Ralph H Hruban

Johns Hopkins University, Baltimore, Maryland, United States

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Publications (887)5476.26 Total impact

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    ABSTRACT: Most cancers in humans are large, measuring centimeters in diameter, composed of many billions of cells. An equivalent mass of normal cells would be highly heterogeneous as a result of the mutations that occur during each cell division. What is remarkable about cancers is their homogeneity - virtually every neoplastic cell within a large cancer contains the same core set of genetic alterations, with heterogeneity confined to mutations that have emerged after the last clonal expansions. How such clones expand within the spatially-constrained three dimensional architecture of a tumor, and come to dominate a large, pre-existing lesion, has never been explained. We here describe a model for tumor evolution that shows how short-range migration and cell turnover can account for rapid cell mixing inside the tumor. With it, we show that even a small selective advantage of a single cell within a large tumor allows the descendants of that cell to replace the precursor mass in a clinically relevant time frame. We also demonstrate that the same mechanisms can be responsible for the rapid onset of resistance to chemotherapy. Our model not only provides novel insights into spatial and temporal aspects of tumor growth but also suggests that targeting short range cellular migratory activity could have dramatic effects on tumor growth rates.
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    ABSTRACT: There are no established guidelines for pathologic diagnosis/reporting of intraductal papillary mucinous neoplasms (IPMNs). An international multidisciplinary group, brought together by the Verona Pancreas Group in Italy-2013, was tasked to devise recommendations. (1) Crucial to rule out invasive carcinoma with extensive (if not complete) sampling. (2) Invasive component is to be documented in a full synoptic report including its size, type, grade, and stage. (3) The term "minimally invasive" should be avoided; instead, invasion size with stage and substaging of T1 (1a, b, c; ≤0.5, >0.5-≤1, >1 cm) is to be documented. (4) Largest diameter of the invasion, not the distance from the nearest duct, is to be used. (5) A category of "indeterminate/(suspicious) for invasion" is acceptable for rare cases. (6) The term "malignant" IPMN should be avoided. (7) The highest grade of dysplasia in the non-invasive component is to be documented separately. (8) Lesion size is to be correlated with imaging findings in cysts with rupture. (9) The main duct diameter and, if possible, its involvement are to be documented; however, it is not required to provide main versus branch duct classification in the resected tumor. (10) Subtyping as gastric/intestinal/pancreatobiliary/oncocytic/mixed is of value. (11) Frozen section is to be performed highly selectively, with appreciation of its shortcomings. (12) These principles also apply to other similar tumoral intraepithelial neoplasms (mucinous cystic neoplasms, intra-ampullary, and intra-biliary/cholecystic). These recommendations will ensure proper communication of salient tumor characteristics to the management teams, accurate comparison of data between analyses, and development of more effective management algorithms.
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    ABSTRACT: The 2010 World Health Organization (WHO) classification recommends that pancreatic neuroendocrine tumors (PanNETs) be graded on the basis of the mitotic rate and Ki67 index, with grade 2 (G2) PanNETs defined as having a mitotic rate of 2 to 20 mitotic figures/10 high-power fields or a Ki67 index of 3% to 20%. Grade 3 (G3) pancreatic neuroendocrine carcinoma (NEC) is defined as having >20 mitotic figures/10 high-power fields or a Ki67 index of >20%. However, some PanNETs show discordance between the mitotic rate and Ki67 index, usually having a Ki67 index in the G3 range but a mitotic rate suggesting G2, prompting us to examine the clinical significance of the Ki67 index in a large series of clinically well-characterized mitotic G2 PanNETs. Mitotic G2 well differentiated PanNETs, surgically resected at our institutions were reviewed. Of those, 19 cases had a Ki67>20% and were selected as the study group of grade-discordant (mitotic count G2/Ki67 index G3) PanNETs. For comparison, 53 grade-concordant (both mitotic count and Ki67 index G2) PanNETs matched for presenting stage with the discordant group as well as 43 morphologically poorly differentiated (either small cell or large cell type) pancreatic NECs were also included. The percentage of Ki67-positive neoplastic cells was quantified by manual counting of at least 500 cells on printed photographic images of "hot spots." The mean Ki67 index for grade-concordant and grade-discordant PanNETs and poorly differentiated NECs were 8.1% (range, 3% to 20%), 40% (range, 24% to 80%), and 70% (range, 40% to 98%), respectively. Overall, patients with grade-discordant PanNETs had significantly longer survival time compared with the patients with poorly differentiated NEC (median survival of 54.1 vs. 11 mo and 5 y survival of 29.1% vs. 16.1%; P=0.002). In addition, the survival time of the patients with grade-discordant PanNETs was shorter than that of the patients with grade-concordant PanNETs (median survival of 67.8 mo and 5 y survival of 62.4%); however, the difference was not statistically significant (P=0.2). Our data support the notion that the mitotic rate and Ki67 index-based grades of PanNETs can be discordant, and when the Ki67 index indicates G3, the clinical outcome is slightly worse. More importantly, we demonstrate that well differentiated PanNETs that are G3 by Ki67 are significantly less aggressive than bona fide poorly differentiated NECs, suggesting that the current WHO G3 category is heterogenous, contains 2 distinct neoplasms, and can be further separated into well differentiated PanNET with an elevated proliferation rate and poorly differentiated NEC.
