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Sample records for ductal hyperplasia ductal

  1. Denture hyperplasia with areas simulating oral inverted ductal papilloma.

    PubMed

    Vargas, Pablo Agustin; Perez, Danyel Elias da Cruz; Jorge, Jacks; Rangel, Ana Lúcia Carrinho Ayrosa; León, Jorge Esquiche; Almeida, Oslei Paes de

    2005-07-01

    Denture hyperplasia is a reactive lesion of the oral mucosa, usually associated to an ill-fitting denture. This lesion is easily diagnosed and in some cases distinct microscopic variations such as osseous, oncocytic and squamous metaplasia may be found. These metaplastic alterations probably are associated with the lymphocytic infiltrate usually present in denture hyperplasia. We present a case of denture hyperplasia containing salivary gland tissue with ductal alterations mimicking an oral inverted ductal papilloma.

  2. The diagnosis and management of pre-invasive breast disease: Ductal carcinoma in situ (DCIS) and atypical ductal hyperplasia (ADH) – current definitions and classification

    PubMed Central

    Pinder, Sarah E; Ellis, Ian O

    2003-01-01

    Intraductal epithelial proliferations of the breast are at present classified into three groups; distinction is made histologically and clinically between usual epithelial hyperplasia and atypical ductal hyperplasia (ADH) and between ADH and ductal carcinoma in situ (DCIS). Although evidence indicates that these boundaries are not ideal on a morphological, immunohistochemical, or genetic basis, this three-tier system is accepted and used at present. The current definitions, histological features, and system of classification of ADH and DCIS are described in this manuscript. PMID:12927035

  3. Association of breast cancer with the finding of atypical ductal hyperplasia at core breast biopsy.

    PubMed Central

    Moore, M M; Hargett, C W; Hanks, J B; Fajardo, L L; Harvey, J A; Frierson, H F; Slingluff, C L

    1997-01-01

    OBJECTIVE: The purpose of the study is to evaluate the prevalence of occult breast carcinoma in surgical breast biopsies performed on nonpalpable breast lesions diagnosed initially as atypical ductal hyperplasia (ADH) by core needle biopsy. BACKGROUND: Atypical ductal hyperplasia is a lesion with significant malignant potential. Some authors note that ADH and ductal carcinoma in situ (DCIS) frequently coexist in the same lesion. The criterion for the diagnosis of DCIS requires involvement of at least two ducts; otherwise, a lesion that is qualitatively consistent with DCIS but quantitatively insufficient is described as atypical ductal hyperplasia. Thus, the finding of ADH in a core needle breast biopsy specimen actually may represent a sample of a true in situ carcinoma. METHODS: Between May 3, 1994, and June 12, 1996, image-guided core biopsies of 510 mammographically identified lesions were performed using a 14-gauge automated device with an average of 7.5 cores obtained per lesion. Atypical ductal hyperplasia was found in 23 (4.5%) of 510 lesions, and surgical excision subsequently was performed in 21 of these cases. In these 21 cases, histopathologic results from core needle and surgical biopsies were reviewed and correlated. RESULTS: Histopathologic study of the 21 surgically excised lesions having ADH in their core needle specimens showed seven (33.3%) with DCIS. CONCLUSIONS: In the authors' patient population, one third of patients with ADH at core biopsy have an occult carcinoma. A core needle breast biopsy finding of ADH for nonpalpable lesions therefore warrants a recommendation for excisional biopsy. Images Figure 1. Figure 2. Figure 3. PMID:9230813

  4. Nodular basement membrane deposits in breast carcinoma and atypical ductal hyperplasia: mimics of collagenous spherulosis.

    PubMed

    Stephenson, T J; Hird, P M; Laing, R W; Davies, J D

    1994-06-01

    Collagenous spherulosis is characterised histologically by the accumulation of hyaline globules containing basement membrane components. Originally described in the breast, it has also been found in skin and salivary gland neoplasms. In the breast it has hitherto always been associated with benign disease and reports have asserted that this is invariably the case, cautioning against the diagnosis of malignancy when the condition is seen. We present here five cases with similar appearances to collagenous spherulosis in routine histology and immunohistochemistry, and ultrastructural studies in one of them, in which the condition was not associated with simple benign breast disease. Two of the cases were associated with invasive carcinomas of unusual histological types, one with intracystic papillary carcinoma, one with comedo ductal carcinoma-in-situ and one with atypical ductal hyperplasia. We suggest that appearances similar to collagenous spherulosis can be associated, either through being formed by a lesion or by collision, with malignancy and warn that on encountering the lesions the pathologist must not assume, as suggested in previous accounts, that it denotes a benign process. This is an important observation since collagenous spherulosis is likely to be encountered more frequently in the range of lesions biopsied in national breast screening programs.

  5. The Status of STAT3 and STAT5 in Human Breast Atypical Ductal Hyperplasia.

    PubMed

    Shi, Aiping; Dong, Jie; Hilsenbeck, Susan; Bi, Lirong; Zhang, Hong; Li, Yi

    2015-01-01

    Signal Transducer and Activation of Transcription factors (STAT3 and STAT5) play important roles in breast epithelial cell differentiation, proliferation, and apoptosis. They have been investigated extensively in established breast cancer, but their activation status in precancerous lesions has not been reported. Formalin-fixed, paraffin-embedded archival tissues from 59 cases of atypical ductal hyperplasia (ADH) and 31 cases of normal human breast tissue as well as 21 cases of usual ductal hyperplasias (UDH) were obtained from the First Hospital of Jilin University, China, and stained for pSTAT3 and pSTAT5 by immunohistochemistry. The median percentage of pSTAT5+ cells in ADH was 12%, not significantly deviant from that in normal breast. The median percentage of pSTAT3+ cells in ADH was 30%, significantly higher than that of normal breast. pSTAT3 and pSTAT5 were exclusive of each other--they were detected in different ADHs or in different cells within the same ADHs. In addition, both pSTAT3 and pSTAT5 were produced in similar percentages of cells in ADHs from cancer-free patients vs. ADHs that were adjacent to an invasive cancer. Our finding of a complementary expression pattern of pSTAT3 and pSTAT5 in ADH suggests that these two transcription factors may have feedback inhibitory effects on each other during early stages of breast cancer evolution, and that disruption of this inverse relationship may be important in the progression from early lesions to cancer, which exhibits positive association between pSTAT3 and pSTAT5. PMID:26146825

  6. The Status of STAT3 and STAT5 in Human Breast Atypical Ductal Hyperplasia

    PubMed Central

    Shi, Aiping; Dong, Jie; Hilsenbeck, Susan; Bi, Lirong; Zhang, Hong; Li, Yi

    2015-01-01

    Signal Transducer and Activation of Transcription factors (STAT3 and STAT5) play important roles in breast epithelial cell differentiation, proliferation, and apoptosis. They have been investigated extensively in established breast cancer, but their activation status in precancerous lesions has not been reported. Formalin-fixed, paraffin-embedded archival tissues from 59 cases of atypical ductal hyperplasia (ADH) and 31 cases of normal human breast tissue as well as 21 cases of usual ductal hyperplasias (UDH) were obtained from the First Hospital of Jilin University, China, and stained for pSTAT3 and pSTAT5 by immunohistochemistry. The median percentage of pSTAT5+ cells in ADH was 12%, not significantly deviant from that in normal breast. The median percentage of pSTAT3+ cells in ADH was 30%, significantly higher than that of normal breast. pSTAT3 and pSTAT5 were exclusive of each other—they were detected in different ADHs or in different cells within the same ADHs. In addition, both pSTAT3 and pSTAT5 were produced in similar percentages of cells in ADHs from cancer-free patients vs. ADHs that were adjacent to an invasive cancer. Our finding of a complementary expression pattern of pSTAT3 and pSTAT5 in ADH suggests that these two transcription factors may have feedback inhibitory effects on each other during early stages of breast cancer evolution, and that disruption of this inverse relationship may be important in the progression from early lesions to cancer, which exhibits positive association between pSTAT3 and pSTAT5. PMID:26146825

  7. Diagnostic underestimation of atypical ductal hyperplasia and ductal carcinoma in situ at percutaneous core needle and vacuum-assisted biopsies of the breast in a Brazilian reference institution*

    PubMed Central

    Badan, Gustavo Machado; Roveda Júnior, Decio; Piato, Sebastião; Fleury, Eduardo de Faria Castro; Campos, Mário Sérgio Dantas; Pecci, Carlos Alberto Ferreira; Ferreira, Felipe Augusto Trocoli; D'Ávila, Camila

    2016-01-01

    Objective To determine the rates of diagnostic underestimation at stereotactic percutaneous core needle biopsies (CNB) and vacuum-assisted biopsies (VABB) of nonpalpable breast lesions, with histopathological results of atypical ductal hyperplasia (ADH) or ductal carcinoma in situ (DCIS) subsequently submitted to surgical excision. As a secondary objective, the frequency of ADH and DCIS was determined for the cases submitted to biopsy. Materials and Methods Retrospective review of 40 cases with diagnosis of ADH or DCIS on the basis of biopsies performed between February 2011 and July 2013, subsequently submitted to surgery, whose histopathological reports were available in the internal information system. Biopsy results were compared with those observed at surgery and the underestimation rate was calculated by means of specific mathematical equations. Results The underestimation rate at CNB was 50% for ADH and 28.57% for DCIS, and at VABB it was 25% for ADH and 14.28% for DCIS. ADH represented 10.25% of all cases undergoing biopsy, whereas DCIS accounted for 23.91%. Conclusion The diagnostic underestimation rate at CNB is two times the rate at VABB. Certainty that the target has been achieved is not the sole determining factor for a reliable diagnosis. Removal of more than 50% of the target lesion should further reduce the risk of underestimation. PMID:26929454

  8. Synchronous invasive ductal carcinoma in encapsulated papillary ductal carcinoma

    PubMed Central

    Regan, J.P.; Casaubon, J.T.; Genelus-Dominique, E.

    2016-01-01

    Encapsulated papillary ductal carcinoma (EPC) of the breast is a rare form of cancer with defining histopathology of encapsulation. These lesions are typically indolent but may rarely have concomitant, synchronous invasive lesions. This report details a 56-year-old black female who presented with a palpable left breast mass. Adenosis with focal fibrous and ductal hyperplasia characteristics were found on core needle biopsy. Excisional biopsy showed EPC with invasive components. A simple mastectomy was performed and a second lesion was identified as invasive ductal carcinoma. EPC typically has good prognosis and a low incidence of invasion. The risk increases in the presence of a second, synchronous lesion as in our case. Management is typically performed with breast conserving methods; however, missing a second lesion is possible. This report provides an overview of the literature and discussion of the role of MRI in preoperative workup. PMID:27562577

  9. Absence of Residual Microcalcifications in Atypical Ductal Hyperplasia Diagnosed via Stereotactic Vacuum-Assisted Breast Biopsy: Is Surgical Excision Obviated?

