound ,Cytokine ,medicine.anatomical_structure ,Biochemistry ,chemistry ,Physiology (medical) ,medicine ,Tumor necrosis factor alpha ,Signal transduction ,Unsaturated fatty acid - Abstract
ω-3 Fatty acid (FA) emulsions reduce LPS-stimulated murine macrophage TNF-α production, but the exact mechanism has yet to be defined. The purpose of this study was to determine the mechanism for ω-3 FA inhibition of macrophage TNF-α production following LPS stimulation. RAW 264.7 cells were pretreated with isocaloric emulsions of ω-3 FA (Omegaven), ω-6 FA (Lipovenos), or DMEM and subsequently exposed to LPS. IκB-α and phospho-IκB-α were determined by Western blotting. NF-κB binding was assessed using the electromobility shift assay, and activity was measured using a luciferase reporter vector. RT-PCR and ELISA quantified TNF-α mRNA and protein levels, respectively. Pretreatment with ω-3 FA inhibited IκB phosphorylation and significantly decreased NF-κB activity. Moreover, ω-3-treated cells demonstrated significant decreases in both TNF-α mRNA and protein expression by 47 and 46%, respectively. These experiments demonstrate that a mechanism for proinflammatory cytokine inhibition in murine macrophages by ω-3 FA is mediated, in part, through inactivation of the NF-κB signal transduction pathway secondary to inhibition of IκB phosphorylation.
- Published
- 2003
45. Conventional hemangiopericytoma
- Author
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Murray F. Brennan, Denis H. Y. Leung, Jonathan J. Lewis, N. Joseph Espat, James M. Woodruff, C. R. Antonescu, and Jingu Shia
- Subjects
Adult ,Male ,Cancer Research ,Solitary fibrous tumor ,medicine.medical_specialty ,Disease ,medicine ,Humans ,Neoplasm Metastasis ,Survival analysis ,Pelvis ,Aged ,Retrospective Studies ,Hemangiopericytoma ,Vascular disease ,business.industry ,Retrospective cohort study ,Middle Aged ,Prognosis ,medicine.disease ,Survival Analysis ,Synovial sarcoma ,Surgery ,Microscopy, Electron ,medicine.anatomical_structure ,Oncology ,Female ,Neoplasm Recurrence, Local ,business - Abstract
Background Hemangiopericytoma (HPC) is a rare vascular tumor, and pathologic distinction from synovial sarcoma and solitary fibrous tumor is a significant problem due to shared histologic features. In the current report the authors defined the clinical behavior and prognosis for patients with HPC. Methods Between July 1982 and February 1998, 62 patients with a diagnosis of primary, recurrent, or metastatic HPC were identified from a prospectively maintained database. The pathology of all cases for which material was available (57 cases) was re-reviewed for histologic confirmation of the HPC diagnosis. Using strict pathologic criteria, including immunohistochemistry and electron microscopy, tumors from 25 of 57 patients qualified for the diagnosis of conventional hemangiopericytoma; those tumors formed the basis of the current report. Survival was determined by the Kaplan-Meier method. Results At the time of initial presentation, 19 patients had primary tumors, 3 had locally recurrent disease, and 3 had metastatic disease. The most frequent anatomic sites for HPC were the extremities, the pelvis, and the head and neck, accounting for 80% of the total cases. The median followup (n = 25) was 49 months (range, 1 to 160 months). The two and five year overall survival rates (n = 25) were 93% and 86% respectively. The disease-specific survival was 86% at last followup. Patients undergoing complete resection (n = 16) showed a 100% median survival at 60 months. Conclusions At present, complete tumor resection for patients with conventional HPC is recommended. However, considering the favorable outcome in this disease, the authors caution against performing operations that may potentially cause loss of function or are limb threatening.
