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Pancreatic Neoplasms: HELP
Articles by Burcu Saka
Based on 15 articles published since 2010
(Why 15 articles?)
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Between 2010 and 2020, B. Saka wrote the following 15 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Molecular genetics of pancreatic neoplasms and their morphologic correlates: an update on recent advances and potential diagnostic applications. 2014

Reid, Michelle D / Saka, Burcu / Balci, Serdar / Goldblum, Andrew S / Adsay, N Volkan. ·Dept of Pathology, Emory University Hospital, 1364 Clifton Rd, NE, Room H180, Atlanta, GA 30322; nadsay@emory.edu. ·Am J Clin Pathol · Pubmed #24436263.

ABSTRACT: OBJECTIVES: To summarize the most clinically and biologically relevant advances in molecular/genetic characteristics of various pancreatic neoplasms, with morphologic correlation. METHODS: Whole-exome sequencing of numerous benign and malignant pancreatic tumors, along with the plethora of highly sensitive molecular studies now available for analyzing these tumors, provide mounting evidence to support the long-held belief that cancer is essentially a genetic disease. These genetic discoveries have not only helped to confirm the age-old, morphology-based classifications of pancreatic neoplasia but have shed new light on their mechanisms. Many of these molecular discoveries are currently being used in preoperative diagnosis. RESULTS: Mutations in KRAS, P16/CDKN2A, TP53, and SMAD4/DPC4 are commonly seen in ductal neoplasia but not in nonductal tumors; ductal adenocarcinomas with SMAD4/DPC4 loss are associated with widespread metastasis and poor prognosis. GNAS and RNF43 mutations have been discovered in most intraductal pancreatic mucinous neoplasms, providing critical molecular fingerprints for their diagnosis. Mutation in DAXX/ATRX is only seen in pancreatic neuroendocrine tumors, making it a useful potential marker in distinguishing these tumors from mimics. CONCLUSIONS: When combined with morphologic observations, molecular studies will increase our understanding of the pathogenesis and morphomolecular signatures associated with specific neoplasms and provide new horizons for precision medicine and targeted therapies.

2 Review Neuroendocrine tumors of the pancreas: current concepts and controversies. 2014

Reid, Michelle D / Balci, Serdar / Saka, Burcu / Adsay, N Volkan. ·Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA. ·Endocr Pathol · Pubmed #24430597.

ABSTRACT: In the past decade, the clinico-pathologic characteristics of neuroendocrine tumors (NETs) in the pancreas have been further elucidated. Previously termed "islet cell tumors/carcinomas" or "endocrine neoplasms", they are now called pancreatic NETs (PanNETs). They occur in relatively younger patients and may arise anywhere in the pancreas. Some are associated with von Hippel-Lindau, MEN1, and other syndromes. It is now widely recognized that, with the exception of tumorlets (minute incipient neoplasms) that occur in some syndromes like MEN1, all PanNETs are malignant, albeit low-grade, and although they have a protracted clinical course and overall 10-year survival of 60-70 %, even low-stage and low-grade examples may recur and/or metastasize on long-term follow-up. Per recent consensus guidelines adopted by both European and North American NET Societies (ENETS and NANETs) and WHO-2010, PanNETs are now graded and staged separately, unlike previous classification schemes that used a combination of grade, stage, and adjunct prognosticators in an attempt to define "benign behavior" or "malignant" categories. For staging, the ENETs proposal may be more applicable than CAP/AJCC, which is based on the staging of exocrine tumors. Current grading of PanNETs is based on mitotic activity and ki-67 index. Other promising prognosticators such as necrosis, CK19, c-kit, and others are still under investigation. It has also been recognized that PanNETs have a rather wide morphologic repertoire including oncocytic, pleomorphic, ductulo-insular, sclerosing, and lipid-rich variants. Most PanNETs are diagnosed by fine needle aspiration biopsy, in which single, monotonous plasmacytoid cells with fair amounts of cytoplasm and distinctive neuroendocrine chromatin are diagnostic. Molecular alterations of PanNETs are also very different than that of ductal or acinar tumors. Loss of expression of DAXX and ATRX proteins has been recently identified in 45 %. Along with these improvements, several controversies remain, including grading, value of current cutoff ranges, and the best methods for counting ki-67 index (manual count by computer-captured image may be the most practical for the time being). More important is the controversial use of the term "carcinoma", which was previously employed in WHO-2004 only for invasive and metastatic cases but has now been made synonymous with grade 3 group of tumors. It is becoming clear that grade 3 group comprises two distinct categories: (1) differentiated but proliferatively more active tumors which typically have ki-67 indices in the 20-50 % range and (2) true poorly differentiated NE carcinomas as defined in the lung, with ki-67 typically >50 %. Further studies are needed to address these controversial aspects of PanNETs.

3 Clinical Trial Low CHD5 expression activates the DNA damage response and predicts poor outcome in patients undergoing adjuvant therapy for resected pancreatic cancer. 2014

Hall, W A / Petrova, A V / Colbert, L E / Hardy, C W / Fisher, S B / Saka, B / Shelton, J W / Warren, M D / Pantazides, B G / Gandhi, K / Kowalski, J / Kooby, D A / El-Rayes, B F / Staley, C A / Volkan Adsay, N / Curran, W J / Landry, J C / Maithel, S K / Yu, D S. ·Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA. · Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University, Atlanta, GA, USA. · Department of Pathology, Winship Cancer Institute, Emory University, Atlanta, GA, USA. · Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Atlanta, GA, USA. · 1] Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University, Atlanta, GA, USA [2] Atlanta Veterans Affairs Medical Center, Atlanta, GA, USA. · Department of Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA. ·Oncogene · Pubmed #24276239.