    PubMed Central

    Youn, Inyoung; Kim, Min Jung; Moon, Hee Jung

    2014-01-01

    Purpose The purpose of our study was to evaluate the underestimation rate of atypical ductal hyperplasia (ADH) on vacuum-assisted breast biopsy (VABB), and to examine the correlation between residual microcalcifications and the underestimation rate of ADH. Methods A retrospective study was performed on 27 women (mean age, 49.2±9.2 years) who underwent additional excision for ADH via VABB for microcalcifications observed by using mammography. The mammographic findings, histopathologic diagnosis of all VABB and surgical specimens, and association of malignancy with residual microcalcifications were evaluated. The underestimation rate of ADH was also calculated. Results Of the 27 women with microcalcifications, nine were upgraded to ductal carcinoma in situ (DCIS); thus, the underestimation rate was 33.3% (9/27). There was no difference in age (p=0.40) and extent of microcalcifications (p=0.10) when comparing benign and malignant cases. Six of 17 patients (35.3%) with remaining calcifications after VABB were upgraded to DCIS, and three of 10 patients (30%) with no residual calcifications after VABB were upgraded (p=1.00). Conclusion The underestimation rate of ADH on VABB was 33.3%. Furthermore, 30% of patients with no remaining calcifications were upgraded to DCIS. Therefore, we conclude that all ADH cases diagnosed via VABB should be excised regardless of the presence of residual microcalcifications. PMID:25320625

  10. Underestimation of cancer in case of diagnosis of atypical ductal hyperplasia (ADH) by vacuum assisted core needle biopsy

    PubMed Central

    Polom, Karol; Murawa, Dawid; Kurzawa, Paweł; Michalak, Michał; Murawa, Paweł

    2012-01-01

    Background With the introduction of mammography screening, we are more often dealing with the diagnosis of precancerous and preinvasive breast lesions. An increasing number of patients are observed to show a premalignant change of ADH (atypical ductal hyperplasia). It also involves a wider use of the vacuum assisted core biopsy as a tool for verifying nonpalpable changes identified by mammography. Aim This paper describes our experience of 134 cases of ADH diagnosed at Mammotome® vacuum core needle biopsy. Material and methods Of 4326 mammotomic biopsies performed at our institution in 2000–2006, ADH was diagnosed in 134 patients (3.1%). Patients underwent surgery to remove the suspected lesion. All histopathological blocks were again reviewed by one pathologist. Clinical, radiological and pathological data were collected for statistical evaluation. Results Underestimation of invasive changes occurred in 12 patients (9%). The only clinicopathologic feature of statistical significance radiologically and pathologically was the presence of radial scar in the mammography. Conclusions More frequent diagnosis of precancerous changes in the mammotomic breast biopsy forces us to establish a clear clinical practice. The problem is the underestimation of invasive changes. The occurrence of radial scar on mammography for diagnosis of the presence of ADH increases the risk of invasive changes. PMID:24377013

  11. Prepubertal exposure to elevated manganese results in estradiol regulated mammary gland ductal differentiation and hyperplasia in female rats

    PubMed Central

    Dearth, Robert K; Hiney, Jill K; Srivastava, Vinod K; Hamilton, Alina M; Dees, William L

    2015-01-01

    Evidence suggests that environmental substances regulating estrogenic pathways during puberty may be detrimental to the developing mammary gland (MG). Manganese (Mn) is a trace mineral required for normal physiological processes. Prepubertal exposure to Mn induces precocious puberty in rats, an event associated with early elevations in puberty-related hormones, including estradiol (E2). However, until now the effect of Mn-induced precocious MG development has not been determined. Therefore, we assessed the ability of prepubertal Mn exposure to advance normal MG development and alter E2 driven pathways involved in tumorigenesis. Sprague Dawley female rats were gavaged daily with either 10 mg/kg manganese chloride (MnCl2) or saline (control) from postnatal day (PND) 12 through PND 30. Blood and MGs were collected on PNDs 30 and 120. Compared to controls, serum E2 levels on PND 30 were elevated (p<0.05) in the Mn-treated group. Mn exposure significantly increased differentiated MG terminal ductal structures and the percentage of MG epithelial cells that stained positive for the proliferative marker, Ki67, at PND 30 (p<0.001) and PND 120 (p < 0.001). Levels of Mn (ppm) were not elevated in these MGs. Mn-treated animals (40%) exhibited reactive stroma and intra-luminal focal hyperplasia in hemotoxylin and eosin stained MGs at PND 120. Furthermore, Mn exposure resulted in elevated protein expression levels of estrogen receptor α, activator protein 2α, phosphorylated (p)-Akt, and p53 in MGs on PND 120, but not on PND 30. Collectively, these data show that exposure to a supplemental dose of Mn causes accelerated pubertal MG growth which can progress to adult hyperplasia; thus, providing evidence that early life Mn exposure may increase susceptibility to breast cancer. PMID:24845367

  12. Increased breast density correlates with the proliferation-seeking radiotracer (99m)Tc(V)-DMSA uptake in florid epithelial hyperplasia and in mixed ductal carcinoma in situ with invasive ductal carcinoma but not in pure invasive ductal carcinoma or in mild epithelial hyperplasia.

    PubMed

    Papantoniou, Vassilios; Valsamaki, Pipitsa; Sotiropoulou, Evangelia; Tsaroucha, Angeliki; Tsiouris, Spyridon; Sotiropoulou, Maria; Marinopoulos, Spyridon; Kounadi, Evangelia; Karianos, Theodore; Fothiadaki, Athina; Archontaki, Aikaterini; Syrgiannis, Konstantinos; Ptohis, Nikolaos; Makris, Nikolaos; Limouris, Georgios; Antsaklis, Aris

    2011-10-01

    The purpose of this study was to assess the relationship of mammographic breast density (BD) and cell proliferation/focal adhesion kinase activation-seeking radiotracer technetium 99m pentavalent dimercaptosuccinic acid (99mTc(V)-DMSA) uptake in women with different breast histologies, that is, mild epithelial hyperplasia (MEH), florid epithelial hyperplasia (FEH), mixed ductal carcinoma in situ with invasive ductal carcinoma (DCIS + IDC), and pure IDC. Fifty-five women with histologically confirmed mammary pathologies were submitted preoperatively to mammography and 99mTc(V)-DMSA scintimammography. The percentage and intensity of 99mTc(V)-DMSA uptake and the percentage of BD were calculated by computer-assisted methods and compared (t-test) between the breast pathologies. In breasts with increased BD, FEH and DCIS + IDC were found. On the contrary, pure IDC and MEH were identified in breasts with significantly lower BD values. In breasts with increased 99mTc(V)-DMSA area and intensity of uptake, FEH was the main lesion found compared to all other histologies. Linear regression analysis between BD and 99mTc(V)-DMSA uptake area and intensity revealed significant coefficients of correlation (r  =  .689, p < .001 and r  =  .582, p < .001, respectively). Increased BD correlates with the presence of FEH and mixed DCIS + IDC but not with pure IDC or MEH. Its close relationship to 99mTc(V)-DMSA, which also showed an affinity to FEH, indicates that stromal microenvironment may constitute a specific substrate leading to progression to different subtypes of cancerous lesions originating from different pathways.

  13. Ductal barriers in mammary epithelium

    PubMed Central

    Owens, Mark B; Hill, Arnold DK; Hopkins, Ann M

    2013-01-01

    Tissue barriers play an integral role in the biology and pathobiology of mammary ductal epithelium. In normal breast physiology, tight and adherens junctions undergo dynamic changes in permeability in response to hormonal and other stimuli, while several of their proteins are directly involved in mammary tumorigenesis. This review describes first the structure of mammary ductal epithelial barriers and their role in normal mammary development, examining the cyclical changes in response to puberty, pregnancy, lactation and involution. It then examines the role of adherens and tight junctions and the participation of their constituent proteins in mammary tumorigenic functions such as migration, invasion and metastasis. Finally, it discusses the potential of these adhesion proteins as both prognostic biomarkers and potential therapeutic targets in breast cancer. PMID:24665412

  14. Possible Prognostic Role of HER2/Neu in Ductal Carcinoma In Situ and Atypical Ductal Proliferative Lesions of the Breast.

    PubMed

    Daoud, Sahar Aly; Ismail, Wesam Maghawri; Abdelhamid, Mohamed Salah; Nabil, Tamer Mohamed; Daoud, Sahar Aly

    2016-01-01

    HER2/neu is a well-established prognostic and predictive factor for invasive breast cancer. However, the role of HER2/neu in ductal breast carcinoma in situ (DCIS) is debated and recent data have suggested that it is mainly linked to in situ local recurrence. Although molecular data suggest that atypical ductal hyperplasia (ADH) and duct carcinoma in situ (DCIS) are related lesions, albeit with vastly different clinical implications, the role of HER2/neu expression in atypical ductal hyperplasia is not well defined either. The aim of this study was to evaluate over expression of HER2/neu in DCIS and cases of ADH in comparison with invasive breast carcinoma. Archival primary breast carcinoma paraffin blocks (n=15), DCIS only (n=10) and ductal epithelial hyperplasia and other breast benign lesions (n=25) were analyzed for HER2/neu immunoexpression. Follow up was available for 40% of the patients. HER2/neu was positive in 80%of both DCIS and invasive carcinoma, and 67% of atypical ductal hyperplasia (ADH) cases. Thus at least a subset of patients with preinvasive breast lesions were positive, which strongly suggests a role for Her2/neu in identifying high-risk patients for malignant transformation. Although these are preliminary data, which need further studies of gene amplification within these patients as well as a larger patient cohort with longer periods of follow up, they support the implementation of routine Her2/neu testing in patients diagnosed as pure DCIS and in florid ADH. PMID:27644608

  15. Inverted ductal papilloma of minor salivary glands.

    PubMed

    Hegarty, D J; Hopper, C; Speight, P M

    1994-08-01

    Inverted ductal papillomas are rare tumours of minor salivary glands. A case is reported on the lower lip of a 50-year-old man. The tumour showed a characteristic endophytic growth pattern and was composed of bulbous papillary projections of basaloid cells dilating and filling the superficial portion of the excretory duct. Histologically, inverted ductal papillomas resemble the inverted papilloma of the nose and paranasal sinuses, but are completely benign and are not associated with malignant change.

  16. Pancreatic mixed ductal-islet tumors. Is this an entity?

    PubMed

    Permert, J; Mogaki, M; Andrén-Sandberg, A; Kazakoff, K; Pour, P M

    1992-02-01

    Thirty-eight human pancreatic cancer specimens were studied for the reactivity of cancer cells with monoclonal antibodies against insulin, glucagon, somatostatin, pancreatic polypeptide (PP), vasoactive intestinal peptide (VIP), gastrin, calcitonin, and with argyrophilic reactivity. Immunoreactivity with one or several antibodies or argyrophilic reactivity were found in 30 (79%) cases. In 17 cases, the number of endocrine cells was excessive and morphologically consistent with the mixed ductal-islet tumor. Although most immunoreactive cells were located at the base of the malignant glands, some had intraepithelial location and were also present in the invasive portion of cancers, indicating their malignant nature. Endocrine cell proliferation were found in the pancreatic tissue adjacent to the carcinoma in 8 out of 12 specimens examined. In these cases, the immunoreactive cells were either distributed among the acinar cells or ductal cells. More endocrine cells were found in the hyperplastic ducts; however, no correlation was found between the degree of hyperplasia and the occurrence of any type of immunoreactive cells. Although several types of endocrine cells occurred in different pancreatic regions (head, body, and tail), PP cells were restricted to tissues taken from the head of the pancreas. Experimental data and similar observations by other investigators led us to conclude that participation of endocrine cells in ductal-type carcinomas is a general phenomenon and does not justify the classification of these lesions to mixed ductal-islet entity. However, because immunoreactive cells were more common and numerous in well-differentiated carcinomas, they may have some prognostic values. PMID:1316418

  17. Current management of ductal carcinoma in situ.

    PubMed

    Barth, A; Brenner, R J; Giuliano, A E

    1995-10-01

    Ductal carcinoma in situ represents a biologically and histologically heterogeneous group of lesions characterized by the proliferation of neoplastic epithelial cells confined to the ducts of the breast. Before screening mammography, ductal carcinoma in situ was considered uncommon; patients were usually diagnosed by a breast mass or bloody nipple discharge, and their treatment was mastectomy. Today it represents 20% to 30% of mammographically detected breast cancers and 10% to 15% of all diagnosed breast cancers in the United States. The invariable progression of this cancer to invasive breast cancer requiring mastectomy has been challenged, but because most patients have been treated with mastectomy, knowledge about ductal carcinoma in situ is limited and primarily based on retrospective data. Further insight will emerge from randomized prospective studies that are near completion. Currently available data indicate that breast-conserving treatments are valid alternatives to mastectomy for most patients with this disease. PMID:7483593

  18. Hsp90 in the continuum of breast ductal carcinogenesis: Evaluation in precursors, preinvasive and ductal carcinoma lesions

