36 results on '"Marina Baretti"'
Search Results
2. 897-B A DNAJB1-PRKACA fusion peptide vaccine combined with ipilimumab and nivolumab elicits polyclonal fusion-specific T cell responses in fibrolamellar carcinoma
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Mark Yarchoan, Paul G Thomas, Allison M Kirk, Jeremy C Crawford, Zeal Kamdar, and Marina Baretti
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2023
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3. A study of using epigenetic modulators to enhance response to pembrolizumab (MK-3475) in microsatellite stable advanced colorectal cancer
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Marina Baretti, Adrian G. Murphy, Marianna Zahurak, Nicole Gianino, Rose Parkinson, Rosalind Walker, Tamara Y. Lopez-Vidal, Lei Zheng, Gary Rosner, Nita Ahuja, Schalper Kurt, and Nilofer S. Azad
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Epigenetic drugs ,Histone deacetylases inhibitors ,DNA methyltransferases inhibitors ,Colorectal cancer ,Microsatellite proficiency ,Immunotherapy ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background Approximately 95% of advanced colorectal cancer patients (CRC) have mismatch repair MMR-proficient (MMRp) tumors, which do not respond to PD1 blockade alone. Preclinical studies have shown that combined histone deacetylases (HDAC) and/or DNA methyltransferases (DNMT) inhibition can induce susceptibility to immune checkpoint therapy and inhibit tumor growth. We conducted a pilot trial evaluating PD-1 immune checkpoint inhibitor therapy in combination with DNMT and HDAC inhibitors in MMRp CRC. The study was designed with a biological endpoint of change in immune cell infiltration, to determine the optimal epigenetic combination that optimizes the tumor microenvironment. This trial was designed to test that hypothesis. Results From January 2016 to November 2018, 27 patients were enrolled with median age of 57 (range 40–69) years. Median progression-free survival and overall survival were 2.79 months and 9.17, respectively. One patient in Arm C achieved a durable partial response by RECIST criteria, lasting for approximately 19 months. The most common treatment-related hematological adverse events in all arms were anemia (62%), lymphopenia (54%) and thrombocytopenia (35%), and non-hematological AEs were anorexia (65%), nausea (77%), and vomiting (73%). Conclusions The combination of 5-azacitidine and romidepsin with pembrolizumab was safe and tolerable in patients with advanced MMRp CRC, but with a minimal activity. Further mechanistic investigations are needed to understand epigenetic-induced immunologic shift and to expand the potential applicability of checkpoint inhibitors in this setting.
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- 2023
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4. Relationship of Hepatocellular Carcinoma Stage and Hepatic Function to Health-Related Quality of Life: A Single Center Analysis
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Amol Gupta, Jane Zorzi, Won Jin Ho, Marina Baretti, Nilofer Saba Azad, Paige Griffith, Doan Dao, Amy Kim, Benjamin Philosophe, Christos Georgiades, Ihab Kamel, Richard Burkhart, Robert Liddell, Kelvin Hong, Christopher Shubert, Kelly Lafaro, Jeffrey Meyer, Robert Anders, William Burns, and Mark Yarchoan
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hepatocellular carcinoma ,health-related quality of life ,Child–Pugh score ,Medicine - Abstract
Health-related quality of life (HRQoL) is known to be an important prognostic indicator and clinical endpoint for patients with hepatocellular carcinoma (HCC). However, the correlation of the Barcelona Clinic Liver Cancer (BCLC) stage with HRQoL in HCC has not been previously studied. We examined the relationship between BCLC stage, Child–Pugh (CP) score, and Eastern Cooperative Oncology Group (ECOG) performance status on HRQoL for patients who presented at a multidisciplinary liver cancer clinic. HRQoL was assessed using the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) questionnaire. Fifty-one patients met our inclusion criteria. The FACT-Hep total and subscales showed no significant association with BCLC stages (p = 0.224). Patients with CP B had significantly more impairment in FACT-Hep than patients with CP A. These data indicate that in patients with HCC, impaired liver function is associated with reduced quality of life, whereas the BCLC stage poorly correlates with quality of life metrics. Impairment of quality of life is common in HCC patients and further studies are warranted to determine the impact of early supportive interventions on HRQoL and survival outcomes.
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- 2023
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5. Impact of the COVID-19 Pandemic on Liver Cancer Staging at a Multidisciplinary Liver Cancer Clinic
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Daniel Li, MD, MA, Angela Y. Jia, MD, PhD, Jane Zorzi, BS, Paige Griffith, MSN, AG-ACNP, BSN, Amy K. Kim, MD, Doan Dao, MD, Robert A. Anders, MD, PhD, Christos Georgiades, MD, PhD, Robert P. Liddell, MD, Kelvin Hong, MD, Nilofer S. Azad, MD, Won Jin Ho, MD, Marina Baretti, MD, Eric Christenson, MD, Azarakhsh Baghdadi, MD, MAS, Ihab R. Kamel, MD, PhD, Jeffrey Meyer, MD, Elie Ghabi, MD, Richard A. Burkhart, MD, Kelly Lafaro, MD, MPH, Jin He, MD, Chris Shubert, MD, and Mark Yarchoan, MD
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Surgery ,RD1-811 - Abstract
Objectives:. To compare liver cancer resectability rates before and during the COVID-19 pandemic. Background:. Liver cancers usually present with nonspecific symptoms or are diagnosed through screening programs for at-risk patients, and early detection can improve patient outcomes. In 2020, the COVID-19 pandemic upended medical care across all specialties, but whether the pandemic was associated with delays in liver cancer diagnosis is not known. Methods:. We performed a retrospective review of all patients evaluated at the Johns Hopkins Multidisciplinary Liver Cancer Clinic from January 2019 to June 2021 with a new diagnosis of suspected or confirmed hepatocellular carcinoma (HCC) or biliary tract cancer (BTC). Results:. There were 456 liver cancer patients (258 HCC and 198 BTC). From January 2019 to March 2020 (pre-pandemic), the surgical resectability rate was 20%. The subsequent 6 months (early pandemic), the resectability rate decreased to 11%. Afterward from October 2020 to June 2021 (late pandemic), the resectability rate increased to 27%. The resectability rate early pandemic was significantly lower than that for pre-pandemic and later pandemic combined (11% lower; 95% confidence interval [CI], 2%–20%). There was no significant difference in resectability rates pre-pandemic and later pandemic (7% difference; 95% CI, –3% to 16%). In subgroup analyses, the early pandemic was associated with a larger impact in BTC resectability rates than HCC resectability rates. Time from BTC symptom onset until Multidisciplinary Liver Clinic evaluation increased by over 6 weeks early pandemic versus pre-pandemic (Hazard Ratio, 0.63; 95% CI, 0.44–0.91). Conclusions:. During the early COVID-19 pandemic, we observed a drop in the percentage of patients presenting with curable liver cancers. This may reflect delays in liver cancer diagnosis and contribute to excess mortality related to the COVID-19 pandemic.
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- 2022
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6. A phase 2 trial of gemcitabine and docetaxel in patients with metastatic colorectal adenocarcinoma with methylated checkpoint with forkhead and ring finger domain promoter and/or microsatellite instability phenotype
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Marina Baretti, Enusha Karunasena, Marianna Zahurak, Rosalind Walker, Yang Zhao, Thomas R. Pisanic 2nd, Tza‐Huei Wang, Tim F. Greten, Austin G. Duffy, Elske Gootjes, Gerrit Meijer, Henk M.W. Verheul, Nita Ahuja, James G. Herman, and Nilofer S. Azad
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Therapeutics. Pharmacology ,RM1-950 ,Public aspects of medicine ,RA1-1270 - Abstract
Abstract We previously reported CHFR methylation in a subset of colorectal cancer (CRC; ∼30%) with high concordance with microsatellite instability (MSI). We also showed that CHFR methylation predicted for sensitivity to docetaxel, whereas the MSI‐high phenotypes were sensitive to gemcitabine. We hypothesized that this subset of patients with CRC would be selectively sensitive to gemcitabine and docetaxel. We enrolled a Phase 2 trial of gemcitabine and docetaxel in patients with MSI‐high and/or CHFR methylated CRC. The primary objective was Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response rate. Enrolled patients were treated with gemcitabine 800 mg/m2 on days 1 and 8 and docetaxel 70 mg/m2 on day 8 of each 21‐day cycle. A total of 6 patients with CHFR‐methylated, MSI‐high CRC were enrolled from September 2012 to August 2016. The study was closed in September of 2017 due to poor accrual prior to reaching the first interim assessment of response rate, which would have occurred at 10 patients. No RECIST criteria tumor responses were observed, with 3 patients (50%) having stable disease as best response, 1 lasting more than 9 months. Median progression‐free survival (PFS) was 1.79 months (95% confidence interval [CI] = 1.28, not available [NA]) and median overall survival (OS) was 15.67 months (95% CI = 4.24, NA). Common grade 3 toxicities were lymphopenia (67%), leukopenia (33%), and anemia (33%). Although negative, this study establishes a proof‐of‐concept for the implementation of epigenetic biomarkers (CHFR methylation/MSI) as inclusion criteria in a prospective clinical trial to optimize combinatorial strategies in the era of personalized medicine. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? CHFR silencing via DNA methylation has been suggested to be predictive of taxane sensitivity in diverse tumors. The frequent association of CHFR methylation with microsatellite instability (MSI) suggested a possible combination therapy with gemcitabine, because the MSI phenotype may result in sensitivity to nucleoside analogues. WHAT QUESTION DID THIS STUDY ADDRESS? We hypothesized that metastatic colorectal cancer (mCRC), which have CHFR methylation and MSI phenotype were sensitive to gemcitabine and docetaxel, and have designed this Phase 2 trial in biomarker‐selected mCRC to test this prediction. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? The study enrolled a molecularly defined subgroup of patients with colorectal cancer (CRC) and showed that the combination is safe in this population. Nevertheless, due to poor enrollment and early termination, no conclusions on the primary and secondary end points could be made. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? This study supports the feasibility of implementing DNA methylation markers in a prospective clinical trial and further efforts toward their application as predictive biomarkers for therapeutic agents in defined subsets of patients are warranted.
