32 results on '"Oberstein, Paul E."'
Search Results
2. Chemotherapy and Immune Checkpoint Blockade for Gastric and Gastroesophageal Junction Adenocarcinoma.
- Author
-
Manji, Gulam A., Lee, Shing, Del Portillo, Armando, May, Michael, Ana, Sarah Sta, Alouani, Emily, Sender, Naomi, Negri, Tiffany, Gautier, Katarzyna, Ge, Liner, Fan, Weijia, Xie, Mengyu, Sethi, Amrita, Schrope, Beth, Tan, Aik Choon, Park, Haeseong, Oberstein, Paul E., Shah, Manish A., and Raufi, Alexander G.
- Published
- 2023
- Full Text
- View/download PDF
3. Reply to ‘H-STS, L-STS and KRJ-I are not authentic GEPNET cell lines’
- Author
-
Alvarez, Mariano J., Yan, Pengrong, Alpaugh, Mary L., Bowden, Michaela, Sicinska, Ewa, Zhou, Chensheng W., Karan, Charles, Realubit, Ronald B., Mundi, Prabhjot S., Grunn, Adina, Jäger, Dirk, Chabot, John A., Fojo, Antonio T., Oberstein, Paul E., Hibshoosh, Hanina, Milsom, Jeffrey W., Kulke, Matthew H., Loda, Massimo, Chiosis, Gabriela, Reidy-Lagunes, Diane L., and Califano, Andrea
- Published
- 2019
- Full Text
- View/download PDF
4. Corrigendum: Tumor infiltrating T cell states and checkpoint inhibitor expression in hepatic and pancreatic malignancies.
- Author
-
Shanshan Wan, Ende Zhao, Ende, Freeman, Daniel, Weissinger, Daniel, Krantz, Benjamin A., Werba, Gregor, Khanna, Lauren G., Siolas, Despina, Oberstein, Paul E., Chattopadhyay, Pratip K., Simeone, Diane M., and Welling, Theodore H.
- Subjects
T cells ,IPILIMUMAB ,TUMORS ,PANCREATIC tumors ,CYTOLOGY - Published
- 2023
- Full Text
- View/download PDF
5. Impact of comprehensive family history and genetic analysis in the multidisciplinary pancreatic tumor clinic setting.
- Author
-
Everett, Jessica N., Dettwyler, Shenin A., Jing, Xiaohong, Stender, Cody, Schmitter, Madeleine, Baptiste, Ariele, Chun, Jennifer, Kawaler, Emily A., Khanna, Lauren G., Gross, Seth A., Gonda, Tamas A., Beri, Nina, Oberstein, Paul E., and Simeone, Diane M.
- Subjects
PANCREATIC tumors ,GENETIC testing ,INTERDISCIPLINARY research ,FAMILY history (Medicine) ,CONTINUUM of care ,PANCREATIC duct ,HEREDITARY cancer syndromes - Abstract
Background: Genetic testing is recommended for all pancreatic ductal adenocarcinoma (PDAC) patients. Prior research demonstrates that multidisciplinary pancreatic cancer clinics (MDPCs) improve treatment‐ and survival‐related outcomes for PDAC patients. However, limited information exists regarding the utility of integrated genetics in the MDPC setting. We hypothesized that incorporating genetics in an MDPC serving both PDAC patients and high‐risk individuals (HRI) could: (1) improve compliance with guideline‐based genetic testing for PDAC patients, and (2) optimize HRI identification and PDAC surveillance participation to improve early detection and survival. Methods: Demographics, genetic testing results, and pedigrees were reviewed for PDAC patients and HRI at one institution over 45 months. Genetic testing analyzed 16 PDAC‐associated genes at minimum. Results: Overall, 969 MDPC subjects were evaluated during the study period; another 56 PDAC patients were seen outside the MDPC. Among 425 MDPC PDAC patients, 333 (78.4%) completed genetic testing; 29 (8.7%) carried a PDAC‐related pathogenic germline variant (PGV). Additionally, 32 (9.6%) met familial pancreatic cancer (FPC) criteria. These PDAC patients had 191 relatives eligible for surveillance or genetic testing. Only 2/56 (3.6%) non‐MDPC PDAC patients completed genetic testing (p < 0.01). Among 544 HRI, 253 (46.5%) had a known PGV or a designation of FPC, and were eligible for surveillance at baseline; of the remainder, 15/291 (5.2%) were eligible following genetic testing and PGV identification. Conclusion: Integrating genetics into the multidisciplinary setting significantly improved genetic testing compliance by reducing logistical barriers for PDAC patients, and clarified cancer risks for their relatives while conserving clinical resources. Overall, we identified 206 individuals newly eligible for surveillance or genetic testing (191 relatives of MDPC PDAC patients, and 15 HRI from this cohort), enabling continuity of care for PDAC patients and at‐risk relatives in one clinic. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
6. Tumor infiltrating T cell states and checkpoint inhibitor expression in hepatic and pancreatic malignancies.
- Author
-
Shanshan Wan, Ende Zhao, Weissinger, Daniel, Krantz, Benjamin A., Werba, Gregor, Freeman, Daniel, Khanna, Lauren G., Siolas, Despina, Oberstein, Paul E., Chattopadhyay, Pratip K., Simeone, Diane M., and Welling, Theodore H.