    PubMed Central

    2010-01-01

    Background Hsp90 (heat shock protein90) is a chaperone protein essential for preserving and regulating the function of various cellular proteins. Elevated Hsp90 expression seems to be a trait of breast cancer and may be an integral part of the coping mechanisms that cancer cells exhibit vis-à-vis stress. This manuscript tries to examine the immunohistochemical expression of Hsp90 all along the continuum of breast ductal lesions encompassing ductal hyperplasia without atypia (DHWithoutA), atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC). Methods Tissue specimens were taken from 30 patients with DHWithoutA, 31 patients with ADH, 51 with DCIS and 51 with IDC. Immunohistochemical assessment of Hsp90 was performed both in the lesion and the adjacent normal breast ducts and lobules; the latter serving as control. Concerning Hsp90 assessment the percentage of positive cells and the intensity were separately analyzed. Subsequently, the Allred score was calculated. Post hoc analysis on the correlations between Hsp90 Allred score and possible predictors (grade, nodal status, tumor size, ER Allred score, PR Allred score, c-erbB-2 status and triple negative status) was conducted in IDC. Results Hsp90 exhibited mainly cytoplasmic immunoreactivity. Hsp90 Allred score exhibited an increasing trend along the continuum of breast ductal lesions (Spearman's rho = 0.169, p = 0.031). Compared to the adjacent normal ducts and lobules, no statistically significant differences were noted in DHwithoutA, ADH and DCIS. Hsp90 expression (intensity, positive cells, Allred score) was higher in IDC, compared to the adjacent normal tissue. Higher Hsp90 expression was observed in grade 2/3 IDCs (borderline association) and tumors of larger size. At the univariable analysis, higher Hsp90 expression was associated with higher ER Allred score, PR Allred score and c-erbB-2 positivity in IDC. Triple-negative IDCs exhibited significantly lower Hsp90

  19. Genetics and Biology of Pancreatic Ductal Adenocarcinoma.

    PubMed

    Dunne, Richard F; Hezel, Aram F

    2015-08-01

    Pancreatic ductal adenocarcinoma remains a clinical challenge. Thus far, enlightenment on the downstream activities of Kras, the tumor's unique metabolic needs, and how the stroma and immune system affect it have remained untranslated to the clinical practice. Given the numbers of diverse therapies in development and a growing knowledge about how to evaluate these systems preclinically and clinically, this is expected to change significantly and for the better over the next 5 years. PMID:26226899

  20. Targeting Pancreatic Ductal Adenocarcinoma Acidic Microenvironment

    NASA Astrophysics Data System (ADS)

    Cruz-Monserrate, Zobeida; Roland, Christina L.; Deng, Defeng; Arumugam, Thiruvengadam; Moshnikova, Anna; Andreev, Oleg A.; Reshetnyak, Yana K.; Logsdon, Craig D.

    2014-03-01

    Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the USA, accounting for ~40,000 deaths annually. The dismal prognosis for PDAC is largely due to its late diagnosis. Currently, the most sensitive diagnosis of PDAC requires invasive procedures, such as endoscopic ultrasonography, which has inherent risks and accuracy that is highly operator dependent. Here we took advantage of a general characteristic of solid tumors, the acidic microenvironment that is generated as a by-product of metabolism, to develop a novel approach of using pH (Low) Insertion Peptides (pHLIPs) for imaging of PDAC. We show that fluorescently labeled pHLIPs can localize and specifically detect PDAC in human xenografts as well as PDAC and PanIN lesions in genetically engineered mouse models. This novel approach may improve detection, differential diagnosis and staging of PDAC.

  1. Aberrant pancreatic ductal organisation: a case report.

    PubMed

    Goel, Shivi; Rustagi, Shaifaly Madan; Saha, Susmita; Mehta, Vandana; Suri, Rajesh Kumar; Rath, Gayatri

    2015-07-01

    Anomalous pancreatic ductal system has always enthralled the anatomists, surgeons, gastroenterologists and radiologists alike. With the growing use of MRCP, ERCP and endoscopic and surgical procedures, the knowledge of anatomical aberrations of pancreaticobiliary tract becomes extremely important. Moreover, the anomalous pancreatic duct morphology may be responsible for atypical gastrointestinal complains. We report an exceptionally rare case of two accessory ventral pancreatic ducts opening separately into the common bile duct proximal to the hepato pancreatic ampulla. Concomitant occurrence of an ectopic major duodenal papilla, 3.8 cm distal to the pyloric end of stomach was also seen. Moreover, the accessory pancreatic duct and the minor duodenal papilla were absent. Clinical implications and embryological description of these rare anomalies are discussed. Awareness of such rare morphological variants can go a long way in assisting effective patient management.

  2. Optical diagnosis of mammary ductal carcinoma using advanced optical technology

    NASA Astrophysics Data System (ADS)

    Wu, Yan; Fu, Fangmeng; Lian, Yuane; Nie, Yuting; Zhuo, Shuangmu; Wang, Chuan; Chen, Jianxin

    2015-02-01

    Clinical imaging techniques for diagnosing breast cancer mainly include X-ray mammography, ultrasound, and magnetic resonance imaging (MRI), which have respective drawbacks. Multiphoton microscopy (MPM) has become a potentially attractive optical technique to bridge the current gap in clinical utility. In this paper, MPM was used to image normal and ductal cancerous breast tissues, based on two-photon excited fluorescence (TPEF) and second harmonic generation (SHG). Our results showed that MPM has the ability to exhibit the microstructure of normal breast tissue, ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) lesions at the molecular level comparable to histopathology. These findings indicate that, with integration of MPM into currently accepted clinical imaging system, it has the potential to make a real-time histological diagnosis of mammary ductal carcinoma in vivo.

  3. Current perspectives of treatment of ductal carcinoma in situ.

    PubMed

    Estévez, Laura G; Alvarez, Isabel; Seguí, Miguel Ángel; Muñoz, Monserrat; Margelí, Mireia; Miró, Cristina; Rubio, Carmen; Lluch, Ana; Tusquets, Ignasi

    2010-11-01

    DCIS is a genetically diverse group of diseases with different prognosis. The similarities between DCIS and ductal infiltrating carcinoma (DIC) suggest that the key step in tumorigenesis is the transformation from high grade ductal hyperplasia to DCIS. The prognostic factors of DCIS include anatomo-pathologic factors, age and molecular factors. The key questions for DCIS management include: which patients are more likely to present an invasive failure; in which an excision is sufficient and who can be spared from radiation therapy. The role of post operative radiation therapy to reduce by 50-60% ipsilateral invasive and non-invasive local failure has been established in four randomized clinical trials. The question whether radiation therapy can be avoided in some patients remains controversial. Treatment with tamoxifen should be recommended to patients with estrogen receptor positive tumors who have been treated with conservative surgery. However, data from randomized trials suggest that addition of tamoxifen to locoregional treatment decreases the recurrence rate of invasive cancer as well as contralateral tumors. Sentinel lymph node biopsy is recommended for patients with clinically palpable, large DCIS in which the risk of microinvasion is high as well as in extensive DCIS requiring mastectomy. Mammography continues to be the best method to detect DCIS. Newer digital mammography improves the detection of microcalcifications. Current ultrasound can detect associated invasive cancer. MRI is also useful in DCIS. Combined with mammography, MRI increases the diagnoses of DCIS. Current trend includes the use of radiology guided-vacuum assisted-large bore needles that allow obtaining larger amounts of tissue, improving diagnostic yield. PMID:20462701

  4. Genetics and biology of pancreatic ductal adenocarcinoma.

    PubMed

    Ying, Haoqiang; Dey, Prasenjit; Yao, Wantong; Kimmelman, Alec C; Draetta, Giulio F; Maitra, Anirban; DePinho, Ronald A

    2016-02-15

    With 5-year survival rates remaining constant at 6% and rising incidences associated with an epidemic in obesity and metabolic syndrome, pancreatic ductal adenocarcinoma (PDAC) is on track to become the second most common cause of cancer-related deaths by 2030. The high mortality rate of PDAC stems primarily from the lack of early diagnosis and ineffective treatment for advanced tumors. During the past decade, the comprehensive atlas of genomic alterations, the prominence of specific pathways, the preclinical validation of such emerging targets, sophisticated preclinical model systems, and the molecular classification of PDAC into specific disease subtypes have all converged to illuminate drug discovery programs with clearer clinical path hypotheses. A deeper understanding of cancer cell biology, particularly altered cancer cell metabolism and impaired DNA repair processes, is providing novel therapeutic strategies that show strong preclinical activity. Elucidation of tumor biology principles, most notably a deeper understanding of the complexity of immune regulation in the tumor microenvironment, has provided an exciting framework to reawaken the immune system to attack PDAC cancer cells. While the long road of translation lies ahead, the path to meaningful clinical progress has never been clearer to improve PDAC patient survival. PMID:26883357

  5. Genetics and biology of pancreatic ductal adenocarcinoma

    PubMed Central

    Ying, Haoqiang; Dey, Prasenjit; Yao, Wantong; Kimmelman, Alec C.; Draetta, Giulio F.; Maitra, Anirban; DePinho, Ronald A.

    2016-01-01

    With 5-year survival rates remaining constant at 6% and rising incidences associated with an epidemic in obesity and metabolic syndrome, pancreatic ductal adenocarcinoma (PDAC) is on track to become the second most common cause of cancer-related deaths by 2030. The high mortality rate of PDAC stems primarily from the lack of early diagnosis and ineffective treatment for advanced tumors. During the past decade, the comprehensive atlas of genomic alterations, the prominence of specific pathways, the preclinical validation of such emerging targets, sophisticated preclinical model systems, and the molecular classification of PDAC into specific disease subtypes have all converged to illuminate drug discovery programs with clearer clinical path hypotheses. A deeper understanding of cancer cell biology, particularly altered cancer cell metabolism and impaired DNA repair processes, is providing novel therapeutic strategies that show strong preclinical activity. Elucidation of tumor biology principles, most notably a deeper understanding of the complexity of immune regulation in the tumor microenvironment, has provided an exciting framework to reawaken the immune system to attack PDAC cancer cells. While the long road of translation lies ahead, the path to meaningful clinical progress has never been clearer to improve PDAC patient survival. PMID:26883357

  6. Interventional Nanotheranostics of Pancreatic Ductal Adenocarcinoma.

    PubMed

    Li, Junjie; Liu, Fengyong; Gupta, Sanjay; Li, Chun

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) accounts for over 90% of all pancreatic cancer. Nanoparticles (NPs) offer new opportunities for image-guided therapy owing to the unique physicochemical properties of the nanoscale effect and the multifunctional capabilities of NPs. However, major obstacles exist for NP-mediated cancer theranostics, especially in PDAC. The hypovascular nature of PDAC may impede the deposition of NPs into the tumor after systemic administration, and most NPs localize predominantly in the mononuclear phagocytic system, leading to a relatively poor tumor-to-surrounding-organ uptake ratio. Image guidance combined with minimally invasive interventional procedures may help circumvent these barriers to poor drug delivery of NPs in PDAC. Interventional treatments allow regional drug delivery, targeted vascular embolization, direct tumor ablation, and the possibility of disrupting the stromal barrier of PDAC. Interventional treatments also have potentially fewer complications, faster recovery, and lower cost compared with conventional therapies. This work is an overview of current image-guided interventional cancer nanotheranostics with specific attention given to their applications for the management of PDAC. PMID:27375787

  7. Interventional Nanotheranostics of Pancreatic Ductal Adenocarcinoma

    PubMed Central

    Li, Junjie; Liu, Fengyong; Gupta, Sanjay; Li, Chun

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) accounts for over 90% of all pancreatic cancer. Nanoparticles (NPs) offer new opportunities for image-guided therapy owing to the unique physicochemical properties of the nanoscale effect and the multifunctional capabilities of NPs. However, major obstacles exist for NP-mediated cancer theranostics, especially in PDAC. The hypovascular nature of PDAC may impede the deposition of NPs into the tumor after systemic administration, and most NPs localize predominantly in the mononuclear phagocytic system, leading to a relatively poor tumor-to-surrounding-organ uptake ratio. Image guidance combined with minimally invasive interventional procedures may help circumvent these barriers to poor drug delivery of NPs in PDAC. Interventional treatments allow regional drug delivery, targeted vascular embolization, direct tumor ablation, and the possibility of disrupting the stromal barrier of PDAC. Interventional treatments also have potentially fewer complications, faster recovery, and lower cost compared with conventional therapies. This work is an overview of current image-guided interventional cancer nanotheranostics with specific attention given to their applications for the management of PDAC. PMID:27375787

  8. Biliary manometry in choledochal cyst with abnormal choledochopancreatico ductal junction.

    PubMed

    Iwai, N; Tokiwa, K; Tsuto, T; Yanagihara, J; Takahashi, T

    1986-10-01

    Intraoperative manometry of the biliary tract and measurement of amylase levels in choledochal cysts were performed in seven patients, aged 14 months to 5 years, with choledochal cysts, in an investigation of the pathophysiology of the biliary tract. An abnormal choledochopancreatico ductal junction was observed in these seven patients by preoperative endoscopic retrograde cholangiopancreaticography (ERCP) or intraoperative cholangiograms. All six patients examined showed a high amylase level in the choledochal cyst (5,450 to 46,500 Somogyi Units). The intraoperative manometry of the biliary tract showed that a remarkable high pressure zone as was found in the area of sphincter of Oddi was not found in the area of abnormal choledochopancreatico ductal junction. The pressure recordings also demonstrated that the sphincter of Oddi pressure in the patient with choledochal cyst was increased by gastrin stimulation. On the contrary, no pressure reaction to gastrin or secretin was found in the area of abnormal choledochopancreatic ductal junction. From these results it seems that free reflux of pancreatic juice into the biliary system occurs, and the reflux stream depends upon the pressure gradient between pancreatic ductal pressure and common bile duct pressure because of the lack of a sphincter function at the choledochopancreatico ductal junction.

