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Ralph H Hruban

Publications and source records attributed to Ralph H Hruban.

At least 19 recordsLinked to original sources
PubMed2026

Intraductal Papillary Squamous Neoplasm (IPSN) of the Pancreas: Histological and Molecular Characterization of a Novel and Distinct Intraductal Cancer Precursor.

We report 6 intraductal papillary squamous neoplasms (IPSNs) of the pancreas, a rare but distinctive tumor whose biological features remain largely unknown. Five cases were investigated using an integrated approach combining histomorphological evaluation, immunohistochemistry, and multiregional molecular profiling through whole-exome DNA sequencing and whole-transcriptome RNA sequencing. Only targeted DNA sequencing was available on a sixth recently diagnosed case. Histologically, the intraductal lesions were characterized by large, confluent papillae with fibrovascular cores lined by multilayered epithelial cells with diffuse squamous differentiation. All cases harbored a concomitant invasive carcinoma. The associated invasive carcinomas consistently included a pancreatic tubular/ductal adenocarcinoma; in 5 cases, a poorly differentiated squamous cell carcinoma was also present, the proportion/features of which met the diagnostic criteria of adenosquamous carcinoma in 2 of them. Genomic analyses revealed that IPSNs and their matched invasive carcinomas shared the majority of somatic alterations, supporting a shared clonal origin for the 2 components. Activating KRAS mutations and biallelic inactivation of CDKN2A were detected in all cases. Recurrent mutations involved members of the SWI/SNF chromatin-remodeling complex and KMT2D. Additionally, FGFR1 and MYC amplifications were identified in 2 distinct cases (1 case each). Molecular alterations restricted to the invasive component involved mediators of the transforming growth factor-β signaling pathway. Transcriptomic profiling demonstrated a basal-like expression pattern in all IPSNs and squamous cell carcinomas, although in 2 cases, the matched pancreatic tubular/ductal adenocarcinoma shifted toward a classical transcriptomic subtype. In conclusion, through integrated histological assessment and multiregional molecular sequencing, we demonstrate that IPSN represents a bona fide precursor of invasive pancreatic cancer, a new addition to the intraductal neoplasms category. This study challenges the current paradigm that pancreatic squamous epithelium plays no role in the initiation of pancreatic carcinogenesis, providing the first evidence of its involvement in early tumorigenic processes and yielding immediate implications for pancreatic tumor classification and biological understanding.

Humans↗
PubMed2025

Multi-omic profiling of intraductal papillary neoplasms of the pancreas reveals distinct patterns and potential markers of progression.

To enable early detection of pancreatic cancer from precancerous lesions, we analyze proteins and glycoproteins from 64 intraductal papillary mucinous neoplasms (IPMNs), 55 cyst fluid samples, 104 pancreatic ductal adenocarcinomas (PDACs), and various types of normal samples using mass spectrometry. High-grade IPMNs show enrichment of glycosylation level and tumor progression pathways compared to low-grade lesions. High-grade IPMN associated proteins, such as PLOD3, IRS2, LGALS9, and Trop-2, are identified and validated using immunolabeling and laser microdissection. Some high-grade associated proteins are also detected in pancreatic cyst fluids, which allows us to link proteins and glycoproteins expressed in neoplastic cells to clinically accessible biospecimens. Altered glycosylation level of extracellular matrix (ECM) proteins is observed in IPMNs compared to normal ducts. Additionally, we identify a subset of IPMNs with PDAC-like features, including elevated expression of ECM proteins. These findings offer insight into progression-associated proteins and emphasize the diagnostic and therapeutic potential of these proteins in pancreatic tumors.

Humans↗
PubMed2006

Spiritual issues of family members in a pancreatic cancer chat room.