- Published
- 2002
46. Virtual reality: Immersive hepatic surgery educational environment
- Author
-
Marcia Edison, W. Scott Helton, Peter Jurek, Fred Dech, Jonathan C. Silverstein, and N. Joseph Espat
- Subjects
medicine.medical_specialty ,education ,Hepatic Veins ,Virtual reality ,User-Computer Interface ,Interactivity ,medicine ,Humans ,Medical physics ,Vena hepatica ,Biliary Tract ,Surgical treatment ,Education, Medical ,Portal Vein ,business.industry ,Liver Diseases ,Visualization ,Surgery ,Occupational training ,Liver ,General Surgery ,Surgical Procedures, Operative ,Hepatic surgery ,Hepatic veins ,business ,Computer-Assisted Instruction - Abstract
Understanding the spatial relationships among the liver segments, and intrahepatic portal and hepatic veins is essential for surgical treatment of liver diseases. Teleimmersive virtual reality enables improved visualization over conventional media because it supports stereo vision, viewer-centered perspective, large angles of view, and interactivity with remote locations. We report a successful pilot study teaching hepatic surgical principles using teleimmersion.We developed a teleimmersive environment for teaching with biomedical models including virtual models of the liver segments and portal and hepatic veins. Using the environment, 1 instructor gave a workshop to 6 senior general surgery residents at 2 physical locations. A 24-question (36-point) examination was administered before and after the workshop.The workshop produced significant improvements in the mean test scores between the pretests and posttests (17.67 to 23.67, P.02). We found no differences between residents who were with the instructor and those at the remote location. Six-month delayed testing demonstrated complete retention of new knowledge.The teleimmersive environment enabled surgeons to overcome some of the barriers to teaching complex surgical anatomic principles. Using teleimmersive environments, surgical educators and trainees can interact from locations worldwide using virtual anatomic information to achieve their educational goals.
- Published
- 2002
47. Omega-3 Fatty Acid Lipid Emulsion Reduces LPS-Stimulated Macrophage TNF-α Production
- Author
-
Tricia A. Babcock, W. Scott Helton, David Hong, and N. Joseph Espat
- Subjects
Lipopolysaccharides ,Microbiology (medical) ,Cell ,Inflammation ,Pharmacology ,Lymphocyte Activation ,Cell Line ,Mice ,Fatty Acids, Omega-3 ,medicine ,Animals ,Macrophage ,Omega 3 fatty acid ,Tumor Necrosis Factor-alpha ,business.industry ,Macrophages ,Eicosapentaenoic acid ,Endotoxins ,Infectious Diseases ,medicine.anatomical_structure ,Eicosapentaenoic Acid ,Cell culture ,Immunology ,Emulsion ,Fatty Acids, Unsaturated ,Emulsions ,Surgery ,Tumor necrosis factor alpha ,medicine.symptom ,business - Abstract
Omega-3 (omega-3) fatty acids (FA), specifically eicosapentaenoic acid (EPA), attenuate cytokine-mediated inflammation. Currently, in the United States, there is no commercial source of omega-3 lipid for clinical use. A clinically used European lipid emulsion, Omegaven, has been shown to have beneficial antiinflammatory effects; however, the mechanisms of its action are not well defined. In the present work, this omega-3 FA emulsion has been evaluated in order to define its effects on TNF-alpha production in a model of LPS-stimulated macrophages.RAW 264.7 cells (1 x 10(6) cell/well) were incubated with DMEM, Omegaven, or an isoenergetic omega-6 lipid emulsion, Lipovenos for 4 h. Cells were washed and then stimulated with LPS (1 microg/mL) or media alone for 3 h. Plate well supernatants were collected and assayed for TNF-alpha production by ELISA. Statistical analysis was performed by ANOVA and post-hoc analyses; the significance was defined as p0.05.Unstimulated RAW cell TNF-alpha production was similar in all groups and60 pg/mL. Lipovenos pretreatment did not alter TNF-alpha production from that of baseline compared to LPS-stimulated cells. Four-hour Omegaven pretreatment significantly reduced TNF-alpha production in LPS-stimulated cells, with a 46% reduction in TNF-alpha from baseline observed.Four-hour omega-3 FA emulsion pretreatment significantly attenuated LPS-stimulated macrophage TNF-alpha production. These data support the contention that antiinflammatory effects of omega-3 FA occur at least in part through the inhibition of macrophage TNF-alpha production in response to endotoxin. Further studies to define the antiinflammatory mechanisms of omega-3 FA on macrophages are warranted. The availability of Omegaven as an experimental treatment and Lipovenos as an equivalent control will be useful for future studies.