  9. Coanda effect on ductal flow in the pulmonary artery.

    PubMed

    Guntheroth, W; Miyaki-Hull, C

    1999-03-01

    The Coanda effect (the tendency of a jet stream to adhere to a boundary wall), and the relevant anatomy, may explain the location of ductal jets within the main pulmonary artery. With the usual insertion of the duct close to the left pulmonary artery, during right ventricular ejection, the ductal jet adheres to the left wall of the main pulmonary artery. When right ventricular ejection is absent in pulmonary atresia, the ductal jet streams down the right wall of the pulmonary artery to the pulmonary valve, reverses, and maintains a parallel column back toward the bifurcation. If the reversed flow is mistaken for ejection from the right ventricle, the diagnosis of pulmonary atresia may be missed. PMID:10082354

  10. Basal cytokeratin phenotypes of myoepithelial cells indicates the origin of ductal carcinomas in situ of the breast.

    PubMed

    Chen, Ling; Yin, Xiaona; Lu, Shanshan; Chen, Guorong; Dong, Lei

    2015-09-01

    Terminal duct lobular unit (TDLU) is widely accepted as the origin of ductal carcinoma in situ of breast. The differentiation states of myoepithelial cells of breast ductal system hint the development of breast hyperplastic lesions. Basal cytokeratin (CK) phenotypes indicate the differentiation of myoepithelial cells. Using antibodies of CK5/6, CK14, and CK17, this study reports the basal CK phenotypes of myoepithelial cells in 20 foci of normal breast, 20 usual ductal hyperplasias, 36 ductal carcinomas in situ (DCIS), and 28 sclerosing adenosis (SA). The results showed that the positive staining of basal CKs of myoepithelial cells in normal ducts were significantly higher than those in normal lobules. The basal CK expression of myoepithelial cells of DCIS and usual ductal hyperplasia was similar to that of normal duct, whereas that of SA was similar to that of normal lobule. We propose a modified model of TDLU origin of intraductal carcinoma that most of DCIS originate from terminal ducts of TDLU, whereas most SA originate from lobules.

  11. Seven consecutive successful clinical islet isolations with pancreatic ductal injection.

    PubMed

    Matsumoto, Shinichi; Noguichi, Hirofumi; Shimoda, Masayuki; Ikemoto, Tetsuya; Naziruddin, Bashoo; Jackson, Andrew; Tamura, Yoshiko; Olson, Greg; Fujita, Yasutaka; Chujo, Daisuke; Takita, Morihito; Kobayashi, Naoya; Onaca, Nicholas; Levy, Marlon

    2010-01-01

    Inconsistent islet isolation is one of the issues of clinical islet transplantation. In the current study, we applied ductal injection to improve the consistency of islet isolation. Seven islet isolations were performed with the ductal injection of ET-Kyoto solution (DI group) and eight islet isolations were performed without the ductal injection (standard group) using brain-dead donor pancreata. Isolated islets were evaluated based on the Edmonton protocol for transplantation. The DI group had significantly higher islet yields (588,566 +/- 64,319 vs. 354,836 +/- 89,649 IE, p < 0.01) and viability (97.3 +/- 1.2% vs. 92.6 +/- 1.2%, p < 0.02) compared with the standard group. All seven isolated islet preparations in the DI group (100%), versus only three out of eight isolated islet preparations (38%) in the standard group met transplantation criteria. The islets from the DI group were transplanted into three type 1 diabetic patients and all three patients became insulin independent. Ductal injection significantly improved quantity and quality of isolated islets and resulted in high success rate of clinical islet transplantation. This simple modification will reduce the risk of failure of clinical islet isolation.

  12. RAF/MEK dependence of KRAS mutant pancreatic ductal adenocarcinomas

    PubMed Central

    Hanrahan, Aphrothiti J.; Solit, David B.

    2016-01-01

    Summary Sentence Studies employing genetically engineered mouse models indicate that RAF activation is sufficient to induce pancreas intraepithelial neoplasms (PanINs) suggesting that MEK inhibitor-based combination approaches may have clinical utility in patients with pancreatic ductal adenocarcinomas. PMID:22886659

  13. Extracellular Ca(2+) sensing in salivary ductal cells.

    PubMed

    Bandyopadhyay, Bidhan C; Swaim, William D; Sarkar, Ankana; Liu, Xibao; Ambudkar, Indu S

    2012-08-31

    Ca(2+) is secreted from the salivary acinar cells as an ionic constituent of primary saliva. Ions such as Na(+) and Cl(-) get reabsorbed whereas primary saliva flows through the salivary ductal system. Although earlier studies have shown that salivary [Ca(2+)] decreases as it flows down the ductal tree into the oral cavity, ductal reabsorption of Ca(2+) remains enigmatic. Here we report a potential role for the G protein-coupled receptor, calcium-sensing receptor (CSR), in the regulation of Ca(2+) reabsorption by salivary gland ducts. Our data show that CSR is present in the apical region of ductal cells where it is co-localized with transient receptor potential canonical 3 (TRPC3). CSR is activated in isolated salivary gland ducts as well as a ductal cell line (SMIE) by altering extracellular [Ca(2+)] or by aromatic amino acid, L-phenylalanine (L-Phe, endogenous component of saliva), as well as neomycin. CSR activation leads to Ca(2+) influx that, in polarized cells grown on a filter support, is initiated in the luminal region. We show that TRPC3 contributes to Ca(2+) entry triggered by CSR activation. Further, stimulation of CSR in SMIE cells enhances the CSR-TRPC3 association as well as surface expression of TRPC3. Together our findings suggest that CSR could serve as a Ca(2+) sensor in the luminal membrane of salivary gland ducts and regulate reabsorption of [Ca(2+)] from the saliva via TRPC3, thus contributing to maintenance of salivary [Ca(2+)]. CSR could therefore be a potentially important protective mechanism against formation of salivary gland stones (sialolithiasis) and infection (sialoadenitis).

  14. Extracellular Ca2+ Sensing in Salivary Ductal Cells*

    PubMed Central

    Bandyopadhyay, Bidhan C.; Swaim, William D.; Sarkar, Ankana; Liu, Xibao; Ambudkar, Indu S.

    2012-01-01

    Ca2+ is secreted from the salivary acinar cells as an ionic constituent of primary saliva. Ions such as Na+ and Cl− get reabsorbed whereas primary saliva flows through the salivary ductal system. Although earlier studies have shown that salivary [Ca2+] decreases as it flows down the ductal tree into the oral cavity, ductal reabsorption of Ca2+ remains enigmatic. Here we report a potential role for the G protein-coupled receptor, calcium-sensing receptor (CSR), in the regulation of Ca2+ reabsorption by salivary gland ducts. Our data show that CSR is present in the apical region of ductal cells where it is co-localized with transient receptor potential canonical 3 (TRPC3). CSR is activated in isolated salivary gland ducts as well as a ductal cell line (SMIE) by altering extracellular [Ca2+] or by aromatic amino acid, l-phenylalanine (l-Phe, endogenous component of saliva), as well as neomycin. CSR activation leads to Ca2+ influx that, in polarized cells grown on a filter support, is initiated in the luminal region. We show that TRPC3 contributes to Ca2+ entry triggered by CSR activation. Further, stimulation of CSR in SMIE cells enhances the CSR-TRPC3 association as well as surface expression of TRPC3. Together our findings suggest that CSR could serve as a Ca2+ sensor in the luminal membrane of salivary gland ducts and regulate reabsorption of [Ca2+] from the saliva via TRPC3, thus contributing to maintenance of salivary [Ca2+]. CSR could therefore be a potentially important protective mechanism against formation of salivary gland stones (sialolithiasis) and infection (sialoadenitis). PMID:22778254

  15. Hybrid Palliation for Ductal-Dependent Systemic Circulation.

    PubMed

    Evans, William N; Galindo, Alvaro; Rothman, Abraham; Ciccolo, Michael L; Carrillo, Sergio A; Acherman, Ruben J; Mayman, Gary A; Cass, Kathleen A; Kip, Katrinka T; Luna, Carlos F; Ludwick, Joseph M; Rollins, Robert C; Castillo, William J; Alexander, John A; Restrepo, Humberto

    2016-06-01

    We reviewed our hybrid palliation experience for 91 neonates, with ductal-dependent systemic circulation, born between August 2007 and October 2015. For analysis, we stratified the 91 patients by a risk factor (RF) score and divided them into three groups: (1) high-risk two-functional ventricles (2V) median RF score of 3 (N = 20); (2) low-risk one-functional ventricle (1V) RF score 0-1 (N = 32); and (3) high-risk 1V RF score ≥2 (N = 39). Midterm survival (median 4 years) by group was: (1) 95 %, (2) 91 %, and (3) 15 %, (p = 0.001). In conclusion, hybrid palliation was associated with excellent midterm results for high-risk 2V and low-risk 1V patients with ductal-dependent systemic circulation. In contrast, high-risk 1V patients had significantly worse outcomes.

  16. Ductal carcinoma in situ - update on risk assessment and management.

    PubMed

    Pang, Jia-Min B; Gorringe, Kylie L; Fox, Stephen B

    2016-01-01

    Ductal carcinoma in situ (DCIS) accounts for ~20-25% of breast cancers. While DCIS is not life-threatening, it may progress to invasive carcinoma over time, and treatment intended to prevent invasive progression may itself cause significant morbidity. Accurate risk assessment is therefore necessary to avoid over- or undertreatment of an individual patient. In this review we will outline the evidence for current management of DCIS, discuss approaches to DCIS risk assessment and challenges facing identification of novel DCIS biomarkers.

  17. Metastatic Male Ductal Breast Cancer Mimicking Obstructing Primary Colon Cancer

    PubMed Central

    Koleilat, Issam; Syal, Anil; Hena, Muhammad

    2010-01-01

    Male breast cancer comprises only about 1% of all breast cancers. Commonly, sites of metastases include the central nervous system, lungs, bones, and even liver. In females, extrahepatic gastrointestinal metastases are unusual but have been reported with various clinical presentations. We are reporting the first case of a male patient with a history of ductal breast carcinoma that developed colonic metastasis and presented with mechanical large bowel obstruction masquerading as primary colon cancer. PMID:23675178

  18. Comparative proteomic analysis of ductal and lobular invasive breast carcinoma.

    PubMed

    Oliveira, N C S; Gomig, T H B; Milioli, H H; Cordeiro, F; Costa, G G; Urban, C A; Lima, R S; Cavalli, I J; Ribeiro, E M S F

    2016-04-04

    Breast cancer is the second most common cancer worldwide and the first among women. Invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) are the two major histological subtypes, and the clinical and molecular differences between them justify the search for new markers to distinguish them. As proteomic analysis allows for a powerful and analytical approach to identify potential biomarkers, we performed a comparative analysis of IDC and ILC samples by using two-dimensional electrophoresis and mass spectrometry. Twenty-three spots were identified corresponding to 10 proteins differentially expressed between the two subtypes. ACTB, ACTG, TPM3, TBA1A, TBA1B, VIME, TPIS, PDIA3, PDIA6, and VTDB were upregulated in ductal carcinoma compared to in lobular carcinoma samples. Overall, these 10 proteins have a key role in oncogenesis. Their specific functions and relevance in cancer initiation and progression are further discussed in this study. The identified peptides represent promising biomarkers for the differentiation of ductal and lobular breast cancer subtypes, and for future interventions based on tailored therapy.