- Subjects
T cells ,IPILIMUMAB ,PANCREATIC tumors ,PANCREATIC duct ,CANCER chemotherapy ,IMMUNOLOGIC memory ,IMMUNE checkpoint proteins - Abstract
Hepato-pancreatico-biliary (HPB) malignancies are difficult-to-treat and continue to to have a high mortality and significant therapeutic resistance to standard therapies. Immune oncology (IO) therapies have demonstrated efficacy in several solid malignancies when combined with chemotherapy, whereas response rates in pancreatic ductal adenocarcinoma (PDA) are poor. While promising in hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), there remains an unmet need to fully leverage IO therapies to treat HPB tumors. We therefore defined T cell subsets in the tumor microenvironment of HPB patients utilizing a novel, multiparameter flow cytometry and bioinformatics analysis. Our findings quantify the T cell phenotypic states in relation to checkpoint receptor expression. We demonstrate the presence of CD103
+ tissue resident memory T cells (TRM), CCR7+ central memory T cells, and CD57+ terminally differentiated effector cells across all HPB cancers, while the anti-tumor function was dampened by expression of multiple co-inhibitory checkpoint receptors. Terminally exhausted T cells lacking co-stimulatory receptors were more prevalent in PDA, whereas partially exhausted T cells expressing both co-inhibitory and co-stimulatory receptors were most prevalent in HCC, especially in early stage. HCC patients had significantly higher TRM with a phenotype that could confer restored activation in response to immune checkpoint therapies. Further, we found a lack of robust alteration in T cell activation state or checkpoint expression in response to chemotherapy in PDA patients. These results support that HCC patients might benefit most from combined checkpoint therapies, whereas efforts other than cytotoxic chemotherapy will likely be necessary to increase overall T cell activation in CCA and PDA for future clinical development. [ABSTRACT FROM AUTHOR]- Published
- 2023
- Full Text
- View/download PDF
7. Use of adjuvant radiation therapy in the management of acinar cell carcinoma of the pancreas: results from the Survival, Epidemiology, and End Results database
- Author
-
Horowitz, David P., Oberstein, Paul E., and Gidea-Addeo, Daniela
- Published
- 2014
- Full Text
- View/download PDF
8. Su1408 YIELD AND IMPACT OF SOMATIC MUTATIONAL ANALYSIS IN EUSGUIDED BIOPSY OF PANCREATIC ADENOCARCINOMA
- Author
-
Dong, Sue, Agarunov, Emil, Khanna, Lauren G., Haber, Gregory B., Janec, Eileen M., Simeone, Diane M., Oberstein, Paul E., and Gonda, Tamas A.
- Published
- 2023
- Full Text
- View/download PDF
9. Metastatic Gastric Large Cell Neuroendocrine Carcinoma: A Case Report and Review of Literature
- Author
-
Oberstein, Paul E., Kenney, Barton, Krishnamoorthy, Saravanan K., Woo, Yanghee, and Saif, Wasif M.
- Published
- 2012
- Full Text
- View/download PDF
10. Cancer surveillance awareness and practice among families at increased risk for pancreatic adenocarcinoma.
- Author
-
Everett, Jessica N., Burgos, Gabriela, Chun, Jennifer, Baptiste, Ariele, Khanna, Lauren G., Oberstein, Paul E., and Simeone, Diane M.
- Subjects
FAMILY communication ,DISEASE risk factors ,PANCREATIC cancer ,FISHER exact test - Abstract
Background: Early detection of pancreatic ductal adenocarcinoma (PDAC) is an important goal for improving survival. Individuals who meet published guidelines for surveillance may be underidentified, and family communication about risk represents a pathway to increasing participation in surveillance. We investigated the uptake of and barriers to surveillance in at-risk relatives of clinic patients.Methods: We conducted a retrospective record review of patients with personal or family history of PDAC evaluated over 12 months. The first relative presenting to clinic (proband) reported surveillance status and reasons for nonparticipation for at-risk relatives. Descriptive analyses and Fisher's exact tests were conducted to evaluate differences in surveillance participation.Results: Among 193 at-risk relatives, 21% were in surveillance. The primary reasons for nonparticipation were lack of awareness (36%) and lack of interest (24%). Neither the sex nor the cancer status of probands impacted surveillance. At-risk relatives with familial pancreatic cancer (FPC) who also carried relevant pathogenic germline variants (PGVs) were more likely to undergo surveillance than those with FPC or PGVs alone (P = .003). Among families with PGVs, 59% of relatives potentially eligible for surveillance had not completed genetic testing.Conclusion: PDAC surveillance is underutilized in high-risk families. Communication interventions to address informational needs and decisional support could improve outcomes. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
11. Experimental microdissection enables functional harmonisation of pancreatic cancer subtypes.
- Author
-
Maurer, Carlo, Holmstrom, Sam R., Jing He, Laise, Pasquale, Tao Su, Ahmed, Aqeel, Hibshoosh, Hanina, Chabot, John A., Oberstein, Paul E., Sepulveda, Antonia R., Genkinger, Jeanine M., Jiapeng Zhang, Iuga, Alina C., Bansal, Mukesh, Califano, Andrea, and Olive, Kenneth P.