ABSTRACT: The DNA damage response (DDR) promotes genome integrity and serves as a cancer barrier in precancerous lesions but paradoxically may promote cancer survival. Genes that activate the DDR when dysregulated could function as useful biomarkers for outcome in cancer patients. Using a siRNA screen in human pancreatic cancer cells, we identified the CHD5 tumor suppressor as a gene, which, when silenced, activates the DDR. We evaluated the relationship of CHD5 expression with DDR activation in human pancreatic cancer cells and the association of CHD5 expression in 80 patients with resected pancreatic adenocarcinoma (PAC) by immunohistochemical analysis with clinical outcome. CHD5 depletion and low CHD5 expression in human pancreatic cancer cells lead to increased H2AX-Ser139 and CHK2-Thr68 phosphorylation and accumulation into nuclear foci. On Kaplan-Meier log-rank survival analysis, patients with low CHD5 expression had a median recurrence-free survival (RFS) of 5.3 vs 15.4 months for patients with high CHD5 expression (P=0.03). In 59 patients receiving adjuvant chemotherapy, low CHD5 expression was associated with decreased RFS (4.5 vs 16.3 months; P=0.001) and overall survival (OS) (7.2 vs 21.6 months; P=0.003). On multivariate Cox regression analysis, low CHD5 expression remained associated with worse OS (HR: 3.187 (95% CI: 1.49-6.81); P=0.003) in patients undergoing adjuvant chemotherapy. Thus, low CHD5 expression activates the DDR and predicts for worse OS in patients with resected PAC receiving adjuvant chemotherapy. Our findings support a model in which dysregulated expression of tumor suppressor genes that induce DDR activation can be utilized as biomarkers for poor outcome.

4 Article Non-ampullary-duodenal carcinomas: clinicopathologic analysis of 47 cases and comparison with ampullary and pancreatic adenocarcinomas. 2017

Xue, Yue / Vanoli, Alessandro / Balci, Serdar / Reid, Michelle M / Saka, Burcu / Bagci, Pelin / Memis, Bahar / Choi, Hyejeong / Ohike, Nobuyike / Tajiri, Takuma / Muraki, Takashi / Quigley, Brian / El-Rayes, Bassel F / Shaib, Walid / Kooby, David / Sarmiento, Juan / Maithel, Shishir K / Knight, Jessica H / Goodman, Michael / Krasinskas, Alyssa M / Adsay, Volkan. ·Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA. · Department of Molecular Medicine, San Matteo Hospital, University of Pavia, Pavia, Italy. · Department of Pathology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea. · Department of Pathology, Showa University Fujigaoka Hospital, Yokohama, Japan. · Department of Pathology, Tokai University Hachioji Hospital, Tokyo, Japan. · Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. · Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA. · Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA. ·Mod Pathol · Pubmed #27739441.

ABSTRACT: Literature on non-ampullary-duodenal carcinomas is limited. We analyzed 47 resected non-ampullary-duodenal carcinomas. Histologically, 78% were tubular-type adenocarcinomas mostly gastro-pancreatobiliary type and only 19% pure intestinal. Immunohistochemistry (n=38) revealed commonness of 'gastro-pancreatobiliary markers' (CK7 55, MUC1 50, MUC5AC 50, and MUC6 34%), whereas 'intestinal markers' were relatively less common (MUC2 36, CK20 42, and CDX2 44%). Squamous and mucinous differentiation were rare (in five each); previously, unrecognized adenocarcinoma patterns were noted (three microcystic/vacuolated, two cribriform, one of comedo-like, oncocytic papillary, and goblet-cell-carcinoid-like). An adenoma component common in ampullary-duodenal cancers was noted in only about a third. Most had plaque-like or ulcerating growth. Mismatch repair protein alterations were detected in 13% (all with plaque-like growth and pushing-border infiltration). When compared with ampullary (n=355) and pancreatic ductal (n=227) carcinomas, non-ampullary-duodenal carcinomas had intermediary pathologic features with mean invasive size of 2.9 cm (vs 1.9, and 3.3) and 59% nodal metastasis (vs 45, and 77%). Its survival (3-, 5-year rates of 57 and 57%) was similar to that of ampullary-duodenal carcinomas (59 and 52%; P=0.78), but was significantly better than the ampullary ductal (41 and 29%, P<0.001) and pancreatic (28 and 18%, P<0.001) carcinomas. In conclusion, non-ampullary-duodenal carcinomas are more histologically heterogeneous than previously appreciated. Their morphologic versatility (commonly showing gastro-pancreatobiliary lineage and hitherto unrecognized patterns), frequent plaque-like growth minus an adenoma component, and frequent expression of gastro-pancreatobiliary markers suggest that many non-ampullary-duodenal carcinomas may arise from Brunner glands or gastric metaplasia or heterotopic pancreatobiliary epithelium. The clinical behavior of non-ampullary-duodenal carcinoma is closer to that of ampullary-duodenal subset of ampullary carcinomas, but is significantly better than that of ampullary ductal and pancreatic cancers. The frequency of mismatch repair protein alterations suggest that routine testing should be considered, especially in the non-ampullary-duodenal carcinomas with plaque-like growth and pushing-border infiltration.

