145 results on '"Venu G Pillarisetty"'
Search Results
2. IL-15 mediated expansion of rare durable memory T cells following adoptive cellular therapy
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Robin L Jones, Erik A Farrar, Jianhong Cao, Venu G Pillarisetty, Stanley R Riddell, Jean Campbell, Brett A Schroeder, Ralph Graeme Black, Shihong Zhang, Karan Kohli, Robert H Pierce, Lu Yao, Theodore Scott Nowicki, Heather Sloan, Dawn Stief, Lee D Cranmer, Douglas S Hawkins, and Edward Y Kim
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background Synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are ideal solid tumors for the development of adoptive cellular therapy (ACT) targeting NY-ESO-1, as a high frequency of tumors homogeneously express this cancer-testes antigen. Data from early phase clinical trials have shown antitumor activity after the adoptive transfer of NY-ESO-1–specific T cells. In these studies, persistence of NY-ESO-1 specific T cells is highly correlated with response to ACT, but patients often continue to have detectable transferred cells in their peripheral blood following progression.Method We performed a phase I clinical trial evaluating the safety of NY-ESO-1–specific endogenous T cells (ETC) following cyclophosphamide conditioning. Peripheral blood mononuclear cells (PBMCs) from treated patients were evaluated by flow cytometry and gene expression analysis as well as through ex vivo culture assays with and without IL-15.Results Four patients were treated in a cohort using ETC targeting NY-ESO-1 following cyclophosphamide conditioning. Treatment was well tolerated without significant toxicity, but all patients ultimately had disease progression. In two of four patients, we obtained post-treatment tumor tissue and in both, NY-ESO-1 antigen was retained despite clear detectable persisting NY-ESO-1–specific T cells in the peripheral blood. Despite a memory phenotype, these persisting cells lacked markers of proliferation or activation. However, in ex vivo culture assays, they could be induced to proliferate and kill tumor using IL-15. These results were also seen in PBMCs from two patients who received gene-engineered T-cell receptor–based products at other centers.Conclusions ETC targeting NY-ESO-1 with single-agent cyclophosphamide alone conditioning was well tolerated in patients with SS and those with MRCL. IL-15 can induce proliferation and activity in persisting NY-ESO-1–specific T cells even in patients with disease progression following ACT. These results support future work evaluating whether IL-15 could be incorporated into ACT trials post-infusion or at the time of progression.
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- 2021
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3. Pancreatic paraganglioma mimicking pancreatic neuroendocrine tumor
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Arezou Abbasi, Kristina M Wakeman, and Venu G Pillarisetty
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Extra-adrenal paragangliomas are rare tumors arising from the chromaffin cells of the autonomic nervous system. Retroperitoneal paragangliomas may present as a pancreatic mass. We present a case of a 61-year-old woman with an incidentally found pancreatic mass (7.2 × 6.5 cm) in the CT scan. EUS- guided FNA result was compatible with pancreatic neuroendocrine tumor. Patient underwent pancreaticoduodenectomy and histopathologic assessment revealed the mass was an extra-adrenal paraganglioma. Preoperative diagnosis of pancreatic paragangliomas can be challenging due to imaging and histopathologic similarities with pancreatic neuroendocrine tumors.
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- 2020
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4. Standardization of perioperative care facilitates safe discharge by postoperative day five after pancreaticoduodenectomy.
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Sara K Daniel, Lucas W Thornblade, Gary N Mann, James O Park, and Venu G Pillarisetty
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Medicine ,Science - Abstract
IntroductionPancreaticoduodenectomy is a complex surgical procedure associated with high morbidity and prolonged length of stay. Enhanced recovery after surgery principles have reduced complications rate and length of stay for multiple types of operations. We hypothesized that implementation of a standardized perioperative care pathway would facilitate safe discharge by five days after pancreaticoduodenectomy.MethodsWe performed a retrospective cohort study of patients undergoing pancreaticoduodenectomy 18 months prior to and 18 months following implementation of a perioperative care pathway at a quaternary center performing high volume pancreatic surgery.ResultsA total of 145 patients underwent pancreaticoduodenectomy (mean age 63 ± 10 years, 52% female), 81 before and 64 following pathway implementation, and the groups were similar in terms of preoperative comorbidities. The percentage of patients discharged within 5 days of surgery increased from 36% to 64% following pathway implementation (p = 0.001), with no observed differences in post-operative serious adverse events (p = 0.34), pancreatic fistula grade B or C (p = 0.28 and p = 0.27 respectively), or delayed gastric emptying (p = 0.46). Multivariate regression analysis showed length of stay ≤5 days three times more likely after pathway implementation. Rates of readmission within 30 days (20% pre- vs. 22% post-pathway (p = 0.75)) and 90 days (27% pre- vs. 36% post-pathway (p = 0.27)) were unchanged after pathway implementation, and were no different between patients discharged before or after day 5 at both 30 days (19% ≤5 days vs. 23% ≥ 6 days (p = 0.68)) and 90 days (32% ≤5 days vs. 30% ≥ 6 days (p = 0.81)).ConclusionsStandardizing perioperative care via enhanced recovery protocols for patients undergoing pancreaticoduodenectomy facilitates safe discharge by post-operative day five.
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- 2018
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5. FOXP3+ lymphocyte density in pancreatic cancer correlates with lymph node metastasis.
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Yongjian Jiang, Zunguo Du, Feng Yang, Yang Di, Ji Li, Zhongwen Zhou, Venu G Pillarisetty, and Deliang Fu
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Medicine ,Science - Abstract
To determine if the density of FOXP3+ lymphocytes in primary tumors and lymph nodes in pancreatic cancer correlates with the presence of lymph node metastases.FOXP3+ lymphocyte density in primary pancreatic cancer tissue and draining lymph nodes was measured using immunohistochemistry. We analyzed the clinical and pathological aspects associated with the accumulation of FOXP3+ lymphocytes in pancreatic cancer. We also analyzed the correlation of density of FOXP3+ lymphocytes in lymph nodes with the nodal status and distance from the primary tumor.FOXP3+ lymphocyte density in pancreatic cancer was significantly higher than in paratumoral pancreatic tissue. The density of FOXP3+ lymphocytes in local tumor tissue correlated significantly with the histological grade and overall lymph node status. Furthermore, FOXP3+ lymphocyte density was significantly higher in positive lymph nodes than in negative ones, while it had no correlation with the distance of the lymph node from the primary tumor.FOXP3+ lymphocyte density in primary tumor tissue in patients with pancreatic cancer correlates with lymph node metastasis. Lymph nodes containing metastases having higher FOXP3+ lymphocyte densities than do negative lymph nodes.
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- 2014
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6. Pancreatic ductal adenocarcinoma contains an effector and regulatory immune cell infiltrate that is altered by multimodal neoadjuvant treatment.
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Kendall C Shibuya, Vikas K Goel, Wei Xiong, Jonathan G Sham, Seth M Pollack, Allison M Leahy, Samuel H Whiting, Matthew M Yeh, Cassian Yee, Stanley R Riddell, and Venu G Pillarisetty
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Medicine ,Science - Abstract
OBJECTIVE:The immune response to pancreatic ductal adenocarcinoma (PDA) may play a role in defining its uniquely aggressive biology; therefore, we sought to clearly define the adaptive immune infiltrate in PDA. DESIGN:We used immunohistochemistry and flow cytometry to characterize the immune infiltrate in human PDA and compared our findings to the patients' peripheral blood. RESULTS:In contrast to the myeloid cell predominant infiltrate seen in murine models, T cells comprised the majority of the hematopoietic cell component of the tumor stroma in human PDA. Most intratumoral CD8+ T cells exhibited an antigen-experienced effector memory cell phenotype and were capable of producing IFN-γ. CD4+ regulatory T cells (Treg) and IL-17 producing T helper cells were significantly more prevalent in tumor than in blood. Consistent with the association with reduced survival in previous studies, we observed higher frequencies of both myeloid cells and Treg in poorly differentiated tumors. The majority of intratumoral T cells expressed the co-inhibitory receptor programmed death-1 (PD-1), suggesting one potential mechanism through which PDA may evade antitumor immunity. Successful multimodal neoadjuvant therapy altered the immunoregulatory balance and was associated with reduced infiltration of both myeloid cells and Treg. CONCLUSION:Our data show that human PDA contains a complex mixture of inflammatory and regulatory immune cells, and that neoadjuvant therapy attenuates the infiltration of intratumoral cells associated with immunosuppression and worsened survival.
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- 2014
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7. A phase II trial of lanreotide for the prevention of postoperative pancreatic fistula
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Venu G. Pillarisetty, Arezou Abbasi, James O. Park, and Jonathan G. Sham
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Pancreatic Fistula ,Pancreatectomy ,Postoperative Complications ,Hepatology ,Risk Factors ,Gastroenterology ,Humans ,Somatostatin ,Pancreaticoduodenectomy ,Retrospective Studies - Abstract
Clinically relevant postoperative pancreatic fistula (CR-POPF) is a significant contributor to morbidity after pancreatectomy. Somatostatin analogues have shown variable efficacy in the prevention of CR-POPF. Lanreotide is a somatostatin analogue ideally suited for perioperative use due to its long half-life and favorable side effect profile.We conducted a phase II single-arm trial of a single dose of preoperative lanreotide (120 mg) in patients undergoing either pancreaticoduodenectomy (PD) or distal pancreatectomy (DP). The primary outcome was development of CR-POPF or intra-abdominal abscess. Secondary outcomes included biochemical leak and overall morbidity.A total of 98 patients completed the study. Sixty-two underwent PD (63.3%) and 36 underwent DP (36.7%). The primary outcome was observed in eight (8%) patients in the overall cohort, one from the DP group and seven from the PD group. Biochemical leak was detected in 12 (12.2%) patients in the overall cohort. Twenty-seven (27.5%) patients developed complications, of which 14 (14.2%) were major complications. Drug-related adverse events were limited to mild skin reactions in two (2%) patients.Patients who received preoperative lanreotide developed CR-POPF at rates significantly lower than historical controls or published literature. This provides strong justification for a randomized controlled trial.