- Subjects
PANCREATIC cancer ,XENOGRAFTS ,MICRODISSECTION ,CARCINOMA - Published
- 2019
- Full Text
- View/download PDF
12. Efficacy and Safety of Sunitinib in Patients with Well-Differentiated Pancreatic Neuroendocrine Tumours.
- Author
-
Raymond, Eric, Kulke, Matthew H., Qin, Shukui, Yu, Xianjun, Schenker, Michael, Cubillo, Antonio, Lou, Wenhui, Tomasek, Jiri, Thiis-Evensen, Espen, Xu, Jian-Ming, Croitoru, Adina E., Khasraw, Mustafa, Sedlackova, Eva, Borbath, Ivan, Ruff, Paul, Oberstein, Paul E., Ito, Tetsuhide, Jia, Liqun, Hammel, Pascal, and Shen, Lin
- Subjects
NEUROENDOCRINOLOGY ,NEUROENDOCRINE tumors ,CANCER cells ,CANCER treatment ,CANCER patients - Abstract
Background: In a phase III study, sunitinib led to a significant increase in progression-free survival (PFS) versus placebo in patients with pancreatic neuroendocrine tumours (panNETs). This study was a post-marketing commitment to support the phase III data. Methods: In this ongoing, open-label, phase IV trial (NCT01525550), patients with progressive, advanced unresectable/metastatic, well-differentiated panNETs received continuous sunitinib 37.5 mg once daily. Eligibility criteria were similar to those of the phase III study. The primary endpoint was investigator-assessed PFS per Response Evaluation Criteria in Solid Tumours v1.0 (RECIST). Other endpoints included PFS per Choi criteria, overall survival (OS), objective response rate (ORR), and adverse events (AEs). Results: Sixty-one treatment-naive and 45 previously treated patients received sunitinib. By March 19, 2016, 82 (77%) patients had discontinued treatment, mainly due to disease progression. Median treatment duration was 11.7 months. Investigator-assessed median PFS per RECIST (95% confidence interval [CI]) was 13.2 months (10.9–16.7): 13.2 (7.4–16.8) and 13.0 (9.2–20.4) in treatment-naive and previously treated patients, respectively. ORR (95% CI) per RECIST was 24.5% (16.7–33.8) in the total population: 21.3% (11.9–33.7) in treatment-naive and 28.9% (16.4–44.3) in previously treated patients. Median OS, although not yet mature, was 37.8 months (95% CI, 33.0–not estimable). The most common treatment-related AEs were neutropenia (53.8%), diarrhoea (46.2%), and leukopenia (43.4%). Conclusions: This phase IV trial confirms sunitinib as an efficacious and safe treatment option in patients with advanced/metastatic, well-differentiated, unresectable panNETs, and supports the phase III study outcomes. AEs were consistent with the known safety profile of sunitinib. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
13. Cholinergic Signaling Directly and Indirectly Suppresses Pancreatic Tumorigenesis and Cancer Stemness
- Author
-
Renz, Bernhard W., Tanaka, Takayuki, Sunagawa, Masaki, Takahasi, Ryota, Macchini, Marina, Dantes, Zahra, Valenti, Giovanni, Ilmer, Matthias, Westphalen, C. Benedikt, Reichert, Maximilian, Oberstein, Paul E., Iuga, Alina C., Werner, Jens, Olive, Kenneth P., and Wang, Timothy C.
- Published
- 2019
- Full Text
- View/download PDF
14. Parasympathetic signaling via Chrm1 directly suppresses pancreatic carcinogenesis and cancer stemness through inhibition of EGFR/MAPK and PI3K/AKT pathway
- Author
-
Renz, Bernhard W., Tanaka, Takayuki Tanaka, Macchini, Marina, Hayakawa, Yoku, Ilmer, Matthias, Takahashi, Ryota, Westphalen, C. Benedikt, Oberstein, Paul E., Iuga, Alina C., Friedmann, Richard A., Werner, Jens, Olive, Kenneth P., and Wang, Timothy C.
- Published
- 2018
- Full Text
- View/download PDF
15. HALO 202: Randomized Phase II Study of PEGPH20 Plus Nab-Paclitaxel/Gemcitabine Versus Nab-Paclitaxel/Gemcitabine in Patients With Untreated, Metastatic Pancreatic Ductal Adenocarcinoma.
- Author
-
Hingorani, Sunil R., Zheng, Lei, Bullock, Andrea J., Seery, Tara E., Harris, William P., Sigal, Darren S., Braiteh, Fadi, Ritch, Paul S., Zalupski, Mark M., Bahary, Nathan, Oberstein, Paul E., Wang-Gillam, Andrea, Wu, Wilson, Chondros, Dimitrios, Jiang, Ping, Khelifa, Sihem, Pu, Jie, Aldrich, Carrie, and Hendifar, Andrew E.
- Published
- 2018
- Full Text
- View/download PDF
16. Stromal Elements Act to Restrain, Rather Than Support, Pancreatic Ductal Adenocarcinoma.
- Author
-
Rhim, Andrew?D., Oberstein, Paul?E., Thomas, Dafydd?H., Mirek, Emily?T., Palermo, Carmine?F., Sastra, Stephen?A., Dekleva, Erin?N., Saunders, Tyler, Becerra, Claudia?P., Tattersall, Ian?W., Westphalen, C.?Benedikt, Kitajewski, Jan, Fernandez-Barrena, Maite?G., Fernandez-Zapico, Martin?E., Iacobuzio-Donahue, Christine, Olive, Kenneth?P., and Stanger, Ben?Z.
- Subjects
- *
PANCREATIC cancer , *HEDGEHOG signaling proteins , *LIGANDS (Biochemistry) , *PROTEIN expression , *NEOPLASTIC cell transformation , *CANCER invasiveness , *LABORATORY mice - Abstract
Summary: Sonic hedgehog (Shh), a soluble ligand overexpressed by neoplastic cells in pancreatic ductal adenocarcinoma (PDAC), drives formation of a fibroblast-rich desmoplastic stroma. To better understand its role in malignant progression, we deleted Shh in a well-defined mouse model of PDAC. As predicted, Shh-deficient tumors had reduced stromal content. Surprisingly, such tumors were more aggressive and exhibited undifferentiated histology, increased vascularity, and heightened proliferation—features that were fully recapitulated in control mice treated with a Smoothened inhibitor. Furthermore, administration of VEGFR blocking antibody selectively improved survival of Shh-deficient tumors, indicating that Hedgehog-driven stroma suppresses tumor growth in part by restraining tumor angiogenesis. Together, these data demonstrate that some components of the tumor stroma can act to restrain tumor growth. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
17. Pancreatic cancer: why is it so hard to treat?
- Author
-
Oberstein, Paul E. and Olive, Kenneth P.
- Abstract
No common malignancy is as rapidly and inevitably fatal as pancreatic ductal adenocarcinoma (PDA). This grim fact has driven substantial research efforts into this disease in recent decades. Unfortunately, the investment has yet to result in a meaningful increase in 5-year survival. This has prompted many pancreatic cancer researchers and advocates to redouble their efforts, but also requires one to step back and ask why the previous efforts were lacking and to consider why pancreatic cancer is so difficult to treat. The difficulties are legion. PDA is characterized by an insidious clinical syndrome, but is rarely diagnosed at a time when surgical resection is feasible. We lack markers of early detection and screening programs remain unproven even in high risk populations. The location of the tumor in the retroperitoneum, the advanced age of patients, and the systemic effects of disease limit the options for local therapy. Chemotherapy may provide a small benefit, but most efforts to improve on the current regimens consistently and stubbornly fail in advanced clinical trials. The molecular and cellular features of ductal pancreatic tumors are aggressive and underlay multiple levels of therapeutic resistance. Non-cell-autonomous features including stromal proliferation, reduced vascular density and immune suppression also contribute to therapeutic resistance. Growing awareness of these the fundamental features of PDA has begun to guide ongoing research efforts. Clinical trials are now specifically targeting these tumor properties and actively focusing on the therapeutic implications of tumor stroma. As reviewed here, reflecting on the fundamental question of why pancreatic cancer is so difficult to treat is a necessary and informative exercise that will aid our efforts to improve patient outcomes. These efforts will lead to improvements in clinical trial design, expand our focus to include the molecular and histologic implications of novel treatment paradigms, and ultimately change the lives of our patients. [ABSTRACT FROM PUBLISHER]