5 Article Pancreatic Ductal Adenocarcinoma is Spread to the Peripancreatic Soft Tissue in the Majority of Resected Cases, Rendering the AJCC T-Stage Protocol (7th Edition) Inapplicable and Insignificant: A Size-Based Staging System (pT1: ≤2, pT2: >2-≤4, pT3: >4 cm) is More Valid and Clinically Relevant. 2016

Saka, Burcu / Balci, Serdar / Basturk, Olca / Bagci, Pelin / Postlewait, Lauren M / Maithel, Shishir / Knight, Jessica / El-Rayes, Bassel / Kooby, David / Sarmiento, Juan / Muraki, Takashi / Oliva, Irma / Bandyopadhyay, Sudeshna / Akkas, Gizem / Goodman, Michael / Reid, Michelle D / Krasinskas, Alyssa / Everett, Rhonda / Adsay, Volkan. ·Department of Pathology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA. · Istanbul Medipol University, Istanbul, Turkey. · Yildirim Beyazit University, Ankara, Turkey. · Department of Pathology, Wayne State University and Karmanos Cancer Institute, Detroit, MI, USA. · Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Department of Pathology, Marmara University, Istanbul, Turkey. · Department of Surgical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA. · Department of Epidemiology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA. · Department of Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA. · Department of General Surgery, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA. · Department of Pathology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA. volkan.adsay@emory.edu. ·Ann Surg Oncol · Pubmed #26832882.

ABSTRACT: BACKGROUND: Most studies have failed to identify any prognostic value of the current T-stage protocol for pancreatic ductal adenocarcinoma (PDAC) by the American Joint Committee on Cancer and the Union for International Cancer Control unless some grouping was performed. METHODS: To document the parameters included in this T-stage protocol, 223 consecutive pancreatoduodenectomy specimens with PDAC were processed by a uniform grossing protocol. RESULTS: Peripancreatic soft tissue (PST) involvement, the main pT3 parameter, was found to be inapplicable and irreproducible due to lack of a true capsule in the pancreas and variability in the amount and distribution of adipose tissue. Furthermore, 91 % of the cases showed carcinoma in the adipose tissue, presumably representing the PST, and thus were classified as pT3. An additional 4.5 % were qualified as pT3 due to extension into adjacent sites. The T-stage defined as such was not found to have any correlation with survival (p = 0.4). A revised T-stage protocol was devised that defined pT1 as 2 cm or smaller, pT2 as >2-4 cm, and pT3 as larger than 4 cm. This revised protocol was tested in 757 consecutive PDACs. The median and 3-year survival rates of this size-based protocol were 26, 18, 13 months, and 40 %, 26 %, 20 %, respectively (p < 0.0001). The association between higher T-stage and shorter survival persisted in N0 cases and in multivariate modeling. Analysis of the Surveillance, Epidemiology, and End Results database also confirmed the survival differences (p < 0.0001). CONCLUSIONS: This study showed that resected PDACs are already spread to various surfaces of the pancreas, leaving only about 4 % of PDACs to truly qualify as pT1/T2, and that the current T-stage protocol does not have any prognostic correlation. In contrast, as shown previously in many studies, size is an important prognosticator, and a size-based T-stage protocol is more applicable and has prognostic value in PDAC.

6 Article Substaging of Lymph Node Status in Resected Pancreatic Ductal Adenocarcinoma Has Strong Prognostic Correlations: Proposal for a Revised N Classification for TNM Staging. 2015

Basturk, Olca / Saka, Burcu / Balci, Serdar / Postlewait, Lauren M / Knight, Jessica / Goodman, Michael / Kooby, David / Sarmiento, Juan M / El-Rayes, Bassel / Choi, Hyejeong / Bagci, Pelin / Krasinskas, Alyssa / Quigley, Brian / Reid, Michelle D / Akkas, Gizem / Maithel, Shishir K / Adsay, Volkan. ·Department of Pathology, New York University, New York, NY, USA. · Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Department of Pathology, Istanbul Medipol University, Istanbul, Turkey. · Department of Pathology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA. · Department of Surgical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA. · Department of Epidemiology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA. · Department of General Surgery, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA. · Department of Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA. · Department of Pathology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA. volkan.adsay@emory.edu. ·Ann Surg Oncol · Pubmed #26362048.

ABSTRACT: BACKGROUND: The current tumor-node-metastasis staging system for the pancreas does not incorporate the number of lymph nodes (LNs) with metastasis. METHODS: Among 1649 pancreaticoduodenectomies, 227 stringently defined pancreatic ductal adenocarcinomas (PDACs) that had undergone a specific approach of LN harvesting were analyzed for the prognostic value of LN substaging protocols used for other gastrointestinal (GI) organs. RESULTS: The median number of LNs harvested was 18, and the median number of LNs with metastasis was 3. Lymph node metastasis was detected in 175 cases (77 %). The number of LNs involved correlated significantly with clinical outcome. When cases were substaged with the protocol already in use for the upper GI organs (N0: no metastasis, N1: metastasis to 1-2 LNs; N2: metastasis to ≥3 LNs), the median overall survival times were 35, 21, and 18 months, and the respective 3-year survival rates were 46, 34, and 20 % (p = 0.004). Analysis of the Surveillance, Epidemiology and End Results (SEER) database also confirmed the survival differences between these substages (median overall survival times of 23, 15, and 14 months and respective 3-year survival rates of 37, 22, and 18 %; p < 0.0001). The substaging protocol for the lower GI organs (N0: no metastasis; N1: metastasis to 1-3 LNs; N2: metastasis to ≥4 LNs) also was significant, with median overall survival times of 35, 21, 18 months and respective 3-year survival rates of 46, 26, and 23 %; p = 0.009). The association between higher N stage and shorter survival persisted with multivariate modeling for both protocols, although the prognostic value of the upper GI protocol appeared to be slightly stronger according to the Akaike Information Criterion method. CONCLUSION: In conclusion, with proper LN harvesting, the LN metastasis rate in PDACs is very high (77 %). Substaging of LN metastasis has significant prognostic value and needs to be considered in the N staging of PDACs. The protocol already in use for other upper GI tract organs, which currently also is proven significant for ampulla, would be preferable, although the lower GI tract protocol also is applicable.