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- 2022
8. Supplementary Data from Systemic Interferon-γ Increases MHC Class I Expression and T-cell Infiltration in Cold Tumors: Results of a Phase 0 Clinical Trial
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Seth M. Pollack, Robin L. Jones, Stanley R. Riddell, Robert H. Pierce, Cassian Yee, Brian A. Van Tine, Lee D. Cranmer, Venu G. Pillarisetty, Qianchuan He, Sydney M. Spadinger, Lu Yao, R. Graeme Black, Karan Kohli, and Shihong Zhang
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Supplementary Tables 1-3 and Supplementary Tables 1-6
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- 2023
9. Data from Systemic Interferon-γ Increases MHC Class I Expression and T-cell Infiltration in Cold Tumors: Results of a Phase 0 Clinical Trial
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Seth M. Pollack, Robin L. Jones, Stanley R. Riddell, Robert H. Pierce, Cassian Yee, Brian A. Van Tine, Lee D. Cranmer, Venu G. Pillarisetty, Qianchuan He, Sydney M. Spadinger, Lu Yao, R. Graeme Black, Karan Kohli, and Shihong Zhang
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Interferon-γ (IFNγ) has been studied as a cancer treatment with limited evidence of clinical benefit. However, it could play a role in cancer immunotherapy combination treatments. Despite high expression of immunogenic cancer–testis antigens, synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) have a cold tumor microenvironment (TME), with few infiltrating T cells and low expression of major histocompatibility complex class I (MHC-I). We hypothesized that IFNγ treatment could drive inflammation in a cold TME, facilitating further immunotherapy. We conducted a phase 0 clinical trial treating 8 SS or MRCL patients with weekly systemic IFNγ. We performed pre- and posttreatment biopsies. IFNγ changed the SS and MRCL TME, inducing tumor-surface MHC-I expression and significant T-cell infiltration (P < 0.05). Gene-expression analysis suggested increased tumor antigen presentation and less exhausted phenotypes of the tumor-infiltrating T cells. Newly emergent antigen-specific humoral and/or T-cell responses were found in 3 of 7 evaluable patients. However, increased expression of PD-L1 was observed on tumor-infiltrating myeloid cells and in some cases tumor cells. These findings suggest that systemic IFNγ used to convert SS and MRCL into “hot” tumors will work in concert with anti–PD-1 therapy to provide patient benefit.
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- 2023
10. A novel rat model for the study of postoperative pancreatic fistula
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Alan F Utria, Kevin P Labadie, Arezou Abbasi, Xianyong Gui, Venu G Pillarisetty, James O Park, and Jonathan G Sham
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Pancreatic Fistula ,Postoperative Complications ,General Veterinary ,Risk Factors ,Animals ,Animal Science and Zoology ,Pancreas ,Rats ,Pancreaticoduodenectomy - Abstract
While over the past several decades mortality after pancreatic surgery has decreased to
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- 2022
11. Supplementary Figure 6 from Mobilization of CD8+ T Cells via CXCR4 Blockade Facilitates PD-1 Checkpoint Therapy in Human Pancreatic Cancer
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Venu G. Pillarisetty, Harlan Robins, Robert H. Pierce, Ian Nicholas Crispe, Raymond Yeung, Teresa S. Kim, Seth M. Pollack, Sara K. Daniel, James O. Park, Marissa Vignali, Arezou Abbasi, Kimberly S. Smythe, Florencia G. Jalikis, Kevin M. Sullivan, Xiuyun Jiang, and Yongwoo David Seo
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Image cytometry methods overview
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- 2023
12. Data from A Phase II Trial of Pembrolizumab and Vorinostat in Recurrent Metastatic Head and Neck Squamous Cell Carcinomas and Salivary Gland Cancer
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Renato Martins, Keith Eaton, Laura Q.M. Chow, Christina S. Baik, Bernardo Goulart, Rafael Santana-Davila, Sylvia M. Lee, Venu G. Pillarisetty, Xiuyun Jiang, Jonathan R. Fromm, Jenna Voutsinas, Qian (Vicky) Wu, and Cristina P. Rodriguez
- Abstract
Purpose:This clinical trial combined pembrolizumab and vorinostat in recurrent/metastatic squamous cell carcinomas of the head and neck (HN), and salivary gland cancer (SGC).Patients and Methods:Patients with progressing incurable HN and SGC, Eastern Cooperative Oncology Group (ECOG) ≤1, no prior immunotherapy, RECIST1.1 measurable disease, and normal organ function were eligible. Pembrolizumab 200 mg was given intravenous every 21 days, and vorinostat 400 mg given orally 5 days on and 2 days off during each 21-day cycle. Primary endpoints were safety and objective response rates.Results:From November 2015 to August 2017, 25 patients with HN and 25 SGC were enrolled. Median age was 61 (range, 33–86) years, 39 (78%) were male, 21 (62%) were never smokers, and 27 (54%) had ECOG 0. In HN, 13 (52%) were p16+ oropharynx. Most common SGC histologies were adenoid cystic 12 (48%), acinic cell 3 (12%), and mucoepidermoid 3 (12%). Adverse events (AEs) in all patients were: 27 (54%) with grade ≥ 1 and 18 (36%) with grade ≥ 3. The most common AEs in all patients were renal insufficiency in seven, (14%), fatigue in six, (12%), and nausea in three (6%). There were three (12%) deaths on study. Responses in HN were complete response (CR) 0, partial response (PR) eight (32%), and stable disease (SD) five (20%). Efficacy in SGCs was CR 0, PR four (16%) in one lymphoepithelioma-like carcinoma, two acinic cell, one adenoid cystic, and SD 14 (56%). In the HN group, median follow-up (mFUP) was 12.6 months, median overall survival (mOS) was 12.6 months, and median progression-free survival (mPFS) was 4.5 months. In SGC, mFUP was 13.1 months, mOS was 14.0 months, and mPFS was 6.9 months.Conclusions:This combination demonstrated activity in HN, with fewer responses in SGC. Toxicities were higher than reported with pembrolizumab alone.
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- 2023
13. Supplementary Tables 1-5 and Supplementary Figure Legends 1-3 from Predicting Survival in Patients Undergoing Resection for Locally Recurrent Retroperitoneal Sarcoma: A Study and Novel Nomogram from TARPSWG
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Alessandro Gronchi, Mark Fairweather, Marco Fiore, Kenneth Cardona, Frits van Coevorden, Elisabetta Pennacchioli, Hans J. Gelderblom, John Mullen, Robert Canter, Sanjay Bagaria, Carol J. Swallow, Carolyn Nessim, Venu G. Pillarisetty, Antonino De Paoli, Eberhard Stoeckle, Vittorio Quagliuolo, Giovanni Grignani, Nita Ahuja, Ricardo Gonzalez, Dirk C. Strauss, Guy Lahat, Jean-Yves Blay, Piotr Rutkowski, Francesco Barretta, Rosalba Miceli, Dario Callegaro, and Chandrajit P. Raut
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Supplementary Tables and Figure Legends
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- 2023
14. Supplementary Data from A Phase II Trial of Pembrolizumab and Vorinostat in Recurrent Metastatic Head and Neck Squamous Cell Carcinomas and Salivary Gland Cancer
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Renato Martins, Keith Eaton, Laura Q.M. Chow, Christina S. Baik, Bernardo Goulart, Rafael Santana-Davila, Sylvia M. Lee, Venu G. Pillarisetty, Xiuyun Jiang, Jonathan R. Fromm, Jenna Voutsinas, Qian (Vicky) Wu, and Cristina P. Rodriguez
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Supplement Figure 1: Synergistic cytotoxic effect of pembrolizumab combined with vorinostat in HNSCC tissue slice culture. HNSCC slices (250 ï�m) were cultured and treated with 20 ï�g/ml of isotype control antibody IgG4 or pembrolizumab, with or without vorinostat (20 ï�M, 100 ï�M) for 6 days. Graph shows the percentage of cleaved-caspase-3+ cells. Unpaired student's tests, P-values are as follows: *p < 0.05, **P < 0.01, ***P< 0.001.