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- 2021
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7. Development, Practice Patterns, and Early Clinical Outcomes of a Multidisciplinary Liver Cancer Clinic
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Angela Y. Jia MD, PhD, Aleksandra Popovic BS, Aditya A. Mohan BS, Jane Zorzi BS, Paige Griffith MSN, AG-ACNP, BSN, Amy K. Kim MD, Robert A. Anders MD, PhD, Richard A. Burkhart MD, Kelly Lafaro MD, MPH, Christos Georgiades MD, PhD, Nilofer S. Azad MD, Robert P. Liddell MD, Marina Baretti MD, Ihab R. Kamel MD, PhD, Amol Narang MD, Mark Yarchoan MD, and Jeffrey Meyer MD
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Multidisciplinary care has been associated with improved survival in patients with primary liver cancers. We report the practice patterns and real world clinical outcomes for patients presenting to the Johns Hopkins Hospital (JHH) multidisciplinary liver clinic (MDLC). We analyzed hepatocellular carcinoma (HCC, n = 100) and biliary tract cancer (BTC, n = 76) patients evaluated at the JHH MDLC in 2019. We describe the conduct of the clinic, consensus decisions for patient management based on stage categories, and describe treatment approaches and outcomes based on these categories. We describe subclassification of BCLC stage C into 2 parts, and subclassification of cholangiocarcinoma into 4 stages. A treatment consensus was finalized on the day of MDLC for the majority of patients (89% in HCC, 87% in BTC), with high adherence to MDLC recommendations (91% in HCC, 100% in BTC). Among patients presenting for a second opinion regarding management, 28% of HCC and 31% of BTC patients were given new therapeutic recommendations. For HCC patients, at a median follow up of 11.7 months (0.7-19.4 months), median OS was not reached in BCLC A and B patients. In BTC patients, at a median follow up of 14.2 months (0.9-21.1 months) the median OS was not reached in patients with resectable or borderline resectable disease, and was 11.9 months in patients with unresectable or metastatic disease. Coordinated expert multidisciplinary care is feasible for primary liver cancers with high adherence to recommendations and a change in treatment for a sizeable minority of patients.
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- 2021
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8. Implantation of a neoantigen-targeted hydrogel vaccine prevents recurrence of pancreatic adenocarcinoma after incomplete resection
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Daniel Delitto, Daniel J. Zabransky, Fangluo Chen, Elizabeth D. Thompson, Jacquelyn W. Zimmerman, Todd D. Armstrong, James M. Leatherman, Reecha Suri, Tamara Y. Lopez-Vidal, Amanda L. Huff, Melissa R. Lyman, Samantha R. Guinn, Marina Baretti, Luciane T. Kagohara, Won Jin Ho, Nilofer S. Azad, William R. Burns, Jin He, Christopher L. Wolfgang, Richard A. Burkhart, Lei Zheng, Mark Yarchoan, Neeha Zaidi, and Elizabeth M. Jaffee
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pancreatic adenocarcinoma ,immunotherapy ,neoantigen ,vaccine ,hydrogel ,surgery ,Immunologic diseases. Allergy ,RC581-607 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Tumor involvement of major vascular structures limits surgical options in pancreatic adenocarcinoma (PDAC), which in turn limits opportunities for cure. Despite advances in locoregional approaches, there is currently no role for incomplete resection. This study evaluated a gelatinized neoantigen-targeted vaccine applied to a grossly positive resection margin in preventing local recurrence. Incomplete surgical resection was performed in mice bearing syngeneic flank Panc02 tumors, leaving a 1 mm rim adherent to the muscle bed. A previously validated vaccine consisting of neoantigen peptides, a stimulator of interferon genes (STING) agonist and AddaVaxTM (termed PancVax) was embedded in a hyaluronic acid hydrogel and applied to the tumor bed. Tumor remnants, regional lymph nodes, and spleens were analyzed using histology, flow cytometry, gene expression profiling, and ELISPOT assays. The immune microenvironment at the tumor margin after surgery alone was characterized by a transient influx of myeloid-derived suppressor cells (MDSCs), prolonged neutrophil influx, and near complete loss of cytotoxic T cells. Application of PancVax gel was associated with enhanced T cell activation in the draining lymph node and expansion of neoantigen-specific T cells in the spleen. Mice implanted with PancVax gel demonstrated no evidence of residual tumor at two weeks postoperatively and healed incisions at two months postoperatively without local recurrence. In summary, application of PancVax gel at a grossly positive tumor margin led to systemic expansion of neoantigen-specific T cells and effectively prevented local recurrence. These findings support further work into locoregional adjuncts to immune modulation in PDAC.
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- 2021
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9. A randomized, phase II trial of oral azacitidine (CC-486) in patients with resected pancreatic adenocarcinoma at high risk for recurrence
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Thatcher R. Heumann, Marina Baretti, Elizabeth A. Sugar, Jennifer N. Durham, Sheila Linden, Tamara Y. Lopez-Vidal, James Leatherman, Leslie Cope, Anup Sharma, Colin D. Weekes, Peter J. O’Dwyer, Kim A. Reiss, Dulabh K. Monga, Nita Ahuja, and Nilofer S. Azad
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Genetics ,Molecular Biology ,Genetics (clinical) ,Developmental Biology - Abstract
BackgroundOf the only 20% of patients with resectable pancreatic ductal adenocarcinoma (rPDA), cancer recurs in 80% of cases. Epigenetic dysregulation is an early hallmark of cancer cells acquiring metastatic potential, and epigenetic modulators may reactivate tumor suppressor genes, delay recurrence, and sensitize PDA to future chemotherapy.MethodsThis was a randomized phase II study (NCT01845805) of CC-486 (oral DNA methyltransferase inhibitor azacitidine) vs. observation (OBS) in rPDA patients harboring high-risk features (stage pN1-2, R1 margins, or elevated CA 19–9 level) with no evidence of disease following standard adjuvant therapy. Patients were randomized to oral CC-486 treatment (300 mg daily on days 1–21 on a 28-day cycle) or OBS for up to 12 cycles or until disease relapse/unacceptable toxicities. Following recurrence, records of next-line therapies, imaging, and survival were obtained. The primary endpoint was progression-free survival (PFS)—time from randomization to recurrence (imaging/biopsy confirmed or death). Secondary endpoints included OS and PFS and ORR and metastatic PFS with subsequent next-line systemic therapy in metastatic setting.ResultsForty-nine patients (24 in CC-486 arm, 25 in OBS arm) were randomized: median age 66 (range 36–81), 53% male, 73% node positive, 49% elevated CA 19–9, 20% R1 resection, 63% and 100% received perioperative concurrent chemoradiation and chemotherapy, respectively. Median time from surgery to randomization was 9.6 mo (range 2.9–36.8). For the CC-486 arm, median treatment duration was 5.6 mo (range 1.3 to 12.8) with 14 treatment-related grade 3 or 4 AEs among 5 patients (22%) resulting in dose-reduction. Four patients (17%) discontinued therapy due to AEs. With median follow-up of 20.3mo (IQR 12.8, 41.4), 38 (79%) of evaluable patients recurred (34 imaging-confirmed, 4 clinically). Median PFS in imagining-confirmed cases was 9.2 and 8.9mo (HR 0.94, 95% CI 0.46–1.87,p = 0.85) for CC-486 and OBS patients, respectively. Median OS (2-yr OS%) was 33.8 (50%) and 26.4 mo (61%) in CC-486 and OBS patients, respectively. (HR 0.98, 95% CI 0.46–2.05,p = 0.96). ORR with subsequent chemotherapy in the metastatic setting was minimal in both arms.ConclusionsTreatment with CC-486 following adjuvant therapy did not prolong time-to-relapse in patients with high-risk rPDA or improve disease response on 1st-line metastatic therapy.