7 Article Substaging Nodal Status in Ampullary Carcinomas has Significant Prognostic Value: Proposed Revised Staging Based on an Analysis of 313 Well-Characterized Cases. 2015

Balci, Serdar / Basturk, Olca / Saka, Burcu / Bagci, Pelin / Postlewait, Lauren M / Tajiri, Takuma / Jang, Kee-Taek / Ohike, Nobuyuki / Kim, Grace E / Krasinskas, Alyssa / Choi, Hyejeong / Sarmiento, Juan M / Kooby, David A / El-Rayes, Bassel F / Knight, Jessica H / Goodman, Michael / Akkas, Gizem / Reid, Michelle D / Maithel, Shishir K / Adsay, Volkan. ·Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA. · Department of Pathology, New York University, New York, NY, USA. · Department of Pathology, İstanbul Medipol University, İstanbul, Turkey. · Division of Surgical Oncology, Department of Surgery, Emory University, Atlanta, GA, USA. · Department of Pathology, Tokai University Hachiouji Hospital, Tokyo, Japan. · Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. · Department of Pathology, Showa University Fujigaoka Hospital, Tokyo, Japan. · Department of Pathology, University of California San Francisco, San Francisco, CA, USA. · Division of General and Gastrointstinal Surgery, Emory University, Atlanta, GA, USA. · Department of Oncology, Emory University, Atlanta, GA, USA. · Department of Epidemiology, Emory University, Atlanta, GA, USA. · Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA. volkan.adsay@emory.edu. ·Ann Surg Oncol · Pubmed #25783680.

ABSTRACT: BACKGROUND: Current nodal staging (N-staging) of ampullary carcinoma in the TNM staging system distinguishes between node-negative (N0) and node-positive (N1) disease but does not consider the metastatic lymph node (LN) number. METHODS: Overall, 313 patients who underwent pancreatoduodenectomy for ampullary adenocarcinoma were categorized as N0, N1 (1-2 metastatic LNs), or N2 (≥3 metastatic LNs), as proposed by Kang et al. Clinicopathological features and overall survival (OS) of the three groups were compared. RESULTS: The median number of LNs examined was 11, and LN metastasis was present in 142 cases (45 %). When LN-positive cases were re-classified according to the proposed staging system, 82 were N1 (26 %) and 60 were N2 (19 %). There was a significant correlation between proposed N-stage and lymphovascular invasion, perineural invasion, increased tumor size (each p < 0.001), and surgical margin positivity (p = 0.001). The median OS in LN-negative cases was significantly longer than that in LN-positive cases (107.5 vs. 32 months; p < 0.001). Patients with N1 and N2 disease had median survivals of 40 and 24.5 months, respectively (p < 0.0001). In addition, 1-, 3-, and 5-year survivals were 88, 76, 62 %, respectively, for N0; 90, 55, 31.5 %, respectively, for N1; and 68, 34, 30 %, respectively for N2 (p < 0.001). Even with multivariate modeling, the association between higher proposed N stage and shorter survival persisted (hazard ratio 1.6 for N1 and 1.9 for N2; p = 0.018). CONCLUSIONS: Classification of nodal status in ampullary carcinomas based on the number of metastatic LNs has a significant prognostic value. A revised N-staging classification system should be incorporated into the TNM staging of ampullary cancers.

8 Article High nuclear hypoxia-inducible factor 1 alpha expression is a predictor of distant recurrence in patients with resected pancreatic adenocarcinoma. 2015

Colbert, Lauren E / Fisher, Sarah B / Balci, Serdar / Saka, Burcu / Chen, Zhengjia / Kim, Sungjin / El-Rayes, Bassel F / Adsay, N Volkan / Maithel, Shishir K / Landry, Jerome C / Curran, Walter J. ·Department of Radiation Oncology, Emory University, Atlanta, Georgia; Winship Cancer Institute, Emory University, Atlanta, Georgia; Memorial Sloan-Kettering Cancer Center, New York, New York. · Winship Cancer Institute, Emory University, Atlanta, Georgia; Division of Surgical Oncology, Department of Surgery, Emory University, Atlanta, Georgia. · Winship Cancer Institute, Emory University, Atlanta, Georgia; Department of Pathology, Emory University, Atlanta, Georgia. · Winship Cancer Institute, Emory University, Atlanta, Georgia; Biostatistics and Bioinformatics Shared Resource, Emory University, Atlanta, Georgia. · Winship Cancer Institute, Emory University, Atlanta, Georgia; Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia. · Winship Cancer Institute, Emory University, Atlanta, Georgia; Department of Pathology, Emory University, Atlanta, Georgia; Biostatistics and Bioinformatics Shared Resource, Emory University, Atlanta, Georgia. · Winship Cancer Institute, Emory University, Atlanta, Georgia; Division of Surgical Oncology, Department of Surgery, Emory University, Atlanta, Georgia; Biostatistics and Bioinformatics Shared Resource, Emory University, Atlanta, Georgia. · Department of Radiation Oncology, Emory University, Atlanta, Georgia; Winship Cancer Institute, Emory University, Atlanta, Georgia; Biostatistics and Bioinformatics Shared Resource, Emory University, Atlanta, Georgia. · Department of Radiation Oncology, Emory University, Atlanta, Georgia; Winship Cancer Institute, Emory University, Atlanta, Georgia; Biostatistics and Bioinformatics Shared Resource, Emory University, Atlanta, Georgia. Electronic address: wcurran@emory.edu. ·Int J Radiat Oncol Biol Phys · Pubmed #25596110.

