Try a new search

Format these results:

Searched for:

person:ea691

in-biosketch:true

Total Results:

17


Promoter methylation of ADAMTS1 and BNC1 as potential biomarkers for early detection of pancreatic cancer in blood

Eissa, Maryam A L; Lerner, Lane; Abdelfatah, Eihab; Shankar, Nakul; Canner, Joseph K; Hasan, Nesrin M; Yaghoobi, Vesal; Huang, Barry; Kerner, Zachary; Takaesu, Felipe; Wolfgang, Christopher; Kwak, Ruby; Ruiz, Michael; Tam, Matthew; Pisanic, Thomas R; Iacobuzio-Donahue, Christine A; Hruban, Ralph H; He, Jin; Wang, Tza-Huei; Wood, Laura D; Sharma, Anup; Ahuja, Nita
BACKGROUND:Despite improvements in cancer management, most pancreatic cancers are still diagnosed at an advanced stage. We have recently identified promoter DNA methylation of the genes ADAMTS1 and BNC1 as potential blood biomarkers of pancreas cancer. In this study, we validate this biomarker panel in peripheral cell-free tumor DNA of patients with pancreatic cancer. RESULTS:Sensitivity and specificity for each gene are as follows: ADAMTS1 87.2% and 95.8% (AUC = 0.91; 95% CI 0.71-0.86) and BNC1 64.1% and 93.7% (AUC = 0.79; 95% CI 0.63-0.78). When using methylation of either gene as a combination panel, sensitivity increases to 97.3% and specificity to 91.6% (AUC = 0.95; 95% CI 0.77-0.90). Adding pre-operative CA 19-9 values to the combined two-gene methylation panel did not improve sensitivity. Methylation of ADAMTS1 was found to be positive in 87.5% (7/8) of stage I, 77.8% (7/9) of stage IIA, and 90% (18/20) of stage IIB disease. Similarly, BNC1 was positive in 62.5% (5/8) of stage I patients, 55.6% (5/9) of stage IIA, and 65% (13/20) of patients with stage IIB disease. The two-gene panel (ADAMTS1 and/or BNC1) was positive in 100% (8/8) of stage I, 88.9% (8/9) of stage IIA, and 100% (20/20) of stage IIB disease. The sensitivity and specificity of the two-gene panel for localized pancreatic cancer (stages I and II), where the cancer is eligible for surgical resection with curative potential, was 94.8% and 91.6% respectively. Additionally, the two-gene panel exhibited an AUC of 0.95 (95% CI 0.90-0.98) compared to 57.1% for CA 19-9 alone. CONCLUSION:The methylation status of ADAMTS1 and BNC1 in cfDNA shows promise for detecting pancreatic cancer during the early stages when curative resection of the tumor is still possible. This minimally invasive blood-based biomarker panel could be used as a promising tool for diagnosis and screening in a select subset of high-risk populations.
PMCID:6451253
PMID: 30953539
ISSN: 1868-7083
CID: 4741092

Postoperative complications following intraoperative radiotherapy in abdominopelvic malignancy: A single institution analysis of 113 consecutive patients

Abdelfatah, Eihab; Page, Andrew; Sacks, Justin; Pierorazio, Phillip; Bivalacqua, Trinity; Efron, Jonathan; Terezakis, Stephanie; Gearhart, Susan; Fang, Sandy; Safar, Bashar; Pawlik, Timothy M; Armour, Elwood; Hacker-Prietz, Amy; Herman, Joseph; Ahuja, Nita
BACKGROUND:Intraoperative radiotherapy (IORT) has advantages over external beam radiation therapy (EBRT). Few studies have described side effects associated with its addition. We evaluated our institution's experience with abdominopelvic IORT to assess safety by postoperative complication rates. METHODS:Prospectively collected IRB-approved database of all patients receiving abdominopelvic IORT (via high dose rate brachytherapy) at Johns Hopkins Hospital between November 2006 and May 2014 was reviewed. Patients were discussed in multidisciplinary conferences. Those selected for IORT were patients for whom curative intent resection was planned for which IORT could improve margin-negative resection and optimize locoregional control. Perioperative complications were classified via Clavien-Dindo scale for postoperative surgical complications. RESULTS:A total of 113 patients were evaluated. Most common diagnosis was sarcoma (50/113, 44%) followed by colorectal cancer (45/113, 40%), most of which were recurrent (84%). There were no perioperative deaths. A total of 57% of patients experienced a complication Grade II or higher: 24% (27/113) Grade II; 27% (30/113) Grade III; 7% (8/113) Grade IV. Wound complications were most common (38%), then gastrointestinal (25%). No radiotherapy variables were significantly associated with complications on uni/multi-variate analysis. CONCLUSIONS:Our institution's experience with IORT demonstrated historically expected postoperative complication rates. IORT is safe, with acceptable perioperative morbidity.
PMCID:5572190
PMID: 28252805
ISSN: 1096-9098
CID: 5272272