    American Journal of Surgical Pathology 02/2015; 39(5). DOI:10.1097/PAS.0000000000000408 · 4.59 Impact Factor
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    ABSTRACT: Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.
    Nature 02/2015; 518(7540):495-501. DOI:10.1038/nature14169 · 42.35 Impact Factor
  • Marcia Irene Canto, Ralph H Hruban
    Gastroenterology 02/2015; DOI:10.1053/j.gastro.2015.02.033 · 13.93 Impact Factor
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    ABSTRACT: Pancreatic neoplasms are morphologically and genetically heterogeneous and include a wide variety of tumors ranging from benign to malignant with an extremely poor clinical outcome. Our understanding of these pancreatic neoplasms has improved significantly with recent advances in cancer sequencing. Awareness of molecular pathogenesis brings new opportunities for early detection, improved prognostication, and personalized gene-specific therapies. Here we review the pathological classification of pancreatic neoplasms from the molecular and genetic perspectives. Copyright © 2015 Elsevier Inc. All rights reserved.
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    ABSTRACT: Purpose: The median survival following surgical resection of pancreatic ductal adenocarcinoma (PDAC) is currently <20 months. However, survival ≥10 years is achieved by a small subset of patients who are defined as very long-term survivors (VLTSs). The goal of this study was to determine whether specific genetic alterations in resected PDACs determined very long-term survival. Experimental Design: We sequenced the exomes of 8 PDACs from patients who survived ≥10 years. Based on the results of the exomic analysis, targeted sequencing of selected genes was performed in a series of 27 additional PDACs from VLTSs. Results: KRAS mutations were identified in 33 of 35 (94%) cancers from VLTSs and represented the most prevalent alteration in our cohort. TP53, SMAD4, and CDKN2A mutations occurred in 69%, 26%, and 17%, respectively. Mutations in RNF43, which have been previously associated with intraductal papillary mucinous neoplasms, were identified in 4 of the 35 cancers (11%). Taken together, our data show no difference in somatic mutations in carcinomas from VLTSs compared to available data from PDACs unselected for survival. Comparison of clinico-pathological features between VLTSs and a matching control group demonstrated that younger age, earlier stage, well/moderate grade of differentiation, and negative resection margins were associated with VLTS. However, more advanced stage, poor grade or nodal disease did not preclude long-term survival. Conclusion: Our results suggest that in most patients somatic mutations in commonly mutated genes are unlikely to be the primary determinant of very long-term survival following surgical resection of PDAC. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 01/2015; 21(8). DOI:10.1158/1078-0432.CCR-14-2600 · 8.19 Impact Factor
  • Hanno Matthaei, Alexander Semaan, Ralph H Hruban
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    ABSTRACT: Cancer is caused by the accumulation of inherited and/or acquired alterations in specific genes. The recent decline in the cost of DNA sequencing has allowed tumor sequencing to be conducted on a large scale, which, in turn, has led to an unprecedented understanding of the genetic events that drive neoplasia. This understanding, when integrated with meticulous histologic analyses and with clinical findings, has direct clinical implications. The recent sequencing of all of the major types of cystic and noncystic neoplasms of the pancreas has revealed opportunities for molecular diagnoses and for personalized treatment. This review summarizes the results from these recent studies focusing on the clinical relevance of genomic data.