ABSTRACT: PURPOSE: To evaluate nuclear hypoxia-inducible factor 1α (HIF-1α) expression as a prognostic factor for distant recurrence (DR) and local recurrence (LR) after pancreatic adenocarcinoma resection. METHODS AND MATERIALS: Tissue specimens were collected from 98 patients with pancreatic adenocarcinoma who underwent resection without neoadjuvant therapy between January 2000 and December 2011. Local recurrence was defined as radiographic or pathologic evidence of progressive disease in the pancreas, pancreatic bed, or associated nodal regions. Distant recurrence was defined as radiographically or pathologically confirmed recurrent disease in other sites. Immunohistochemical staining was performed and scored by an independent pathologist blinded to patient outcomes. High HIF-1α overall expression score was defined as high percentage and intensity staining and thus score >1.33. Univariate analysis was performed for HIF-1α score with LR alone and with DR. Multivariate logistic regression was used to determine predictors of LR and DR. RESULTS: Median follow-up time for all patients was 16.3 months. Eight patients (8%) demonstrated isolated LR, 26 patients (26.5%) had isolated DR, and 13 patients had both LR and DR. Fifty-three patients (54%) had high HIF-1α expression, and 45 patients (46%) had low HIF-1α expression. High HIF-1α expression was significantly associated with DR (P=.03), and low HIF-1α expression was significantly associated with isolated LR (P=.03). On multivariate logistic regression analysis, high HIF-1α was the only significant predictor of DR (odds ratio 2.46 [95% confidence interval 1.06-5.72]; P=.03). In patients with a known recurrence, an HIF-1α score ≥2.5 demonstrated a specificity of 100% for DR. CONCLUSIONS: High HIF-1α expression is a significant predictor of distant failure versus isolated local failure in patients undergoing resection of pancreatic adenocarcinoma. Expression of HIF-1α may have utility in determining candidates for adjuvant local radiation therapy and systemic chemotherapy.

9 Article Calculation of the Ki67 index in pancreatic neuroendocrine tumors: a comparative analysis of four counting methodologies. 2015

Reid, Michelle D / Bagci, Pelin / Ohike, Nobuyuki / Saka, Burcu / Erbarut Seven, Ipek / Dursun, Nevra / Balci, Serdar / Gucer, Hasan / Jang, Kee-Taek / Tajiri, Takuma / Basturk, Olca / Kong, So Yeon / Goodman, Michael / Akkas, Gizem / Adsay, Volkan. ·Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA. · Department of Pathology, Marmara University, Istanbul, Turkey. · Department of Pathology, Showa University School of Medicine, Tokyo, Japan. · Department of Pathology, Medipol University, Istanbul, Turkey. · Department of Pathology, Istanbul Education and Training Hospital, Istanbul, Turkey. · Department of Pathology, Yildirim Beyazit University, Ankara, Turkey. · Department of Pathology, RTE University, Rize, Turkey. · Department of Pathology, Samsung Medical Center, Seoul, Korea. · Department of Pathology, Tokai University Hachiouji Hospital, Tokyo, Japan. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Department of Pathology, Department of Epidemiology, Emory University, Atlanta, GA, USA. ·Mod Pathol · Pubmed #25412850.

ABSTRACT: Ki67 index is now an essential part of classification of pancreatic neuroendocrine tumors. However, its adaptation into daily practice has been fraught with challenges related to counting methodology. In this study, three reviewers used four counting methodologies to calculate Ki67 index in 68 well-differentiated pancreatic neuroendocrine tumors: (1) 'eye-ball' estimation, which has been advocated as reliable and is widely used; (2) automated counting by image analyzer; (3) manual eye-counting (eye under a microscope without a grid); and (4) manual count of camera-captured/printed image. Pearson's correlation (R) was used to measure pair-wise correlation among three reviewers using all four methodologies. Average level of agreement was calculated using mean of R values. The results showed that: (1) 'eye-balling' was least expensive and fastest (average time <1 min) but had poor reliability and reproducibility. (2) Automated count was the most expensive and least practical with major impact on turnaround time (limited by machine and personnel accessibility), and, more importantly, had inaccuracies in overcounting unwanted material. (3) Manual eye count had no additional cost, averaged 6 min, but proved impractical and poorly reproducible. (4) Camera-captured/printed image was most reliable, had highest reproducibility, but took longer than 'eye-balling'. In conclusion, based on its comparatively low cost/benefit ratio and reproducibility, camera-captured/printed image appears to be the most practical for calculating Ki67 index. Although automated counting is generally advertised as the gold standard for index calculation, in this study it was not as accurate or cost-effective as camera-captured/printed image and was highly operator-dependent. 'Eye-balling' produces highly inaccurate and unreliable results, and is not recommended for routine use.