PURPOSE/OBJECTIVES: To describe spiritual issues addressed by users of a pancreatic cancer informational Web site. DESIGN: Qualitative, descriptive. SETTING: The patient and family chat room of Johns Hopkins Hospital's pancreatic cancer Web site. SAMPLE: 600 postings on the pancreatic cancer Web site. METHODS: Identification of categories and themes in Web postings using the constant comparison method of content analysis. MAIN RESEARCH VARIABLES: Spirituality, relationship of the person posting a message (poster) to the person with cancer. FINDINGS: Relationship of the poster to the person with pancreatic cancer was explicit in 68% (n = 410) of the 600 postings, and 83% of those 410 postings indicated that the poster was a family member. Issues of spirituality appeared in 19% (n = 114) of the 600 postings and addressed four themes: spiritual convergence, reframing suffering, hope, and acceptance of the power of God and eternal life. Six percent of postings were by family members reporting on the death of their loved ones, suggesting that the site also served a bereavement function. CONCLUSIONS: Family members of patients with pancreatic cancer sought and received spiritual comfort in a variety of forms in an Internet-based cancer chat room. IMPLICATIONS FOR NURSING: Nurse developers of cancer information Web sites should periodically assess how the sites are being used and apply the information to the refinement of the sites to better meet user needs. Further study is needed to develop and evaluate cancer Web sites as an evolving medium for providing spiritual support to family members of patients with life-threatening forms of cancer.

Attitude to Death↗
PubMed2006

Precancer: a conceptual working definition -- results of a Consensus Conference.

BACKGROUND: Precancers are lesions that precede the appearance of invasive cancers. The successful prevention or treatment of precancers has the potential to eliminate deaths due to cancer. METHODS: A National Cancer Institute-sponsored Conference on Precancer was convened on November 8-9, 2004, at The George Washington University Medical Center, Washington, DC. A definition of precancers was developed over 2 days of Conference discussions. RESULTS: The following five criteria define a precancer: (1) evidence must exist that the precancer is associated with an increased risk of cancer; (2) when a precancer progresses to cancer, the resulting cancer arises from cells within the precancer; (3) a precancer differs from the normal tissue from which it arises; (4) a precancer differs from the cancer into which it develops, although it has some, but not all, of the molecular and phenotypic properties that characterize the cancer; (5) there is a method by which the precancer can be diagnosed. CONCLUSIONS: The Conference participants developed a general definition for precancers that would provide a consistent and clinically useful way of distinguishing precancers from all other types of lesions. It was recognized that many precancerous lesions may not meet this strict definition, but the group felt it was necessary to define criteria that will help standardize clinical and biological studies. Furthermore, a set of defining criteria for putative precancer lesions will permit pathologists to build a diagnostically useful taxonomy of precancers based on specified clinical and biological properties. Precancers thus characterized can be classified into clinically relevant sub-groups based on shared properties (i.e. biomarkers, oncogenes, common metabolic pathways, responses to therapy, etc.). Publications that introduce newly described precancer entities should describe how each of the five defining criteria apply. This manuscript reviews the proposed definition of precancers and suggests how pathologists, oncologists and cancer researchers may determine when these criteria are satisfied.

Humans↗
PubMed2006

Differentiating pancreatic lesions by microarray and QPCR analysis of pancreatic juice RNAs.

BACKGROUND: The gene expression profile of pancreatic cancer is significantly different from that of normal pancreas. Differences in gene expression are detectable using microarrays, but microarrays have traditionally been applied to pancreatic cancer tissue obtained from surgical resection. We hypothesized that gene expression alterations indicative of pancreatic cancer can be detected by profiling the RNA of pancreatic juice. METHODS: We performed oligonucleotide microarray analysis on RNA isolated from pancreatic juice obtained endoscopically after secretin stimulation from six patients with pancreatic cancer and ten patients with nonneoplastic diseases of the pancreas or upper gastrointestinal tract. Extracted RNA was subjected to two rounds of linear RNA amplification, and then hybridized with U133A or X3P gene chips (Affymetrix). RESULTS: Using the U133A or X3P chips, 37 and 133 gene fragments respectively, were identified as being at least 3-fold more abundant in the pancreatic juice of patients with pancreatic cancer compared to the noncancer controls (p<0.05, Mann-Whitney test). For example, pancreatic juice from patients with pancreatic cancer contained increased levels of IL8, IFITM1, fibrinogen, osteopontin, CXCR4, DAF and NNMT RNA, genes that have been previously reported as overexpressed in primary pancreatic cancers or pancreatic cancer cell lines relative to control tissues. CONCLUSIONS: These results demonstrate that RNA analysis of pancreatic juice can reveal some of the same RNA alterations found in invasive pancreatic cancers. RNA analysis of pancreatic juice deserves further investigation to determine its utility as a tool for the evaluation of pancreatic lesions.