- Published
- 2013
- Full Text
- View/download PDF
18. Uptake and Patterns of Use of Gemcitabine for Metastatic Pancreatic Cancer: A Population-Based Study.
- Author
-
Oberstein, Paul E., Hershman, Dawn L., Khanna, Lauren G., Chabot, John A., Insel, Beverly J., and Neugut, Alfred I.
- Subjects
- *
DEOXYCYTIDINE , *PANCREATIC cancer treatment , *POPULATION biology , *DRUG approval , *CANCER chemotherapy , *ADENOCARCINOMA , *HEALTH outcome assessment , *DIAGNOSIS - Abstract
Gemcitabine was approved for advanced pancreatic cancer in 1996. We investigated uptake and predictors of its use. We identified 3,231 individuals > 65 years in the SEER-Medicare database with stage IV pancreatic adenocarcinoma, diagnosed between 1998-2005, who survived >30 days. Of these, 54% received chemotherapy, 93% with gemcitabine. Gemcitabine nonreceipt was associated with advanced age and unmarried (OR: 0.65, 95% CI: 0.55-0.76). Diagnosis in 2004-2005 versus 1998-2000 was more likely to receive gemcitabine (OR: 1.51, 95% CI: 1.23-1.84) as were higher SES patients (highest versus lowest quintile, OR: 2.14, 95% CI: 1.60-2.85). Gemcitabine was rapidly adopted among elderly advanced pancreatic cancer patients; several factors are associated with use. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
19. Safety and Efficacy of Everolimus in Adult Patients with Neuroendocrine Tumors.
- Author
-
Oberstein, Paul E. and Saif, M. Wasif
- Subjects
- *
ANTINEOPLASTIC agents , *CLINICAL trials , *NEUROENDOCRINE tumors , *HEALTH outcome assessment , *PANCREATIC tumors , *PATIENT monitoring , *SAFETY , *RAPAMYCIN , *TREATMENT effectiveness - Abstract
Neuroendocrine tumors (NETs) consist of a diverse family of tumors which are derived from the neuroendocrine system. Most NETs are well or moderately differentiated tumors with a relatively indolent growth pattern. However, these tumors can cause significant clinical disease due to release of functional products that mediate the carcinoid syndrome and other diverse sequela. They also can grow progressively and cause symptoms from local invasion or distant metastasis. NETs are optimally treated with surgery and somatosatin analogs (SSA's) to control symptoms but are relatively insensitive to systemic chemotherapy. As a result, patients with advanced unresectable NETs have a poor prognosis. In 2011, two targeted therapies, sunitinib and everolimus were approved in the subset of progressive pancreatic NETs (pNETs). Everolimus is an oral inhibitor of the growth stimulatory mTOR pathway. In Phase 2 trials in NETs and pNETs, everolimus was well tolerated and associated with some response and widespread disease stabilization. In follow-up, randomized Phase 3 trials, everolimus was compared to placebo. In the RADIANT-2 trial, everolimus and a somatostatin analog were used in patients with functional NETs and treatment was associated with an improvement in progression-free survival (PFS). In the RADIANT-3 trial, patients with pNET were randomized to receive everolimus or placebo along with best supportive care. Everolimus was again associated with improvement in PFS compared to placebo and it has been approved by the FDA for patients with progressive pNET. Everolimus is associated with frequent low grade toxicity but is also notable for increased rates of infection as well as non-infectious pneumonitis. mTOR inhibition with everolimus represents a significant advance in the treatment of advanced neuroendocrine tumors. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
20. Pancreatic Neuroendocrine Tumors: Entering a New Era.
- Author
-
Oberstein, Paul E., Remotti, Helen, Wasif Saif, Muhammad, and Libutti, Steven K.
- Published
- 2012
21. Novel Agents in the Treatment of Unresectable Neuroendocrine Tumors.
- Author
-
Oberstein, Paul E. and Saif, Muhammad Wasif
- Published
- 2011
22. Devimistat (CPI-613) With Modified Fluorouarcil, Oxaliplatin, Irinotecan, and Leucovorin (FFX) Versus FFX for Patients With Metastatic Adenocarcinoma of the Pancreas: The Phase III AVENGER 500 Study.