- Published
- 2002
48. Abstract CT109: HITM-SIR: Phase Ib trial of CAR-T hepatic artery infusions and selective internal radiation therapy for liver metastases
- Author
-
Ethan A. Prince, Prajna Guha, Li Juan Wang, Marissa Cunetta, Vincent Armenio, Richard P. Junghans, Steven C. Katz, N. Joseph Espat, and Ashley E. Moody
- Subjects
Cancer Research ,medicine.medical_specialty ,business.industry ,Selective internal radiation therapy ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,medicine ,030211 gastroenterology & hepatology ,Radiology ,Car t cells ,business ,Artery - Abstract
OBJECTIVES: There are no effective treatment options for patients with unresectable CEA+ liver metastases (LM) from gastrointestinal adenocarcinoma refractory to conventional systemic therapy. In the previous Hepatic Immunotherapy for Metastases (HITM) phase I study we demonstrated the safety and biologic activity of anti-CEA CAR-T cell hepatic artery infusions (HAI). HITM-SIR was a single arm phase Ib trial testing anti-CEA CAR-T HAI followed by selective internal radiation therapy (SIRT) in patients with refractory CEA+ LM. METHODOLOGY: We enrolled 8 patients with unresectable, chemotherapy refractory CEA+ LM and 6/8 completed the study. Two patients were withdrawn for disease progression prior to CAR-T infusion and biliary obstruction due to centrally located disease. Limited extrahepatic disease (EHD) was permitted. Subjects received 3 HAI of anti-CEA CAR-T cells (1e10 cells per dose) along with low dose continuous IL-2 infusions (50,000 IU/kg/day). SIRT was administered in standard fashion 2 weeks following the 3rd CAR-T HAI. Primary objective was to establish safety of the CAR-T/SIRT combination. Secondary objectives included response assessed by modified RECIST (mRECIST), immune-related response criteria (irRC), and tumor marker kinetics. RESULTS: The mean age for enrolled subjects was 54.6 years (39-61) with 3 women and 5 men. Histologies (completed patients): 2 colon, 2 rectal, and 2 pancreas. This heavily pre-treated, advanced disease group of patients received an average of 2.3 lines of prior chemotherapy, 3/6 had >10 LM, and the average largest LM size was 7.3 cm. The average transduction efficiency as measured by CAR expression was 60.4%, with 90.9% viability, and an average production time for >3e10 cells of 13.8 days. There were no grade (G) 4/5 events related to the CAR-T, SIRT, or combination. Toxicities included G 1/2 liver function test elevations (n=5/6), fever (n=5/6), hypereosinophilia (n=2/6), and edema (n=2/6). G3 toxicities included colitis (n=2/6), fever (n=2/6), and edema (n=2/6). One patient experienced a hypertensive crisis during a single CAR-T infusion but tolerated 2 infusions without incident. All colitis episodes resolved with IL-2 dose reductions. Post-SIRT serum CEA decreases were noted in 2/6 patients (-40% and -71%) with CA19-9 decreases in 2/5 detectable patients (-31% and -32%). When considering all on-study time points, 5/6 patients had CEA responses (mean decrease 59.7%) and 4/5 patients expressing CA 19-9 decreases (mean 59.6%). At completion of the study, 3/6 patients had stable disease (SD) in the liver by mRECIST and irRC, and 3/6 SD overall by irRC. Target liver lesion decreases in size among patients with SD ranged from 6-28%. Regression of extrahepatic tumors or abscopal effects were noted in 2/6 at lung and bone sites. One patient remains without evidence of viable liver disease at 10.8 months follow-up. The median overall survival time for all patients is 6.9 months (range 3.8-10.8+). CONCLUSIONS: Following this phase Ib trial, the recommended phase 2 dose for anti-CEA CAR-T HITM infusions is 1010 cells with or without SIRT. The favorable safety profile and evidence of biologic activity indicate that CAR-T HITM infusions should be further studied in a phase 2 trial. Clinical trial information: NCT02416466. Citation Format: Steven C. Katz, Ethan Prince, Marissa Cunetta, Prajna Guha, Ashley Moody, Vincent Armenio, Li J. Wang, N. Joseph Espat, Richard P. Junghans. HITM-SIR: Phase Ib trial of CAR-T hepatic artery infusions and selective internal radiation therapy for liver metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT109. doi:10.1158/1538-7445.AM2017-CT109