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    ABSTRACT: The significance of indeterminate pulmonary nodules (IPNs) in patients undergoing resection of pancreatic ductal adenocarcinoma (PDAC) is unknown. We sought to define the prevalence and impact of IPN in such patients. We studied all patients who underwent surgical resection of PDAC between 1980 and 2013. IPN was defined as ≥1 well-defined lung nodule(s) less than 3 cm in diameter. Survival was assessed using univariate and multivariate Cox models. Of the 2306 resected patients, 374 (16.2 %) had a preoperative chest computed tomography (CT) scan. Of these patients, 183 (49 %) had ≥1 IPN. Demographic and clinicopathological characteristics were similar among patients with or without IPN (all P > 0.05). Median survival was comparable among patients who did (15.6 months) or did not (18.0 months) have IPN (P = 0.66). Of the 183 patients with IPN, 29 (16 %) progressed to clinically recognizable metastatic lung disease compared to 13 % without IPN (P = 0.38). The presence of >1 IPN was associated with the development of lung metastasis (relative risk 1.58, 95 % CI 1.03-2.4; P = 0.05). However, lung metastasis was not associated with survival (P = 0.24). An IPN proved to be a lung metastasis in only one of six patients with PDAC undergoing surgical resection in this study. Survival was not impacted, even among patients who developed lung metastasis. Patients with PDAC who have IPN should not be precluded from surgical consideration.
    Journal of Gastrointestinal Surgery 01/2015; DOI:10.1007/s11605-014-2740-9 · 2.39 Impact Factor
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    Laura D Wood, Ralph H Hruban
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    ABSTRACT: Pancreatic cancer is a deadly disease with a dismal prognosis. However, recent advances in sequencing and bioinformatic technology have led to the systematic characterization of the genomes of all major tumor types in the pancreas. This characterization has revealed the unique genomic landscape of each tumor type. This knowledge will pave the way for improved diagnostic and therapeutic approaches to pancreatic tumors that take advantage of the genetic alterations in these neoplasms.
    01/2015; 49(1):13-22. DOI:10.4132/jptm.2014.12.26
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    ABSTRACT: We investigated the incremental diagnostic yield of S-MRCP in a population with high prevalence of small pancreatic cysts.
    European Journal of Radiology 01/2015; 84(4). DOI:10.1016/j.ejrad.2014.12.028 · 2.16 Impact Factor
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    ABSTRACT: OBJECTIVE. Pancreatic adenocarcinoma is a rapidly progressive malignancy characterized by its tendency for early metastatic spread. MDCT is the primary diagnostic modality for the preoperative staging of patients with pancreatic cancer, with an accuracy established in multiple studies. However, for a variety of reasons, there is often a prolonged interval between staging MDCT and the surgical intervention. This study examines the relationship between the interval between imaging and surgery and the accuracy of MDCT in determining the presence or absence of metastatic disease at surgery in patients with pancreatic cancer. MATERIALS AND METHODS. Patients were identified who had undergone surgery for pancreatic cancer at our institution with a dedicated preoperative pancreas-protocol MDCT performed in our department. Findings from the preoperative MDCT report were correlated with the operative findings, as well as the time between imaging and surgery. RESULTS. Two hundred ninety-two MDCT scans were performed on 256 patients who underwent exploration for pancreatic adenocarcinoma. The patients had a median age of 67 years (range, 30-95 years), and 51.6% (132/256) were male. The median time between MDCT and surgical exploration was 15.5 days (range, 1-198 days). MDCT correctly predicted the absence of metastatic disease at surgery in 233 of 274 (85.0%) studies. MDCT was more accurate in predicting the absence of metastatic disease if the study was performed within 25 days of surgery than it was if the study was performed within more than 25 days of surgery (89.3% vs 77.0%; p = 0.0097). Furthermore, regression models showed that the negative predictive value of a given MDCT significantly decreased after approximately 4 weeks. CONCLUSION. MDCT is an accurate method to stage patients with pancreatic cancer, but its accuracy in excluding distant metastatic disease depreciates over time. Patients should undergo a repeat MDCT within 25 days of any planned definitive operative intervention for pancreatic cancer to avoid unexpectedly finding metastatic disease at surgery.