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- 2023
15. Supplementary Figure 2 from Predicting Survival in Patients Undergoing Resection for Locally Recurrent Retroperitoneal Sarcoma: A Study and Novel Nomogram from TARPSWG
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Alessandro Gronchi, Mark Fairweather, Marco Fiore, Kenneth Cardona, Frits van Coevorden, Elisabetta Pennacchioli, Hans J. Gelderblom, John Mullen, Robert Canter, Sanjay Bagaria, Carol J. Swallow, Carolyn Nessim, Venu G. Pillarisetty, Antonino De Paoli, Eberhard Stoeckle, Vittorio Quagliuolo, Giovanni Grignani, Nita Ahuja, Ricardo Gonzalez, Dirk C. Strauss, Guy Lahat, Jean-Yves Blay, Piotr Rutkowski, Francesco Barretta, Rosalba Miceli, Dario Callegaro, and Chandrajit P. Raut
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Supplementary Figure 2
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- 2023
16. Supplementary Figure 5 from Mobilization of CD8+ T Cells via CXCR4 Blockade Facilitates PD-1 Checkpoint Therapy in Human Pancreatic Cancer
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Venu G. Pillarisetty, Harlan Robins, Robert H. Pierce, Ian Nicholas Crispe, Raymond Yeung, Teresa S. Kim, Seth M. Pollack, Sara K. Daniel, James O. Park, Marissa Vignali, Arezou Abbasi, Kimberly S. Smythe, Florencia G. Jalikis, Kevin M. Sullivan, Xiuyun Jiang, and Yongwoo David Seo
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Live microscopy analysis of CD8+ T cell distribution in slice cultures
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- 2023
17. Supplementary Figure 1B from Predicting Survival in Patients Undergoing Resection for Locally Recurrent Retroperitoneal Sarcoma: A Study and Novel Nomogram from TARPSWG
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Alessandro Gronchi, Mark Fairweather, Marco Fiore, Kenneth Cardona, Frits van Coevorden, Elisabetta Pennacchioli, Hans J. Gelderblom, John Mullen, Robert Canter, Sanjay Bagaria, Carol J. Swallow, Carolyn Nessim, Venu G. Pillarisetty, Antonino De Paoli, Eberhard Stoeckle, Vittorio Quagliuolo, Giovanni Grignani, Nita Ahuja, Ricardo Gonzalez, Dirk C. Strauss, Guy Lahat, Jean-Yves Blay, Piotr Rutkowski, Francesco Barretta, Rosalba Miceli, Dario Callegaro, and Chandrajit P. Raut
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Supplementary Figure 1F
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- 2023
18. Supplementary Figure 3 from Predicting Survival in Patients Undergoing Resection for Locally Recurrent Retroperitoneal Sarcoma: A Study and Novel Nomogram from TARPSWG
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Alessandro Gronchi, Mark Fairweather, Marco Fiore, Kenneth Cardona, Frits van Coevorden, Elisabetta Pennacchioli, Hans J. Gelderblom, John Mullen, Robert Canter, Sanjay Bagaria, Carol J. Swallow, Carolyn Nessim, Venu G. Pillarisetty, Antonino De Paoli, Eberhard Stoeckle, Vittorio Quagliuolo, Giovanni Grignani, Nita Ahuja, Ricardo Gonzalez, Dirk C. Strauss, Guy Lahat, Jean-Yves Blay, Piotr Rutkowski, Francesco Barretta, Rosalba Miceli, Dario Callegaro, and Chandrajit P. Raut
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Supplementary Figure 3
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- 2023
19. Supplementary Figure 3 from Mobilization of CD8+ T Cells via CXCR4 Blockade Facilitates PD-1 Checkpoint Therapy in Human Pancreatic Cancer
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Venu G. Pillarisetty, Harlan Robins, Robert H. Pierce, Ian Nicholas Crispe, Raymond Yeung, Teresa S. Kim, Seth M. Pollack, Sara K. Daniel, James O. Park, Marissa Vignali, Arezou Abbasi, Kimberly S. Smythe, Florencia G. Jalikis, Kevin M. Sullivan, Xiuyun Jiang, and Yongwoo David Seo
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PDA tumor slice culture platform utilized for multimodal analysis before and after ex vivo immune modulation
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- 2023
20. Supplementary Figure 2 from Mobilization of CD8+ T Cells via CXCR4 Blockade Facilitates PD-1 Checkpoint Therapy in Human Pancreatic Cancer
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Venu G. Pillarisetty, Harlan Robins, Robert H. Pierce, Ian Nicholas Crispe, Raymond Yeung, Teresa S. Kim, Seth M. Pollack, Sara K. Daniel, James O. Park, Marissa Vignali, Arezou Abbasi, Kimberly S. Smythe, Florencia G. Jalikis, Kevin M. Sullivan, Xiuyun Jiang, and Yongwoo David Seo
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TCR overlap analysis
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- 2023
21. Data from Mobilization of CD8+ T Cells via CXCR4 Blockade Facilitates PD-1 Checkpoint Therapy in Human Pancreatic Cancer
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Venu G. Pillarisetty, Harlan Robins, Robert H. Pierce, Ian Nicholas Crispe, Raymond Yeung, Teresa S. Kim, Seth M. Pollack, Sara K. Daniel, James O. Park, Marissa Vignali, Arezou Abbasi, Kimberly S. Smythe, Florencia G. Jalikis, Kevin M. Sullivan, Xiuyun Jiang, and Yongwoo David Seo
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Purpose:Pancreatic ductal adenocarcinoma (PDA) is rarely cured, and single-agent immune checkpoint inhibition has not demonstrated clinical benefit despite the presence of large numbers of CD8+ T cells. We hypothesized that tumor-infiltrating CD8+ T cells harbor latent antitumor activity that can be reactivated using combination immunotherapy.Experimental Design:Preserved human PDA specimens were analyzed using multiplex IHC (mIHC) and T-cell receptor (TCR) sequencing. Fresh tumor was treated in organotypic slice culture to test the effects of combination PD-1 and CXCR4 blockade. Slices were analyzed using IHC, flow cytometry, and live fluorescent microscopy to assess tumor kill, in addition to T-cell expansion and mobilization.Results:mIHC demonstrated fewer CD8+ T cells in juxtatumoral stroma containing carcinoma cells than in stroma devoid of them. Using TCR sequencing, we found clonal expansion in each tumor; high-frequency clones had multiple DNA rearrangements coding for the same amino acid binding sequence, which suggests response to common tumor antigens. Treatment of fresh human PDA slices with combination PD-1 and CXCR4 blockade led to increased tumor cell death concomitant with lymphocyte expansion. Live microscopy after combination therapy demonstrated CD8+ T-cell migration into the juxtatumoral compartment and rapid increase in tumor cell apoptosis.Conclusions:Endogenous tumor-reactive T cells are present within the human PDA tumor microenvironment and can be reactivated by combined blockade of PD-1 and CXCR4. This provides a new basis for the rational selection of combination immunotherapy for PDA.See related commentary by Medina and Miller, p. 3747
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- 2023
22. Supplementary Table 1 from Mobilization of CD8+ T Cells via CXCR4 Blockade Facilitates PD-1 Checkpoint Therapy in Human Pancreatic Cancer
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Venu G. Pillarisetty, Harlan Robins, Robert H. Pierce, Ian Nicholas Crispe, Raymond Yeung, Teresa S. Kim, Seth M. Pollack, Sara K. Daniel, James O. Park, Marissa Vignali, Arezou Abbasi, Kimberly S. Smythe, Florencia G. Jalikis, Kevin M. Sullivan, Xiuyun Jiang, and Yongwoo David Seo
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Patient demographic and tumor pathology
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- 2023
23. Supplementary Figure 1 from Mobilization of CD8+ T Cells via CXCR4 Blockade Facilitates PD-1 Checkpoint Therapy in Human Pancreatic Cancer
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Venu G. Pillarisetty, Harlan Robins, Robert H. Pierce, Ian Nicholas Crispe, Raymond Yeung, Teresa S. Kim, Seth M. Pollack, Sara K. Daniel, James O. Park, Marissa Vignali, Arezou Abbasi, Kimberly S. Smythe, Florencia G. Jalikis, Kevin M. Sullivan, Xiuyun Jiang, and Yongwoo David Seo
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Image cytometry infiltration results by layer
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- 2023
24. Data from Predicting Survival in Patients Undergoing Resection for Locally Recurrent Retroperitoneal Sarcoma: A Study and Novel Nomogram from TARPSWG
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Alessandro Gronchi, Mark Fairweather, Marco Fiore, Kenneth Cardona, Frits van Coevorden, Elisabetta Pennacchioli, Hans J. Gelderblom, John Mullen, Robert Canter, Sanjay Bagaria, Carol J. Swallow, Carolyn Nessim, Venu G. Pillarisetty, Antonino De Paoli, Eberhard Stoeckle, Vittorio Quagliuolo, Giovanni Grignani, Nita Ahuja, Ricardo Gonzalez, Dirk C. Strauss, Guy Lahat, Jean-Yves Blay, Piotr Rutkowski, Francesco Barretta, Rosalba Miceli, Dario Callegaro, and Chandrajit P. Raut
- Abstract
Purpose:The role of surgery for first relapse locally recurrent retroperitoneal sarcoma (RPS-LR1) is uncertain. We report outcomes of the largest RPS-LR1 series and propose a new prognostic nomogram.Experimental Design:Patients with consecutive RPS-LR1 without distant metastases who underwent resection at 22 centers (2002–2011) were included. Endpoints were disease-free and overall survival (DFS, OS) and crude-cumulative-incidence (CCI) of local/distant recurrence from second surgery. Nomograms predicting DFS and OS from second surgery were developed and validated (calibration plots); discrimination was assessed (Harrell C index).Results:Of 684 patients identified, full prognostic variable data were available for 602. Initial surgery for primary RPS was performed at our institutions in 188 patients (31%) and elsewhere in 414 (69%). At a median follow-up of 119 months [Interquartile range (IQR), 80–169] from initial surgery and 75 months (IQR 50–105) from second surgery, 6-year DFS and OS were 19.2% [95% confidence interval (CI), 16.0–23.0%] and 54.1% (95% CI, 49.8–58.8%), respectively. Recurrence patterns and survival probability were histology-specific, with liposarcoma subtypes having the highest 6-year CCI of second local recurrence (LR, 60.2%–70.9%) and leiomyosarcoma (LMS) having higher 6-year CCI of distant metastasis (DM, 36.3%). Nomograms included age at second surgery, multifocality, grade, completeness of second surgery, histology, chemotherapy/radiotherapy at first surgery, and number of organs resected at first surgery. OS and DFS nomograms showed good calibration and discriminative ability (C index 0.70 and 0.67, respectively).Conclusions:We developed nomograms to predict DFS and OS for patients undergoing RPS-LR1 resection. Nomograms provide individualized, disease-relevant estimations of survival for RPS-LR1 patients and assist in clinical decisions.
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- 2023
25. Supplementary Figure 4 from Mobilization of CD8+ T Cells via CXCR4 Blockade Facilitates PD-1 Checkpoint Therapy in Human Pancreatic Cancer
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Venu G. Pillarisetty, Harlan Robins, Robert H. Pierce, Ian Nicholas Crispe, Raymond Yeung, Teresa S. Kim, Seth M. Pollack, Sara K. Daniel, James O. Park, Marissa Vignali, Arezou Abbasi, Kimberly S. Smythe, Florencia G. Jalikis, Kevin M. Sullivan, Xiuyun Jiang, and Yongwoo David Seo
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Combination immunotherapy tumor slice culture experiment replicates
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- 2023
26. Leiomyosarcoma of the inferior vena cava: An uncommon malignancy requiring unique reconstructive approaches
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Kristin E. Goodsell, Jeremy M. Sharib, Venu G. Pillarisetty, and Jonathan G. Sham
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Surgery ,General Medicine - Published
- 2023
27. Combination immunotherapy for pancreatic cancer: challenges and future considerations
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Gustavo C. L. Gössling, David B. Zhen, Venu G. Pillarisetty, and E. Gabriela Chiorean
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Pancreatic Neoplasms ,Immunology ,Tumor Microenvironment ,Immunology and Allergy ,Humans ,Immunotherapy ,Immune Checkpoint Inhibitors ,Carcinoma, Pancreatic Ductal - Abstract
Immune checkpoint inhibitors (ICI) have not yielded significant efficacy in pancreatic ductal adenocarcinoma (PDA), despite the role of the innate and adaptive immune systems on progression and survival. However, recently identified pathways have identified new targets and generated promising clinical investigations into promoting an effective immune-mediated antitumor response in PDA.We review biological mechanisms associated with immunotherapy resistance and outline strategies for therapeutic combinations with established and novel therapies in PDA.Pancreatic cancers rarely benefit from treatment with ICI due to an immunosuppressive tumor microenvironment (TME). New understandings of factors associated with the suppressive TME include low- and poor-quality neoantigens, constrained effector T cells infiltration, and the presence of a dense, suppressive myeloid cell population. These findings have been translated into new clinical investigations evaluating novel therapies in combination with ICI and/or standard systemic chemotherapy and radiotherapy. The epithelial, immune, and stromal compartments are intricately related in PDA, and the framework for successful targeting of this disease requires a comprehensive and personalized approach.