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- 2022
10. Clinical Outcomes in Fibrolamellar Hepatocellular Carcinoma Treated with Immune Checkpoint Inhibitors
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Krista Y. Chen, Aleksandra Popovic, David Hsiehchen, Marina Baretti, Paige Griffith, Ranjan Bista, Azarakhsh Baghdadi, Ihab R. Kamel, Sanford M. Simon, Rachael D. Migler, and Mark Yarchoan
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Cancer Research ,Oncology ,fibrolamellar hepatocellular carcinoma ,liver cancer ,immune checkpoint inhibitor ,anti-PD-1 therapy - Abstract
Background: Fibrolamellar hepatocellular carcinoma (FLC) is a rare form of liver cancer primarily affecting children and young adults. Although considered a subset of hepatocellular carcinoma (HCC), FLC has unique molecular and pathologic characteristics, suggesting that it may require different treatment. Immune checkpoint inhibitors (ICIs) are used in the treatment of HCC, but efficacy and safety in FLC has not been characterized. Methods: We performed a multicenter retrospective analysis of patients with FLC to determine responses to ICI therapy. Response rates were assessed based on RECIST 1.1 criteria, and Kaplan–Meier statistics were used for progression-free survival (PFS) and overall survival (OS). Results: FLC tumors were characterized by low tumor mutational burden (TMB) and absent PD-L1 expression. We identified 19 patients who received ICIs, including 15 who received ICI therapy alone [programmed death receptor 1 (PD-1) inhibitor, +/− cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitor]. Objective tumor responses were observed in 3/19 patients (15.8%), including 2/15 patients (13.3%) who received ICIs alone, all partial responses. Median PFS and OS were 5.5 and 26.0 months, respectively. Grade 3–4 immune related adverse events were observed in 4/19 (21.1%) patients. Conclusions: ICI therapy has modest clinical activity in FLC, and novel therapeutic combinations are needed.
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- 2022
11. Prognostic Implications of the Immune Tumor Microenvironment in Patients With Pancreatic and Gastrointestinal Neuroendocrine Tumors
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Haiying Xu, Anil Kotte, Marina Baretti, Robert A. Anders, Feriyl Bhaijee, Marianna Zahurak, Timothy M. Pawlik, Elizabeth L. Engle, Ana De Jesus-Acosta, and Qingfeng Zhu
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Adult ,Male ,medicine.medical_specialty ,Time Factors ,Adolescent ,CD3 Complex ,T-Lymphocytes ,Endocrinology, Diabetes and Metabolism ,Programmed Cell Death 1 Receptor ,Neuroendocrine tumors ,Gastroenterology ,B7-H1 Antigen ,Young Adult ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,0302 clinical medicine ,Endocrinology ,Immune system ,Internal medicine ,PD-L1 ,Biomarkers, Tumor ,Tumor Microenvironment ,Internal Medicine ,medicine ,Humans ,Aged ,Gastrointestinal Neoplasms ,Retrospective Studies ,Tumor microenvironment ,Hepatology ,biology ,Tumor-infiltrating lymphocytes ,business.industry ,Odds ratio ,Middle Aged ,medicine.disease ,Progression-Free Survival ,Pancreatic Neoplasms ,Neuroendocrine Tumors ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,biology.protein ,Female ,030211 gastroenterology & hepatology ,Pancreas ,business ,CD8 - Abstract
OBJECTIVES The aim of this study was to characterize the tumor microenvironment of patients with gastroenteropancreatic neuroendocrine tumors relative to progression-free survival (PFS). METHODS Immune profiling for CD3, CD8, programmed death-1/programmed death-ligand 1, and indoleamine 2,3-dioxygenase expression in 2 cohorts of gastroenteropancreatic neuroendocrine tumors: patients with short PFS (
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- 2021
12. Clinical, Genomic, and Transcriptomic Data Profiling of Biliary Tract Cancer Reveals Subtype-Specific Immune Signatures
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Kabir Mody, Prerna Jain, Sherif M. El-Refai, Nilofer S. Azad, Daniel J. Zabransky, Marina Baretti, Rachna T. Shroff, R. Katie Kelley, Anthony B. El-Khouiery, Adam J. Hockenberry, Denise Lau, Gregory B. Lesinski, and Mark Yarchoan
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Intrahepatic ,Cancer Research ,Human Genome ,Genomics ,Cholangiocarcinoma ,Proto-Oncogene Proteins p21(ras) ,Bile Ducts, Intrahepatic ,Biliary Tract Neoplasms ,Rare Diseases ,Bile Duct Neoplasms ,Oncology ,Tumor Microenvironment ,Genetics ,Humans ,2.1 Biological and endogenous factors ,Gallbladder Neoplasms ,Bile Ducts ,Transcriptome ,Digestive Diseases ,Biotechnology ,Cancer - Abstract
PURPOSE Biliary tract cancers (BTCs) are aggressive cancers that carry a poor prognosis. An enhanced understanding of the immune landscape of anatomically and molecularly defined subsets of BTC may improve patient selection for immunotherapy and inform immune-based combination treatment strategies. METHODS We analyzed deidentified clinical, genomic, and transcriptomic data from the Tempus database to determine the mutational frequency and mutational clustering across the three major BTC subtypes (intrahepatic cholangiocarcinoma [IHC], extrahepatic cholangiocarcinoma, and gallbladder cancer). We subsequently determined the relationship between specific molecular alterations and anatomical subsets and features of the BTC immune microenvironment. RESULTS We analyzed 454 samples of BTC, of which the most commonly detected alterations were TP53 (42.5%), CDKN2A (23.4%), ARID1A (19.6%), BAP1 (15.5%), KRAS (15%), CDKN2B (14.2%), PBRM1 (11.7%), IDH1 (11.7%), TERT (8.4%), KMT2C (10.4%) and LRP1B (8.4%), and FGFR2 fusions (8.7%). Potentially actionable molecular alterations were identified in 30.5% of BTCs including 39.1% of IHC. Integrative cluster analysis revealed four distinct molecular clusters, with cluster 4 predominately associated with FGFR2 rearrangements and BAP1 mutations in IHC. Immune-related biomarkers indicative of an inflamed tumor-immune microenvironment were elevated in gallbladder cancers and in cluster 1, which was enriched for TP53, KRAS, and ATM mutations. Multiple common driver genes, including TP53, FGFR2, IDH1, TERT, BRAF, and BAP1, were individually associated with unique BTC immune microenvironments. CONCLUSION BTC subtypes exhibit diverse DNA alterations, RNA inflammatory signatures, and immune biomarkers. The association between specific BTC anatomical subsets, molecular alterations, and immunophenotypes highlights new opportunities for therapeutic development.
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- 2022
13. Abstract CT036: Safety and immunogenicity of a first-in-human mutant KRAS long peptide vaccine combined with ipilimumab/nivolumab in resected pancreatic cancer: Preliminary analysis from a phase I study
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Saurav D. Haldar, Amanda Huff, Thatcher R. Heumann, Maureen Berg, Anna Ferguson, Su Jin Lim, Hao Wang, Amy M. Thomas, Julie M. Nauroth, Marina Baretti, Katherine M. Bever, Mark Yarchoan, Daniel A. Laheru, Elizabeth M. Jaffee, Nilofer S. Azad, and Neeha Zaidi
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Cancer Research ,Oncology - Abstract
Background: Novel strategies are needed to decrease the high recurrence rates of pancreatic ductal adenocarcinoma (PDAC) after curative-intent surgery. Mutant KRAS (mKRAS) is an oncogenic driver found in approximately 90% of PDAC that has emerged as a target for neoantigen-specific vaccination. Methods: This is a single-arm, open-label, first-in-human phase I study of a pooled synthetic long peptide (SLP) vaccine targeting six mKRAS subtypes (G12D, G12R, G12V, G12A, G12C, G13D) combined with ipilimumab/nivolumab (ipi/nivo) in patients with resected PDAC (NCT04117087). Key inclusion criteria: presence of a vaccine-targeted KRAS mutation, disease-free status after completing adjuvant chemotherapy within 6 months of enrollment. Priming phase: mKRAS vaccine given on days 1, 8, 15, and 22 along with ipi 1 mg/kg every 6 weeks for 2 doses and nivo 3 mg/kg every 3 weeks for 4 doses. Boost phase: mKRAS vaccine given on weeks 13, 21, 29, 37, and 45 along with nivo 480 mg every 4 weeks for 10 doses. Co-primary endpoints: safety, mKRAS-specific T cell response. Secondary endpoints: disease-free survival (DFS), overall survival (OS). Results: At the time of data cutoff (December 1, 2022), 11 patients were treated with a median follow-up time of 10.7 months. 8/11 patients achieved a mKRAS-specific T cell response, defined as >5-fold change in IFN-gamma-producing mKRAS-specific T cells within 17 weeks post-vaccination, as assessed by serial ELISpot. The median fold change in IFN-gamma-producing mKRAS-specific T cells within 17 weeks post-vaccination was 10.2 (range: 1.5-686.3). The majority of all adverse events were grade 1 (79.5%) or grade 2 (15.2%) in severity per NCI CTCAE v5.0. Four grade 3 immune-related adverse events (pneumonitis, adrenal insufficiency, arthralgias, myalgias) and discontinuation of checkpoint blockade occurred in 2/11 patients. The median DFS for the entire cohort was 6.4 months and not reached for OS. Patients who mounted a mKRAS-specific T cell response demonstrated a significant improvement in median DFS compared to immune non-responders (not reached vs 2.8 months, p = 0.045). Conclusions: The combination of a pooled SLP mKRAS vaccine and dual checkpoint blockade is tolerable and immunogenic in patients with resected PDAC. Induction of an mKRAS-specific T cell response is associated with improved DFS in this cohort. Ongoing correlative studies will apply multi-omic approaches to identify novel biomarkers of immune response and resistance. Citation Format: Saurav D. Haldar, Amanda Huff, Thatcher R. Heumann, Maureen Berg, Anna Ferguson, Su Jin Lim, Hao Wang, Amy M. Thomas, Julie M. Nauroth, Marina Baretti, Katherine M. Bever, Mark Yarchoan, Daniel A. Laheru, Elizabeth M. Jaffee, Nilofer S. Azad, Neeha Zaidi. Safety and immunogenicity of a first-in-human mutant KRAS long peptide vaccine combined with ipilimumab/nivolumab in resected pancreatic cancer: Preliminary analysis from a phase I study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT036.