    American Journal of Roentgenology 01/2015; 204(1):W37-42. DOI:10.2214/AJR.13.12439 · 2.74 Impact Factor
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    ABSTRACT: Pancreatic cancer is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. Tractable methods to identify and interrogate pathways involved in pancreatic tumorigenesis are urgently needed. We established organoid models from normal and neoplastic murine and human pancreas tissues. Pancreatic organoids can be rapidly generated from resected tumors and biopsies, survive cryopreservation, and exhibit ductal- and disease-stage-specific characteristics. Orthotopically transplanted neoplastic organoids recapitulate the full spectrum of tumor development by forming early-grade neoplasms that progress to locally invasive and metastatic carcinomas. Due to their ability to be genetically manipulated, organoids are a platform to probe genetic cooperation. Comprehensive transcriptional and proteomic analyses organoids revealed genes and pathways altered during disease progression. The confirmation of many of these protein changes in human tissues demonstrates that organoids are a facile model of murine pancreatic system to discover characteristics of this deadly malignancy.
    Cell 12/2014; DOI:10.1016/j.cell.2014.12.021 · 33.12 Impact Factor
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    ABSTRACT: Purpose The purpose of the study is to evaluate the CT appearance and pattern of metastatic disease of patients with surgically resected well-differentiated duodenal neuroendocrine tumors who underwent pre-operative dual-phase CT. Methods Clinical and pathologic records and CT images of 28 patients (average age 58.0 years) following Whipple procedure were retrospectively reviewed. The size, morphology (polypoid, intraluminal mass or wall thickening, intramural mass), location, CT attenuation in the arterial and venous phases, and the presence of lymph node or liver metastases were recorded. Results On CT, 19 patients (67.8%) had neuroendocrine tumors manifested as polypoid or intraluminal masses (38 lesions, multiple tumors in 3 patients), 4 patients (14.3%) had tumors manifested as wall thickening or intramural masses, and in 5 patients (17.9%), the primary tumor was not visualized. Lesions not seen at CT were less than 0.8 cm on pathologic diagnosis. The mean size of polypoid tumors on CT was 1.2 cm (range 0.3–3.8 cm); 24 tumors were 1.0 cm or smaller, and 14 tumors were larger than 1.0 cm. Most lesions were hypervascular in the arterial phase (19/23 patients) with an increase in tumor enhancement in the venous phase in 14 patients (60.9%), decrease in enhancement in 7 patients (30.4%), and no change in enhancement in 2 patients (8.7%). Thirteen patients (46.4%) had metastatic disease from carcinoid tumor, most commonly regional enhancing lymphadenopathy. Conclusion Duodenal carcinoid tumors commonly appear as an enhancing mass in either the arterial or venous phases. If a primary tumor is not seen in the duodenum, adjacent enhancing lymphadenopathy can be a clue to the presence of a duodenal carcinoid tumor.
    Abdominal Imaging 12/2014; DOI:10.1007/s00261-014-0322-7 · 1.73 Impact Factor
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    ABSTRACT: Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are precursor lesions that progress to invasive cancer through progressively worsening dysplasia. Although smoking is an established risk factor for pancreatic adenocarcinoma, potential associations with IPMN grade of dysplasia remain unclear. Pancreatic resections for IPMN from 1995 to 2013 were retrospectively reviewed. A total of 446 patients in which the smoking status was documented were identified. Smoking history was positive in 47 % of patients. Of smokers, 50 % had branch-duct, 14 % had main-duct, and 36 % had mixed-type IPMN. Patients with main-duct IPMN were more commonly smokers (65 %), compared to smoking history in 46 % with mixed and 44 % with branch-duct IPMN (p = 0.03). High-grade dysplasia occurred in 25 % of smokers and 21 % of nonsmokers (p = 0.32), and invasive carcinoma in 25 % of smokers and 25 % nonsmokers (p = 0.95). On multivariate analysis, duct size was independently associated with high-grade dysplasia (OR = 3.17, 95 %CI = 1.79-5.64, p < 0.001). Presence of mural nodules (OR = 3.34, 95 %CI = 1.82-6.12, p < 0.001), duct size (OR = 3.87, 95 %CI = 2.21-6.75, p < 0.001), and symptoms (OR = 7.10, 95 %CI = 3.80-13.08, p < 0.001), but not smoking history (OR = 1.10, 95 %CI = 0.64-1.88, p = 0.73), were independent predictors of invasive carcinoma. Median overall survival was 70 months for smokers and 88 months for nonsmokers (p = 0.68). Positive smoking history correlated with duct type classification but does not appear to be a risk factor for harboring high-grade dysplasia or invasive carcinoma in IPMNs.