- Author
-
Philip PA, Sahai V, Bahary N, Mahipal A, Kasi A, Rocha Lima CMS, Alistar AT, Oberstein PE, Golan T, Metges JP, Lacy J, Fountzilas C, Lopez CD, Ducreux M, Hammel P, Salem M, Bajor D, Benson AB, Luther S, Pardee T, and Van Cutsem E
- Abstract
Purpose: Metastatic pancreatic adenocarcinoma (mPC) remains a difficult-to-treat disease. Fluorouarcil, oxaliplatin, irinotecan, and leucovorin (FFX) is a standard first-line therapy for mPC for patients with a favorable performance status and good organ function. In a phase I study, devimistat (CPI-613) in combination with modified FFX (mFFX) was deemed safe and exhibited promising efficacy in mPC., Methods: The AVENGER 500 trial (ClinicalTrials.gov identifier: NCT03504423) is a global, randomized phase III trial conducted at 74 sites across six countries to investigate the efficacy and safety of devimistat in combination with mFFX (experimental arm) compared with standard-dose FFX (control arm) in treatment-naïve patients with mPC. Treatment, administered in once-every-2-weeks cycles until disease progression or intolerable toxicity, included intravenous devimistat at 500 mg/m
2 total per day on days 1 and 3 in the experimental arm. The primary end point of the study was overall survival (OS)., Results: Five hundred and twenty-eight patients were randomly assigned (266 in the experimental arm and 262 in the control arm). The median OS was 11.10 months for devimistat plus mFFX versus 11.73 months for FFX (hazard ratio [HR], 0.95 [95% CI, 0.77 to 1.18]; P = .655) and median progression-free survival was 7.8 months versus 8.0 months, respectively (HR, 0.99 [95% CI, 0.76 to 1.29]; P = .94). Grade ≥3 treatment-emergent adverse events with >10% frequency in the devimistat plus mFFX arm versus the FFX arm were neutropenia (29.0% v 34.5%), diarrhea (11.2% v 19.6%), hypokalemia (13.1% v 14.9%), anemia (13.9% v 13.6%), thrombocytopenia (11.6% v 13.6%), and fatigue (10.8% v 11.5%), respectively., Conclusion: Devimistat in combination with mFFX did not improve long- and short-term mPC patient outcomes compared with standard FFX. There were no new toxicity signals with the addition of devimistat.- Published
- 2024
- Full Text
- View/download PDF
23. Blockade of IL-1β and PD-1 with combination chemotherapy reduces systemic myeloid suppression in metastatic pancreatic cancer with heterogeneous effects in the tumor.
- Author
-
Oberstein PE, Dias Costa A, Kawaler EA, Cardot-Ruffino V, Rahma OE, Beri N, Singh H, Abrams TA, Biller LH, Cleary J, Enzinger P, Huffman BM, McCleary NJ, Perez KJ, Rubinson DA, Schlechter BL, Surana R, Yurgelun MB, Wang SJ, Remland J, Brais LK, Bollenrucher N, Chang E, Ali LR, Lenehan PJ, Dolgalev I, Werba G, Lima C, Keheler CE, Sullivan KM, Dougan M, Hajdu C, Dajee M, Pelletier MR, Nazeer S, Squires M, Bar-Sagi D, Wolpin BM, Nowak JA, Simeone DM, and Dougan SK
- Abstract
Innate inflammation promotes tumor development, although the role of innate inflammatory cytokines in established human tumors is unclear. Here we report clinical and translational results from a phase Ib trial testing whether IL-1β blockade in human pancreatic cancer would alleviate myeloid immunosuppression and reveal antitumor T-cell responses to PD-1 blockade. Patients with treatment-naïve advanced pancreatic ductal adenocarcinoma (n=10) were treated with canakinumab, a high-affinity monoclonal human anti-interleukin-1β (IL-1β), the PD-1 blocking antibody spartalizumab, and gemcitabine/n(ab)paclitaxel. Analysis of paired peripheral blood from patients in the trial versus patients receiving multiagent chemotherapy showed a modest increase in HLA-DR+CD38+ activated CD8+ T cells and a decrease in circulating monocytic myeloid-derived suppressor cells (MDSCs) by flow cytometry for patients in the trial, but not in controls. Similarly, we used patient serum to differentiate monocytic MDSCs in vitro and showed that functional inhibition of T-cell proliferation was reduced when using on-treatment serum samples from patients in the trial but not when using serum from patients treated with chemotherapy alone. Within the tumor we observed few changes in suppressive myeloid-cell populations or activated T cells as assessed by single-cell transcriptional profiling or multiplex immunofluorescence, although increases in CD8+ T cells suggest that improvements in the tumor immune microenvironment might be revealed by a larger study. Overall, the data indicate that exposure to PD-1 and IL-1β blockade induced a modest reactivation of peripheral CD8+ T cells and decreased circulating monocytic MDSCs; however, these changes did not lead to similarly uniform alterations in the tumor microenvironment.
- Published
- 2024
- Full Text
- View/download PDF
24. Corrigendum: Tumor infiltrating T cell states and checkpoint inhibitor expression in hepatic and pancreatic malignancies.
- Author
-
Wan S, Zhao E, Freeman D, Weissinger D, Krantz BA, Werba G, Khanna LG, Siolas D, Oberstein PE, Chattopadhyay PK, Simeone DM, and Welling TH
- Abstract
[This corrects the article DOI: 10.3389/fimmu.2023.1067352.]., (Copyright © 2023 Wan, Zhao, Freeman, Weissinger, Krantz, Werba, Khanna, Siolas, Oberstein, Chattopadhyay, Simeone and Welling.)
- Published
- 2023
- Full Text
- View/download PDF
25. Tumor infiltrating T cell states and checkpoint inhibitor expression in hepatic and pancreatic malignancies.
- Author
-
Wan S, Zhao E, Weissinger D, Krantz BA, Werba G, Freeman D, Khanna LG, Siolas D, Oberstein PE, Chattopadhyay PK, Simeone DM, and Welling TH
- Subjects
- Humans, Bile Ducts, Intrahepatic metabolism, Tumor Microenvironment, Pancreatic Neoplasms, Carcinoma, Hepatocellular, Liver Neoplasms, Pancreatic Neoplasms, Biliary Tract Neoplasms, Carcinoma, Pancreatic Ductal drug therapy, Carcinoma, Pancreatic Ductal pathology, Bile Duct Neoplasms
- Abstract
Hepato-pancreatico-biliary (HPB) malignancies are difficult-to-treat and continue to to have a high mortality and significant therapeutic resistance to standard therapies. Immune oncology (IO) therapies have demonstrated efficacy in several solid malignancies when combined with chemotherapy, whereas response rates in pancreatic ductal adenocarcinoma (PDA) are poor. While promising in hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), there remains an unmet need to fully leverage IO therapies to treat HPB tumors. We therefore defined T cell subsets in the tumor microenvironment of HPB patients utilizing a novel, multiparameter flow cytometry and bioinformatics analysis. Our findings quantify the T cell phenotypic states in relation to checkpoint receptor expression. We demonstrate the presence of CD103
+ tissue resident memory T cells (TRM ), CCR7+ central memory T cells, and CD57+ terminally differentiated effector cells across all HPB cancers, while the anti-tumor function was dampened by expression of multiple co-inhibitory checkpoint receptors. Terminally exhausted T cells lacking co-stimulatory receptors were more prevalent in PDA, whereas partially exhausted T cells expressing both co-inhibitory and co-stimulatory receptors were most prevalent in HCC, especially in early stage. HCC patients had significantly higher TRM with a phenotype that could confer restored activation in response to immune checkpoint therapies. Further, we found a lack of robust alteration in T cell activation state or checkpoint expression in response to chemotherapy in PDA patients. These results support that HCC patients might benefit most from combined checkpoint therapies, whereas efforts other than cytotoxic chemotherapy will likely be necessary to increase overall T cell activation in CCA and PDA for future clinical development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wan, Zhao, Weissinger, Krantz, Werba, Freeman, Khanna, Siolas, Oberstein, Chattopadhyay, Simeone and Welling.)- Published
- 2023
- Full Text
- View/download PDF
26. Elevated dietary carbohydrate and glycemic intake associate with an altered oral microbial ecosystem in two large U.S. cohorts.