10 Article CHD7 expression predicts survival outcomes in patients with resected pancreatic cancer. 2014

Colbert, Lauren E / Petrova, Aleksandra V / Fisher, Sarah B / Pantazides, Brooke G / Madden, Matthew Z / Hardy, Claire W / Warren, Matthew D / Pan, Yunfeng / Nagaraju, Ganji P / Liu, Elaine A / Saka, Burcu / Hall, William A / Shelton, Joseph W / Gandhi, Khanjan / Pauly, Rini / Kowalski, Jeanne / Kooby, David A / El-Rayes, Bassel F / Staley, Charles A / Adsay, N Volkan / Curran, Walter J / Landry, Jerome C / Maithel, Shishir K / Yu, David S. ·Authors' Affiliations: Departments of Radiation Oncology, Medical Oncology, and Pathology; Division of Surgical Oncology, Department of Surgery; Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University; and Atlanta Veterans Affairs Medical Center, Atlanta, Georgia. · Authors' Affiliations: Departments of Radiation Oncology, Medical Oncology, and Pathology; Division of Surgical Oncology, Department of Surgery; Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University; and Atlanta Veterans Affairs Medical Center, Atlanta, GeorgiaAuthors' Affiliations: Departments of Radiation Oncology, Medical Oncology, and Pathology; Division of Surgical Oncology, Department of Surgery; Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University; and Atlanta Veterans Affairs Medical Center, Atlanta, Georgia. · Authors' Affiliations: Departments of Radiation Oncology, Medical Oncology, and Pathology; Division of Surgical Oncology, Department of Surgery; Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University; and Atlanta Veterans Affairs Medical Center, Atlanta, Georgia dsyu@emory.edu. ·Cancer Res · Pubmed #24626090.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with poor outcomes with current therapies. Gemcitabine is the primary adjuvant drug used clinically, but its effectiveness is limited. In this study, our objective was to use a rationale-driven approach to identify novel biomarkers for outcome in patients with early-stage resected PDAC treated with adjuvant gemcitabine. Using a synthetic lethal screen in human PDAC cells, we identified 93 genes, including 55 genes linked to DNA damage responses (DDR), that demonstrated gemcitabine sensitization when silenced, including CHD7, which functions in chromatin remodeling. CHD7 depletion sensitized PDAC cells to gemcitabine and delayed their growth in tumor xenografts. Moreover, CHD7 silencing impaired ATR-dependent phosphorylation of CHK1 and increased DNA damage induced by gemcitabine. CHD7 was dysregulated, ranking above the 90th percentile in differential expression in a panel of PDAC clinical specimens, highlighting its potential as a biomarker. Immunohistochemical analysis of specimens from 59 patients with resected PDAC receiving adjuvant gemcitabine revealed that low CHD7 expression was associated with increased recurrence-free survival (RFS) and overall survival (OS), in univariate and multivariate analyses. Notably, CHD7 expression was not associated with RFS or OS for patients not receiving gemcitabine. Thus, low CHD7 expression was correlated selectively with gemcitabine sensitivity in this patient population. These results supported our rationale-driven strategy to exploit dysregulated DDR pathways in PDAC to identify genetic determinants of gemcitabine sensitivity, identifying CHD7 as a novel biomarker candidate to evaluate further for individualizing PDAC treatment.

11 Article Poorly differentiated neuroendocrine carcinomas of the pancreas: a clinicopathologic analysis of 44 cases. 2014

Basturk, Olca / Tang, Laura / Hruban, Ralph H / Adsay, Volkan / Yang, Zhaohai / Krasinskas, Alyssa M / Vakiani, Efsevia / La Rosa, Stefano / Jang, Kee-Taek / Frankel, Wendy L / Liu, Xiuli / Zhang, Lizhi / Giordano, Thomas J / Bellizzi, Andrew M / Chen, Jey-Hsin / Shi, Chanjuan / Allen, Peter / Reidy, Diane L / Wolfgang, Christopher L / Saka, Burcu / Rezaee, Neda / Deshpande, Vikram / Klimstra, David S. ·Departments of *Pathology ***Surgery †††Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY †Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center ‡‡‡Department of Surgery, Johns Hopkins University, Baltimore, MD ‡Department of Pathology, Emory University, Atlanta, GA §Department of Pathology, Penn State Hershey MC, Hershey ∥Department of Pathology, University of Pittsburgh, Pittsburgh, PA **Department of Pathology, Ohio State University, Columbus ††Department of Pathology, Cleveland Clinic, Cleveland, OH ‡‡Department of Pathology, Mayo Clinic, Rochester, MN §§Department of Pathology, University of Michigan, Ann Arbor, MI ∥∥Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, IA ¶¶Department of Pathology, Indiana University, Indianapolis, IN ##Department of Pathology, Vanderbilt University, Nashville, TN §§§Department of Pathology, Massachusetts General Hospital, Boston, MA ¶Department of Pathology, Ospedale di Circolo, Varese, Italy #Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. ·Am J Surg Pathol · Pubmed #24503751.

ABSTRACT: BACKGROUND: In the pancreas, poorly differentiated neuroendocrine carcinomas include small cell carcinoma and large cell neuroendocrine carcinoma and are rare; data regarding their pathologic and clinical features are very limited. DESIGN: A total of 107 pancreatic resections originally diagnosed as poorly differentiated neuroendocrine carcinomas were reassessed using the classification and grading (mitotic rate/Ki67 index) criteria put forth by the World Health Organization in 2010 for the gastroenteropancreatic system. Immunohistochemical labeling for neuroendocrine and acinar differentiation markers was performed. Sixty-three cases were reclassified, mostly as well-differentiated neuroendocrine tumor (NET) or acinar cell carcinoma, and eliminated. The clinicopathologic features and survival of the remaining 44 poorly differentiated neuroendocrine carcinomas were further assessed. RESULTS: The mean patient age was 59 years (range, 21 to 82 y), and the male/female ratio was 1.4. Twenty-seven tumors were located in the head of the pancreas, 3 in the body, and 11 in the tail. The median tumor size was 4 cm (range, 2 to 18 cm). Twenty-seven tumors were large cell neuroendocrine carcinomas, and 17 were small cell carcinomas (mean mitotic rate, 37/10 and 51/10 HPF; mean Ki67 index, 66% and 75%, respectively). Eight tumors had combined components, mostly adenocarcinomas. In addition, 2 tumors had components of well-differentiated NET. Eighty-eight percent of the patients had nodal or distant metastatic disease at presentation, and an additional 7% developed metastases subsequently. Follow-up information was available for 43 patients; 33 died of disease, with a median survival of 11 months (range, 0 to 104 mo); 8 were alive with disease, with a median follow-up of 19.5 months (range, 0 to 71 mo). The 2- and 5-year survival rates were 22.5% and 16.1%, respectively. CONCLUSIONS: Poorly differentiated neuroendocrine carcinoma of the pancreas is a highly aggressive neoplasm, with frequent metastases and poor survival. Most patients die within less than a year. Most (61%) are large cell neuroendocrine carcinomas. Well-differentiated NET and acinar cell carcinoma are often misdiagnosed as poorly differentiated neuroendocrine carcinoma, emphasizing that diagnostic criteria need to be clearly followed to ensure accurate diagnosis.