    Journal of Gastrointestinal Surgery 12/2014; 19(4). DOI:10.1007/s11605-014-2714-y · 2.39 Impact Factor
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    ABSTRACT: & Aims: Pancreatic imaging can identify neoplastic cysts but not microscopic neoplasms. Mutation analysis of pancreatic fluid following secretin stimulation might identify microscopic neoplasias in the pancreatic duct system. We determined the prevalence of mutations in KRAS and GNAS genes in pancreatic juice from subjects undergoing endoscopic ultrasound for suspected pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasms, or pancreatic adenocarcinoma. Secretin-stimulated juice samples were collected from the duodenum of 272 subjects enrolled in Cancer of the Pancreas Screening studies; 194 subjects were screened because of a family history of, or genetic predisposition to, pancreatic cancer and 78 were evaluated for pancreatic cancer (n=30) or other disorders (controls: pancreatic cysts, pancreatitis, or normal pancreata, n=48 ). Mutations were detected by digital high-resolution melt-curve analysis and pyrosequencing. The number of replicates containing a mutation determined the mutation score. KRAS mutations were detected in pancreatic juice from larger percentages of subjects with pancreatic cancer (73%) or undergoing cancer screening (50%) than controls (19%) (P=.0005). A greater proportion of patients with pancreatic cancer had at least 1 KRAS mutation detected 3 or more times (47%) than screened subjects (21%) or controls (6%, P=.002). Among screened subjects, mutations in KRAS (but not GNAS) were found in similar percentages of patients with or without pancreatic cysts. However, a greater proportion of patients over 50 ys old had KRAS mutations (54.6%) than younger patients (36.3%) (P=.032); the older subjects also more mutations in KRAS (P=.02). Mutations in KRAS are detected in pancreatic juice from the duodenum of 73% of patients with pancreatic cancer, and 50% of asymptomatic individuals with a high risk for pancreatic cancer. However, KRAS mutations are detected in pancreatic juice from 19% of controls. Mutations detected in individuals without pancreatic abnormalities, based on imaging analyses, likely arise from small PanIN lesions. ClinicalTrials.gov no: NCT00438906 and NCT00714701. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.
    Clinical Gastroenterology and Hepatology 12/2014; 13(5). DOI:10.1016/j.cgh.2014.11.028 · 6.53 Impact Factor
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    ABSTRACT: A 3 day old infant with persistent severe hypoglycemia was found to have a cystic pancreatic tumor. Cessation of glucose infusion led to severe hypoglycemia. Pancreaticoduodenectomy was performed and revealed an intraductal papillary mucinous neoplasm (IPMN) with high-grade dysplasia. Sequencing of the IPMN revealed a KRAS gene mutation not present in surrounding normal tissues. Deep sequencing of the patient’s blood for KRAS mutations showed no evidence of mosaicism. Whole exome sequencing of the blood of the patient and both parents revealed a de novo germline SKIL mutation in the child that was not present in either parent. This suggests a possible role for SKIL in the pathogenesis of pancreatic tumors.
    Pancreatology 10/2014; 15(2). DOI:10.1016/j.pan.2014.10.009 · 2.50 Impact Factor
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    ABSTRACT: Neurofibromatosis 1 is a hereditary syndrome characterized by the development of numerous benign neurofibromas, a small subset of which progress to malignant peripheral nerve sheath tumors (MPNSTs). To better understand the genetic basis for MPNSTs, we performed genome-wide or targeted sequencing on 50 cases. Sixteen MPNSTs but none of the neurofibromas tested were found to have somatic mutations in SUZ12, implicating it as having a central role in malignant transformation.