- Author
-
Monson KR, Peters BA, Usyk M, Um CY, Oberstein PE, McCullough ML, Purdue MP, Freedman ND, Hayes RB, and Ahn J
- Subjects
- Cohort Studies, United States, Glycemic Load, Surveys and Questionnaires, Actinomyces classification, Actinomyces isolation & purification, Gemella classification, Gemella isolation & purification, Humans, Male, Female, Middle Aged, Aged, Dietary Carbohydrates adverse effects, Glycemic Index, Gastrointestinal Microbiome, Mouth microbiology, Leptotrichia classification, Leptotrichia isolation & purification, Diet, Carbohydrate Loading adverse effects, Neoplasms epidemiology, Neoplasms microbiology
- Abstract
The human oral microbiome is associated with chronic diseases including cancer. However, our understanding of its relationship with diet is limited. We assessed the associations between carbohydrate and glycemic index (GI) with oral microbiome composition in 834 non-diabetic subjects from the NCI-PLCO and ACS-CPSII cohorts. The oral microbiome was characterized using 16Sv3-4 rRNA-sequencing from oral mouthwash samples. Daily carbohydrate and GI were assessed from food frequency questionnaires. We used linear regression, permutational MANOVA, and negative binomial Generalized Linear Models (GLM) to test associations of diet with α- and β-diversity and taxon abundance (adjusting for age, sex, cohort, BMI, smoking, caloric intake, and alcohol). A q-value (FDR-adjusted P-value) of <0.05 was considered significant. Oral bacterial α-diversity trended higher in participants in the highest quintiles of carbohydrate intake, with marginally increased richness and Shannon diversity (p-trend=0.06 and 0.07). Greater carbohydrate intake was associated with greater abundance of class Fusobacteriia (q=0.02) and genus Leptotrichia (q=0.01) and with lesser abundance of an Actinomyces OTU (q=4.7E-04). Higher GI was significantly related to greater abundance of genus Gemella (q=0.001). This large, nationwide study provides evidence that diets high in carbohydrates and GI may influence the oral microbiome., Competing Interests: Competing interests: The authors declare no competing financial interests
- Published
- 2022
- Full Text
- View/download PDF
27. Multiplexed single-cell analysis reveals prognostic and nonprognostic T cell types in human colorectal cancer.
- Author
-
Masuda K, Kornberg A, Miller J, Lin S, Suek N, Botella T, Secener KA, Bacarella AM, Cheng L, Ingham M, Rosario V, Al-Mazrou AM, Lee-Kong SA, Kiran RP, Stoeckius M, Smibert P, Del Portillo A, Oberstein PE, Sims PA, Yan KS, and Han A
- Subjects
- CD8-Positive T-Lymphocytes, Humans, Prognosis, T-Lymphocyte Subsets, Colorectal Neoplasms metabolism, Single-Cell Analysis
- Abstract
Clinical outcomes in colorectal cancer (CRC) correlate with T cell infiltrates, but the specific contributions of heterogenous T cell types remain unclear. To investigate the diverse function of T cells in CRC, we profiled 37,931 T cells from tumors and adjacent normal colon of 16 patients with CRC with respect to transcriptome, TCR sequence, and cell surface markers. Our analysis identified phenotypically and functionally distinguishable effector T cell types. We employed single-cell gene signatures from these T cell subsets to query the TCGA database to assess their prognostic significance. We found 2 distinct cytotoxic T cell types. GZMK+KLRG1+ cytotoxic T cells were enriched in CRC patients with good outcomes. GNLY+CD103+ cytotoxic T cells with a dysfunctional phenotype were not associated with good outcomes, despite coexpression of CD39 and CD103, markers that denote tumor reactivity. We found 2 distinct Treg subtypes associated with opposite outcomes. While total Tregs were associated with good outcomes, CD38+ Tregs were associated with bad outcomes independently of stage and possessed a highly suppressive phenotype, suggesting that they inhibit antitumor immunity in CRC. These findings highlight the potential utility of these subpopulations in predicting outcomes and support the potential for novel therapies directed at CD38+ Tregs or CD8+CD103+ T cells.
- Published
- 2022
- Full Text
- View/download PDF
28. Noninvasive Young's modulus visualization of fibrosis progression and delineation of pancreatic ductal adenocarcinoma (PDAC) tumors using Harmonic Motion Elastography (HME) in vivo .