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- 2023
14. Abstract 3679: DNAJB1-PRKACA fusion in fibrolamellar hepatocellular carcinoma induces glutamine addiction and an immunosuppressive tumor microenvironment
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Zeal Kamdar, Tamara Lopez-Vidal, Kathryn Howe, Kabeer Munjal, Ali Saeed, Daniel Zabransky, Daniel Shu, Gabriella Longway, Emma Kartalia, James Leatherman, Aditya Mohan, Pratik Khare, Cissy Zhang, Anne Le, Erika Pearce, Mark Furth, Marina Baretti, Robert Leone, Elizabeth Jaffee, and Mark Yarchoan
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Cancer Research ,Oncology - Abstract
Fibrolamellar hepatocellular carcinoma (FLC) is a rare and often lethal form of liver cancer that primarily affects children and young adults. A fusion between DNAJB1, a heat shock chaperone protein, and PRKACA, the catalytic domain of protein kinase A (PKA) has been identified as a signature genomic event in FLC, but the effect of this fusion on the tumor immune microenvironment is not understood. We created an orthotopic, syngeneic model of FLC (TIBx-FLC) by inducing the DNAJB1-PRKACA fusion in a murine hepatoblastoma-derived cell line (TIBx). CD8 T cells isolated from TIBx-FLC tumors demonstrated markedly impaired activation as compared to CD8 T cells isolated from control TIBx tumors. We investigated metabolic programming as a potential mechanism for DNAJB1-PRKACA immunosuppression in FLC. Labeled glucose metabolomics performed on TIBx-FLC and TIBx tumor cells demonstrated a metabolic shift away from aerobic metabolism to an increased glucose contribution towards the hexosamine biosynthetic pathway and purine synthesis, which requires glutamine as a nitrogen source. As compared to the parental TIBx cell line, the TIBx-FLC cell line demonstrated high sensitivity to glutamine antagonism in vitro, consistent with glutamine addiction. Systemic treatment of BALB/c mice bearing TIBx-FLC tumors with JHU-083, a glutamine antagonist, in combination with immune checkpoint inhibitor therapy enhanced survival as compared to vehicle or monotherapy. These data identify altered glutamine metabolism as a target in FLC, and may provide an explanation for immune suppression seen in the FLC tumor microenvironment. Citation Format: Zeal Kamdar, Tamara Lopez-Vidal, Kathryn Howe, Kabeer Munjal, Ali Saeed, Daniel Zabransky, Daniel Shu, Gabriella Longway, Emma Kartalia, James Leatherman, Aditya Mohan, Pratik Khare, Cissy Zhang, Anne Le, Erika Pearce, Mark Furth, Marina Baretti, Robert Leone, Elizabeth Jaffee, Mark Yarchoan. DNAJB1-PRKACA fusion in fibrolamellar hepatocellular carcinoma induces glutamine addiction and an immunosuppressive tumor microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3679.
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- 2023
15. Surgical Debulking for Refractory Hyperammonemic Encephalopathy in Fibrolamellar Hepatocellular Carcinoma
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Marina Baretti, Mark Yarchoan, Meral Gunay-Aygun, Madelena Brancati, Anna Ferguson, Vinod Kumar Reddy Solipuram, Jill A. Fahrner, Paige Griffith, Tomoaki Kato, Daniel A. Laheru, Dylan Hardenbergh, Yuxuan Wang, Xiao P. Peng, Chris Shubert, Lucy X. Chen, Alexander Y. Kim, and Harish Gopalakrishna
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Adult ,Male ,Orotic acid ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,Arginine ,Bilirubin ,Gastroenterology ,Article ,Excretion ,chemistry.chemical_compound ,Ammonia ,Internal medicine ,medicine ,Citrulline ,Humans ,Hyperammonemia ,Creatinine ,Hepatology ,Liver Neoplasms ,Cytoreduction Surgical Procedures ,Ornithine ,medicine.disease ,Treatment Outcome ,chemistry ,Hepatic Encephalopathy ,medicine.drug - Abstract
A 26-year-old male with a two-year history of FLC developed progressive somnolence and disorientation. Treatment history for FLC had included cytotoxic chemotherapy, lenvatinib, and immunotherapy. A CT scan confirmed extensive stage FLC with numerous liver, lung, and pelvic metastasis. Laboratory results showed bilirubin 0.3 mg/dL, creatinine 0.4 mg/dl, leukocytes of 9.5x109 /L, hemoglobin 11.2 g/dL, platelets 369x109 /L, and ammonia 247 µmol/L (reference range: 0-32 µmol/L). Plasma amino acid analysis revealed relatively low citrulline (14 µmol/L), arginine (32 µmol/L), and ornithine (35 µmol/L). Urinary orotic acid excretion was markedly elevated at 149 mmol/mol creat (reference range: 0.68-3.52 mmol/mol creat).
- Published
- 2021
16. Expanding the immunotherapy roadmap for hepatocellular carcinoma
- Author
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Marina Baretti, Amy K. Kim, and Robert A. Anders
- Subjects
Cancer Research ,Carcinoma, Hepatocellular ,Nivolumab ,Oncology ,Liver Neoplasms ,Humans ,Immunologic Factors ,Immunotherapy ,Sorafenib ,Article - Abstract
In a recent Lancet Oncology article, Yau et al. report the CheckMate 459 trial results. This is the first phase III trial comparing the single-agent anti-programmed death protein 1 (PD-1) therapy nivolumab to the tyrosine kinase inhibitor sorafenib for treatment-naive patients with advanced hepatocellular carcinoma.
- Published
- 2022
17. Chemoradiation-induced alteration of programmed death-ligand 1, CD8+ tumor-infiltrating lymphocytes and mucin expression in rectal cancer
- Author
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Marina Baretti, Qingfeng Zhu, Wei Fu, Jeffrey Meyer, Hao Wang, Robert A. Anders, and Nilofer S. Azad
- Subjects
Lymphocytes, Tumor-Infiltrating ,Oncology ,Rectal Neoplasms ,Programmed Cell Death 1 Receptor ,Mucins ,Humans ,Adenocarcinoma ,CD8-Positive T-Lymphocytes ,Prognosis ,B7-H1 Antigen - Abstract
DNA damage and resulting neoantigen formation is considered a mechanism for synergy between radiotherapy and PD-1/PD-L1 pathway inhibition to induce antitumor immune response. We investigated neoadjuvant chemoradiotherapy (nCRT)-induced changes in CD8+ tumor infiltrating lymphocyte, PD-L1 and mucin expression in rectal cancer patients.Tumor samples of rectal adenocarcinoma patients undergoing resection between 2008-2014 with (PD-L1 expression on TCs was identified in 7.6% (6/79) of nCRT specimens (nCRT exposure was associated with a non-significant difference in PD-L1 expression in rectal adenocarcinoma patients, possibly due to sample size limitations. Further mechanistic investigations and comprehensive immune analysis are needed to understand nCRT-induced immunologic shift in rectal cancer and to expand the applicability of checkpoint inhibitors in this setting.