  19. Comparative proteomic analysis of ductal and lobular invasive breast carcinoma.

    PubMed

    Oliveira, N C S; Gomig, T H B; Milioli, H H; Cordeiro, F; Costa, G G; Urban, C A; Lima, R S; Cavalli, I J; Ribeiro, E M S F

    2016-01-01

    Breast cancer is the second most common cancer worldwide and the first among women. Invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) are the two major histological subtypes, and the clinical and molecular differences between them justify the search for new markers to distinguish them. As proteomic analysis allows for a powerful and analytical approach to identify potential biomarkers, we performed a comparative analysis of IDC and ILC samples by using two-dimensional electrophoresis and mass spectrometry. Twenty-three spots were identified corresponding to 10 proteins differentially expressed between the two subtypes. ACTB, ACTG, TPM3, TBA1A, TBA1B, VIME, TPIS, PDIA3, PDIA6, and VTDB were upregulated in ductal carcinoma compared to in lobular carcinoma samples. Overall, these 10 proteins have a key role in oncogenesis. Their specific functions and relevance in cancer initiation and progression are further discussed in this study. The identified peptides represent promising biomarkers for the differentiation of ductal and lobular breast cancer subtypes, and for future interventions based on tailored therapy. PMID:27173185

  20. Isolation, culture and genetic manipulation of mouse pancreatic ductal cells.

    PubMed

    Reichert, Maximilian; Takano, Shigetsugu; Heeg, Steffen; Bakir, Basil; Botta, Gregory P; Rustgi, Anil K

    2013-01-01

    The most common subtype of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). PDAC resembles duct cells morphologically and, to some extent, at a molecular level. Recently, genetic-lineage labeling has become popular in the field of tumor biology in order to study cell-fate decisions or to trace cancer cells in the mouse. However, certain biological questions require a nongenetic labeling approach to purify a distinct cell population in the pancreas. Here we describe a protocol for isolating mouse pancreatic ductal epithelial cells and ductlike cells directly in vivo using ductal-specific Dolichos biflorus agglutinin (DBA) lectin labeling followed by magnetic bead separation. Isolated cells can be cultured (in two or three dimensions), manipulated by lentiviral transduction to modulate gene expression and directly used for molecular studies. This approach is fast (~4 h), affordable, results in cells with high viability, can be performed on the bench and is applicable to virtually all genetic and nongenetic disease models of the pancreas. PMID:23787893

  1. Isolation, culture and genetic manipulation of mouse pancreatic ductal cells

    PubMed Central

    Reichert, Maximilian; Takano, Shigetsugu; Heeg, Steffen; Bakir, Basil; Botta, Gregory P; Rustgi, Anil K

    2014-01-01

    The most common subtype of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). pDac resembles duct cells morphologically and, to some extent, at a molecular level. recently, genetic-lineage labeling has become popular in the field of tumor biology in order to study cell-fate decisions or to trace cancer cells in the mouse. However, certain biological questions require a nongenetic labeling approach to purify a distinct cell population in the pancreas. Here we describe a protocol for isolating mouse pancreatic ductal epithelial cells and duct-like cells directly in vivo using ductal-specific Dolichos biflorus agglutinin (DBA) lectin labeling followed by magnetic bead separation. Isolated cells can be cultured (in two or three dimensions), manipulated by lentiviral transduction to modulate gene expression and directly used for molecular studies. this approach is fast (∼4 h), affordable, results in cells with high viability, can be performed on the bench and is applicable to virtually all genetic and nongenetic disease models of the pancreas. PMID:23787893

  2. Infrequent Loss of Luminal Differentiation in Ductal Breast Cancer Metastasis

    PubMed Central

    Calvo, Julia; Sánchez-Cid, Lourdes; Muñoz, Montserrat; Lozano, Juan José; Thomson, Timothy M.; Fernández, Pedro L.

    2013-01-01

    Lymph node involvement is a major prognostic variable in breast cancer. Whether the molecular mechanisms that drive breast cancer cells to colonize lymph nodes are shared with their capacity to form distant metastases is yet to be established. In a transcriptomic survey aimed at identifying molecular factors associated with lymph node involvement of ductal breast cancer, we found that luminal differentiation, assessed by the expression of estrogen receptor (ER) and/or progesterone receptor (PR) and GATA3, was only infrequently lost in node-positive primary tumors and in matched lymph node metastases. The transcription factor GATA3 critically determines luminal lineage specification of mammary epithelium and is widely considered a tumor and metastasis suppressor in breast cancer. Strong expression of GATA3 and ER in a majority of primary node-positive ductal breast cancer was corroborated by quantitative RT-PCR and immunohistochemistry in the initial sample set, and by immunohistochemistry in an additional set from 167 patients diagnosed of node-negative and –positive primary infiltrating ductal breast cancer, including 102 samples from loco-regional lymph node metastases matched to their primary tumors, as well as 37 distant metastases. These observations suggest that loss of luminal differentiation is not a major factor driving the ability of breast cancer cells to colonize regional lymph nodes. PMID:24205108

  3. Vascular and ductal elastotic changes in pancreatic cancer.

    PubMed

    Lakiotaki, Eleftheria; Sakellariou, Stratigoula; Evangelou, Kostantinos; Liapis, George; Patsouris, Efstratios; Delladetsima, Ioanna

    2016-03-01

    This study aims to identify and define the type and frequency of elastotic alterations of vessels and ducts in pancreatic ductal carcinoma (PDAC) and evaluate its diagnostic significance. Representative tissue from 36 Whipple specimens, stained with Verhoeff's Van-Gieson, was studied focusing on the density and distribution of elastic fibers in walls of vessels and ducts, in perivascular and periductal tissue and in tumor stroma. Vessels and ducts within the carcinoma, at tumor periphery and in non-tumoral pancreas were grouped and examined separately. Vimentin and α-SMA immunostains were used for the depiction of fibroblasts and myofibroblasts. Histochemistry revealed mild to severe elastotic changes of vessels and ducts in all examined cases. Vascular and ductal elastosis was more prominent within the tumor and diminished at tumor periphery. In tumor stroma and non-tumoral pancreatic tissue mild or no elastosis was identified. α-SMA+ cells were observed in large numbers in tumor stroma and as a ring around carcinomatous structures. There were scant α-SMA+ cells around elastotic and non-elastotic vessels. Conclusively, vascular and ductal elastosis is a tumor-associated phenomenon in PDAC. Its presence is indicative of benignity acquiring a possible diagnostic role. PMID:26619815

  4. Acinar-to-ductal metaplasia accompanies c-myc-induced exocrine pancreatic cancer progression in transgenic rodents.

    PubMed

    Grippo, Paul J; Sandgren, Eric P

    2012-09-01

    Several important characteristics of exocrine pancreatic tumor pathogenesis remain incompletely defined, including identification of the cell of origin. Most human pancreatic neoplasms are ductal adenocarcinomas. However, acinar cells have been proposed as the source of some ductal neoplasms through a process of acinar-to-ductal metaplasia. The oncogenic transcription factor c-myc is associated with human pancreatic neoplasms. Transgenic mice overexpressing c-myc under control of acinar cell-specific elastase (Ela) gene regulatory elements not only develop acinar cell carcinomas but also mixed neoplasms that display both acinar-like neoplastic cells and duct-like neoplastic cells. In this report, we demonstrate that, first, c-myc is sufficient to induce acinar hyperplasia, though neoplastic lesions develop focally. Second, cell proliferation remains elevated in the neoplastic duct cell compartment of mixed neoplasms. Third, the proliferation/apoptosis ratio in cells from all lesion types remains constant, suggesting that differential regulation of these processes is not a feature of cancer progression in this model. Fourth, before the development of mixed neoplasms, there is transcriptional activation of the duct cell-specific cytokeratin-19 gene promoter in multicellular foci of amylase-positive acinar neoplasms. This observation provides direct evidence for metaplasia as the mechanism underlying development of ductal neoplastic cells within the context of an acinar neoplasm and suggests that the stimulus for this transformation acts over a multicellular domain or field within a neoplasm. Finally, focal ductal elements develop in some acinar cell carcinomas in Ela-c-myc transgenic rats, indicating that myc-associated acinar-to-ductal metaplasia is not restricted to the mouse.

  5. Comparative characterization of stroma cells and ductal epithelium in chronic pancreatitis and pancreatic ductal adenocarcinoma.

    PubMed

    Helm, Ole; Mennrich, Ruben; Petrick, Domantas; Goebel, Lisa; Freitag-Wolf, Sandra; Röder, Christian; Kalthoff, Holger; Röcken, Christoph; Sipos, Bence; Kabelitz, Dieter; Schäfer, Heiner; Oberg, Hans-Heinrich; Wesch, Daniela; Sebens, Susanne

    2014-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive stroma being also present in chronic pancreatitis (CP). Using immunohistochemistry, the stroma of CP and PDAC was comprehensively analyzed and correlated with epithelial/carcinoma-related alterations and clinicopathological patient characteristics. While there were no significant differences between CP and PDAC regarding the distribution of CD3+ T cells and α-SMA+ fibroblasts, proportions of CD4+ and CD8+ T cells were significantly lower and numbers of CD25+(CD4+) and FoxP3+(CD4+) regulatory T cells were greater in PDAC compared with CP. Macrophages were more prevalent in CP, but localized more closely to carcinoma cells in PDAC, as were γδ-T cells. Duct-related FoxP3 and L1CAM expression increased from CP to PDAC, while vimentin expression was similarly abundant in both diseases. Moreover, stromal and epithelial compartments of well-differentiated tumors and CPs shared considerable similarities, while moderately and poorly differentiated tumors significantly differed from CP tissues. Analysis of 27 parameters within each pancreatic disease revealed a significant correlation of i) CD4+ and FoxP3+CD4+ T cells with FoxP3 expression in PDAC cells, ii) α-SMA+ fibroblasts with L1CAM expression and proliferation in PDAC cells, iii) CD3 and CD8 expression with γδ-TCR expression in both pancreatic diseases and iv) CD68+ and CD163+ macrophages with vimentin expression in PDAC cells. High expression of FoxP3, vimentin and L1CAM in PDAC cells as well as a tumor-related localization of macrophages each tended to correlate with higher tumor grade. Multivariate survival analysis revealed a younger age at time of surgery as a positive prognostic marker for PDAC patients with the most frequently operated disease stage T3N1M0. Overall this study identified several interrelationships between stroma and epithelial/carcinoma cells in PDACs but also in CP, which in light of previous experimental data

  6. Human ductal adenocarcinomas of the pancreas express extracellular matrix proteins.

    PubMed Central

    Löhr, M.; Trautmann, B.; Göttler, M.; Peters, S.; Zauner, I.; Maillet, B.; Klöppel, G.

    1994-01-01

    Pancreatic ductal adenocarcinomas are characterised by a dense connective tissue reaction. To test the hypothesis that stroma components are synthesised and produced by the tumour cells themselves, eight cell lines as well as six xenografted tumours from human ductal adenocarcinomas of the pancreas were examined for the expression of extracellular matrix proteins (ECM), using cDNA probes and antibodies to collagen types I, III and IV, vitronectin, fibronectin, undulin and laminin. All tumour cell lines (CAPAN-1, CAPAN-2, AsPC-1, BxPC-3, PANC-1, PaCa-2, PaCa-3, PaCa-44) and xenografted human pancreatic tumours expressed at least one of the examined ECM at the RNA (collagen type IV > laminin = fibronectin = vitronectin > collagen type III > undulin > collagen type I) or protein level (collagen type IV = collagen type III > vitronectin > laminin > collagen type I = fibronectin > undulin). In nude mouse tumours expression of laminin and collagen I was most pronounced in well-differentiated carcinomas. In a few tumours, collagen type III, vitronectin and undulin were expressed on the luminal side of the neoplastic glands, suggesting loss of normal polar differentiation. Incubation with fetal calf serum modulated ECM RNA levels to a varying extent in all but one cell line (AsPC-1). The results suggest that human pancreatic ductal adenocarcinomas cells are capable of synthesising and producing extracellular matrix proteins in vitro and in vivo, but that the extent and pattern of ECM expression differs between the various tumours and conditions tested. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:8286197

  7. Ductal carcinoma in situ - update on risk assessment and management.

    PubMed

    Pang, Jia-Min B; Gorringe, Kylie L; Fox, Stephen B

    2016-01-01

    Ductal carcinoma in situ (DCIS) accounts for ~20-25% of breast cancers. While DCIS is not life-threatening, it may progress to invasive carcinoma over time, and treatment intended to prevent invasive progression may itself cause significant morbidity. Accurate risk assessment is therefore necessary to avoid over- or undertreatment of an individual patient. In this review we will outline the evidence for current management of DCIS, discuss approaches to DCIS risk assessment and challenges facing identification of novel DCIS biomarkers. PMID:26768032