Patterns of PD-L1 expression and CD8 T cell infiltration in gastric adenocarcinomas and associated immune stroma

Thompson, Elizabeth D; Zahurak, Marianna; Murphy, Adrian; Cornish, Toby; Cuka, Nathan; Abdelfatah, Eihab; Yang, Stephen; Duncan, Mark; Ahuja, Nita; Taube, Janis M; Anders, Robert A; Kelly, Ronan J
OBJECTIVE:Recent data supports a significant role for immune checkpoint inhibitors in the treatment of solid tumours. Here, we evaluate gastric and gastro-oesophageal junction (G/GEJ) adenocarcinomas for their expression of programmed death-ligand 1 (PD-L1), infiltration by CD8+ T cells and the relationship of both factors to patient survival. DESIGN:Thirty-four resections of primary invasive G/GEJ were stained by immunohistochemistry for PD-L1 and CD8 and by DNA in situ hybridisation for Epstein-Barr virus (EBV). CD8+ T cell densities both within tumours and at the tumour-stromal interface were analysed using whole slide digital imaging. Patient survival was evaluated according to PD-L1 status and CD8 density. RESULTS:) were associated with worse progression-free survival (PFS) and overall survival (OS). CONCLUSIONS:PD-L1 is expressed on both tumour cells and in the immune stroma across all stages and histologies of G/GEJ. Surprisingly, we demonstrate that increasing CD8 infiltration is correlated with impaired PFS and OS. Patients with higher CD8+ T cell densities also have higher PD-L1 expression, indicating an adaptive immune resistance mechanism may be occurring. Further characterisation of the G/GEJ immune microenvironment may highlight targets for immune-based therapy.
PMID: 26801886
ISSN: 1468-3288
CID: 5305512

Hypomethylating agents synergize with irinotecan to improve response to chemotherapy in colorectal cancer cells

Sharma, Anup; Vatapalli, Rajita; Abdelfatah, Eihab; Wyatt McMahon, K; Kerner, Zachary; A Guzzetta, Angela; Singh, Jasvinder; Zahnow, Cynthia; B Baylin, Stephen; Yerram, Sashidhar; Hu, Yue; Azad, Nilofer; Ahuja, Nita
Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. In the metastatic setting, the majority of patients respond to initial therapies but eventually develop resistance and progress. In this study, we test the hypothesis that priming with epigenetic therapy sensitizes CRC cell lines, which were previously resistant to subsequent chemotherapeutic agents. When multiple CRC cell lines are first exposed to 500 nM of the DNA demethylating agent, 5-aza-cytidine (AZA) in-vitro, and the cells then established as in-vivo xenografts in untreated NOD-SCID mice; there is an enhanced response to cytotoxic chemotherapy with agents commonly used in CRC treatment. For irinotecan (IRI), growth diminished by 16-62 fold as assessed, by both proliferation (IC50) and anchorage independent cell growth soft agar assays. Treatment of resistant HCT116 cell line along with in-vivo, for CRC line xenografts, AZA plus IRI again exhibits this synergistic response with significant improvement in survival and tumor regression in the mice. Genome-wide expression correlates changes in pathways for cell adhesion and DNA repair with the above responses. A Phase 1/2 clinical trial testing this concept is already underway testing the clinical efficacy of this concept in IRI resistant, metastatic CRC (NCT01896856).
PMID: 28445481
ISSN: 1932-6203
CID: 5305532