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- 2022
28. Emerging interleukin targets in the tumour microenvironment: implications for the treatment of gastrointestinal tumours
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Lindsay Kathleen Dickerson, Jason A Carter, Karan Kohli, and Venu G Pillarisetty
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Gastroenterology - Abstract
The effectiveness of antitumour immunity is dependent on intricate cytokine networks. Interleukins (ILs) are important mediators of complex interactions within the tumour microenvironment, including regulation of tumour-infiltrating lymphocyte proliferation, differentiation, migration and activation. Our evolving and increasingly nuanced understanding of the cell type-specific and heterogeneous effects of IL signalling has presented unique opportunities to fine-tune elaborate IL networks and engineer new targeted immunotherapeutics. In this review, we provide a primer for clinicians on the challenges and potential of IL-based treatment. We specifically detail the roles of IL-2, IL-10, IL-12 and IL-15 in shaping the tumour-immune landscape of gastrointestinal malignancies, paying particular attention to promising preclinical findings, early-stage clinical research and innovative therapeutic approaches that may properly place ILs to the forefront of immunotherapy regimens.
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- 2023
29. Analysis of Differentiation Changes and Outcomes at Time of First Recurrence of Retroperitoneal Liposarcoma by Transatlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG)
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Robert J. Canter, Marco Fiore, Piotr Rutkowski, Sanjay P. Bagaria, Giovanni Grignani, Jean-Yves Blay, Antonino De Paoli, Francesco Barretta, Eberhard Stoeckle, Guy Lahat, Winan J. van Houdt, John T. Mullen, Rosalba Miceli, Nita Ahuja, Elisabetta Pennacchioli, Dario Callegaro, Alessandro Gronchi, Venu G. Pillarisetty, Chandrajit P. Raut, Dirk C. Strauss, Kenneth Cardona, Carol J. Swallow, Carolyn Nessim, Mark Fairweather, Vittorio Quagliuolo, Ricardo J. Gonzalez, and Yvonne Schrage
- Subjects
medicine.medical_specialty ,business.industry ,Incidence (epidemiology) ,medicine.disease ,Gastroenterology ,Primary tumor ,Resection ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,Surgical oncology ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Retroperitoneal sarcoma ,030211 gastroenterology & hepatology ,Surgery ,Retroperitoneal liposarcoma ,Sarcoma ,business ,First Recurrence - Abstract
Local recurrence following resection of retroperitoneal liposarcoma (RLPS) is common. Well-differentiated (WD) and dedifferentiated (DD) RLPS are distinct entities with differing outcomes. A few reports suggest that WDLPS can recur as DDLPS and that DDLPS can recur as WDLPS. This study evaluates whether this change in differentiation from the primary tumor to the first local recurrence impacts long-term outcomes. Retrospective review from 22 sarcoma centers identified consecutive patients who underwent resection for a first locally recurrent RLPS from January 2002 to December 2011. Outcomes measured included overall survival, local recurrence, and distant metastasis. A total of 421 RPLS patients were identified. Of the 230 patients with primary DDLPS, 34 (15%) presented WDLPS upon recurrence (DD → WD); and of the 191 patients with primary WDLPS, 54 (28%) presented DDLPS upon recurrence (WD → DD). The 6-year overall survival probabilities (95% CI) for DD → DD, DD → WD, WD → WD, and WD → DD were 40% (32–48%), 73% (58–92%), 76% (68–85%), and 56% (43–73%) (p < 0.001), respectively. The 6-year second local recurrence incidence was 66% (59–73%), 63% (48–82%), 66% (57–76%), and 77% (66–90%), respectively. The 6-year distant metastasis incidence was 13% (9–19%), 3% (0.4–22%), 5% (2–11%), and 4% (1–16%), respectively. On multivariable analysis, DD → WD was associated with improved overall survival when compared with DD → DD (p < 0.001). Moreover, WD → DD was associated with a higher risk of LR (p = 0.025) A change in RLPS differentiation from primary tumor to first local recurrence appears to impact survival. These findings may be useful in counseling patients on their prognosis and subsequent management.
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- 2021
30. IWATE criteria are associated with perioperative outcomes in robotic hepatectomy: a retrospective review of 225 resections
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Kevin M. Sullivan, Alex W. Lois, Lindsay K. Dickerson, Sara K. Daniel, Raymond S. Yeung, Jonathan G. Sham, Kyle S. Bilodeau, James O. Park, Jaqueline Valdez Gonzalez, Alan F. Utria, Kevin P. Labadie, Venu G. Pillarisetty, David J. Droullard, Kathryn E. McNevin, John Calhoun, and Yongwoo D. Seo
- Subjects
medicine.medical_specialty ,medicine.medical_treatment ,030230 surgery ,Article ,03 medical and health sciences ,Postoperative Complications ,0302 clinical medicine ,Robotic Surgical Procedures ,Minimally invasive surgery ,Internal medicine ,Hepatectomy ,Humans ,Medicine ,Robotic surgery ,Intrahepatic Cholangiocarcinoma ,Robotic hepatectomy ,Retrospective Studies ,business.industry ,Liver Neoplasms ,Confounding ,Perioperative ,Length of Stay ,Hepatology ,medicine.disease ,Surgery ,Bile Ducts, Intrahepatic ,Bile Duct Neoplasms ,IWATE criteria ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Laparoscopy ,business ,Abdominal surgery - Abstract
Background Robotic hepatectomy (RH) is increasingly utilized for minor and major liver resections. The IWATE criteria were developed to classify minimally invasive liver resections by difficulty. The objective of this study was to apply the IWATE criteria in RH and to describe perioperative and oncologic outcomes of RH over the last decade at our institution. Methods Perioperative and oncologic outcomes of patients who underwent RH between 2011 and 2019 were retrospectively collected. The difficulty level of each operation was assessed using the IWATE criteria, and outcomes were compared at each level. Univariate linear regression was performed to characterize the relationship between IWATE criteria and perioperative outcomes (OR time, EBL, and LOS), and a multivariable model was also developed to address potential confounding by patient characteristics (age, sex, BMI, prior abdominal surgery, ASA class, and simultaneous non-hepatectomy operation). Results Two hundred and twenty-five RH were performed. Median IWATE criteria for RH were 6 (IQR 5–9), with low, intermediate, advanced, and expert resections accounting for 23% (n = 51), 34% (n = 77), 32% (n = 72), and 11% (n = 25) of resections, respectively. The majority of resections were parenchymal-sparing approaches, including anatomic segmentectomies and non-anatomic partial resections. 30-day complication rate was 14%, conversion to open surgery occurred in 9 patients (4%), and there were no deaths within 30 days postoperatively. In the univariate linear regression analysis, IWATE criteria were positively associated with OR time, EBL, and LOS. In the multivariable model, IWATE criteria were independently associated with greater OR time, EBL, and LOS. Two-year overall survival for hepatocellular carcinoma and intrahepatic cholangiocarcinoma was 94% and 50%, respectively. Conclusion In conclusion, the IWATE criteria are associated with surgical outcomes after RH. This series highlights the utility of RH for difficult hepatic resections, particularly parenchymal-sparing resections in the posterosuperior sector, extending the indication of minimally invasive hepatectomy in experienced hands and potentially offering select patients an alternative to open hepatectomy or other less definitive liver-directed treatment options.
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- 2021
31. Key chemokines direct migration of immune cells in solid tumors
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Karan Kohli, Venu G. Pillarisetty, and Teresa S. Kim
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0301 basic medicine ,Cancer Research ,Chemokine ,animal diseases ,chemical and pharmacologic phenomena ,Context (language use) ,Review Article ,Biology ,03 medical and health sciences ,Chemokine receptor ,0302 clinical medicine ,Immune system ,Cell Movement ,Neoplasms ,Tumor Microenvironment ,Humans ,Molecular Biology ,Immune cell infiltration ,Cancer immunology ,Tumor microenvironment ,Effector ,biochemical phenomena, metabolism, and nutrition ,030104 developmental biology ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,bacteria ,Tumour immunology ,Molecular Medicine ,Chemokines - Abstract
Immune cell infiltration into solid tumors, their movement within the tumor microenvironment (TME), and interaction with other immune cells are controlled by their directed migration towards gradients of chemokines. Dysregulated chemokine signaling in TME favors the growth of tumors, exclusion of effector immune cells, and abundance of immunosuppressive cells. Key chemokines directing the migration of immune cells into tumor tissue have been identified. In this review, we discuss well-studied chemokine receptors that regulate migration of effector and immunosuppressive immune cells in the context of cancer immunology. We discuss preclinical models that have described the role of respective chemokine receptors in immune cell migration into TME and review preclinical and clinical studies that target chemokine signaling as standalone or combination therapies.