Chronic Disease↗
PubMed2006

Resected periampullary adenocarcinoma: 5-year survivors and their 6- to 10-year follow-up.

BACKGROUND: Many studies have reported 5-year survival data after pancreaticoduodenectomy for periampullary adenocarcinoma. This study evaluates 10-year survival in patients surviving 5 years after initial surgery. METHODS: We reviewed all patients undergoing pancreaticoduodenectomy for periampullary adenocarcinoma from April 1970 to July 1999 at a single institution. All 5-year survivors were identified, and their subsequent 5-year survival was compared with the actuarial survival of the general population starting at 70 years of age. RESULTS: Nine hundred fifteen patients underwent pancreaticoduodenectomy for periampullary adenocarcinoma. Follow-up was complete on 890 patients. There were 201 (23%) 5-year survivors with a median age of 65 years at initial surgery; 51% were male and 92% were Caucasian. For the 5-year survivors, the carcinoma origin was pancreatic in 46%, ampullary in 25%, distal bile duct in 17%, and duodenal in 12%. For all 5-year survivors, the subsequent 5-year actuarial survival rate was 65%, with a median survival after achieving the 5-year landmark of 7.9 additional years. The subsequent 5-year survival by site of tumor origin was 55% for pancreatic, 66% for ampullary, 74% for bile duct, and 85% for duodenal cancer. For the age-matched population, the 5-year survival rate was 87% (P<.001 when compared with those with all periampullary cancers). CONCLUSIONS: While the 5-year survival rate for all patients with resected periampullary adenocarcinoma is only 23%, these data imply that attainment of the 5-year survival landmark carries with it an improved survival for the subsequent 5 years. While the survival rate was less than that of the age-matched population, 65% of 5-year survivors survived 5 more years, bringing them to the 10-year postresection landmark.

Adenocarcinoma↗
PubMed2006

Identifying allelic loss and homozygous deletions in pancreatic cancer without matched normals using high-density single-nucleotide polymorphism arrays.

Recent advances in oligonucleotide arrays and whole-genome complexity reduction data analysis now permit the evaluation of tens of thousands of single-nucleotide polymorphisms simultaneously for a genome-wide analysis of allelic status. Using these arrays, we created high-resolution allelotype maps of 26 pancreatic cancer cell lines. The areas of heterozygosity implicitly served to reveal regions of allelic loss. The array-derived maps were verified by a panel of 317 microsatellite markers used in a subset of seven samples, showing a 97.1% concordance between heterozygous calls. Three matched tumor/normal pairs were used to estimate the false-negative and potential false-positive rates for identifying loss of heterozygosity: 3.6 regions (average minimal region of loss, 720,228 bp) and 2.3 regions (average heterozygous gap distance, 4,434,994 bp) per genome, respectively. Genomic fractional allelic loss calculations showed that cumulative levels of allelic loss ranged widely from 17.1% to 79.9% of the haploid genome length. Regional increases in "NoCall" frequencies combined with copy number loss estimates were used to identify 41 homozygous deletions (19 first reports), implicating an additional 13 regions disrupted in pancreatic cancer. Unexpectedly, 23 of these occurred in just two lines (BxPc3 and MiaPaCa2), suggesting the existence of at least two subclasses of chromosomal instability (CIN) patterns, distinguished here by allelic loss and copy number changes (original CIN) and those also highly enriched in the genomic "holes" of homozygous deletions (holey CIN). This study provides previously unavailable high-resolution allelotype and deletion breakpoint maps in widely shared pancreatic cancer cell lines and effectively eliminates the need for matched normal tissue to define informative loci.

Cell Line, Tumor↗
PubMed2006

A proposed clinical test for monitoring fluoropyrimidine therapy: detection and stability of thymidylate synthase ternary complexes.