    Nature Genetics 10/2014; 46(11). DOI:10.1038/ng.3116 · 29.65 Impact Factor
  • Ralph H Hruban, David S Klimstra
    Seminars in Diagnostic Pathology 09/2014; DOI:10.1053/j.semdp.2014.08.006 · 1.80 Impact Factor
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    ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is nearly uniformly lethal, with a median overall survival in 2014 of only 6 months. The genetic progression of sporadic PDAC (SPC) is well established, with common somatic alterations in KRAS, p16/CDKN2A, TP53, and SMAD4/DPC4. Up to 10 % of all PDAC cases occur in families with two or more affected first-degree relatives (familial pancreatic cancer, FPC), but these cases do not appear to present at an obviously earlier age of onset. This is unusual because most familial cancer syndrome patients present at a substantially younger age than that of corresponding sporadic cases. Here we collated the reported age of onset for FPC and SPC from the literature. We then used an integrated approach including whole exomic sequencing, whole genome sequencing, RNA sequencing, and high density SNP microarrays to study a cohort of FPC cell lines and corresponding germline samples. We show that the four major SPC driver genes are also consistently altered in FPC and that each of the four detection strategies was able to detect the mutations in these genes, with one exception. We conclude that FPC undergoes a similar somatic molecular pathogenesis as SPC, and that the same gene targets can be used for early detection and minimal residual disease testing in FPC patients.
    Familial Cancer 09/2014; DOI:10.1007/s10689-014-9755-y · 1.62 Impact Factor

Publication Stats

53k Citations
5,476.26 Total Impact Points


  • 1990–2015
    • Johns Hopkins University
      • • Department of Pathology
      • • Department of Radiology
      • • Department of Surgery
      • • Department of Medicine
      • • Department of Otolaryngology - Head and Neck Surgery
      Baltimore, Maryland, United States
  • 1984–2015
    • Johns Hopkins Medicine
      • • Department of Surgery
      • • Department of Pathology
      • • Department of Radiology and Radiological Science
      Baltimore, Maryland, United States
  • 2013
    • Duke University Medical Center
      • Department of Pathology
      Durham, North Carolina, United States
    • University of Colorado
      • Division of GI, Tumor and Endocrine Surgery
      Denver, CO, United States
  • 2011
    • CUNY Graduate Center
      New York, New York, United States
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 2009
    • Cambridge Institute for Medical Research
      Cambridge, England, United Kingdom
  • 1991–2009
    • Memorial Sloan-Kettering Cancer Center
      • • Department of Pathology
      • • Department of Surgery
      New York City, NY, United States
  • 2008
    • Shizuoka Cancer Center
      Sizuoka, Shizuoka, Japan
  • 2007
    • Cold Spring Harbor Laboratory
      Cold Spring Harbor, New York, United States
  • 2006
    • Louisiana State University in Shreveport
      Shreveport, Louisiana, United States
    • Creighton University
      Omaha, Nebraska, United States
  • 2005
    • Sapienza University of Rome
      Roma, Latium, Italy
    • Dartmouth–Hitchcock Medical Center
      Lebanon, New Hampshire, United States
  • 2004
    • Temple University
      Filadelfia, Pennsylvania, United States
    • Kagoshima University
      • Graduate School of Medical and Dental Sciences
      Kagosima, Kagoshima, Japan
  • 2003
    • University of Oxford
      • Nuffield Division of Clinical Laboratory Sciences
      Oxford, England, United Kingdom
    • Mayo Clinic - Rochester
      • Department of Health Science Research
      Rochester, Minnesota, United States
    • Wayne State University
      • Department of Pathology
      Detroit, MI, United States
  • 2000–2003
    • University of Texas Southwestern Medical Center
      • Department of Pathology
      Dallas, Texas, United States
  • 2002
    • Sidney Health Center
      Sydney, New South Wales, Australia
  • 1998–2002
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • Department of Pathology
      Amsterdamo, North Holland, Netherlands
    • University of California, San Francisco
      San Francisco, California, United States
  • 1999
    • William Penn University
      Filadelfia, Pennsylvania, United States
  • 1995–1999
    • University of Amsterdam
      • Department of Pathology
      Amsterdamo, North Holland, Netherlands
    • University of Chicago
      Chicago, Illinois, United States
  • 1993
    • Greater Baltimore Medical Center
      Baltimore, Maryland, United States
  • 1992
    • University of Massachusetts Boston
      Boston, Massachusetts, United States