12 Article Having pancreatic cancer with tumoral loss of ATM and normal TP53 protein expression is associated with a poorer prognosis. 2014

Kim, Haeryoung / Saka, Burcu / Knight, Spencer / Borges, Michael / Childs, Erica / Klein, Alison / Wolfgang, Christopher / Herman, Joseph / Adsay, Volkan N / Hruban, Ralph H / Goggins, Michael. ·Authors' Affiliations: Departments of Pathology, Medicine, Oncology, Surgery and Radiation Oncology, and Molecular Radiation Sciences, The Sol Goldman Pancreatic Cancer Research Center; Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins Medical Institutions, Baltimore, Maryland; Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea; and Department of Pathology, Emory University Hospital, Atlanta, Georgia. ·Clin Cancer Res · Pubmed #24486587.

ABSTRACT: PURPOSE: To determine how often loss of ataxia-telangiectasia-mutated (ATM) protein expression occurs in primary pancreatic ductal adenocarcinomas and to determine its prognostic significance. EXPERIMENTAL DESIGN: The expression of ATM and TP53 was determined by immunohistochemistry in 397 surgically resected pancreatic ductal adenocarcinomas (Hopkins; Johns Hopkins Medical Institutions, Baltimore, MD), a second set of 159 cases (Emory; Emory University Hospital, Atlanta, GA), and 21 cancers after neoadjuvant chemoradiotherapy. Expression was correlated with the clinicopathologic parameters, including survival. RESULTS: Tumoral ATM loss was observed in one cancer known to have biallelic inactivation of ATM and 50 of the first 396 (12.8%) cases, significantly more often in patients with a family history of pancreatic cancer (12/49; 24.5%) than in those without (38/347; 11.0%; P = 0.019). In the Hopkins series, ATM loss was associated with a significantly decreased overall survival in patients whose cancers had normal TP53 expression (P = 0.019) and was a significant independent predictor of decreased overall survival (P = 0.014). Seventeen (10.7%) of 159 Emory cases had tumoral ATM loss and tumoral ATM loss/normal TP53 was associated with poorer overall survival (P = 0.1). Multivariate analysis of the combined Hopkins/Emory cases found that tumoral ATM loss/normal TP53 was an independent predictor of decreased overall survival [HR = 2.61; confidence interval (CI), 1.27-5.37; P = 0.009]. Of 21 cancers examined after neoadjuvant chemoradiotherapy, one had tumoral loss of ATM; it had no histologic evidence of tumor response. CONCLUSIONS: Tumoral loss of ATM protein was detected more often in patients with a family history of pancreatic cancer than in those without. Patients whose pancreatic cancers had loss of ATM but normal TP53 had worse overall survival after pancreatic resection.

13 Article Whipple made simple for surgical pathologists: orientation, dissection, and sampling of pancreaticoduodenectomy specimens for a more practical and accurate evaluation of pancreatic, distal common bile duct, and ampullary tumors. 2014

Adsay, N Volkan / Basturk, Olca / Saka, Burcu / Bagci, Pelin / Ozdemir, Denizhan / Balci, Serdar / Sarmiento, Juan M / Kooby, David A / Staley, Charles / Maithel, Shishir K / Everett, Rhonda / Cheng, Jeanette D / Thirabanjasak, Duangpeng / Weaver, Donald W. ·Departments of *Pathology ‡General Surgery §Surgical Oncology, Emory University School of Medicine and Winship Cancer Institute ∥Department of Pathology, Piedmont Hospital, Atlanta, GA †Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY Departments of ¶Pathology #General Surgery, Wayne State University and Karmanos Cancer Institute, Detroit, MI. ·Am J Surg Pathol · Pubmed #24451278.

ABSTRACT: Pancreaticoduodenectomy (PD) specimens present a challenge for surgical pathologists because of the relative rarity of these specimens, combined with the anatomic complexity. Here, we describe our experience on the orientation, dissection, and sampling of PD specimens for a more practical and accurate evaluation of pancreatic, distal common bile duct (CBD), and ampullary tumors. For orientation of PDs, identification of the "trapezoid," created by the vascular bed at the center, the pancreatic neck margin on the left, and the uncinate margin on the right, is of outmost importance in finding all the pertinent margins of the specimen including the CBD, which is located at the upper right edge of this trapezoid. After orientation, all the margins can be sampled. We submit the uncinate margin entirely as a perpendicular inked margin because this adipose tissue-rich area often reveals subtle satellite carcinomas that are grossly invisible, and, with this approach, the number of R1 resections has doubled in our experience. Then, to ensure proper identification of all lymph nodes (LNs), we utilize the orange-peeling approach, in which the soft tissue surrounding the pancreatic head is shaved off in 7 arbitrarily defined regions, which also serve as shaved samples of the so-called "peripancreatic soft tissue" that defines pT3 in the current American Joint Committee on Cancer TNM. With this approach, our LN count increased from 6 to 14 and LN positivity rate from 50% to 73%. In addition, in 90% of pancreatic ductal adenocarcinomas there are grossly undetected microfoci of carcinoma. For determination of the primary site and the extent of the tumor, we believe bisectioning of the pancreatic head, instead of axial (transverse) slicing, is the most revealing approach. In addition, documentation of the findings in the duodenal surface of the ampulla is crucial for ampullary carcinomas and their recent site-specific categorization into 4 categories. Therefore, we probe both the CBD and the pancreatic duct from distal to the ampulla and cut the pancreatic head to the ampulla at a plane that goes through both ducts. Then, we sample the bisected pancreatic head depending on the findings of the case. For example, for proper staging of ampullary carcinomas, it is imperative to take the sections perpendicular to the duodenal serosa at the "groove" area, as ampullary carcinomas often extend to this region. Amputative (axial) sectioning of the ampulla, although good for documentation of the peri-Oddi spread of the intra-ampullary tumors, unfortunately disallows documentation of mucosal spread of the papilla of Vater tumors (those arising from the edge of the ampulla, where the ducts transition to duodenal mucosa and extending) into the neighboring duodenum. Axial sectioning also often fails to document tumor spread to the "groove" area. In conclusion, knowledge of the gross characteristics of the anatomic hallmarks is essential for proper dissection of PD specimens. The approach described above allows practical and accurate documentation and staging of pancreas, distal CBD, and ampullary cancers.