- Author
-
Nabavizadeh A, Payen T, Iuga AC, Sagalovskiy IR, Desrouilleres D, Saharkhiz N, Palermo CF, Sastra SA, Oberstein PE, Rosario V, Kluger MD, Schrope BA, Chabot JA, Olive KP, and Konofagou EE
- Subjects
- Adult, Aged, Aged, 80 and over, Animals, Disease Progression, Female, Fibrosis diagnostic imaging, Humans, Male, Mice, Middle Aged, Neoplasm Staging, Carcinoma, Pancreatic Ductal diagnostic imaging, Elastic Modulus, Elasticity Imaging Techniques methods, Pancreas diagnostic imaging, Pancreas pathology, Pancreatic Neoplasms diagnostic imaging
- Abstract
Background and aims : Poor specificity and predictive values of current cross-sectional radiological imaging methods in evaluation of pancreatic adenocarcinoma (PDAC) limit the clinical capability to accurately stage the tumor pre-operatively and provide optimal surgical treatment and improve patient outcomes. Methods : In this study, we applied Harmonic Motion Elastography (HME), a quantitative ultrasound-based imaging method to calculate Young's modulus (YM) in PDAC mouse models (n = 30) and human pancreatic resection specimens of PDAC (n=32). We compared the YM to the collagen assessment by Picrosirius red (PSR) stain on corresponding histologic sections. Results : HME is capable of differentiating between different levels of fibrosis in transgenic mice. In mice without pancreatic fibrosis, the measured YM was 4.2 ± 1.3 kPa, in fibrotic murine pancreata, YM was 5.5 ± 2.0 kPa and in murine PDAC tumors, YM was 11.3 ± 1.7 kPa. The corresponding PSR values were 2.0 ± 0.8 %, 9.8 ± 3.4 %, and 13.2 ± 1.2%, respectively. In addition, three regions within each human surgical PDAC specimen were assessed: tumor, which had both the highest Young's modulus (YM > 40 kPa) and collagen density (PSR > 40 %); non-neoplastic adjacent pancreas, which had the lowest Young's modulus (YM < 15 kPa) and collagen density (PSR < 10%) and a transitional peri-lesional region between the tumor and non-neoplastic pancreas with an intermediate value of measured Young's modulus (15 kPa < YM < 40 kPa) and collagen density (15% < PSR < 35 %). Conclusion : In conclusion, a non-invasive, quantitative imaging tool for detecting, staging and delineating PDAC tumor margins based on the change in collagen density was developed., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)
- Published
- 2020
- Full Text
- View/download PDF
29. Harmonic Motion Imaging of Pancreatic Tumor Stiffness Indicates Disease State and Treatment Response.
- Author
-
Payen T, Oberstein PE, Saharkhiz N, Palermo CF, Sastra SA, Han Y, Nabavizadeh A, Sagalovskiy IR, Orelli B, Rosario V, Desrouilleres D, Remotti H, Kluger MD, Schrope BA, Chabot JA, Iuga AC, Konofagou EE, and Olive KP
- Subjects
- Aged, Aged, 80 and over, Animals, Diagnosis, Differential, Disease Models, Animal, Female, Humans, Male, Mice, Mice, Inbred BALB C, Mice, Transgenic, Middle Aged, Motion, Neoplasm Staging, Pancreatic Neoplasms diagnostic imaging, Treatment Outcome, Elasticity Imaging Techniques methods, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms pathology, Phantoms, Imaging, Signal Processing, Computer-Assisted instrumentation, Ultrasonography methods
- Abstract
Purpose: Pancreatic ductal adenocarcinoma (PDA) is a common, deadly cancer that is challenging both to diagnose and to manage. Its hallmark is an expansive, desmoplastic stroma characterized by high mechanical stiffness. In this study, we sought to leverage this feature of PDA for two purposes: differential diagnosis and monitoring of response to treatment., Experimental Design: Harmonic motion imaging (HMI) is a functional ultrasound technique that yields a quantitative relative measurement of stiffness suitable for comparisons between individuals and over time. We used HMI to quantify pancreatic stiffness in mouse models of pancreatitis and PDA as well as in a series of freshly resected human pancreatic cancer specimens., Results: In mice, we learned that stiffness increased during progression from preneoplasia to adenocarcinoma and also effectively distinguished PDA from several forms of pancreatitis. In human specimens, the distinction of tumors versus adjacent pancreatitis or normal pancreas tissue was even more stark. Moreover, in both mice and humans, stiffness increased in proportion to tumor size, indicating that tuning of mechanical stiffness is an ongoing process during tumor progression. Finally, using a brca2-mutant mouse model of PDA that is sensitive to cisplatin, we found that tissue stiffness decreases when tumors respond successfully to chemotherapy. Consistent with this observation, we found that tumor tissues from patients who had undergone neoadjuvant therapy were less stiff than those of untreated patients., Conclusions: These findings support further development of HMI for clinical applications in disease staging and treatment response assessment in PDA., (©2019 American Association for Cancer Research.)
- Published
- 2020
- Full Text
- View/download PDF
30. Cholinergic Signaling via Muscarinic Receptors Directly and Indirectly Suppresses Pancreatic Tumorigenesis and Cancer Stemness.
- Author
-
Renz BW, Tanaka T, Sunagawa M, Takahashi R, Jiang Z, Macchini M, Dantes Z, Valenti G, White RA, Middelhoff MA, Ilmer M, Oberstein PE, Angele MK, Deng H, Hayakawa Y, Westphalen CB, Werner J, Remotti H, Reichert M, Tailor YH, Nagar K, Friedman RA, Iuga AC, Olive KP, and Wang TC
- Subjects
- Animals, Carcinoma, Pancreatic Ductal metabolism, Carcinoma, Pancreatic Ductal pathology, Cell Transformation, Neoplastic metabolism, Cell Transformation, Neoplastic pathology, Genes, ras, Humans, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms pathology, Signal Transduction, Carcinoma, Pancreatic Ductal prevention & control, Cell Transformation, Neoplastic drug effects, Cholinergic Agents pharmacology, Neoplastic Stem Cells drug effects, Pancreatic Neoplasms prevention & control, Receptor, Muscarinic M1 physiology
- Abstract
In many solid tumors, parasympathetic input is provided by the vagus nerve, which has been shown to modulate tumor growth. However, whether cholinergic signaling directly regulates progression of pancreatic ductal adenocarcinoma (PDAC) has not been defined. Here, we found that subdiaphragmatic vagotomy in LSL- Kras
+/G12D ; Pdx1 -Cre (KC) mice accelerated PDAC development, whereas treatment with the systemic muscarinic agonist bethanechol restored the normal KC phenotype, thereby suppressing the accelerated tumorigenesis caused by vagotomy. In LSL- Kras+/G12D ;LSL- Trp53+/R172H ; Pdx1 -Cre mice with established PDAC, bethanechol significantly extended survival. These effects were mediated in part through CHRM1, which inhibited downstream MAPK/EGFR and PI3K/AKT pathways in PDAC cells. Enhanced cholinergic signaling led to a suppression of the cancer stem cell (CSC) compartment, CD11b+ myeloid cells, TNFα levels, and metastatic growth in the liver. Therefore, these data suggest that cholinergic signaling directly and indirectly suppresses growth of PDAC cells, and therapies that stimulate muscarinic receptors may be useful in the treatment of PDAC. Significance: Subdiaphragmatic vagotomy or Chrm1 knockout accelerates pancreatic tumorigenesis, in part via expansion of the CSC compartment. Systemic administration of a muscarinic agonist suppresses tumorigenesis through MAPK and PI3K/AKT signaling, in early stages of tumor growth and in more advanced, metastatic disease. Therefore, CHRM1 may represent a potentially attractive therapeutic target. Cancer Discov; 8(11); 1458-73. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1333 ., (©2018 American Association for Cancer Research.)- Published