Long-term outcomes in treatment of retroperitoneal sarcomas: A 15 year single-institution evaluation of prognostic features

Abdelfatah, Eihab; Guzzetta, Angela A; Nagarajan, Neeraja; Wolfgang, Christopher L; Pawlik, Timothy M; Choti, Michael A; Schulick, Richard; Montgomery, Elizabeth A; Meyer, Christian; Thornton, Katherine; Herman, Joseph; Terezakis, Stephanie; Frassica, Deborah; Ahuja, Nita
BACKGROUND:Retroperitoneal sarcomas are connective tissue tumors arising in the retroperitoneum. Surgical resection is the mainstay of treatment. Debate has arisen over extent of resection, changes in histological classification/grading, and interest in incorporating radiotherapy. Therefore, we reviewed our institution's experience to evaluate prognostic factors. METHODS:Retrospective chart review of all primary RPS patients at Johns Hopkins Hospital from 1994 to 2010. Histologic diagnosis and grading were re-evaluated with current criteria. Prognostic factors for survival, and recurrence were assessed. RESULTS:One hundred thirty-one primary RPS patients met inclusion criteria. Median survival for patients who undergo en-bloc resection to negative margins (R0/R1) is 81.7 months. Surgical margins and grade were the most important factors for survival along with age, gender, presence of metastases and resection of ≥5 organs. Five-year survival for R0/R1 resection was 60%, similar to compartmental resection. Radiotherapy significantly decreased local recurrence (P = 0.026) on multivariate analysis. Grade in leiomyosarcomas and dedifferentiation in liposarcomas dictated patterns of local versus distal recurrence. CONCLUSIONS:En bloc surgical resection to R0/R1 margins remains the cornerstone of therapy and provides comparable outcomes to compartmental resections. Grade remains important for prognosis, and histology dictates recurrence patterns. Radiotherapy appears promising for local control and warrants further investigation. J. Surg. Oncol. 2016;114:56-64. © 2016 Wiley Periodicals, Inc.
PMCID:4917421
PMID: 27076350
ISSN: 1096-9098
CID: 4743652

Epigenetic therapy in gastrointestinal cancer: the right combination

Abdelfatah, Eihab; Kerner, Zachary; Nanda, Nainika; Ahuja, Nita
Epigenetics is a relatively recent field of molecular biology that has arisen over the past 25 years. Cancer is now understood to be a disease of widespread epigenetic dysregulation that interacts extensively with underlying genetic mutations. The development of drugs targeting these processes has rapidly progressed; with several drugs already FDA approved as first-line therapy in hematological malignancies. Gastrointestinal (GI) cancers possess high degrees of epigenetic dysregulation, exemplified by subtypes such as CpG island methylator phenotype (CIMP), and the potential benefit of epigenetic therapy in these cancers is evident. The application of epigenetic drugs in solid tumors, including GI cancers, is just emerging, with increased understanding of the cancer epigenome. In this review, we provide a brief overview of cancer epigenetics and the epigenetic targets of therapy including deoxyribonucleic acid (DNA) methylation, histone modifications, and chromatin remodeling. We discuss the epigenetic drugs currently in use, with a focus on DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors, and explain the pharmacokinetic and mechanistic challenges in their application. We present the strategies employed in incorporating these drugs into the treatment of GI cancers, and explain the concept of the cancer stem cell in epigenetic reprogramming and reversal of chemo resistance. We discuss the most promising combination strategies in GI cancers including: (1) epigenetic sensitization to radiotherapy, (2) epigenetic sensitization to cytotoxic chemotherapy, and (3) epigenetic immune modulation and priming for immune therapy. Finally, we present preclinical and clinical trial data employing these strategies thus far in various GI cancers including colorectal, esophageal, gastric, and pancreatic cancer.
PMCID:4913338
PMID: 27366224
ISSN: 1756-283x
CID: 5305522

Prognostic epigenetics

Chapter by: Abdelfatah, Eihab; Sharma, A; El Eissa, M; Ahuja, N
in: Medical epigenetics by Tollefsbol, Trygve O [Ed]
Amsterdam : Elsevier/Academic Press, [2016]
pp. -
ISBN: 9780128032398
CID: 5328342