5-fluorouracil forms classic (covalent, ternary) complexes consisting of thymidylate synthase, fluoro-deoxyuridine monophosphate, and 5,10-methylene tetrahydrofolate. Despite a high pharmacologic interest in the classic complexes formed in cells treated with fluorouracil anticancer agents, the in vivo stability of the complexes and the possible interference in complex formation by other coadministered compounds have not been adequately described. We visualized classic complexes unaccompanied by unbound thymidylate synthase, inferring complete enzymatic inhibition, in 5-fluorouracil-treated S. cerevisiae and cancer cells in vitro and in murine tumors in vivo treated with 5-fluorouracil. Classic complexes persisted 13 days in cancer cells after a pulse of 5-fluorouracil. Classic complexes were reduced to absent in cancer cells in which the older antifolates methotrexate and aminopterin, or the modern antifolates pemetrexed and tomudex, were coadministered with 5-fluorouracil. Classic complexes were, however, detected when an alternate drug, 5-fluorodeoxyuridine, was administered with methotrexate. We visualized classic complexes at fifteen minutes to seven days after an acute single dose of 5-fluorouracil in mouse tumor models, in tumors and normal tissues. Using the same assay, we detected unbound thymidylate synthase in untreated human tissues, supporting the future use of this assay in evaluating the most appropriate dose of fluoropyrimidine and coadministered agents in clinical settings.

Animals↗
PubMed2006

An in vivo platform for translational drug development in pancreatic cancer.

Effective development of targeted anticancer agents includes the definition of the optimal biological dose and biomarkers of drug activity. Currently available preclinical models are not optimal to this end. We aimed at generating a model for translational drug development using pancreatic cancer as a prototype. Resected pancreatic cancers from 14 patients were xenografted and expanded in successive groups of nude mice to develop cohorts of tumor-bearing mice suitable for drug therapy in simulated early clinical trials. The xenografted tumors maintain their fundamental genotypic features despite serial passages and recapitulate the genetic heterogeneity of pancreatic cancer. The in vivo platform is useful for integrating drug screening with biomarker discovery. Passages of tumors in successive cohorts of mice do not change their susceptibility to anticancer agents and represent a perpetual live bank, facilitating the application of new technologies that will result in the creation of an integrated stable database of tumor-drug response data and biomarkers.

Animals↗
PubMed2006

Positive immunohistochemical staining of KIT in solid-pseudopapillary neoplasms of the pancreas is not associated with KIT/PDGFRA mutations.

Solid-pseudopapillary neoplasms of the pancreas are uncommon neoplasms of low malignant potential and of uncertain histogenesis. A small percentage of patients develop metastatic disease and some succumb to disease. The management of patients with metastatic disease or unresectable tumor, and patients who are just not good surgical candidates is problematic. Novel therapy targets are needed. Successful treatment of metastatic and unresectable gastrointestinal stromal tumors with KIT kinase inhibitor, imatinib mesylate (Gleevec), makes it intriguing to look at the status of KIT in solid-pseudopapillary neoplasms of the pancreas. In this study, we investigated KIT expression in 50 solid-pseudopapillary neoplasms by immunohistochemical staining. Of the 50 (50%) solid-pseudopapillary neoplasms, 25 showed diffuse expression (in >50% neoplastic cells) of KIT and additional five (10%) cases showed focal staining (in 10-50% neoplastic cells). Expression of KIT was not associated with tumor behavior and prognosis. A subset of 11 cases showing diffuse KIT expression detected by immunohistochemical staining were further evaluated for the presence of activating mutations in KIT exons 9, 11, 13 and 17, and PDGFRA exons 12 and 18 using PCR amplification followed by direct sequencing. However, no KIT or PDGFRA mutations were identified in any of these 11 cases tested, suggesting that the overexpression of KIT is probably not due to activating mutations in KIT or PDGFRA. The exact mechanism of KIT overexpression in solid-pseudopapillary neoplasms remains to be elucidated. One possible mechanism is gene dose effect (increased copies of KIT gene). Experience in gastrointestinal stromal tumors and other tumors have shown that mutation-mediated activation of KIT or PDGFRA is a prerequisite for clinical response with imatinib mesylate. Thus, lack of mutations in KIT or PDGFRA in solid-pseudopapillary neoplasms suggests that imatinib mesylate is less likely to be effective in the treatment for patients with metastatic disease or unresectable tumor, and patients who are just not good surgical candidates.

Adolescent↗
PubMed2006

Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study.