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- 2021
32. Postoperative Morbidity After Resection of Recurrent Retroperitoneal Sarcoma: A Report from the Transatlantic Australasian RPS Working Group (TARPSWG)
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Antonino De Paoli, Venu G. Pillarisetty, Kenneth Cardona, Mark Fairweather, Jean-Yves Blay, Guy Lahat, Carol J. Swallow, Dario Callegaro, Chandrajit P. Raut, Francesco Barretta, Alessandro Gronchi, Dirk C. Strauss, Nita Ahuja, Piotr Rutkowski, John T. Mullen, Elisabetta Pennacchioli, Winan J. van Houdt, Giovanni Grignani, Eberhard Stoeckle, Robert J. Canter, Vittorio Quagliuolo, Rosalba Miceli, Sanjay P. Bagaria, Yvonne Schrage, Carolyn Nessim, Marco Fiore, and Ricardo J. Gonzalez
- Subjects
medicine.medical_specialty ,business.industry ,Incidence (epidemiology) ,Mortality rate ,Perioperative ,Liposarcoma ,medicine.disease ,Surgery ,Resection ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,Surgical oncology ,030220 oncology & carcinogenesis ,Medicine ,Retroperitoneal sarcoma ,030211 gastroenterology & hepatology ,Sarcoma ,business - Abstract
This study aimed to evaluate perioperative morbidity after surgery for first locally recurrent (LR1) retroperitoneal sarcoma (RPS). Data concerning the safety of resecting recurrent RPS are lacking. Data were collected on all patients undergoing resection of RPS-LR1 at 22 Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG) centers from 2002 to 2011. Uni- and multivariable logistic models were fitted to study the association between major (Clavien-Dindo grade ≥ 3) complications and patient/surgery characteristics as well as outcome. The resected organ score, a method of standardizing the number of organs resected, as previously described by the TARPSWG, was used. The 681 patients in this study had a median age of 59 years, and 51.8% were female. The most common histologic subtype was de-differentiated liposarcoma (43%), the median resected organ score was 1, and 83.3% of the patients achieved an R0 or R1 resection. Major complications occurred for 16% of the patients, and the 90-day mortality rate was 0.4%. In the multivariable analysis, a transfusion requirement was found to be a significant predictor of major complications (p
- Published
- 2021
33. The CXCL12-CXCR4/CXCR7 axis as a mechanism of immune resistance in gastrointestinal malignancies
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Y. David Seo, Sara K. Daniel, and Venu G. Pillarisetty
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0301 basic medicine ,MAPK/ERK pathway ,Receptors, CXCR4 ,Cancer Research ,Chemokine ,medicine.medical_treatment ,Apoptosis ,CXCR4 ,03 medical and health sciences ,0302 clinical medicine ,Tumor Microenvironment ,medicine ,Humans ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Gastrointestinal Neoplasms ,Receptors, CXCR ,Tumor microenvironment ,CXCR4 antagonist ,biology ,Cell adhesion molecule ,business.industry ,Immunotherapy ,Chemokine CXCL12 ,030104 developmental biology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,biological phenomena, cell phenomena, and immunity ,business ,Signal Transduction - Abstract
Single agent checkpoint inhibitor therapy has not been effective for most gastrointestinal solid tumors, but combination therapy with drugs targeting additional immunosuppressive pathways is being attempted. One such pathway, the CXCL12-CXCR4/CXCR7 chemokine axis, has attracted attention due to its effects on tumor cell survival and metastasis as well as immune cell migration. CXCL12 is a small protein that functions in normal hematopoietic stem cell homing in addition to repair of damaged tissue. Binding of CXCL12 to CXCR4 leads to activation of G protein signaling kinases such as P13K/mTOR and MEK/ERK while binding to CXCR7 leads to β-arrestin mediated signaling. While some gastric and colorectal carcinoma cells have been shown to make CXCL12, the primary source in pancreatic cancer and peritoneal metastases is cancer-associated fibroblasts. Binding of CXCL12 to CXCR4 and CXCR7 on tumor cells leads to anti-apoptotic signaling through Bcl-2 and survivin upregulation, as well as promotion of the epithelial-to-mesechymal transition through the Rho-ROCK pathway and alterations in cell adhesion molecules. High levels of CXCL12 seen in the bone marrow, liver, and spleen could partially explain why these are popular sites of metastases for many tumors. CXCL12 is a chemoattractant for lymphocytes at lower levels, but becomes chemorepellant at higher levels; it is unclear exactly what gradient exists in the tumor microenvironment and how this influences tumor-infiltrating lymphocytes. AMD3100 (Plerixafor or Mozobil) is a small molecule CXCR4 antagonist and is the most frequently used drug targeting the CXCL12-CXCR4/CXCR7 axis in clinical trials for gastrointestinal solid tumors currently. Other small molecules and monoclonal antibodies against CXCR4 are being trialed. Further understanding of the CXCL12- CXCR4/CXCR7 chemokine axis in the tumor microenvironment will allow more effective targeting of this pathway in combination immunotherapy.
- Published
- 2020
34. DNA Damage Repair Defects and Survival Outcomes for Patients With Resected Pancreatic Ductal Adenocarcinoma
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Marc R. Radke, Elena G. Chiorean, Deepti M. Reddi, Venu G. Pillarisetty, Kelsey Baker, Elizabeth M. Swisher, Amy Chang, Kit Man Wong, Andrew L. Coveler, David Bing Zhen, and Mary W. Redman
- Subjects
Time Factors ,Pancreatic ductal adenocarcinoma ,Hepatology ,business.industry ,Endocrinology, Diabetes and Metabolism ,Recombinational DNA Repair ,DNA Damage Repair ,Article ,Pancreatic Neoplasms ,Pancreatectomy ,Treatment Outcome ,Endocrinology ,Text mining ,Mutation ,Biomarkers, Tumor ,Internal Medicine ,Cancer research ,Humans ,Medicine ,business ,Carcinoma, Pancreatic Ductal ,DNA Damage ,Retrospective Studies - Published
- 2021
35. A Phase II Trial of Pembrolizumab and Vorinostat in Recurrent Metastatic Head and Neck Squamous Cell Carcinomas and Salivary Gland Cancer
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Jenna M. Voutsinas, Laura Q.M. Chow, Renato G. Martins, Venu G. Pillarisetty, Keith D. Eaton, Jonathan R. Fromm, Christina S. Baik, Rafael Santana-Davila, Bernardo H. L. Goulart, Sylvia Lee, Xiuyun Jiang, Cristina P. Rodriguez, and Qian Vicky Wu
- Subjects
Adult ,Male ,0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Nausea ,Pembrolizumab ,Antibodies, Monoclonal, Humanized ,Adenoid ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Carcinoma ,medicine ,Humans ,Neoplasm Metastasis ,Adverse effect ,Survival rate ,Aged ,Aged, 80 and over ,Vorinostat ,Squamous Cell Carcinoma of Head and Neck ,business.industry ,Middle Aged ,Salivary Gland Neoplasms ,medicine.disease ,Survival Rate ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Drug Resistance, Neoplasm ,Head and Neck Neoplasms ,Salivary gland cancer ,030220 oncology & carcinogenesis ,HN group ,Female ,Neoplasm Recurrence, Local ,medicine.symptom ,business - Abstract
Purpose: This clinical trial combined pembrolizumab and vorinostat in recurrent/metastatic squamous cell carcinomas of the head and neck (HN), and salivary gland cancer (SGC). Patients and Methods: Patients with progressing incurable HN and SGC, Eastern Cooperative Oncology Group (ECOG) ≤1, no prior immunotherapy, RECIST1.1 measurable disease, and normal organ function were eligible. Pembrolizumab 200 mg was given intravenous every 21 days, and vorinostat 400 mg given orally 5 days on and 2 days off during each 21-day cycle. Primary endpoints were safety and objective response rates. Results: From November 2015 to August 2017, 25 patients with HN and 25 SGC were enrolled. Median age was 61 (range, 33–86) years, 39 (78%) were male, 21 (62%) were never smokers, and 27 (54%) had ECOG 0. In HN, 13 (52%) were p16+ oropharynx. Most common SGC histologies were adenoid cystic 12 (48%), acinic cell 3 (12%), and mucoepidermoid 3 (12%). Adverse events (AEs) in all patients were: 27 (54%) with grade ≥ 1 and 18 (36%) with grade ≥ 3. The most common AEs in all patients were renal insufficiency in seven, (14%), fatigue in six, (12%), and nausea in three (6%). There were three (12%) deaths on study. Responses in HN were complete response (CR) 0, partial response (PR) eight (32%), and stable disease (SD) five (20%). Efficacy in SGCs was CR 0, PR four (16%) in one lymphoepithelioma-like carcinoma, two acinic cell, one adenoid cystic, and SD 14 (56%). In the HN group, median follow-up (mFUP) was 12.6 months, median overall survival (mOS) was 12.6 months, and median progression-free survival (mPFS) was 4.5 months. In SGC, mFUP was 13.1 months, mOS was 14.0 months, and mPFS was 6.9 months. Conclusions: This combination demonstrated activity in HN, with fewer responses in SGC. Toxicities were higher than reported with pembrolizumab alone.
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- 2020
36. Challenges in assessing solid tumor responses to immunotherapy
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Louis F. Chai, Venu G. Pillarisetty, Steven C. Katz, and Ethan A. Prince
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Immune checkpoint inhibitors ,medicine.medical_treatment ,Immunotherapy ,Cytotoxic chemotherapy ,World health ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Response Evaluation Criteria in Solid Tumors ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Molecular Medicine ,In patient ,Solid tumor ,Molecular Biology ,Pseudoprogression - Abstract
With the advent of immunotherapy as an integral component of multidisciplinary solid tumor treatment, we are confronted by an unfamiliar and novel pattern of radiographic responses to treatment. Enlargement of tumors or even new lesions may not represent progression, but rather reflect what will ultimately evolve into a clinically beneficial response. In addition, the kinetics of radiographic changes in response to immunotherapy treatments may be distinct from what has been observed with cytotoxic chemotherapy and radiation. The phenomenon of pseudoprogression has been documented in patients receiving immunotherapeutic agents, such as checkpoint inhibitors and cellular therapies. Currently, there are no clinical response guidelines that adequately account for pseudoprogression and solid tumor responses to immunotherapy in general. Even so, response criteria have evolved to account for the radiographic manifestations of novel therapies. The evolution of World Health Organization (WHO) criteria and Response Evaluation Criteria in Solid Tumors (RECIST), along with the emergence of immune-related response criteria (irRC) and the immune Response Evaluation Criteria in Solid Tumors (iRECIST) reflect the need for new frameworks. This review evaluates the relationship between pseudoprogression, clinical outcomes, and our current understanding of the biology of pseudoprogression. To achieve our goal, we discuss unusual response patterns in patients receiving immunotherapy. We seek to develop a deeper understanding of radiographic responses to immunotherapy such that clinical benefit is not underappreciated in individual patients and during clinical investigation.