- Published
- 2022
18. Contributors
- Author
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Débora Kristina Alves-Fernandes, Ana Luisa Pedroso Ayub, Nilofer S. Azad, Khalil Azizian, Marina Baretti, Nikola Bowden, Kate H. Brettingham-Moore, Jessica Buck, Dayna Challis, Jonathan Dow, Raelene Endersby, Shinjini Ganguly, Anthony Ghanem, Sebastiano Giallongo, Peter M. Glazer, Nassim Gorjizadeh, Negar Gorjizadeh, Miriam Galvonas Jasiulionis, Philippe Johann To Berens, Ansar Karimian, Marcela Teatin Latancia, Giovana da Silva Leandro, Oriana Lo Re, Carlos Frederico Martins Menck, Omar Y. Mian, Tomoko Miyake, Jean Molinier, Apiwat Mutirangura, Bruna de Oliveira Perestrelo, Guilherme Cavalcante Pessoa, Nathalia Quintero-Ruiz, Salimata Ousmane Sall, Margarida A. Santos, Mikio Shimada, Moein Shirzad, Hieu T. Van, and Manlio Vinciguerra
- Published
- 2022
19. Epigenetic therapy and DNA damage response
- Author
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Marina Baretti and Nilofer S. Azad
- Published
- 2022
20. Epigenetic modifiers synergize with immune-checkpoint blockade to enhance long-lasting antitumor efficacy
- Author
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Mark Yarchoan and Marina Baretti
- Subjects
Pyridines ,T-Lymphocytes ,Mice, SCID ,Histone Deacetylases ,Epigenesis, Genetic ,chemistry.chemical_compound ,Mice ,Immune system ,Antineoplastic Agents, Immunological ,Antigen ,Antigens, Neoplasm ,Mice, Inbred NOD ,Neoplasms ,Cell Line, Tumor ,medicine ,Tumor Microenvironment ,Animals ,Humans ,Epigenetics ,Immune Checkpoint Inhibitors ,Mice, Knockout ,Entinostat ,Mechanism (biology) ,business.industry ,Immunity ,Cancer ,General Medicine ,medicine.disease ,Immune checkpoint ,Blockade ,Histone Deacetylase Inhibitors ,Mice, Inbred C57BL ,chemistry ,Urinary Bladder Neoplasms ,Benzamides ,Cancer research ,Commentary ,Immunotherapy ,business ,Immunocompetence ,Research Article - Abstract
Although immune-checkpoint inhibitors (ICIs) have been a remarkable advancement in bladder cancer treatment, the response rate to single-agent ICIs remains suboptimal. There has been substantial interest in the use of epigenetic agents to enhance ICI efficacy, although precisely how these agents potentiate ICI response has not been fully elucidated. We identified entinostat, a selective HDAC1/3 inhibitor, as a potent antitumor agent in our immune-competent bladder cancer mouse models (BBN963 and BBN966). We demonstrate that entinostat selectively promoted immune editing of tumor neoantigens, effectively remodeling the tumor immune microenvironment, resulting in a robust antitumor response that was cell autonomous, dependent upon antigen presentation, and associated with increased numbers of neoantigen-specific T cells. Finally, combination treatment with anti–PD-1 and entinostat led to complete responses and conferred long-term immunologic memory. Our work defines a tumor cell–autonomous mechanism of action for entinostat and a strong preclinical rationale for the combined use of entinostat and PD-1 blockade in bladder cancer.
- Published
- 2021
21. Successful Treatment With Scrambler Therapy for Radial and Femoral Nerve Injuries After Extracorporeal Membrane Oxygenation
- Author
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Thomas J. Smith, Marina Baretti, Mark Yarchoan, and Anna Ferguson
- Subjects
medicine.medical_specialty ,Text mining ,Femoral nerve ,Scrambler therapy ,business.industry ,medicine.medical_treatment ,Extracorporeal membrane oxygenation ,medicine ,General Medicine ,business ,Article ,Surgery - Published
- 2021
22. Precision Cancer Trials With Immunomodulatory Agents
- Author
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Nilofer S. Azad and Marina Baretti
- Subjects
0301 basic medicine ,Cancer Research ,MEDLINE ,Pembrolizumab ,Computational biology ,Medical Oncology ,DNA Mismatch Repair ,03 medical and health sciences ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Neoplasms ,Biomarkers, Tumor ,Humans ,Medicine ,Molecular Targeted Therapy ,Precision Medicine ,Clinical Trials as Topic ,business.industry ,Cancer ,medicine.disease ,Treatment efficacy ,Gene Expression Regulation, Neoplastic ,Clinical trial ,Important research ,Treatment Outcome ,030104 developmental biology ,Oncology ,Drug development ,030220 oncology & carcinogenesis ,Disease Susceptibility ,Nivolumab ,business ,Signal Transduction - Abstract
Advances in high-throughput technologies have yielded impressive insights into the molecular biology behind cancers, resulting in a powerful ally for the development of biomarkers-selected clinical trials, which are critical for translating our genomic knowledge into clinically meaningful outcomes. "Basket studies" or histology-agnostic clinical trials in biomarker-defined populations represent an important research strategy to continue making progress in this field. The recent accelerated US Food and Drug Administration approvals of anti-programmed death 1 pembrolizumab and nivolumab for mismatch repair-deficient cancers, as well as larotrectinib for cancers carrying TRK fusions, support the fundamental premise that some cancers may be best classified based on molecular phenotype and not site of origin. The studies that were conducted showing the efficacy of this approach serve as validation of the basket study paradigm. In the field of immune oncology, the advent of tumor agnostic strategies represents an important step toward discovering biomarkers of response and elucidating mechanisms of treatment efficacy and resistance across a variety of cancer types. We present a review and discussion of the progress in biomarker-defined approaches to drug development in immunology.
- Published
- 2019
23. The role of epigenetic therapies in colorectal cancer
- Author
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Marina Baretti and Nilofer S. Azad
- Subjects
Epigenomics ,0301 basic medicine ,Cancer Research ,Colorectal cancer ,Antineoplastic Agents ,Translational research ,Bioinformatics ,03 medical and health sciences ,medicine ,Animals ,Humans ,Epigenetics ,business.industry ,Acetylation ,Epigenome ,DNA Methylation ,medicine.disease ,digestive system diseases ,Chromatin ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Oncology ,DNA methylation ,Histone deacetylase ,Colorectal Neoplasms ,business ,Epigenetic therapy - Abstract
Although developments in the diagnosis and therapy of colorectal cancer (CRC) have been made in the last decade, much work remains to be done as it remains the second leading cause of cancer death. It is now well established that epigenetic events, together with genetic alterations, are key events in initiation and progression of CRC. Epigenetics refers to heritable alterations in gene expression that do not involve changes in the DNA sequence. These alterations include DNA methylation, histone alterations, chromatin remodelers, and noncoding RNAs. In CRC, aberrations in epigenome may also involve in the development of drug resistance to conventional drugs such as 5-fluorouracil, oxaliplatin, and irinotecan. Thus, it has been suggested that combined therapies with epigenetic agents may reverse drug resistance. In this regard, DNA methyltransferase inhibitors and histone deacetylase inhibitors have been extensively investigated in CRC. The aim of this review is to provide a brief overview of the preclinical data that represent a proof of principle for the employment of epigenetic agents in CRC with a focus on the advantages of combinatorial therapy over single-drug treatment. We will also critically discuss the results and limitations of initial clinical experiences of epigenetic-based therapy in CRC and summarize ongoing clinical trials. Nevertheless, since recent translational research suggest that epigenetic modulators play a key role in augmenting immunogenicity of the tumor microenvironment and in restoring immune recognition, we will also highlight the recent developments of combinations strategies of immunotherapies and epigenetic therapies in CRC, summarizing preclinical, and clinical data to signify this evolving and promising field for CRC treatment.