- Published
- 2017
49. Extended treatment with adjuvant imatinib (IM) for patients (pts) with high-risk primary gastrointestinal stromal tumor (GIST): The PERSIST-5 study
- Author
-
Johannes E. Wolff, Robert G. Maki, N. Joseph Espat, Dejka M. Araujo, Chandrajit P. Raut, Ronald P. DeMatteo, and Toni Faith Williams
- Subjects
0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Tumor size ,GiST ,business.industry ,medicine.medical_treatment ,Imatinib ,Complete resection ,Gastroenterology ,Mitotic Count ,Surgery ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Clinical endpoint ,Stromal tumor ,business ,Adjuvant ,medicine.drug - Abstract
11009 Background: Adjuvant IM reduces risk of recurrence and improves survival in pts with high-risk primary GIST. Joensuu et al 2016 demonstrated higher 5-yr overall survival (OS) rates of 91.9% vs 85.3% in pts treated with adjuvant IM for 3 vs 1 yr, respectively. It is unknown if further extension of treatment duration can improve outcome. Methods: PERSIST-5 is a single-arm, phase II trial that enrolled pts ≥18 yrs of age, who underwent macroscopically complete resection of primary KIT (+) GIST with high risk of recurrence within 12 wks prior to IM treatment. High risk was defined as primary GIST (any site) ≥2 cm with a mitotic count ≥ 5/50 HPF or non-gastric primary GIST ≥5 cm. Pts were treated with IM 400 mg/d for 5 yrs or until progression, relapse, or intolerance. Primary endpoint was recurrence-free survival (RFS, defined as time of treatment start to first recurrence or death). Results: IM was administered to 91 pts with a median age of 60 yrs (range 30-90). Median tumor size was 6.5 cm (range 2.3-30 cm; 55% gastric origin). Median treatment duration was 55.7 mos (range, 0.5-75). Forty-six (50.5%) pts completed study treatment. The 5- and 8-yr estimated RFS rates were 90% (95% CI, 80-95) and 81% (95% CI, 62-91), respectively. The 5- and 8 year OS rate was 95% (95% CI, 86-99). There were 7 recurrences; 1 pt recurred and died while on IM ( PDGFRA D842V mutation) and 6 pts recurred after IM discontinuation. Two pts died after IM discontinuation, unrelated to study treatment and without recurrence. Forty-five pts discontinued study treatment; common reasons included patient choice (20%), adverse events (AEs, 17%), protocol deviation (4%), and loss of follow-up (4%). The most common AEs of all grades (regardless of relationship to IM) were nausea (71%), diarrhea (63%), fatigue (50%), muscle spasm (41%), vomiting (39%), and periorbital edema (34%). Conclusions: Five yrs of IM treatment was effective in preventing recurrence in pts with sensitive mutations who underwent resection of primary GIST. Nearly half of the patients discontinued treatment early, and most recurrences occurred after IM discontinuation. Clinical trial information: NCT00867113.
- Published
- 2017
50. Targeted deletion of liver myeloid derived suppressor cells by inhibition of STAT3 dependent survival pathways to rescue CAR-T function
- Author
-
Jillian Gardell, Prajna Guha, Marissa Cunetta, Matthew Lima, Josephine Darpolor, N. Joseph Espat, Richard P. Junghans, and Steven C Katz
- Subjects
Immunology ,Immunology and Allergy - Abstract
Myeloid derived suppressor cells (MDSC) subvert anti-tumor immunity. Previously we reported that the GM-CSF/ JAK2/STAT3 axis drives liver MDSC (L-MDSC) proliferation and CAR-T suppression. We hypothesized that STAT3 supports L-MDSC survival and suppressive function by inhibiting apoptosis. We treated liver metastasis (LM) in mice with STAT3 inhibitors (STATTIC or BBI) or with vehicle control. STAT3 inhibition caused a significant reduction in tumor burden (p
- Published
- 2017
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