BACKGROUND & AIMS: Individuals with a strong family history of pancreatic cancer and persons with Peutz-Jeghers syndrome (PJS) have an increased risk for pancreatic cancer. This study screened for early pancreatic neoplasia and compared the pancreatic abnormalities in high-risk individuals and control subjects. METHODS: High-risk individuals with PJS or a strong family history of pancreatic cancer were prospectively evaluated with baseline and 12-month computed tomography (CT) scan and endoscopic ultrasonography (EUS). If EUS was abnormal, EUS-fine-needle aspiration and endoscopic retrograde cholangiopancreatography (ERCP) were performed. Surgery was offered to patients with potentially neoplastic lesions. Radiologic findings and pathologic diagnoses were compared. Patients undergoing EUS and/or ERCP for benign non-pancreatic indications were concurrently enrolled as control subjects. RESULTS: Seventy-eight high-risk patients (72 from familial pancreatic cancer kindreds, 6 PJS) and 149 control patients were studied. To date, 8 patients with pancreatic neoplasia have been confirmed by surgery or fine-needle aspiration (10% yield of screening); 6 patients had 8 benign intraductal papillary mucinous neoplasms (IPMNs), 1 had an IPMN that progressed to invasive ductal adenocarcinoma, and 1 had pancreatic intraepithelial neoplasia. EUS and CT also diagnosed 3 patients with 5 extrapancreatic neoplasms. At EUS and ERCP abnormalities suggestive of chronic pancreatitis were more common in high-risk patients than in control subjects. CONCLUSIONS: Screening EUS and CT diagnosed significant asymptomatic pancreatic and extrapancreatic neoplasms in high-risk individuals. IPMN should be considered a part of the phenotype of familial pancreatic cancer. Abnormalities suggestive of chronic pancreatitis are identified more commonly at EUS and ERCP in high-risk individuals.

Adult↗
PubMed2006

Real-time detection of mesothelin in pancreatic cancer cell line supernatant using an acoustic wave immunosensor.

BACKGROUND: An acoustic wave immunosensor was developed to illustrate the viability of such devices in early detection of molecular cancer biomarkers. The methods described here involve a real-time, less invasive technique for detecting mesothelin, a protein that has been linked to pancreatic and ovarian cancer. METHODS: Antibodies were immobilized on the gold surface of the device via a self-assembled alkanethiol monolayer. Supernatant from two different pancreatic cancer cell-lines (PL1 and CAPAN2) containing an unknown concentration of mesothelin was tested for the protein by a flow-through analytical technique in three types of experiments. Binding of the mesothelin to the immobilized antibody layer caused a shift in the device's resonant frequency, which was correlated to the concentration of supernatant. A reference sensor was used to correct for frequency shifts caused by pressure or viscosity effects from the injection of the supernatant solution. RESULTS: Repeated experiments indicate that the sensors are capable of nanogram detection thresholds of mesothelin proteins at room temperature and in complex mixture. CONCLUSIONS: Acoustic wave device biosensors have the potential to become a valuable tool in screening for pancreatic as well as other types of cancers. The main features include real-time detection, high sensitivity, and ease of use.

Antibodies, Monoclonal↗
PubMed2006

Pathology of genetically engineered mouse models of pancreatic exocrine cancer: consensus report and recommendations.

Several diverse genetically engineered mouse models of pancreatic exocrine neoplasia have been developed. These mouse models have a spectrum of pathologic changes; however, until now, there has been no uniform nomenclature to characterize these changes. An international workshop, sponsored by The National Cancer Institute and the University of Pennsylvania, was held from December 1 to 3, 2004 with the goal of establishing an internationally accepted uniform nomenclature for the pathology of genetically engineered mouse models of pancreatic exocrine neoplasia. The pancreatic pathology in 12 existing mouse models of pancreatic neoplasia was reviewed at this workshop, and a standardized nomenclature with definitions and associated images was developed. It is our intention that this nomenclature will standardize the reporting of genetically engineered mouse models of pancreatic exocrine neoplasia, that it will facilitate comparisons between genetically engineered mouse models and human pancreatic disease, and that it will be broad enough to accommodate newly emerging mouse models of pancreatic neoplasia.

Animals↗
PubMed2006

Mist1-KrasG12D knock-in mice develop mixed differentiation metastatic exocrine pancreatic carcinoma and hepatocellular carcinoma.