- Published
- 2018
24. 1470P Oral azacitidine (CC-486) in patients with resected pancreatic adenocarcinoma at high risk for recurrence
- Author
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T.R. Heumann, Nilofer S. Azad, Elizabeth A. Sugar, Colin D. Weekes, S. Liden, D.K. Monga, James M. Leatherman, N. Ahuja, A. Sharma, Peter O'Dwyer, T.Y. Lopez-Vidal, K.A. Reiss Binder, T. Miles, Marina Baretti, and J. Durhman
- Subjects
medicine.medical_specialty ,Oncology ,business.industry ,Internal medicine ,Medicine ,Adenocarcinoma ,In patient ,Hematology ,business ,medicine.disease ,Gastroenterology ,Oral Azacitidine - Published
- 2021
25. A phase 2 trial of gemcitabine and docetaxel in patients with metastatic colorectal adenocarcinoma with methylated checkpoint with forkhead and ring finger domain promoter and/or microsatellite instability phenotype
- Author
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Gerrit A. Meijer, Marianna Zahurak, Nilofer S. Azad, Thomas R. Pisanic, Tza-Huei Wang, Elske Gootjes, Rosalind Walker, Enusha Karunasena, Marina Baretti, Nita Ahuja, Yang Zhao, James G. Herman, Henk M.W. Verheul, Tim F. Greten, Austin G. Duffy, Internal medicine, and CCA - Cancer Treatment and quality of life
- Subjects
Oncology ,Male ,Colorectal cancer ,Cell Cycle Proteins ,Docetaxel ,Deoxycytidine ,Epigenesis, Genetic ,Tumours of the digestive tract Radboud Institute for Health Sciences [Radboudumc 14] ,CHFR ,Antineoplastic Combined Chemotherapy Protocols ,General Pharmacology, Toxicology and Pharmaceutics ,Poly-ADP-Ribose Binding Proteins ,Promoter Regions, Genetic ,education.field_of_study ,General Neuroscience ,General Medicine ,Articles ,Middle Aged ,Progression-Free Survival ,Neoplasm Proteins ,Response Evaluation Criteria in Solid Tumors ,Female ,Microsatellite Instability ,Public aspects of medicine ,RA1-1270 ,Colorectal Neoplasms ,medicine.drug ,medicine.medical_specialty ,Ubiquitin-Protein Ligases ,Population ,Clinical Decision-Making ,RM1-950 ,Adenocarcinoma ,Proof of Concept Study ,General Biochemistry, Genetics and Molecular Biology ,Article ,Internal medicine ,medicine ,Biomarkers, Tumor ,Humans ,education ,Aged ,Taxane ,business.industry ,Research ,Microsatellite instability ,DNA Methylation ,medicine.disease ,Gemcitabine ,Drug Resistance, Neoplasm ,Therapeutics. Pharmacology ,business - Abstract
Contains fulltext : 235395.pdf (Publisher’s version ) (Open Access) We previously reported CHFR methylation in a subset of colorectal cancer (CRC; ∼30%) with high concordance with microsatellite instability (MSI). We also showed that CHFR methylation predicted for sensitivity to docetaxel, whereas the MSI-high phenotypes were sensitive to gemcitabine. We hypothesized that this subset of patients with CRC would be selectively sensitive to gemcitabine and docetaxel. We enrolled a Phase 2 trial of gemcitabine and docetaxel in patients with MSI-high and/or CHFR methylated CRC. The primary objective was Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response rate. Enrolled patients were treated with gemcitabine 800 mg/m(2) on days 1 and 8 and docetaxel 70 mg/m(2) on day 8 of each 21-day cycle. A total of 6 patients with CHFR-methylated, MSI-high CRC were enrolled from September 2012 to August 2016. The study was closed in September of 2017 due to poor accrual prior to reaching the first interim assessment of response rate, which would have occurred at 10 patients. No RECIST criteria tumor responses were observed, with 3 patients (50%) having stable disease as best response, 1 lasting more than 9 months. Median progression-free survival (PFS) was 1.79 months (95% confidence interval [CI] = 1.28, not available [NA]) and median overall survival (OS) was 15.67 months (95% CI = 4.24, NA). Common grade 3 toxicities were lymphopenia (67%), leukopenia (33%), and anemia (33%). Although negative, this study establishes a proof-of-concept for the implementation of epigenetic biomarkers (CHFR methylation/MSI) as inclusion criteria in a prospective clinical trial to optimize combinatorial strategies in the era of personalized medicine. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? CHFR silencing via DNA methylation has been suggested to be predictive of taxane sensitivity in diverse tumors. The frequent association of CHFR methylation with microsatellite instability (MSI) suggested a possible combination therapy with gemcitabine, because the MSI phenotype may result in sensitivity to nucleoside analogues. WHAT QUESTION DID THIS STUDY ADDRESS? We hypothesized that metastatic colorectal cancer (mCRC), which have CHFR methylation and MSI phenotype were sensitive to gemcitabine and docetaxel, and have designed this Phase 2 trial in biomarker-selected mCRC to test this prediction. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? The study enrolled a molecularly defined subgroup of patients with colorectal cancer (CRC) and showed that the combination is safe in this population. Nevertheless, due to poor enrollment and early termination, no conclusions on the primary and secondary end points could be made. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? This study supports the feasibility of implementing DNA methylation markers in a prospective clinical trial and further efforts toward their application as predictive biomarkers for therapeutic agents in defined subsets of patients are warranted.
- Published
- 2020
26. DNA mismatch repair in cancer
- Author
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Dung T. Le and Marina Baretti
- Subjects
0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,DNA Mismatch Repair ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,Cancer immunotherapy ,Neoplasms ,Tumor Microenvironment ,Humans ,Medicine ,Pharmacology (medical) ,Epigenetics ,neoplasms ,Pharmacology ,business.industry ,nutritional and metabolic diseases ,Microsatellite instability ,Immunotherapy ,medicine.disease ,Phenotype ,digestive system diseases ,Lynch syndrome ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,Microsatellite Instability ,DNA mismatch repair ,business - Abstract
Microsatellite instability (MSI) refers to the hypermutator phenotype secondary to frequent polymorphism in short repetitive DNA sequences and single nucleotide substitution, as consequence of DNA mismatch repair (MMR) deficiency. MSI secondary to germline mutation in DNA MMR proteins is the molecular fingerprint of Lynch syndrome (LS), while epigenetic inactivation of these genes is more commonly found in sporadic MSI tumors. MSI occurs at different frequencies across malignancies, although original methods to assess MSI or MMR deficiency have been developed mostly in LS related cancers. Here we will discuss the current methods to detect MSI/MMR deficiency with a focus of new tools which are emerging as highly sensitive detector for MSI across multiple tumor types. Due to high frequencies of non-synonymous mutations, the presence of frameshift-mutated neoantigens, which can trigger a more robust and long-lasting immune response and strong TIL infiltration with tumor eradication, MSI has emerged as an important predictor of sensitivity for immunotherapy-based strategies, as showed by the recent FDA's first histology agnostic-accelerated approval to immune checkpoint inhibitors for refractory, adult and pediatric, MMR deficient (dMMR) or MSI high (MSI-H) tumors. Moreover, it is known that MSI status may predict cancer response/resistance to certain chemotherapies. Here we will describe the complex interplay between the genetic and clinical-pathological features of MSI/dMMR tumors and the cancer immunotherapy, with a focus on the predictive and prognostic role of MMR status for immune checkpoint inhibitors (ICIs) and providing some suggestions on how to conceive better predictive markers for immunotherapy in the next future.
- Published
- 2018
27. An analysis of genetic heterogeneity in untreated cancers
- Author
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Jeffrey M. Gerold, Kenneth W. Kinzler, Alvin Makohon-Moore, Christine A. Iacobuzio-Donahue, Martin A. Nowak, Nilofer S. Azad, Johannes G. Reiter, Adil Daud, Bert Vogelstein, and Marina Baretti
- Subjects
Skin Neoplasms ,General Mathematics ,Biopsy ,Biology ,medicine.disease_cause ,Medical Oncology ,Medical and Health Sciences ,Article ,Epigenesis, Genetic ,03 medical and health sciences ,Genetic Heterogeneity ,0302 clinical medicine ,Text mining ,Genetic ,medicine ,Genetics ,Animals ,Humans ,2.1 Biological and endogenous factors ,Clinical significance ,Oncology & Carcinogenesis ,Neoplasm Metastasis ,Aetiology ,Gene ,Epigenesis ,Cancer ,Mutation ,Clinical Trials as Topic ,screening and diagnosis ,medicine.diagnostic_test ,Genetic heterogeneity ,business.industry ,Applied Mathematics ,medicine.disease ,4.1 Discovery and preclinical testing of markers and technologies ,Detection ,030220 oncology & carcinogenesis ,Cancer research ,business - Abstract
Genetic intratumoural heterogeneity is a natural consequence of imperfect DNA replication. Any two randomly selected cells, whether normal or cancerous, are therefore genetically different. Here, we review the different forms of genetic heterogeneity in cancer and re-analyse the extent of genetic heterogeneity within seven types of untreated epithelial cancers, with particular regard to its clinical relevance. We find that the homogeneity of predicted functional mutations indriver genes is the rule rather than the exception. In primary tumours with multiple samples, 97% of driver-gene mutations in 38 patients were homogeneous. Moreover, among metastases from the same primary tumour, 100% of the driver mutations in 17 patients were homogeneous. With a single biopsy of a primary tumour in 14 patients, the likelihood of missing a functional driver-gene mutation that was present in all metastases was 2.6%. Furthermore, all functional driver-gene mutations detected in these 14 primary tumours were present among all their metastases. Finally, we found that individual metastatic lesions responded concordantly to targeted therapies in 91% of 44patients. These analyses indicate that the cells within the primary tumours that gave rise to metastases are genetically homogeneous with respect to functional driver-gene mutations, and we suggest that future efforts to develop combination therapies have the potential to be curative.