  8. Adjuvant, neoadjuvant, and experimental regimens in overcoming pancreatic ductal adenocarcinoma

    PubMed Central

    Wysocka, Olga; Kulbacka, Julita; Saczko, Jolanta

    2016-01-01

    Pancreatic cancer is one of the most aggressive and deadly malignancies. Despite better understanding of its biology and pathogenesis, contemporary treatment regimens are still insufficient. Along with the introduction of new treatment agents and combination therapy, the response rates are increasing, but these scores do not go with overall survival, and results are frequently conflicting. Therefore, contemporary medicine faces the challenge of expanding the knowledge base and practice on all grounds – pathology, factor risk, diagnosis, and finally surgical and palliative treatment of this disease. This paper provides a review of current adjuvant and neoadjuvant regimens and the role of experimental therapies in pancreatic ductal adenocarcinoma. PMID:27713776

  9. Myoepithelial Cell Differentiation Markers in Ductal Carcinoma in Situ Progression

    PubMed Central

    Russell, Tanya D.; Jindal, Sonali; Agunbiade, Samiat; Gao, Dexiang; Troxell, Megan; Borges, Virginia F.; Schedin, Pepper

    2016-01-01

    We describe a preclinical model that investigates progression of early-stage ductal carcinoma in situ (DCIS) and report that compromised myoepithelial cell differentiation occurs before transition to invasive disease. Human breast cancer MCF10DCIS.com cells were delivered into the mouse mammary teat by intraductal injection in the absence of surgical manipulations and accompanying wound-healing confounders. DCIS-like lesions developed throughout the mammary ducts with full representation of human DCIS histologic patterns. Tumor cells were incorporated into the normal mammary epithelium, developed ductal intraepithelial neoplasia and DCIS, and progressed to invasive carcinoma, suggesting the model provides a rigorous approach to study early stages of breast cancer progression. Mammary glands were evaluated for myoepithelium integrity with immunohistochemical assays. Progressive loss of the myoepithelial cell differentiation markers p63, calponin, and α-smooth muscle actin was observed in the mouse myoepithelium surrounding DCIS-involved ducts. p63 loss was an early indicator, calponin loss intermediate, and α-smooth muscle actin a later indicator of compromised myoepithelium. Loss of myoepithelial calponin was specifically associated with gain of the basal marker p63 in adjacent tumor cells. In single time point biopsies obtained from 16 women diagnosed with pure DCIS, a similar loss in myoepithelial cell markers was observed. These results suggest that further research is warranted into the role of myoepithelial cell p63 and calponin expression on DCIS progression to invasive disease. PMID:26343330

  10. Predictors of disease progression in ductal carcinoma in situ of the breast and vascular patterns.

    PubMed

    Adler, Esther H; Sunkara, Jaya L; Patchefsky, Arthur S; Koss, Leopold G; Oktay, Maja H

    2012-04-01

    Breast carcinoma-induced angiogenesis helps meet growing metabolic needs of tumors and progressively increases with malignant transformation of benign ducts to ductal carcinoma in situ (DCIS) and ductal carcinoma in situ to invasive carcinoma. There are conflicting data regarding the difference in angiogenesis in low-, intermediate-, and high-grade ductal carcinoma in situ. If angiogenesis is related to ductal carcinoma in situ progression, the types of ductal carcinoma in situ with more aggressive biologic potential would have different vascular patterns than the less aggressive ones. In this study, we classified 51 cases of ductal carcinoma in situ as low (10-20 years to progression to invasive carcinoma), moderate, or high aggressive (2-5 years to progression to invasive carcinoma), based on criteria outlined by Tsikitis and Chung (Am J Clin Oncol 2006; 29:305), which takes into account nuclear grade, mitotic rate, Ki-67, Her2Neu, P53, estrogen, and progesterone receptor expression. We correlated these 3 groups of ductal carcinoma in situ with the extent of periductal and stromal vascularity and the presence and type of vascular breaks. No association of aggressive biologic behavior of ductal carcinoma in situ with any vascular pattern was found. Moreover, no correlation was found between vascular patterns and classifiers of aggressiveness, microvascular density, or outcome (local recurrence, invasive carcinoma, or metastatic disease). To validate our cohort, we confirmed expected correlations of all measured parameters of aggressiveness by correlating them with each other. In summary, vascular patterns in ductal carcinoma in situ do not correlate with the predictors of aggressive behavior, suggesting that the biologic potential of ductal carcinoma in situ is independent of angiogenesis.

  11. CD44 expression in intraoral salivary ductal papillomas and oral papillary squamous cell carcinoma.

    PubMed

    Fitzpatrick, Sarah G; Montague, Lindsay J; Cohen, Donald M; Bhattacharyya, Indraneel

    2013-06-01

    CD44 is a transmembrane adhesion molecule which has been previously shown to be useful in the differentiation of benign papillary lesions from invasive carcinoma in several different areas including sinonasal mucosa and breast tissue. CD44 expression has previously been shown to be lost in invasive carcinoma and retained in benign papillary lesions in both of the above locations. In addition, studies have evaluated oral mucosal lesions for CD44 expression and found a loss with invasive squamous cell carcinoma when compared to normal epithelium, hyperplasia, and squamous papillomas, which stained particularly strongly. To the best of our knowledge, no study has evaluated CD44 expression when comparing salivary ductal papillomas in comparison to oral papillary SCCA. In this study 18 cases of intraductal papilloma were compared to 19 cases of oral papillary SCCA. Within the ductal papilloma group, all cases stained either absent (6%), weakly (33%), or moderately (61%) with 76% expressing the stain diffusely and 24% focally. In comparison, the papillary squamous cell carcinoma cases expressed the CD44 moderately (26%) or strongly (74%) with 100 % showing diffuse staining. Thus, the CD44 expression was contrary to expectation based on previous studies, which we hypothesize is due to the extremely well differentiated nature of papillary SCCA which expressed CD44 staining compatible with levels previously reported with oral squamous papillomas than invasive carcinoma.

  12. Genomic differences between pure ductal carcinoma in situ and synchronous ductal carcinoma in situ with invasive breast cancer

    PubMed Central

    Kim, Min Sung; Baek, In-Pyo; Lee, Sung Hak; Kim, Tae-Min; Chung, Yeun-Jun; Lee, Sug Hyung

    2015-01-01

    Although ductal carcinoma in situ (DCIS) precedes invasive ductal carcinoma (IDC), the related genomic alterations remain unknown. To identify the genomic landscape of DCIS and better understand the mechanisms behind progression to IDC, we performed whole-exome sequencing and copy number profiling for six cases of pure DCIS and five pairs of synchronous DCIS and IDC. Pure DCIS harbored well-known mutations (e.g., TP53, PIK3CA and AKT1), copy number alterations (CNAs) and chromothripses, but had significantly fewer driver genes and co-occurrence of mutation/CNAs than synchronous DCIS-IDC. We found neither recurrent nor significantly mutated genes with synchronous DCIS-IDC compared to pure DCIS, indicating that there may not be a single determinant for pure DCIS progression to IDC. Of note, synchronous DCIS genomes were closer to IDC than pure DCIS. Among the clinicopathologic parameters, progesterone receptor (PR)-negative status was associated with increased mutations, CNAs, co-occurrence of mutations/CNAs and driver mutations. Our results indicate that although pure DCIS has already acquired some drivers, more changes are needed to progress to IDC. In addition, IDC-associated DCIS is more aggressive than pure DCIS at genomic level and should really be considered IDC. Finally, the data suggest that PR-negativity could be used to predict aggressive breast cancer genotypes. PMID:25831047

  13. [Ductal carcinoma in situ: the balance between over- and undertreatment].

    PubMed

    Groen, Emma J; Elshof, Lotte E; Rutgers, Emiel J Th; Winter-Warnars, Hillegonda A O; Lips, Esther H; Wesseling, Jelle

    2016-01-01

    Since population-based breast cancer screening was implemented in the Netherlands, the incidence of Ductal Carcinoma In Situ of the breast, regarded as a non-obligate precursor lesion of breast cancer, has strongly increased. However, the incidence of invasive breast cancer has not decreased. This suggests that a percentage of all the DCIS lesions would never have become symptomatic if no screening was performed. This phenomenon is known as 'overdiagnosis'. Nonetheless, almost all DCIS lesions are managed surgically, often followed by radiotherapy in those having breast-conserving treatment, to avoid potential progression to breast cancer. To prevent potential over- or undertreatment, further studies are required to distinguish low from high risk DCIS. Ultimately this could help avoid non-beneficial intensive treatment for women with low risk DCIS.

  14. Current Trends in the Management of Ductal Carcinoma In Situ.

    PubMed

    Park, Tristen S; Hwang, E Shelley

    2016-09-15

    Ductal carcinoma in situ (DCIS), once a rare entity, now comprises up to 30% of newly diagnosed breast cancers detected on mammography. It is now appreciated as a widely heterogeneous disease, with indolent lesions of minimal clinical significance on one end of the spectrum, and aggressive lesions with malignant invasive potential on the other. Therefore, the traditional guideline-concordant approach to treatment with surgery, radiation, and endocrine therapy may lead to overtreatment of certain patients, and insufficient treatment of others. Risk assessment using clinical and molecular prognostic tools is being investigated, addressing the possibility of delineating subpopulations that may be treated with more tailored therapy. This review will summarize the current trends in the diagnosis and management of DCIS and will highlight ongoing trials that are shaping future management of this entity. PMID:27633413

  15. Congestive heart failure from suspected ductal closure in utero.

    PubMed

    Arcilla, R A; Thilenius, O G; Ranniger, K

    1969-07-01

    This is the 1st case report of a ductal closure occurring during fetal growth. The case was a spontaneous delivery in cephalic presentation from a 31-year-old gravida 3, para 3 Black woman who had been treated with isoniazid and spreptomycin up to 2 months before her delivery. Gestational age was 37 weeks when the fetus was delivered weighing 3.15 kgm. The cord had been wrapped around the fetus's neck, and breathing was delayed 2 minutes. In the nursery, the baby's general condition was poor, and congestive heart failure was diagnosed. The newborn had trieuspid insufficiency, severe heart failure, and acidosis at birth. These disappeared the next day. Hemodynamic studies when the baby was 4 hours old showed a large cone-shaped ductus arteriousus extending from the pulmonary artery but ending blindly at the aortic end.

  16. Targeting mTOR in Pancreatic Ductal Adenocarcinoma

    PubMed Central

    Iriana, Sentia; Ahmed, Shahzad; Gong, Jun; Annamalai, Alagappan Anand; Tuli, Richard; Hendifar, Andrew Eugene

    2016-01-01

    Treatment options for advanced pancreatic ductal adenocarcinoma (PDAC) are limited; however, new therapies targeting specific tumor-related molecular characteristics may help certain patient cohorts. Emerging preclinical data have shown that inhibition of mammalian target of rapamycin (mTOR) in specific KRAS-dependent PDAC subtypes leads to inhibition of tumorigenesis in vitro and in vivo. Early phase II studies of mono-mTOR inhibition have not shown promise. However, studies have shown that combined inhibition of multiple steps along the mTOR signaling pathway may lead to sustained responses by targeting mechanisms of tumor resistance. Coordinated inhibition of mTOR along with specific KRAS-dependent mutations in molecularly defined PDAC subpopulations may offer a viable alternative for treatment in the future. PMID:27200288