14 Article Pronecrotic mixed lineage kinase domain-like protein expression is a prognostic biomarker in patients with early-stage resected pancreatic adenocarcinoma. 2013

Colbert, Lauren E / Fisher, Sarah B / Hardy, Claire W / Hall, William A / Saka, Burcu / Shelton, Joseph W / Petrova, Aleksandra V / Warren, Matthew D / Pantazides, Brooke G / Gandhi, Khanjan / Kowalski, Jeanne / Kooby, David A / El-Rayes, Bassel F / Staley, Charles A / Adsay, N Volkan / Curran, Walter J / Landry, Jerome C / Maithel, Shishir K / Yu, David S. ·Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia. ·Cancer · Pubmed #23720157.

ABSTRACT: BACKGROUND: Mixed lineage kinase domain-like protein (MLKL) is a necrosome component mediating programmed necrosis that may be an important determinant of cancer cell death. The goal of the current study was to evaluate the prognostic value of MLKL expression in patients with pancreatic adenocarcinoma (PAC). METHODS: Tissue from 80 patients was collected from a prospectively maintained database of patients with PAC who underwent pancreaticoduodenectomy between January 2000 and October 2008. Immunohistochemistry analysis was performed and scored using an established scoring system. Kaplan-Meier survival curves were generated for recurrence-free survival (RFS) and overall survival (OS) for all patients and for patients receiving adjuvant chemotherapy. MLKL scores were correlated with RFS and OS using univariate and multivariate Cox regression analyses incorporating clinically relevant covariates. RESULTS: The median age of the patients was 63 years and 53% were men. Low MLKL expression was associated with decreased OS (6 months vs 17 months; P = .006). In the subset of 59 patients who received adjuvant chemotherapy, low MLKL expression was associated with decreased RFS (5 months vs 15 months; P = .006) and decreased OS (6 months vs 19 months; P < .0001). On multivariate analysis, low MLKL expression was associated with poor OS in all patients (hazards ratio, 4.6 [95% confidence interval, 1.6-13.8]; P = .006) and in patients receiving adjuvant chemotherapy (hazards ratio, 8.1 [95% confidence interval, 2.2-29.2]; P = .002). CONCLUSIONS: Low expression of MLKL is associated with decreased OS in patients with resected PAC and decreased RFS and OS in the subset of patients with resected PAC who receive adjuvant chemotherapy. The use of this biomarker in patients with PAC may provide important prognostic information.

15 Article KRAS mutant allele-specific imbalance is associated with worse prognosis in pancreatic cancer and progression to undifferentiated carcinoma of the pancreas. 2013

Krasinskas, Alyssa M / Moser, A James / Saka, Burcu / Adsay, N Volkan / Chiosea, Simion I. ·Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. ·Mod Pathol · Pubmed #23599154.

ABSTRACT: KRAS codon 12 mutations are present in about 90% of ductal adenocarcinomas and in undifferentiated carcinomas of the pancreas. The role of KRAS copy number changes and resulting KRAS mutant allele-specific imbalance (MASI) in ductal adenocarcinoma (n=94), and its progression into undifferentiated carcinoma of the pancreas (n=25) was studied by direct sequencing and KRAS fluorescence in situ hybridization (FISH). Semi-quantitative evaluation of sequencing electropherograms showed KRAS MASI (ie, mutant allele peak higher than or equal to the wild-type allele peak) in 22 (18.4%) cases. KRAS FISH (performed on 45 cases) revealed a trend for more frequent KRAS amplification among cases with KRAS MASI (7/20, 35% vs 3/25, 12%, P=0.08). KRAS amplification by FISH was seen only in undifferentiated carcinomas (10/24, 42% vs 0/21 pancreatic ductal adenocarcinoma, 0%, P=0.0007). In 6 of 11 cases with both undifferentiated and well-differentiated components, transition to undifferentiated carcinoma was associated with an increase in KRAS copy number, due to amplification and/or chromosome 12 hyperploidy. Pancreatic carcinomas with KRAS MASI (compared to those without MASI) were predominantly undifferentiated (16/22, 73% vs 9/97, 9%, P<0.001), more likely to present at clinical stage IV (5/22, 23% vs 7/97, 7%, P=0.009), and were associated with shorter overall survival (9 months, 95% confidence interval, 5-13, vs 22 months, 95% confidence interval, 17-27; P=0.015) and shorter disease-free survival (5 months, 95% confidence interval, 2-8 vs 13 months, 95% confidence interval, 10-16; P=0.02). Our findings suggest that in a subset of ductal adenocarcinomas, KRAS MASI correlates with the progression to undifferentiated carcinoma of the pancreas.