- Published
- 2019
28. The Significance of Ascites in Patients With Pancreatic Ductal Adenocarcinoma: A Case-Control Study
- Author
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Dung T. Le, Amol Narang, Bhargavi Pulluri, Christopher L. Wolfgang, Hua Ling Tsai, Lei Zheng, Daniel A. Laheru, Marina Baretti, Amanda L. Blackford, Ana De Jesus-Acosta, and Joseph M. Herman
- Subjects
Adult ,Male ,medicine.medical_specialty ,Pancreatic ductal adenocarcinoma ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,Kaplan-Meier Estimate ,Gastroenterology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Pancreatectomy ,Internal medicine ,Ascites ,Internal Medicine ,Carcinoma ,medicine ,Humans ,In patient ,Aged ,Proportional Hazards Models ,Retrospective Studies ,Aged, 80 and over ,Hepatology ,Proportional hazards model ,business.industry ,Case-control study ,Retrospective cohort study ,Middle Aged ,medicine.disease ,Prognosis ,digestive system diseases ,Pancreatic Neoplasms ,030220 oncology & carcinogenesis ,Localized disease ,Case-Control Studies ,030211 gastroenterology & hepatology ,Female ,medicine.symptom ,business ,Carcinoma, Pancreatic Ductal - Abstract
OBJECTIVE: Limited data exist on the impact of ascites in pancreatic ductal adenocarcinoma (PDAC). We evaluated the survival outcomes of patients with PDAC and ascites. METHODS: Retrospective, single-institution, case-control study including patients with newly diagnosed PDAC from 2007 to 2016. One hundred fifty-four patients with ascites at diagnosis (case group) and 154 controls were matched on age, sex, stage, Eastern Cooperative Oncology Group performance, surgical treatment, lymph node, and margin status. Ascites was defined as computed tomography–detected fluid in the pelvic/peritoneal cavity. Overall survival was compared between groups via Cox proportional hazards models with a gamma frailty term to account for the correlation between matched pairs on entire cohort and by disease stages for subgroup analysis. RESULTS: The 154 matched cases included 24 resectable, 19 borderline resectable, 51 locally advanced, and 60 metastatic disease. Patients with ascites had higher risk of death compared with those without (conditional hazard ratio, 1.58; 95% confidence interval, 1.23–2.03; P < 0.001). Stratified analysis showed a significant association between ascites and poor prognosis in patients with localized disease (conditional hazard ratio, 1.62; 95% confidence interval, 1.18–2.24; P = 0.003). CONCLUSIONS: Radiographic ascites is a poor prognostic factor in PDAC. Our findings may aid physicians in considering systemic therapy prior to attempting local treatments.
- Published
- 2019
29. Clinical value of chip-based digital-PCR platform for the detection of circulating DNA in metastatic colorectal cancer
- Author
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David Sefrioui, Nasrin Sarafan-Vasseur, Ludivine Beaussire, Marina Baretti, Alice Gangloff, France Blanchard, Florian Clatot, Jean-Christophe Sabourin, Richard Sesboüé, Thierry Frebourg, Pierre Michel, Frédéric Di Fiore, Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hépato-Gastroentérologie [CHU Rouen], Hôpital Charles Nicolle [Rouen]-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Groupe d'étude des proliférations lymphoïdes (GPL), and Service d'Anatomie et Cytologie Pathologique [CHU Rouen]
- Subjects
Adult ,Male ,Oncology ,medicine.medical_specialty ,Colorectal cancer ,[SDV]Life Sciences [q-bio] ,Kaplan-Meier Estimate ,Polymerase Chain Reaction ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Mutational status ,Digital polymerase chain reaction ,Neoplasm Metastasis ,ComputingMilieux_MISCELLANEOUS ,Aged ,030304 developmental biology ,Aged, 80 and over ,0303 health sciences ,Hepatology ,business.industry ,Gastroenterology ,Cancer ,DNA, Neoplasm ,Middle Aged ,Prognosis ,medicine.disease ,Molecular biology ,3. Good health ,Survival Rate ,Genes, ras ,chemistry ,Quartile ,030220 oncology & carcinogenesis ,Mutation ,Clinical value ,Circulating DNA ,Female ,Colorectal Neoplasms ,business ,DNA - Abstract
The detection of circulating DNA is considered a promising strategy in cancer patients. Digital PCR has emerged as a sensitive method able to quantify both circulating free and tumour DNA.The aim of this study was to prospectively evaluate the clinical value of a chip-based digital PCR for the detection of circulating DNA.Digital PCR was used in 34 metastatic colorectal cancer patients to detect and quantify circulating free and tumour DNA based on K-ras mutational status. Clinical outcomes were analyzed according to circulating DNA measurements.Digital PCR yielded a detection rate of 69% for circulating tumour DNA. The median concentrations of circulating free and tumour DNA were 20 and 6.8 ng/mL, respectively, with significant correlation between both biomarkers (p0.001). Median overall survival was 4.8 months in patients with high circulating free DNA (75% quartile) versus not reached in patients with a low level (25% quartile) (p=0.029). Moreover, median overall survival was significantly decreased in patients with detectable circulating tumour DNA compared to those without (respectively 11.8 months versus not reached, p=0.04).Chip-based digital PCR is a simple and non-invasive method allowing the efficient detection of circulating DNA. Our results highlight that levels of these circulating markers may have a potential prognostic value.
- Published
- 2015
30. SILVELUL project: Immunohistochemical panel analyses as potential predictive and prognostic factors in pancreatic neuroendocrine tumours (PanNET) treated with CAPTEM or everolimus
- Author
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Imanol Arozarena, Maria Luisa Gomez-Dorronsoro, Saioa Goñi, M. Benavent, A. De Jesus-Acosta, V. Alonso, G. Crespo Herrero, V. Arrazubi Arrula, Marta Llanos, Ana Custodio, Marina Baretti, Iranzu González-Borja, B. López de San Vicente, C. López, R. Grandez, M.C. Riesco Martínez, A. Viudez, A. Carmona Bayonas, and P. Jiménez-Fonseca
- Subjects
Oncology ,medicine.medical_specialty ,Prognostic factor ,Everolimus ,Clinical variables ,business.industry ,O-6-methylguanine-DNA methyltransferase ,Hematology ,Prognostic score ,Internal medicine ,Distribution pattern ,medicine ,Immunohistochemistry ,In patient ,business ,medicine.drug - Abstract
Background Previously our group showed the potential use of a score based on MGMT, NDRG-1 and PHLDA-3 immunohistochemistry (IHC) expression as predictor of outcome in operated PanNET. The present multicenter project is retrospectively analyzing the predictive/prognosis role of MGMT, NDRG-1 and PHLDA-3 in patients with advanced PanNET treated CAPTEM or everolimus. Methods IHC nuclear staining for MGMT and PHLDA-3 is being scored as 0, 1-5%, 6-50% and ≥ 51%. For NDRG-1, we are using a cytoplasmic score from 0 to 3 based on staining intensity and distribution pattern (patched or diffuse). Results Until now, clinical and samples data from 96 patients (110 samples) has been collected ad are currently being analyzed. Based on our previous results, we will develop an imunohistochemistry prognostic score (IPS, score from 0 to 4) and try to correlate it with clinical variables collected in our database. Conclusions As we described previously in operated PanNET, we will try to describe the potential role of IPS as predictive/ prognostic factor in advanced PanNET. More mature results of this work will be presented during 2019 ESMO Congress. Legal entity responsible for the study Navarrabiomed Biomedical Research Center, Pamplona, Navarra, Spain. Funding GETNE. Disclosure All authors have declared no conflicts of interest.
- Published
- 2019
31. Targeting the epigenome of pancreatic cancer for therapy: challenges and opportunities
- Author
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Marina Baretti, Nita Ahuja, and Nilofer S. Azad
- Subjects
Tumor microenvironment ,business.industry ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Disease ,Epigenome ,Immunotherapy ,medicine.disease ,Chromatin ,Therapeutic approach ,Endocrinology ,Oncology ,Pancreatic cancer ,Internal Medicine ,medicine ,Cancer research ,Epigenetics ,business - Abstract
In 2018, there was an estimated 55,440 new cases of pancreatic adenocarcinoma (PDAC) in the United States. Generally, most new cases are in an advanced stage, usually due to the lack of symptoms during the early stages of the disease. Currently, the vast majority of therapeutic regimens have shown only modest effects in this setting, and median survival ranges from 6 to 11 months. Indeed, better therapies for these patients are urgently needed. Epigenetics refers to the somatically heritable differences in gene expression not attributable to intrinsic alterations in the primary sequence of DNA. Core elements of the epigenetic regulation of gene expression include how DNA is packaged around nucleosomes, how chromatin and nucleosomes are modified by a complex series of enzymes and their subsequent interactions with proteins that recognize these modifications. The recognition of the essential role of epigenetic alterations in the development and progression of PDAC has revolutionized our knowledge of this disease and has immediate translational implications for targeting epigenetic abnormalities in PDAC for therapeutic purposes. Moreover, recent work with epigenetic modulatory drugs (EMDs) has shown that these agents may be capable of altering the immunogenicity of the tumor microenvironment (TME), to reverse immune suppression and to ‘prime’ tumors for immunotherapy. This review summarizes the current knowledge of epigenetic alterations in PDAC with a focus on the translational application of targeting epigenetic-based events as new therapeutic approach for this disease.