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- 2019
37. Impact of enhanced recovery protocols after pancreatoduodenectomy: meta-analysis
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Christoph Kuemmerli, Christoph Tschuor, Meidai Kasai, Adnan A Alseidi, Gianpaolo Balzano, Stefan Bouwense, Marco Braga, Mariëlle Coolsen, Sara K Daniel, Christos Dervenis, Massimo Falconi, Dae Wook Hwang, Daniel J Kagedan, Song Cheol Kim, Harish Lavu, Tingbo Liang, Daniel Nussbaum, Stefano Partelli, Michael J Passeri, Nicolò Pecorelli, Sastha Ahanatha Pillai, Venu G Pillarisetty, Michael J Pucci, Wei Su, Robert P Sutcliffe, Bobby Tingstedt, Marion van der Kolk, Dionisios Vrochides, Alice Wei, Caroline Williamsson, Charles J Yeo, Sabino Zani, Efstratios Zouros, Mohammed Abu Hilal, Kuemmerli, Christoph, Tschuor, Christoph, Kasai, Meidai, Alseidi, Adnan A, Balzano, Gianpaolo, Bouwense, Stefan, Braga, Marco, Coolsen, Mariëlle, Daniel, Sara K, Dervenis, Christo, Falconi, Massimo, Hwang, Dae Wook, Kagedan, Daniel J, Kim, Song Cheol, Lavu, Harish, Liang, Tingbo, Nussbaum, Daniel, Partelli, Stefano, Passeri, Michael J, Pecorelli, Nicolò, Pillai, Sastha Ahanatha, Pillarisetty, Venu G, Pucci, Michael J, Su, Wei, Sutcliffe, Robert P, Tingstedt, Bobby, van der Kolk, Marion, Vrochides, Dionisio, Wei, Alice, Williamsson, Caroline, Yeo, Charles J, Zani, Sabino, Zouros, Efstratio, and Abu Hilal, Mohammed
- Subjects
COMPLICATIONS ,Postoperative Complications/prevention & control ,FAST-TRACK SURGERY ,LENGTH-OF-STAY ,Recovery of Function ,Length of Stay ,PANCREATIC SURGERY ,Patient Readmission ,Pancreaticoduodenectomy ,PATHWAY ,COLORECTAL SURGERY ,Postoperative Complications ,MANAGEMENT ,IMPLEMENTATION ,PROGRAM ,Humans ,Surgery ,Pancreaticoduodenectomy/adverse effects ,PERIOPERATIVE CARE ,Enhanced Recovery After Surgery - Abstract
Background This individual-patient data meta-analysis investigated the effects of enhanced recovery after surgery (ERAS) protocols compared with conventional care on postoperative outcomes in patients undergoing pancreatoduodenectomy.Methods The Cochrane Library, MEDLINE, Embase, Scopus, and Web of Science were searched systematically for articles reporting outcomes of ERAS after pancreatoduodenectomy published up to August 2020. Comparative studies were included. Main outcomes were postoperative functional recovery elements, postoperative morbidity, duration of hospital stay, and readmission.Results Individual-patient data were obtained from 17 of 31 eligible studies comprising 3108 patients. Time to liquid (mean difference (MD) -3.23 (95 per cent c.i. -4.62 to -1.85) days; P < 0.001) and solid (-3.84 (-5.09 to -2.60) days; P < 0.001) intake, time to passage of first stool (MD -1.38 (-1.82 to -0.94) days; P < 0.001) and time to removal of the nasogastric tube (3.03 (-4.87 to -1.18) days; P = 0.001) were reduced with ERAS. ERAS was associated with lower overall morbidity (risk difference (RD) -0.04, 95 per cent c.i. -0.08 to -0.01; P = 0.015), less delayed gastric emptying (RD -0.11, -0.22 to -0.01; P = 0.039) and a shorter duration of hospital stay (MD -2.33 (-2.98 to -1.69) days; P < 0.001) without a higher readmission rate.Conclusion ERAS improved postoperative outcome after pancreatoduodenectomy. Implementation should be encouraged.Lay SummaryEnhanced recovery protocols consist of interdisciplinary interventions aimed at standardizing care and reducing the impact of surgical stress. They often include a short period of preoperative fasting during the night before surgery, early removal of lines and surgical drains, early food intake and mobilization out of bed on the day of surgery. This study gives a summary of reports assessing such care protocols in patients undergoing pancreatic head surgery, and assesses the impact of these protocols on functional recovery in an analysis of individual-patient data. The study revealed the true benefits of enhanced recovery protocols, including shorter time to food intake, earlier bowel activity, fewer complications after surgery, and a shorter hospital stay compared with conventional care.
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- 2021
38. Blockade of interleukin 10 potentiates antitumour immune function in human colorectal cancer liver metastases
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Kevin M Sullivan, Xiuyun Jiang, Prajna Guha, Christopher Lausted, Jason A Carter, Cynthia Hsu, Kevin P Labadie, Karan Kohli, Heidi L Kenerson, Sara K Daniel, Xiaowei Yan, Changting Meng, Arezou Abbasi, Marina Chan, Y David Seo, James O Park, Ian Nicholas Crispe, Raymond S Yeung, Teresa S Kim, Taranjit S Gujral, Qiang Tian, Steven C Katz, and Venu G Pillarisetty
- Subjects
Gastroenterology - Abstract
ObjectiveProgrammed cell death protein 1 (PD-1) checkpoint inhibition and adoptive cellular therapy have had limited success in patients with microsatellite stable colorectal cancer liver metastases (CRLM). We sought to evaluate the effect of interleukin 10 (IL-10) blockade on endogenous T cell and chimeric antigen receptor T (CAR-T) cell antitumour function in CRLM slice cultures.DesignWe created organotypic slice cultures from human CRLM (n=38 patients’ tumours) and tested the antitumour effects of a neutralising antibody against IL-10 (αIL-10) both alone as treatment and in combination with exogenously administered carcinoembryonic antigen (CEA)-specific CAR-T cells. We evaluated slice cultures with single and multiplex immunohistochemistry, in situ hybridisation, single-cell RNA sequencing, reverse-phase protein arrays and time-lapse fluorescent microscopy.ResultsαIL-10 generated a 1.8-fold increase in T cell-mediated carcinoma cell death in human CRLM slice cultures. αIL-10 significantly increased proportions of CD8+T cells without exhaustion transcription changes, and increased human leukocyte antigen - DR isotype (HLA-DR) expression of macrophages. The antitumour effects of αIL-10 were reversed by major histocompatibility complex class I or II (MHC-I or MHC-II) blockade, confirming the essential role of antigen presenting cells. Interrupting IL-10 signalling also rescued murine CAR-T cell proliferation and cytotoxicity from myeloid cell-mediated immunosuppression. In human CRLM slices, αIL-10 increased CEA-specific CAR-T cell activation and CAR-T cell-mediated cytotoxicity, with nearly 70% carcinoma cell apoptosis across multiple human tumours. Pretreatment with an IL-10 receptor blocking antibody also potentiated CAR-T function.ConclusionNeutralising the effects of IL-10 in human CRLM has therapeutic potential as a stand-alone treatment and to augment the function of adoptively transferred CAR-T cells.
- Published
- 2021
39. Neuroendocrine and Adrenal Tumors, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology
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Arash Kardan, Thomas J. Giordano, Thorvardur R. Halfdanarson, Jennifer A. Chan, Lawrence S. Blaszkowsky, Christopher H. Lieu, Pamela Brock, Anthony P. Heaney, Boris W. Kuvshinoff, Satya Das, Whitney S. Goldner, Al B. Benson, Cindy Hochstetler, Beth Lynn, Heloisa P. Soares, Craig R. Sussman, Fouad Kandeel, Jin He, Daniel M. Halperin, Emily K. Bergsland, Jonathan R. Strosberg, Nataliya Uboha, Sajid A. Khan, Terence Z. Wong, Kimberly A. Miller, Michael C. Soulen, Martin J. Heslin, Venu G. Pillarisetty, Manisha H. Shah, Paxton V. Dickson, Nikolaos A. Trikalinos, Namrata Vijayvergia, Shagufta Shaheen, Diane Lauren Reidy, Sarimar N Agosto Salgado, and Paul T. Fanta
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,Adrenal Gland Neoplasms ,Neuroendocrine tumors ,Medical Oncology ,Surgical methods ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Genetic risk ,Stage (cooking) ,Multiple endocrine neoplasia ,Adrenal tumors ,business.industry ,Adrenal gland ,Poorly differentiated ,medicine.disease ,Neuroendocrine Tumors ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,business - Abstract
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroendocrine and Adrenal Gland Tumors focus on the diagnosis, treatment, and management of patients with neuroendocrine tumors (NETs), adrenal tumors, pheochromocytomas, paragangliomas, and multiple endocrine neoplasia. NETs are generally subclassified by site of origin, stage, and histologic characteristics. Appropriate diagnosis and treatment of NETs often involves collaboration between specialists in multiple disciplines, using specific biochemical, radiologic, and surgical methods. Specialists include pathologists, endocrinologists, radiologists (including nuclear medicine specialists), and medical, radiation, and surgical oncologists. These guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine and adrenal tumors and are intended to assist with clinical decision-making. This article is focused on the 2021 NCCN Guidelines principles of genetic risk assessment and counseling and recommendations for well-differentiated grade 3 NETs, poorly differentiated neuroendocrine carcinomas, adrenal tumors, pheochromocytomas, and paragangliomas.
- Published
- 2021
40. Epidermoid Cyst within an Intrapancreatic Accessory Spleen Mimicking a Pancreatic Cystic Neoplasm
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Venu G Pillarisetty, Arezou Abbasi, Florencia G Jalikis, and Lisa K Koch
- Subjects
education.field_of_study ,Pathology ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Splenectomy ,Population ,Epidermoid cyst ,Accessory spleen ,Malignancy ,medicine.disease ,Pancreatic cystic neoplasm ,medicine ,Differential diagnosis ,business ,Complication ,education - Abstract
Although intra-abdominal accessory spleens are commonly found in 10-30% of the general population, epidermoid cyst within an intrapancreatic accessory spleen (ECIPAS) is an extremely rare entity and is often misdiagnosed preoperatively as a cystic malignancy. We present the case of a 51-year-old man who was referred to our clinic because of an incidentally found pancreatic tail cystic mass. Due to CA 19-9 level over 2000 and high suspicion of malignancy, the patient underwent distal pancreatectomy with splenectomy. Histopathological analysis revealed a squamous epithelial lining with splenic parenchyma within the cyst wall, which was consistent with ECIPAS. The patient was discharged on postoperative day 4 without any complication. As this disease may mimic malignancy with no characteristic features in preoperative imaging, it should be considered in the differential diagnosis of pancreatic cystic lesions.