  17. Cytokines as Biomarkers of Pancreatic Ductal Adenocarcinoma: A Systematic Review

    PubMed Central

    Yako, Yandiswa Yolanda; Kruger, Deirdré; Smith, Martin; Brand, Martin

    2016-01-01

    Objectives A systematic review of the role of cytokines in clinical medicine as diagnostic, prognostic, or predictive biomarkers in pancreatic ductal adenocarcinoma was undertaken. Materials and Methods A systematic review was conducted according to the 2009 PRISMA guidelines. PubMed database was searched for all original articles on the topic of interest published until June 2015, and this was supplemented with references cited in relevant articles. Studies were evaluated for risk of bias using the Quality in Prognosis Studies tools. Results Forty one cytokines were investigated with relation to pancreatic ductal adenocarcinoma (PDAC) in 65 studies, ten of which were analyzed by more than three studies. Six cytokines (interleukin[IL]-1β, -6, -8, -10, vascular endothelial growth factor, and transforming growth factor) were consistently reported to be increased in PDAC by more than four studies; irrespective of sample type; method of measurement; or statistical analysis model used. When evaluated as part of distinct panels that included CA19-9, IL-1β, -6 and -8 improved the performance of CA19-9 alone in differentiating PDAC from healthy controls. For example, a panel comprising IL-1β, IL-8, and CA 19–9 had a sensitivity of 94.1% vs 85.9%, specificity of 100% vs 96.3%, and area under the curve of 0.984 vs 0.925. The above-mentioned cytokines were associated with the severity of PDAC. IL-2, -6, -10, VEGF, and TGF levels were reported to be altered after patients received therapy or surgery. However, studies did not show any evidence of their ability to predict treatment response. Conclusion Our review demonstrates that there is insufficient evidence to support the role of individual cytokines as diagnostic, predictive or prognostic biomarkers for PDAC. However, emerging evidence indicates that a panel of cytokines may be a better tool for discriminating PDAC from other non-malignant pancreatic diseases or healthy individuals. PMID:27170998

  18. Severity of the ductal shunt: a comparison of different markers

    PubMed Central

    El Hajjar, M; Vaksmann, G; Rakza, T; Kongolo, G; Storme, L

    2005-01-01

    Background: When the ductus arteriosus (DA) is patent, the ductal shunt is proportional to the ratio of left ventricular output (LVO) to systemic blood flow. Systemic blood flow can be estimated by measuring flow in the superior vena cava (SVC). Objective: To re-evaluate the accuracy of standard echocardiographic markers of patent ductus arteriosus (PDA) using LVO/SVC flow ratio. Methods: Prospective study. Preterm infants of 24–30 weeks gestational age and postnatal age less than 48 hours. The following echocardiographic criteria were measured: left atrial to aortic root ratio (LA/Ao); DA diameter by B mode and colour Doppler; mean and end diastolic flow velocity of the left pulmonary artery (LPA); LVO; SVC flow. Results: Twenty three preterm infants were enrolled (median gestational age 28 weeks (range 24–30), median birth weight 840 g (500–1440)). The DA was closed in eight (mean (SD) LVO/SVC 2.4 (0.3)) and open in 15 (mean (SD) LVO/SVC 4.5 (0.6)). An LA/Ao ratio ⩾1.4, a DA diameter ⩾1.4 mm/kg, and a mean and end diastolic flow velocity of LPA respectively ⩾0.42 and ⩾0.20 m/s identified an LVO/SVC ⩾4 with a sensitivity and a specificity above 90%. Conclusion: This study indicates that LA/Ao ratio, DA diameter, and mean and end diastolic flow velocity of the LPA are accurate markers of PDA. These standard echocardiographic variables are easy to measure and need less skill and resources than direct measurements of ductal shunt. PMID:16113155

  19. Dietary patterns and risk of ductal carcinoma of the breast: a factor analysis in Uruguay.

    PubMed

    Ronco, Alvaro L; De Stefani, Eduardo; Deneo-Pellegrini, Hugo; Boffetta, Paolo; Aune, Dagfinn; Silva, Cecilia; Landó, Gabriel; Luaces, María E; Acosta, Gisele; Mendilaharsu, María

    2010-01-01

    Breast cancer (BC) shows very high incidence rates in Uruguayan women. The present factor analysis of ductal carcinoma of the breast, the most frequent histological type of this malignancy both in Uruguay and in the World, was conducted at a prepaid hospital of Montevideo, Uruguay. We identified 111 cases with ductal BC and 222 controls with normal mammograms. A factor analysis was conducted using 39 food groups, allowing retention of six factors analyzed through logistic regression in order to obtain odds ratios (OR) associated with ductal BC. The low fat and non-alcoholic beverage patterns were inversely associated (OR=0.30 and OR=0.45, respectively) with risk. Conversely, the fatty cheese pattern was positively associated (OR=4.17) as well as the fried white meat (OR=2.28) and Western patterns (OR 2.13). Ductal BC shared similar dietary risk patterns as those identified by studies not discriminating between histologic type of breast cancer. PMID:21198261

  20. Primary infiltrating ductal carcinoma of the axillary breast with metastasis to the contralateral chest wall.

    PubMed

    Sun, Li-Min; Meng, Fan-Yun; Chang, Nai-Jen; Lu, Chiao-Yi; Lu, Tsung-Hsien; Liang, Ji-An; Chung, Li-Min

    2013-06-01

    Primary infiltrating ductal carcinoma of the axillary breast is rare and has a high frequency of lymph node (LN) involvement. We report a woman with primary infiltrating ductal carcinoma arising from the right axillary breast with metastasis to the contralateral chest wall. Excisional biopsy of the left chest wall nodule and the right axillary mass was carried out and both showed invasive ductal carcinomas histologically. The lesion of the right axillary mass arose from the breast tissue, rather than the LN. Further surgery proved the right axillary LN metastasis. After further review, a primary infiltrating ductal carcinoma of the right axillary breast with metastasis to axillary LNs and contralateral chest wall was diagnosed. The patient also received chemotherapy and radiation and there was no evidence of tumor recurrence after treatment. The present report demonstrated a rare case with uncommon manifestation. Lesions of uncertain origin around the periphery of the breast should be suspected for breast carcinoma. PMID:23602213

  1. Assessment of ductal blood flow in newborns with obstructive left heart lesions by cardiovascular magnetic resonance

    PubMed Central

    2013-01-01

    Background Newborns with obstructive left heart lesions often depend on a patent ductus arteriosus to sustain the systemic circulation. Our aims were to validate the direct measurement of ductal flow, and to characterize the magnitude, determinants and hemodynamic effects of patent ductus arteriosus in newborns with obstructive left heart lesions by cardiovascular magnetic resonance (CMR). Methods In this retrospective study, the CMR and clinical information of newborns with obstructive left heart lesions were reviewed. The feasibility and validity of measuring ductal flow and the correlations between ductal flow and ventricular volumes, ascending aortic flow, post-ductal oxygen saturation and Qp:Qs were assessed. Results The CMR examinations of 32 newborns were included. It was possible to measure the ductal flow in all of them, with moderate-to-good agreement between measured and calculated ductal flow volume. The flow was bidirectional in all patients, with a net right-to-left shunt in 72%. Net ductal flow correlated inversely with ascending aortic flow (Rho −0.63; p 0.0002), post-ductal oxygen saturation (Rho −0.58; p 0.0004), Qp:Qs (Rho −0.43; p 0.02), and with left ventricular end-diastolic volume index (Rho −0.38; p 0.04). There was no correlation with the diameter of the ductus. The contribution of ductus flow to the systemic circulation correlated with the left ventricular end-diastolic volume index (Rho −0.47; p 0.02). Conclusions Direct measurement of ductal flow in newborns with obstructive left heart lesions is feasible. From these measurements, we were able to demonstrate that patients with smaller left ventricles and lower ascending aortic flow have a greater contribution of ductal flow to the systemic circulation. The size of the ductus arteriosus does not predict net ductal flow. Phase-contrast CMR can be an adjunct method for the assessment of the physiology for very ill neonate patients. PMID:23714046

  2. Treatment of parotid ductal stenosis and concomitant resolution of autonomic symptomatology.

    PubMed

    Gear, Kim J; Hay, K David; Stumpel, Jacqui

    2002-11-01

    Salivary retention and recurrent sialadenitis as a result of ductal stenosis is an uncommon condition that presents difficult management problems. Ductal dilation with small angioplasty balloons is recognized to be of low morbidity and can eliminate the possible need for surgical intervention. This case report is interesting in that the successful treatment of parotid duct stenosis was accompanied by the resolution of a spectrum of autonomic symptoms that had seriously compromised the patient's quality of life.

  3. Histopathologcial and clonal study of combined lobular and ductal carcinoma of the breast.

    PubMed

    Tazaki, Eri; Shishido-Hara, Yukiko; Mizutani, Natsuko; Nomura, Sachiyo; Isaka, Hirotsugu; Ito, Hiroki; Imi, Kentaro; Imoto, Shigeru; Kamma, Hiroshi

    2013-06-01

    Lobular carcinoma in situ (LCIS) clinically constitutes a risk factor for the subsequent development of either invasive lobular carcinoma (ILC) or invasive ductal carcinoma (IDC). In order to approach the possibility of this common precursor of both ILC and IDC, we investigated combined lobular and ductal carcinomas. Thirty-two cases of lobular carcinoma were picked up out of 773 cases of operated breast carcinomas. The histopathological detailed re-examination using immunostain of E-cadherin and β-catenin revealed a rather high frequency of combined lobular carcinomas than previous reports. Clinicopathologically, combined lobular carcinomas were younger and smaller than pure lobular carcinomas, and the cytological atypia was relatively low. These results suggested that combined lobular carcinomas could be detected in the earlier stage of breast cancer. Furthermore, the lobular and ductal components of combined carcinomas coexisted in the neighborhood and were distributed contiguously. The immunohistochemical phenotypes of both components were accorded in most combined cases. A genetic analysis using methylation-specific PCR on the HUMARA gene demonstrated that the same allele was inactivated in both lobular and ductal components in all detectable cases of combined carcinoma. Therefore, it is reasonable to assume that both lobular and ductal components of combined carcinomas are clonal and derived from the LCIS as the common precursor lesion, which may contradict the conventional concept that the lobular and ductal carcinomas arise from distinct differentiation pathways.

  4. Effect of Metformin on Breast Ductal Carcinoma In Situ Proliferation in a Randomized Presurgical Trial.

    PubMed

    DeCensi, Andrea; Puntoni, Matteo; Guerrieri-Gonzaga, Aliana; Cazzaniga, Massimiliano; Serrano, Davide; Lazzeroni, Matteo; Vingiani, Andrea; Gentilini, Oreste; Petrera, Marilena; Viale, Giuseppe; Cuzick, Jack; Bonanni, Bernardo; Pruneri, Giancarlo

    2015-10-01

    Metformin is associated with lower breast cancer risk in epidemiologic studies and showed decreased proliferation in HER2-positive breast cancer in a presurgical trial. To provide insight into its preventive potential, we measured proliferation by Ki-67 labeling index (LI) of intraepithelial lesions surrounding breast cancer. We randomly assigned 200 nondiabetic patients diagnosed with invasive breast cancer in core biopsies to metformin, 1,700 mg or placebo once daily for 28 days before surgery. Upon surgery, five to seven specimens of cancer adjacent (≤1 cm) and distant (>1 cm) tissue were screened for LCIS, ductal carcinoma in situ (DCIS), and ductal hyperplasia (DH). The prevalence of LCIS, DCIS, and DH was 4.5% (9/200), 67% (133/200), and 35% (69/200), respectively. Overall, metformin did not affect Ki-67 LI in premalignant disorders. The median posttreatment Ki-67 LI (IQR) in the metformin and placebo arm was, respectively, 15% (5-15) versus 5% (4-6) in LCIS (P = 0.1), 12% (8-20) versus 10% (7-24) in DCIS (P = 0.9), and 3% (1-4) versus 3% (1-4) in DH (P = 0.5). However, posttreatment Ki-67 in HER2-positive DCIS lesions was significantly lower in women randomized to metformin especially when ER was coexpressed: 22% (11-32) versus 35% (30-40) in HER2-positive DCIS (n = 22, P = .06); 12% (7-18) versus 32% (27-42) in ER-positive/HER2-positive DCIS (n = 15, P = .004). Eight of 22 (36%) HER2-positive DCIS were adjacent to HER2-negative invasive breast cancer. In tissue samples obtained following 4 weeks of study drug, proliferation was lower in HER2-positive DCIS for women randomized to metformin versus placebo. An adjuvant trial incorporating metformin in HER2-positive DCIS is warranted. PMID:26276754

  5. Stem cells as the root of pancreatic ductal adenocarcinoma

    SciTech Connect

    Balic, Anamaria; Dorado, Jorge; Alonso-Gomez, Mercedes; Heeschen, Christopher

    2012-04-01

    Emerging evidence suggests that stem cells play a crucial role not only in the generation and maintenance of different tissues, but also in the development and progression of malignancies. For the many solid cancers, it has now been shown that they harbor a distinct subpopulation of cancer cells that bear stem cell features and therefore, these cells are termed cancer stem cells (CSC) or tumor-propagating cells. CSC are exclusively tumorigenic and essential drivers for tumor progression and metastasis. Moreover, it has been shown that pancreatic ductal adenocarcinoma does not only contain one homogeneous population of CSC rather than diverse subpopulations that may have evolved during tumor progression. One of these populations is called migrating CSC and can be characterized by CXCR4 co-expression. Only these cells are capable of evading the primary tumor and traveling to distant sites such as the liver as the preferred site of metastatic spread. Clinically even more important, however, is the observation that CSC are highly resistant to chemo- and radiotherapy resulting in their relative enrichment during treatment and rapid relapse of disease. Many laboratories are now working on the further in-depth characterization of these cells, which may eventually allow for the identification of their Achilles heal and lead to novel treatment modalities for fighting this deadly disease.