- Published
- 2019
32. AB049. P-17. A phase II study of HDAC inhibition to sensitize to immunotherapy in advanced cholangiocarcinoma
- Author
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Brian J. Christmas, Jennifer N. Durham, Marina Baretti, Nilofer S. Azad, Elizabeth M. Jaffee, Rosalind Walker, and Leslie Cope
- Subjects
business.industry ,medicine.medical_treatment ,Poster Abstracts ,medicine ,Cancer research ,Phases of clinical research ,Immunotherapy ,business - Abstract
BACKGROUND: Immune checkpoint inhibitors (ICIs) have unlocked the promise of modulating the immune tumor microenvironment (TME) in the battle against cancer, but it remains unclear whether they might be useful for cholangiocarcinoma (CCA). Our laboratory has explored entinostat, a histone deacetylase inhibitor (HDACi) to alter the function of suppressive myeloid derived suppressor cells (MDSC) in favor of recruiting T cells in murine pancreatic ductal adenocarcinoma (PDAC) models, showing improved survival when given with anti-PD1 therapy. We hypothesize that the HDACi entinostat may prime an ICI-insensitive cancer into a more sensitive one. METHODS: An open-label, two-arm study enrolling patients with histologically confirmed advanced CCA or PDAC, who have progressed after at least one line of therapy. Eligibility criteria include measurable disease, PS ≤1, good end organ function and no history of autoimmune disease. Patients receive entinostat 5 mg oral once a week. After a fourteen-day lead in with entinostat monotherapy, patients receive entinostat 5 mg oral once a week plus nivolumab 240 mg every two weeks until progression or unacceptable toxicities. Patients undergo tumor biopsy and have research bloods drawn at baseline and after two weeks of entinostat lead-in therapy, and on week 6. An optional biopsy is performed at the time of progression. The study is planned with 27 subjects per histology based on a Simon’s two-stage design that allows early termination for lack of efficacy. The primary objective of the trial is ORR, by RECIST 1.1. Secondary objectives include PFS, OS, safety and immunological correlates to evaluate the effect of HDAC inhibition on the TME by interrogating clinical specimens. RESULTS: The clinical study has been activated in November 2017. The accrual is still ongoing. Ten patients with a diagnosis of CCA and 22 with PDAC have been enrolled. Blood samples and tumor biopsies are being drawn, processed, and stored for accrued patients. The analysis will be performed in a single batched analysis at the conclusion of the study accrual. CONCLUSIONS: This clinical trial is the first to test HDAC + immune checkpoint inhibition in pancreatobiliary cancers. If our project is successful, we have the potential to increase therapeutic options for CCA and PDAC patients (clinical trial information: NCT03250273).
- Published
- 2019
33. Chemoradiation-induced alteration of programmed death-ligand 1 and CD8+ tumor-infiltrating lymphocytes in rectal cancer
- Author
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Wei Fu, Robert A. Anders, Qingfeng Zhu, Hao Wang, Nilofer S. Azad, and Marina Baretti
- Subjects
Cancer Research ,DNA damage ,Colorectal cancer ,business.industry ,Tumor-infiltrating lymphocytes ,medicine.medical_treatment ,Ligand (biochemistry) ,medicine.disease ,Radiation therapy ,Immune system ,Oncology ,Cancer research ,medicine ,business ,CD8 ,Programmed death - Abstract
570 Background: DNA damage and subsequent neoantigen formation has been hypothesized as a mechanismfor radiotherapy and PD-1/PD-L1 pathway inhibition to synergize in an antitumor immune response. We investigated neoadjuvant chemoradiotherapy (nCRT)-induced changes in CD8+ tumor infiltrating lymphocyte, PD-L1 and mucin expression in rectal cancer patients as compared to patients who did not receive nCRT. Methods: Tumor samples were collected from rectal adenocarcinoma patients who had undergone resection between 2008-2014 with (n = 62) or without (n = 17) nCRT treatment. Tissue sections were stained with CD8 and PD-L1 antibodies for immunohistochemistry. Whole slides images were acquired at 20x magnification. The prevalence of positive CD8 stained cells was recorded in tumor, interface tumor side, interface background rectal side. Image analysis (HALO Indica Labs) was used to determine the density (# of cells/surface area analyzed) of CD8 expressing lymphocytes. The percentage of PD-L1 membranous expression was manually counted in tumor cells (TC), tumor stroma (TS) and invasive front (IF). Mucin expression was determined as the percentage of the mucin area in the whole tumor mass area. Results: PD-L1 expression on TCs was identified in 7.7 % (6/78) of specimens. All 6 cases had received nCRT (p = 0.33). 80% and 75.5% of the nCRT cases showed PD-L1 expression on TS and IF respectively, versus 20% (p = 0.55) and 24.5% (p = 0.56) in non-nCRT cases. The median densities of CD8+ infiltrating T lymphocytes in tumor, interface tumor side, interface background rectal side did not differ significantly between the two groups (p = 0.79, p = 0.47, p = 0.22). No nCRT-changes in mucin expression observed in the 28 evaluable cases (p = 0.25). Conclusions: nCRT exposure was associated with a non-significant difference in PD-L1 expression on TS and IF cells in patients with rectal adenocarcinoma as compared to non-nCRT case, possibly due to sample size limitations. Further mechanistic investigations and comprehensive analysis of other immune checkpoints are needed to understand nCRT-induced immunologic shift in rectal cancer and to expand the potential applicability of checkpoint inhibitors in this setting.
- Published
- 2019
34. The impact of the immune microenvironment in patients with GEP-NETs
- Author
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Robert A. Anders, Marianna Zahurak, Marina Baretti, Qingfeng Zhu, Timothy M. Pawlik, and Ana De Jesus-Acosta
- Subjects
Cancer Research ,Immune system ,Oncology ,business.industry ,Immune microenvironment ,Cancer research ,medicine ,In patient ,Neuroendocrine tumors ,medicine.disease ,business - Abstract
267 Background: The immune microenvironment in neuroendocrine tumors (NETs) remains largely unexplored with very limited data evaluating its impact on survival. We aimed to characterize the immune microenvironment and lymphocytic infiltrate in patients with gastroenteropancreatic (GEP) NET. Methods: We performed comprehensive immune profiling for CD3, CD8, PD-1, IDO, and PD-L1 expression in two cohorts of patients with primary GEP-NET: patients who had short progression free survival (PFS) ≤ 4 years (n = 12) or long PFS > 4 years (n = 14) following surgical resection. Tumor associated immune infiltrates in the tumor, inner and outer invasive front were recorded and quantified. The percentage of PD-L1 membranous expression was manually counted in tumor, stroma and invasive front. To account for the correlation among multiple samples within the same patient, generalized estimating equations (GEE) were used for model estimation and hypothesis testing. Results: Patients with shorter PFS had larger primary tumor size compared to patients with longer PFS (Wilcoxon p value = 0.02), with no statistically significant differences in Ki-67 expression. For all patients univariate GEE results showed a higher mean expression of CD3+, CD8+, and PD-1+ cells at the interface (inner and outer) as compared to the tumor region: 1.28 (95% CI: 0.98, 1.58, p < 0.0001), 0.99 (95% CI: 0.67, 1.32, p = 0.0005) and 1.38 (95% CI: 0.90, 1.38, p < 0.0001) respectively. Comparison between the two groups showed that tumors from patients with a longer PFS had higher intratumoral CD3+ TILs densities than did those from patients who had a shortened PFS (0.88, 95% CI: 0.44, 1.31, p = 0.004). Intratumoral expression of CD8+TILs, and IDO+ cells tended to be higher in the long PFS group (p = 0.143 and 0.29 respectively). While the probability of positive PD-L1 expression did not differ according to location, it was higher in patients with shortened PFS (odds ratio = 1.96; 95% CI: 0.64, 5.93), though not significant. Conclusions: Higher intratumoral T cell infiltrate (CD3+) is associated with a favorable outcome and longer PFS following resection for GEP-NETs. Immune escape is a potential mechanism for disease progression and warrants further investigation as a therapeutic strategy for this disease.
- Published
- 2019
35. Entinostat in combination with nivolumab for patients with advanced cholangiocarcinoma and pancreatic adenocarcinoma
- Author
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Nilofer S. Azad, Elizabeth M. Jaffee, Brian Christmas, Rosalind Walker, Leslie Cope, Amber-Lynn Mitcheltree, Jennifer N. Durham, and Marina Baretti
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Entinostat ,business.industry ,medicine.medical_treatment ,medicine.disease ,chemistry.chemical_compound ,Immune system ,chemistry ,Cancer immunotherapy ,Internal medicine ,medicine ,Adenocarcinoma ,Nivolumab ,Antibody therapy ,business - Abstract
TPS4151Background: The use of antibody therapy targeting immune checkpoints has become a major focus of cancer immunotherapy, with the most compelling activity seen in the minority of patients with...
- Published
- 2018
36. Prognostic and predictive value of MET deregulation in non-small cell lung cancer
- Author
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Giovanna, Finocchiaro, Luca, Toschi, Letizia, Gianoncelli, Marina, Baretti, and Armando, Santoro
- Subjects
Review Article - Abstract
Recent progress in cancer biology has led to the discovery of increasing number of oncogene alterations that have dramatically changed the paradigm of lung cancer treatment. MET is a tyrosine kinase receptor for the hepatocyte growth factor (HGF) that is deregulated in several malignancies, including non-small cell lung cancer (NSCLC). Abnormal MET-HGF signaling pathway activation can occur via different mechanisms, including HGF and/or MET overexpression, MET gene amplification, mutations or rearrangements. MET protein overexpression and increased MET gene number have been identified as poor prognostic factors in several series of surgically resected NSCLC making this receptor an attractive target for cancer treatment. Several clinical trials have recently evaluated the activity of a variety of anti-MET strategies in NSCLC patients with or without molecular selection with a variable degree of success, underscoring the need of establishing the best predictive biomarker for the identification of responding patients.
- Published
- 2015
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