- Published
- 2020
41. Systemic Interferon-γ Increases MHC Class I Expression and T-cell Infiltration in Cold Tumors: Results of a Phase 0 Clinical Trial
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Seth M. Pollack, Stanley R. Riddell, Venu G. Pillarisetty, Qianchuan He, Cassian Yee, Robin L. Jones, Robert H. Pierce, R. Graeme Black, Lee D. Cranmer, Shihong Zhang, Brian A. Van Tine, Sydney Spadinger, Lu Yao, and Karan Kohli
- Subjects
Adult ,Male ,0301 basic medicine ,Cancer Research ,Biopsy ,T-Lymphocytes ,medicine.medical_treatment ,Immunology ,Major histocompatibility complex ,Article ,Immunophenotyping ,Interferon-gamma ,Sarcoma, Synovial ,Young Adult ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,0302 clinical medicine ,Antigen ,Cancer immunotherapy ,Antigens, Neoplasm ,MHC class I ,medicine ,Humans ,Aged ,Tumor microenvironment ,biology ,business.industry ,Histocompatibility Antigens Class I ,Immunotherapy ,Middle Aged ,Liposarcoma, Myxoid ,Tumor antigen ,030104 developmental biology ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Cytokines ,Female ,business ,Biomarkers - Abstract
Interferon-γ (IFNγ) has been studied as a cancer treatment with limited evidence of clinical benefit. However, it could play a role in cancer immunotherapy combination treatments. Despite high expression of immunogenic cancer–testis antigens, synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) have a cold tumor microenvironment (TME), with few infiltrating T cells and low expression of major histocompatibility complex class I (MHC-I). We hypothesized that IFNγ treatment could drive inflammation in a cold TME, facilitating further immunotherapy. We conducted a phase 0 clinical trial treating 8 SS or MRCL patients with weekly systemic IFNγ. We performed pre- and posttreatment biopsies. IFNγ changed the SS and MRCL TME, inducing tumor-surface MHC-I expression and significant T-cell infiltration (P < 0.05). Gene-expression analysis suggested increased tumor antigen presentation and less exhausted phenotypes of the tumor-infiltrating T cells. Newly emergent antigen-specific humoral and/or T-cell responses were found in 3 of 7 evaluable patients. However, increased expression of PD-L1 was observed on tumor-infiltrating myeloid cells and in some cases tumor cells. These findings suggest that systemic IFNγ used to convert SS and MRCL into “hot” tumors will work in concert with anti–PD-1 therapy to provide patient benefit.
- Published
- 2019
42. Hypoxia as a barrier to immunotherapy in pancreatic adenocarcinoma
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Kevin M. Sullivan, Sara K. Daniel, Venu G. Pillarisetty, and Kevin P. Labadie
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0301 basic medicine ,medicine.medical_treatment ,T cell ,Medicine (miscellaneous) ,Review ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,Cytotoxic T cell ,Hypoxia ,Tumor microenvironment ,lcsh:R5-920 ,Solid tumor ,Chemistry ,Immunotherapy ,Pancreatic cancer ,030104 developmental biology ,Cytokine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Myeloid-derived Suppressor Cell ,Molecular Medicine ,lcsh:Medicine (General) - Abstract
Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with limited response to cytotoxic chemoradiotherapy, as well as newer immunotherapies. The PDA tumor microenvironment contains infiltrating immune cells including cytotoxic T cells; however, there is an overall immunosuppressive milieu. Hypoxia is a known element of the solid tumor microenvironment and may promote tumor survival. Through various mechanisms including, but not limited to, those mediated by HIF-1α, hypoxia also leads to increased tumor proliferation and metabolic changes. Furthermore, epithelial to mesenchymal transition is promoted through several pathways, including NOTCH and c-MET, regulated by hypoxia. Hypoxia-promoted changes also contribute to the immunosuppressive phenotype seen in many different cell types within the microenvironment and thereby may inhibit an effective immune system response to PDA. Pancreatic stellate cells (PSCs) and myofibroblasts appear to contribute to the recruitment of myeloid derived suppressor cells (MDSCs) and B cells in PDA via cytokines increased due to hypoxia. PSCs also increase collagen secretion in response to HIF-1α, which promotes a fibrotic stroma that alters T cell homing and migration. In hypoxic environments, B cells contribute to cytotoxic T cell exhaustion and produce chemokines to attract more immunosuppressive regulatory T cells. MDSCs inhibit T cell metabolism by hoarding key amino acids, modulate T cell homing by cleaving L-selectin, and prevent T cell activation by increasing PD-L1 expression. Immunosuppressive M2 phenotype macrophages promote T cell anergy via increased nitric oxide (NO) and decreased arginine in hypoxia. Increased numbers of regulatory T cells are seen in hypoxia which prevent effector T cell activation through cytokine production and increased CTLA-4. Effective immunotherapy for pancreatic adenocarcinoma and other solid tumors will need to help counteract the immunosuppressive nature of hypoxia-induced changes in the tumor microenvironment. Promising studies will look at combination therapies involving checkpoint inhibitors, chemokine inhibitors, and possible targeting of hypoxia. While no model is perfect, assuring that models incorporate the effects of hypoxia on cancer cells, stromal cells, and effector immune cells will be crucial in developing successful therapies.
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- 2019
43. Hypoxia-inducible lentiviral gene expression in engineered human macrophages
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Harrison K Chinn, Jennifer L Gardell, Lisa R Matsumoto, Kevin P Labadie, Tara N Mihailovic, Nicole A P Lieberman, Amira Davis, Venu G Pillarisetty, and Courtney A Crane
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Pharmacology ,Cancer Research ,Macrophages ,Lentivirus ,Immunology ,Gene Expression ,Cell Hypoxia ,Mice ,Oncology ,Tumor Microenvironment ,Animals ,Cytokines ,Humans ,Molecular Medicine ,Immunology and Allergy - Abstract
BackgroundHuman immune cells, including monocyte-derived macrophages, can be engineered to deliver proinflammatory cytokines, bispecific antibodies, and chimeric antigen receptors to support immune responses in different disease settings. When gene expression is regulated by constitutively active promoters, lentiviral payload gene expression is unregulated, and can result in potentially toxic quantities of proteins. Regulated delivery of lentivirally encoded proteins may allow localized or conditional therapeutic protein expression to support safe delivery of adoptively transferred, genetically modified cells with reduced capacity for systemic toxicities.MethodsIn this study, we engineered human macrophages to express genes regulated by hypoxia responsive elements included in the lentiviral promoter region to drive conditional lentiviral gene expression only under hypoxic conditions. We tested transduced macrophages cultured in hypoxic conditions for the transient induced expression of reporter genes and the secreted cytokine, interleukin-12. Expression of hypoxia-regulated genes was investigated both transcriptionally and translationally, and in the presence of human tumor cells in a slice culture system. Finally, hypoxia-regulated gene expression was evaluated in a subcutaneous humanized-mouse cancer model.ResultsEngineered macrophages were shown to conditionally and tranisently express lentivirally encoded gene protein products, including IL-12 in hypoxic conditions in vitro. On return to normoxic conditions, lentiviral payload expression returned to basal levels. Reporter genes under the control of hypoxia response elements were upregulated under hypoxic conditions in the presence of human colorectal carcinoma cells and in the hypoxic xenograft model of glioblastoma, suggesting utility for systemic engineered cell delivery capable of localized gene delivery in cancer.ConclusionsMacrophages engineered to express hypoxia-regulated payloads have the potential to be administered systemically and conditionally express proteins in tissues with hypoxic conditions. In contrast to immune cells that function or survive poorly in hypoxic conditions, macrophages maintain a proinflammatory phenotype that may support continued gene and protein expression when regulated by conditional hypoxia responsive elements and naturally traffic to hypoxic microenvironments, making them ideal vehicles for therapeutic payloads to hypoxic tissues, such as solid tumors. With the ability to fine-tune delivery of potent proteins in response to endogenous microenvironments, macrophage-based cellular therapies may therefore be designed for different disease settings.
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- 2022
44. Neoantigen-specific CD4+ T cells in human melanoma have diverse differentiation states and correlate with CD8+ T cell, macrophage, and B cell function
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Joshua R. Veatch, Sylvia M. Lee, Carolyn Shasha, Naina Singhi, Julia L. Szeto, Ata S. Moshiri, Teresa S. Kim, Kimberly Smythe, Paul Kong, Matthew Fitzgibbon, Brenda Jesernig, Shailender Bhatia, Scott S. Tykodi, Evan T. Hall, David R. Byrd, John A. Thompson, Venu G. Pillarisetty, Thomas Duhen, A. McGarry Houghton, Evan Newell, Raphael Gottardo, and Stanley R. Riddell
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CD4-Positive T-Lymphocytes ,Mice ,Cancer Research ,Oncology ,Antigens, Neoplasm ,Macrophages ,Tumor Microenvironment ,Animals ,Humans ,CD8-Positive T-Lymphocytes ,Melanoma ,Article - Abstract
CD4(+) T cells that recognize tumor antigens are required for immune checkpoint inhibitor efficacy in murine models but their contributions in human cancer are unclear. We used single cell RNA sequencing and T cell receptor sequences to identify signatures and functional correlates of tumor specific CD4(+) T cells infiltrating human melanoma. Conventional CD4(+) T cells that recognize tumor neoantigens express CXCL13 and are subdivided into clusters expressing memory and T follicular helper markers, and those expressing cytolytic markers, inhibitory receptors, and IFN-γ. The frequency of CXCL13(+) CD4(+) T cells in the tumor correlated with the transcriptional states of CD8(+) T cells and macrophages, maturation of B cells, and patient survival. Similar correlations were observed in a breast cancer cohort. These results identify phenotypes and functional correlates of tumor specific CD4(+) T cells in melanoma and suggest the possibility of using such cells to modify the tumor microenvironment.