Despite the prevalence of oncogenic Kras mutations in the earliest stages of pancreatic ductal adenocarcinoma, the cellular compartment in which oncogenic Kras initiates tumorigenesis remains unknown. To address this, we have gene targeted KrasG12D into the open reading frame of Mist1, a basic helix-loop-helix transcription factor that is expressed during pancreatic development and required for proper pancreatic acinar organization. Although the pancreata of Mist1(KrasG12D/+) mutant mice predictably exhibited acinar metaplasia and dysplasia, the frequent death of these mice from invasive and metastatic pancreatic cancer with mixed histologic characteristics, including acinar, cystic, and ductal features, was unexpected and in contrast to previously described mutant mice that ectopically expressed the Kras oncogene in either acinar or ductal compartments. Interestingly, many of the mutant mice developed hepatocellular carcinoma, implicating Mist1(KrasG12D/+) cells in both pancreatic and hepatic neoplasia. Concomitant Trp53+/- mutation cooperated with Mist1(KrasG12D/+) to accelerate lethality and was associated with advanced histopathologic findings, including parenchymal liver metastasis. These findings suggest that Mist1-expressing cells represent a permissive compartment for transformation by oncogenic Kras in pancreatic tumorigenesis.

Animals↗
PubMed2006

Pancreatic cancer in mice and man: the Penn Workshop 2004.

A three-day conference cosponsored by the National Cancer Institute Mouse Models of Human Cancer Consortium and the Abramson Cancer Center of the University of Pennsylvania was convened on December 1, 2004, in Philadelphia, Pennsylvania. The purpose of the conference was to compare the histopathologic changes in murine models of exocrine pancreatic cancer to human disease and to discuss potential preclinical applications of these models. The participants of this international meeting included over 100 physicians and scientists with expertise in pancreatic cancer pathology, therapy, detection, and biology, and they were organized accordingly into working groups. The format of the meeting was a series of short presentations by individual participants followed by working group breakout sessions. The working groups presented their reports on the final day of the conference, and highlights of selected individual presentations and working group recommendations are summarized here and in an accompanying pathology consensus report.

Animals↗
PubMed2006

Molecular pathogenesis of pancreatic cancer.

Pancreatic cancer is fundamentally a disease of inherited and acquired mutations in cancer-related genes. The genes targeted in pancreatic cancer include tumor-suppressor genes (p16/CDKN2A, TP53 and SMAD4), oncogenes (KRAS, BRAF, AKT2, MYB, and AIB1), and genome-maintenance genes (MLH1, MSH2, BRAC2 and other Fanconi anemia genes). An understanding of the cancer-related genes that are altered in pancreatic cancer has a number of clinical applications including genetic counseling for individuals with a family history of cancer, early detection of pancreatic neoplasia, and mechanism-based therapies for patients with advanced disease. This chapter will provide an overview of the molecular pathogenesis of pancreatic cancer with emphasis on clinical applications.

Carcinoma in Situ↗
PubMed2006

Differences in survival for patients with resectable versus unresectable metastases from pancreatic islet cell cancer.

Well-differentiated islet cell tumors can be associated with aggressive biology, resulting in early metastases to the liver. This study was carried out to determine whether survival for patients with malignant islet cell tumors and synchronous liver metastases is affected by complete surgical resection. Thirty-one patients with synchronous liver metastases from islet cell cancer underwent surgical exploration with the intent for complete tumor resection, and all patients underwent resection of the pancreatic primary. The patients were divided into two groups, those with resectable versus unresectable liver metastases. Twenty-six of 31 (84%) patients underwent complete resection of both the primary tumor and all liver metastases, and 5 (16%) patients underwent only complete resection of the pancreatic primary without liver resection. To extirpate the primary tumor, a pancreaticoduodenectomy was performed in 11 of the 26 (42%) completely resected patients and in 4 of the 5 (80%) incompletely resected patients, P = NS. The remainder of the patients underwent distal pancreatectomy. There were no statistical differences in primary tumor size, lymph node metastases, or adjuvant treatments between patients with resected and unresected liver metastases. The median overall survival for the completely resected group was 78 months, longer than the 17 months for the group with unresectable liver metastases (P = 0.06). Complete tumor resection (or the tumor biology that allows such complete resection) affords a survival advantage to patients with metastatic islet cell tumors of the pancreas. Patterns of liver metastases from islet cell tumors, specifically multiple bilobar metastases that are not amenable to resection and/or ablation, predict a poor outcome despite resection of the primary pancreatic tumor.

Adult↗