- 2018
- Full Text
- View/download PDF
31. Olaparib in combination with irinotecan, cisplatin, and mitomycin C in patients with advanced pancreatic cancer.
- Author
-
Yarchoan M, Myzak MC, Johnson BA 3rd, De Jesus-Acosta A, Le DT, Jaffee EM, Azad NS, Donehower RC, Zheng L, Oberstein PE, Fine RL, Laheru DA, and Goggins M
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Biomarkers, Tumor, Camptothecin administration & dosage, Camptothecin analogs & derivatives, Cisplatin administration & dosage, Female, Humans, Irinotecan, Male, Middle Aged, Mitomycin administration & dosage, Neoplasm Staging, Pancreatic Neoplasms genetics, Phthalazines administration & dosage, Piperazines administration & dosage, Retreatment, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms pathology
- Abstract
Background: Olaparib is an oral inhibitor of polyadenosine 5'-diphosphoribose polymerization (PARP) that has previously shown signs of activity in patients with BRCA mutations and pancreatic ductal adenocarcinoma (PDAC)., Patients and Methods: In this phase 1 dose-escalation trial in patients with unresectable PDAC, we determined the maximum tolerated dose (MTD) of olaparib (tablet formulation) in combination with irinotecan 70 mg/m2 on days 1 and 8 and cisplatin 25 mg/m2 on days 1 and 8 of a 28-day cycle (olaparib plus IC). We then studied the safety and tolerability of adding mitomycin C 5 mg/m2 on day 1 to this regimen (olaparib plus ICM)., Results: 18 patients with unresectable PDAC were enrolled. The MTD of olaparib plus IC was olaparib 100 mg twice-daily on days 1 and 8. The addition of mitomycin C to this dose level was not tolerated. Grade ≥3 drug-related adverse events (AEs) were encountered in 16 patients (89%). The most common grade ≥3 drug-related toxicities included neutropenia (89%), lymphopenia (72%), and anemia (22%). Two patients (11%), both of whom had remained on study for more than 12 cycles, developed drug-related myelodysplastic syndrome (MDS). The objective response rate (ORR) for all evaluable patients was 23%. One patient who carried a deleterious germline BRCA2 mutation had a durable clinical response lasting more than four years, but died from complications of treatment-related MDS., Conclusions: Olaparib had substantial toxicity when combined with IC or ICM in patients with PDAC, and this treatment combination did not have an acceptable risk/benefit profile for further study. However, durable clinical responses were observed in a subset of patients and further clinical investigation of PARP inhibitors in PDAC is warranted., Trial Registration: This clinical trial was registered on ClinicalTrials.gov as NCT01296763.
- Published
- 2017
- Full Text
- View/download PDF
32. First-line treatment for advanced pancreatic cancer. Highlights from the "2011 ASCO Gastrointestinal Cancers Symposium". San Francisco, CA, USA. January 20-22, 2011.
- Author
-
Oberstein PE and Saif MW
- Subjects
- Benzenesulfonates administration & dosage, Capecitabine, Clinical Trials as Topic, Deoxycytidine administration & dosage, Deoxycytidine analogs & derivatives, Erlotinib Hydrochloride, Fluorouracil administration & dosage, Fluorouracil analogs & derivatives, Humans, Lapatinib, Medicine, Chinese Traditional, Niacinamide analogs & derivatives, Pancreatic Neoplasms pathology, Pancreatic Neoplasms therapy, Phenylurea Compounds, Pyridines administration & dosage, Quinazolines administration & dosage, Sorafenib, Treatment Outcome, Gemcitabine, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Pancreatic Neoplasms drug therapy
- Abstract
Pancreatic adenocarcinoma remains a treatment-refractory cancer. Although pancreatic adenocarcinoma is only the 10th most common cause of new cancer in the United States, it is the fourth most common cause of cancer-related death. Most cases are not suitable for resection and a majority is metastatic at presentation. Gemcitabine, with or without erlotinib, has been the standard chemotherapy in this setting but the benefit is only modest. Because gemcitabine has been considered a standard treatment for advanced pancreatic cancer for the past decade, several randomized trials have tested the combination of gemcitabine plus a second agent, including platinum based agents, topoisomerase inhibitors, taxanes, bevacizumab and cetuximab, as biologically "targeted" agents. At large this approach has not been successful and novel strategies are clearly needed. In this article, the authors summarizes the data from the 2011 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, including: Abstract #175 (review of survival data in a large cohort); Abstract #286 (rapid change in prescriber patterns after the suggestion of benefit of a new regimen, FOLFIRINOX); Abstracts #238, #277, #304, and #315 (phase II trials looking at combinations that utilized EGFR blockade); Abstracts #221, #266, and #284 (phase I/II trials including VEGF blockade, anticoagulation, and traditional Chinese medicines).
- Published
- 2011
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.