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- 2022
45. Analysis of Differentiation Changes and Outcomes at Time of First Recurrence of Retroperitoneal Liposarcoma by Transatlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG)
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Carolyn, Nessim, Chandrajit P, Raut, Dario, Callegaro, Francesco, Barretta, Rosalba, Miceli, Mark, Fairweather, Jean-Yves, Blay, Dirk, Strauss, Piotr, Rutkowski, Nita, Ahuja, Ricardo, Gonzalez, Giovanni, Grignani, Vittorio, Quagliuolo, Eberhard, Stoeckle, Guy, Lahat, Antonino, De Paoli, Venu G, Pillarisetty, Robert J, Canter, John T, Mullen, Elisabetta, Pennacchioli, Winan, van Houdt, Carol J, Swallow, Yvonne, Schrage, Kenneth, Cardona, Marco, Fiore, Alessandro, Gronchi, and Sanjay P, Bagaria
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Humans ,Sarcoma ,Liposarcoma ,Retroperitoneal Neoplasms ,Neoplasm Recurrence, Local ,Retrospective Studies - Abstract
Local recurrence following resection of retroperitoneal liposarcoma (RLPS) is common. Well-differentiated (WD) and dedifferentiated (DD) RLPS are distinct entities with differing outcomes. A few reports suggest that WDLPS can recur as DDLPS and that DDLPS can recur as WDLPS. This study evaluates whether this change in differentiation from the primary tumor to the first local recurrence impacts long-term outcomes.Retrospective review from 22 sarcoma centers identified consecutive patients who underwent resection for a first locally recurrent RLPS from January 2002 to December 2011. Outcomes measured included overall survival, local recurrence, and distant metastasis.A total of 421 RPLS patients were identified. Of the 230 patients with primary DDLPS, 34 (15%) presented WDLPS upon recurrence (DD → WD); and of the 191 patients with primary WDLPS, 54 (28%) presented DDLPS upon recurrence (WD → DD). The 6-year overall survival probabilities (95% CI) for DD → DD, DD → WD, WD → WD, and WD → DD were 40% (32-48%), 73% (58-92%), 76% (68-85%), and 56% (43-73%) (p0.001), respectively. The 6-year second local recurrence incidence was 66% (59-73%), 63% (48-82%), 66% (57-76%), and 77% (66-90%), respectively. The 6-year distant metastasis incidence was 13% (9-19%), 3% (0.4-22%), 5% (2-11%), and 4% (1-16%), respectively. On multivariable analysis, DD → WD was associated with improved overall survival when compared with DD → DD (p0.001). Moreover, WD → DD was associated with a higher risk of LR (p = 0.025) CONCLUSION: A change in RLPS differentiation from primary tumor to first local recurrence appears to impact survival. These findings may be useful in counseling patients on their prognosis and subsequent management.
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- 2020
46. Dendritic Cells in the Tumor Microenvironment
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Karan, Kohli and Venu G, Pillarisetty
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Cell Movement ,Neoplasms ,Tumor Microenvironment ,Humans ,Dendritic Cells ,Adaptive Immunity - Abstract
Dendritic cells (DCs) are professional antigen-presenting cells (APCs) of the immune system. They capture foreign antigens and can present them to lymphocytes, that is, T cells and B cells, to activate them. DCs are the most potent of all immune cells at inducing the adaptive immune system. Thus, the presence of DCs at the anatomical site of the immune challenge is imperative for the immune system to mount an effective immune response. From the anatomical site of the immune challenge, DCs cargo antigens to the draining lymph nodes, specialized immune organs where adaptive immunity is generated. DCs are heterogeneous as a type of immune cell, and various subsets of DCs have been reported and their functions described. In this chapter, we discuss various aspects of DC development and function. We further discuss how various tumor microenvironments can affect DC development, function, and migration, thus evading a strong adaptive immune response.
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- 2020
47. Genetically engineered macrophages persist in solid tumors and locally deliver therapeutic proteins to activate immune responses
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Shannon A Kreuser, Venu G. Pillarisetty, Robert H. Pierce, Nicole A P Lieberman, Courtney A. Crane, Michael C. Jensen, Stephanie Balcaitis, Kimberly S. Smythe, Lisa R Matsumoto, Kole DeGolier, Virginia Hoglund, Katherine J. Brempelis, Chibawanye I. Ene, Amira Davis, Kevin P. Labadie, Harrison Chinn, Richard G. Ellenbogen, Eric C. Holland, Jason K. Yokoyama, Brooke M Prieskorn, Kara White Moyes, Sara K. Daniel, Courtney M Cowan, and Jean S. Campbell
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Cancer Research ,Chemokine ,medicine.medical_treatment ,Immunology ,cell engineering ,CD19 ,Mice ,Immune system ,Neoplasms ,medicine ,Tumor Microenvironment ,Immunology and Allergy ,Animals ,Humans ,RC254-282 ,Pharmacology ,Tumor microenvironment ,biology ,Immune Cell Therapies and Immune Cell Engineering ,Melanoma ,Macrophages ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Immunotherapy ,medicine.disease ,Chimeric antigen receptor ,Disease Models, Animal ,Oncology ,biology.protein ,Cancer research ,Molecular Medicine ,Genetic Engineering ,Ex vivo - Abstract
BackgroundThough currently approved immunotherapies, including chimeric antigen receptor T cells and checkpoint blockade antibodies, have been successfully used to treat hematological and some solid tumor cancers, many solid tumors remain resistant to these modes of treatment. In solid tumors, the development of effective antitumor immune responses is hampered by restricted immune cell infiltration and an immunosuppressive tumor microenvironment (TME). An immunotherapy that infiltrates and persists in the solid TME, while providing local, stable levels of therapeutic to activate or reinvigorate antitumor immunity could overcome these challenges faced by current immunotherapies.MethodsUsing lentivirus-driven engineering, we programmed human and murine macrophages to express therapeutic payloads, including Interleukin (IL)-12. In vitro coculture studies were used to evaluate the effect of genetically engineered macrophages (GEMs) secreting IL-12 on T cells and on the GEMs themselves. The effects of IL-12 GEMs on gene expression profiles within the TME and tumor burden were evaluated in syngeneic mouse models of glioblastoma and melanoma and in human tumor slices isolated from patients with advanced gastrointestinal malignancies.ResultsHere, we present a cellular immunotherapy platform using lentivirus-driven genetic engineering of human and mouse macrophages to constitutively express proteins, including secreted cytokines and full-length checkpoint antibodies, as well as cytoplasmic and surface proteins that overcomes these barriers. GEMs traffic to, persist in, and express lentiviral payloads in xenograft mouse models of glioblastoma, and express a non-signaling truncated CD19 surface protein for elimination. IL-12-secreting GEMs activated T cells and induced interferon-gamma (IFNγ) in vitro and slowed tumor growth resulting in extended survival in vivo. In a syngeneic glioblastoma model, IFNγ signaling cascades were also observed in mice treated with mouse bone-marrow-derived GEMs secreting murine IL-12. These findings were reproduced in ex vivo tumor slices comprised of intact MEs. In this setting, IL-12 GEMs induced tumor cell death, chemokines and IFNγ-stimulated genes and proteins.ConclusionsOur data demonstrate that GEMs can precisely deliver titratable doses of therapeutic proteins to the TME to improve safety, tissue penetrance, targeted delivery and pharmacokinetics.
- Published
- 2020
48. Correction to: Postoperative Morbidity After Resection of Recurrent Retroperitoneal Sarcoma: A Report from the Transatlantic Australasian RPS Working Group (TARPSWG)
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Carolyn Nessim, Chandrajit P. Raut, Dario Callegaro, Francesco Barretta, Rosalba Miceli, Mark Fairweather, Piotr Rutkowski, Jean-Yves Blay, Dirk Strauss, Ricardo Gonzalez, Nita Ahuja, Giovanni Grignani, Vittorio Quagliuolo, Eberhard Stoeckle, Antonino De Paoli, Venu G. Pillarisetty, Carol J. Swallow, Sanjay P. Bagaria, Robert J. Canter, John T. Mullen, Yvonne Schrage, Elisabetta Pennacchioli, Winan van Houdt, Kenneth Cardona, Marco Fiore, Alessandro Gronchi, and Guy Lahat
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Oncology ,Surgery - Published
- 2022
49. Correction to: Analysis of Differentiation Changes and Outcomes at Time of First Recurrence of Retroperitoneal Liposarcoma by Transatlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG)
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Carolyn Nessim, Chandrajit P. Raut, Dario Callegaro, Francesco Barretta, Rosalba Miceli, Mark Fairweather, Jean-Yves Blay, Dirk Strauss, Piotr Rutkowski, Nita Ahuja, Ricardo Gonzalez, Giovanni Grignani, Vittorio Quagliuolo, Eberhard Stoeckle, Guy Lahat, Antonino De Paoli, Venu G. Pillarisetty, Robert J. Canter, John T. Mullen, Elisabetta Pennacchioli, Winan van Houdt, Carol J. Swallow, Yvonne Schrage, Kenneth Cardona, Marco Fiore, Alessandro Gronchi, and Sanjay P. Bagaria
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Oncology ,Surgery - Published
- 2022
50. Correction: ASO Visual Abstract: An Analysis of Differentiation Changes and Outcomes at the First Recurrence of Retroperitoneal Liposarcoma by the Transatlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG)
- Author
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Carolyn Nessim, Chandrajit P. Raut, Dario Callegaro, Francesco Barretta, Rosalba Miceli, Mark Fairweather, Jean-Yves Blay, Dirk Strauss, Piotr Rutkowski, Nita Ahuja, Ricardo Gonzalez, Giovanni Grignani, Vittorio Quagliuolo, Eberhard Stoeckle, Guy Lahat, Antonino De Paoli, Venu G. Pillarisetty, Robert J. Canter, John T. Mullen, Elisabetta Pennacchioli, Winan van Houdt, Carol J. Swallow, Yvonne Schrage, Kenneth Cardona, Marco Fiore, Alessandro Gronchi, and Sanjay P. Bagaria
- Subjects
Oncology ,Surgery - Published
- 2022
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