  6. Circulating IL-35 in pancreatic ductal adenocarcinoma patients.

    PubMed

    Jin, Peng; Ren, He; Sun, Wei; Xin, Wen; Zhang, Huan; Hao, Jihui

    2014-01-01

    IL-35 is a novel inhibitory cytokine that is mainly produced by regulatory T-cells (Tregs) and is required for Treg-mediated immunosuppression. However, the plasma levels of IL-35 in patients with pancreatic ductal adenocarcinoma (PDAC) have never been investigated. In this study, we found that plasma IL-35 levels more significantly increased in PDAC patients than in normal controls (134.53 ± 92.45 pg/mL vs. 14.26 ± 6.56 pg/mL). IL-35 mRNA levels were positively correlated with plasma IL-35 levels (EBI3, R = 0.925, p<0.01; p35, R = 0.916, p<0.01). Furthermore, IL-35 expression levels were associated with lymph node metastasis (p = 0.001) and late tumor stage (p = 0.002). For the resected patients, high IL-35 expression levels were associated with large tumor size (p<0.01), higher TNM classification T staging (p<0.05), and late tumor stage (p<0.05). In conclusion, circulating IL-35 in PDAC patients significantly increased, suggesting that regulating the expression of IL-35 may provide a new possible target for the treatment of PDAC patients, especially for the resectable ones.

  7. Exploiting the neoantigen landscape for immunotherapy of pancreatic ductal adenocarcinoma

    PubMed Central

    Bailey, Peter; Chang, David K.; Forget, Marie-Andrée; Lucas, Francis A. San; Alvarez, Hector A.; Haymaker, Cara; Chattopadhyay, Chandrani; Kim, Sun-Hee; Ekmekcioglu, Suhendan; Grimm, Elizabeth A.; Biankin, Andrew V.; Hwu, Patrick; Maitra, Anirban; Roszik, Jason

    2016-01-01

    Immunotherapy approaches for pancreatic ductal adenocarcinoma (PDAC) have met with limited success. It has been postulated that a low mutation load may lead to a paucity of T cells within the tumor microenvironment (TME). However, it is also possible that while neoantigens are present, an effective immune response cannot be generated due to an immune suppressive TME. To discern whether targetable neoantigens exist in PDAC, we performed a comprehensive study using genomic profiles of 221 PDAC cases extracted from public databases. Our findings reveal that: (a) nearly all PDAC samples harbor potentially targetable neoantigens; (b) T cells are present but generally show a reduced activation signature; and (c) markers of efficient antigen presentation are associated with a reduced signature of markers characterizing cytotoxic T cells. These findings suggest that despite the presence of tumor specific neoepitopes, T cell activation is actively suppressed in PDAC. Further, we identify iNOS as a potential mediator of immune suppression that might be actionable using pharmacological avenues. PMID:27762323

  8. Ductal adenocarcinoma of the prostate: histogenesis, biology and clinicopathological features.

    PubMed

    Seipel, Amanda H; Delahunt, Brett; Samaratunga, Hemamali; Egevad, Lars

    2016-08-01

    Ductal adenocarcinoma of the prostate (DAC) is recognised as a subtype of prostatic adenocarcinoma, but its diagnostic criteria and biology remain controversial. DAC was first thought to stem from Müllerian duct remnants, but further studies suggest a prostatic origin. DAC is composed of tall, columnar, pseudostratified epithelium with a papillary, cribriform, glandular or solid architecture. The diagnosis is based on morphology alone with papillary architecture being the most helpful diagnostic feature. The tumour is rare in a pure form and most cases are combined with acinar adenocarcinoma. The most common differential diagnoses of DAC are intraductal carcinoma of the prostate and high-grade prostatic intraepithelial neoplasia. Patients often present at an advanced clinicopathological stage. High rates of extra-prostatic extension, seminal vesicle invasion, local and regional metastases, and positive surgical margins are seen after radical prostatectomy. DAC metastasises to sites that are less commonly seen for prostate cancer such as lung, brain, testis and penis. The morphology and the unusual metastatic locations make the accurate diagnosis of metastases challenging, but a positive immunostain for prostate specific markers may be helpful. The correct identification of DAC has implications for treatment as well as outcome. PMID:27321992

  9. In situ clinical evidence that zinc levels are decreased in breast invasive ductal carcinoma

    PubMed Central

    Zou, Jing; Franklin, Renty B.

    2016-01-01

    Purpose Altered zinc levels in malignant cells versus their normal cells have important implications in the development and progression of several cancers. Prostate, pancreatic, and hepatocellular carcinomas exhibit consistent marked zinc decrease in situ in the malignant cells, and other cancers (such as kidney, lung, and thyroid) also exhibit decreased tissue zinc levels. However, zinc levels are increased in breast cancer tissue compared to breast normal tissue, and the contemporary dominant view is that zinc is increased in invasive ductal carcinoma. This has important implications regarding the role and effects of zinc in breast malignancy compared to other cancers, which caused us to initiate this study to either confirm or challenge the contemporary view of an increased zinc level in the invasive ductal malignant cells. Methods We employed dithizone staining of breast tissue sections and tissue cores to determine the relative in situ cellular zinc levels specifically in the invasive ductal malignant cells as compared to normal ductal epithelium. This approach had not been employed in any of the reported breast studies. Results The results revealed that the zinc levels are consistently and markedly decreased in the ductal malignant cells as compared with higher prominent zinc levels in the normal ductal epithelium. Decreased zinc is evident in Grade 1 well-differentiated malignancy and in Grade 2 and Grade 3 carcinomas. Among the twenty-five cancer cases in this study, none exhibited increased zinc in the invasive ductal carcinoma compared to the zinc level in the normal ductal epithelium. Conclusions The decreased zinc levels in breast invasive ductal carcinoma is consistent with prostate, pancreatic, and liver carcinomas in which the decrease in zinc is a required event in the development of malignancy to prevent cytotoxicity that would result from the higher zinc levels in the normal cells. This new understanding requires a redirection in elucidating the

  10. Hypofractionated Radiation Therapy for Breast Ductal Carcinoma In Situ

    SciTech Connect

    Hathout, Lara; Hijal, Tarek; Théberge, Valérie; Fortin, Bernard; Vulpe, Horia; Hogue, Jean-Charles; Lambert, Christine; Bahig, Houda; and others

    2013-12-01

    Purpose: Conventional radiation therapy (RT) administered in 25 fractions after breast-conserving surgery (BCS) is the standard treatment for ductal carcinoma in situ (DCIS) of the breast. Although accelerated hypofractionated regimens in 16 fractions have been shown to be equivalent to conventional RT for invasive breast cancer, few studies have reported results of using hypofractionated RT in DCIS. Methods and Materials: In this multicenter collaborative effort, we retrospectively reviewed the records of all women with DCIS at 3 institutions treated with BCS followed by hypofractionated whole-breast RT (WBRT) delivered in 16 fractions. Results: Between 2003 and 2010, 440 patients with DCIS underwent BCS followed by hypofractionated WBRT in 16 fractions for a total dose of 42.5 Gy (2.66 Gy per fraction). Boost RT to the surgical bed was given to 125 patients (28%) at a median dose of 10 Gy in 4 fractions (2.5 Gy per fraction). After a median follow-up time of 4.4 years, 14 patients had an ipsilateral local relapse, resulting in a local recurrence-free survival of 97% at 5 years. Positive surgical margins, high nuclear grade, age less than 50 years, and a premenopausal status were all statistically associated with an increased occurrence of local recurrence. Tumor hormone receptor status, use of adjuvant hormonal therapy, and administration of additional boost RT did not have an impact on local control in our cohort. On multivariate analysis, positive margins, premenopausal status, and nuclear grade 3 tumors had a statistically significant worse local control rate. Conclusions: Hypofractionated RT using 42.5 Gy in 16 fractions provides excellent local control for patients with DCIS undergoing BCS.

  11. The prognostic role of desmoplastic stroma in pancreatic ductal adenocarcinoma

    PubMed Central

    Soonawalla, Zahir; Liu, Stanley; O'Neill, Eric; Mukherjee, Somnath; McKenna, W. Gillies; Muschel, Ruth; Fokas, Emmanouil

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant desmoplastic stroma. We examined the prognostic value of stroma density and activity in patients with resectable PDAC treated with surgery and adjuvant gemcitabine-based chemotherapy. FFPE-tissue from the pancreatectomy of 145 patients was immunohistochemically stained for haematoxylin-eosin and Masson's trichrome to assess stroma density, and alpha-smooth muscle actin (αSMA) expression for activated pancreatic stellate cells. Their expression was correlated with clinicopathological characteristics as well as overall survival (OS), progression-free survival (PFS), local progression-free survival (LPFS) and distant metastases free-survival (DMFS). After a mean follow-up of 20 months (range, 2–69 months), the median OS was 21 months and the 3-year OS was 35.7%. In multivariate analysis, highly-dense stroma was an independent prognostic parameter for OS (p = 0.001), PFS (p = 0.007), LPFS (p = 0.001) and DMFS (p = 0.002), while αSMA expression lacked significance. Interestingly, highly-dense stroma retained significance for the four clinical endpoints only in early (pT1–2) but not late (pT3–4) stage tumors. Additionally, late pT-stage (pT3–4), the presence of lymph node metastases (pN+ vs pN0), perineural/neural invasion and administration of adjuvant chemotherapy also correlated with prognosis in multivariate analysis. Altogether, stroma density constitutes an independent prognostic marker in PDAC patients treated with adjuvant chemotherapy. Our findings highlight the dynamic complexity of desmoplasia and indicate that highly-dense stroma is correlated with better outcome. Further validation of the prognostic value of stroma as a biomarker and its role in PDAC patients after adjuvant chemotherapy is warranted and will be performed in a prospective study. PMID:26716653

  12. Proinflammatory Cytokines Induce Endocrine Differentiation in Pancreatic Ductal Cells via STAT3-Dependent NGN3 Activation.

    PubMed

    Valdez, Ivan Achel; Dirice, Ercument; Gupta, Manoj K; Shirakawa, Jun; Teo, Adrian Kee Keong; Kulkarni, Rohit N

    2016-04-19

    A major goal of diabetes research is to develop strategies that replenish pancreatic insulin-producing beta cells. One emerging strategy is to harness pancreatic plasticity-the ability of pancreatic cells to undergo cellular interconversions-a phenomenon implicated in physiological stress and pancreatic injury. Here, we investigate the effects of inflammatory cytokine stress on the differentiation potential of ductal cells in a human cell line, in mouse ductal cells by pancreatic intraductal injection, and during the progression of autoimmune diabetes in the non-obese diabetic (NOD) mouse model. We find that inflammatory cytokine insults stimulate epithelial-to-mesenchymal transition (EMT) as well as the endocrine program in human pancreatic ductal cells via STAT3-dependent NGN3 activation. Furthermore, we show that inflammatory cytokines activate ductal-to-endocrine cell reprogramming in vivo independent of hyperglycemic stress. Together, our findings provide evidence that inflammatory cytokines direct ductal-to-endocrine cell differentiation, with implications for beta cell regeneration. PMID:27068459

  13. Slug inhibits pancreatic cancer initiation by blocking Kras-induced acinar-ductal metaplasia

    PubMed Central

    Ebine, Kazumi; Chow, Christina R.; DeCant, Brian T.; Hattaway, Holly Z.; Grippo, Paul J.; Kumar, Krishan; Munshi, Hidayatullah G.

    2016-01-01

    Cells in the pancreas that have undergone acinar-ductal metaplasia (ADM) can transform into premalignant cells that can eventually become cancerous. Although the epithelial-mesenchymal transition regulator Snail (Snai1) can cooperate with Kras in acinar cells to enhance ADM development, the contribution of Snail-related protein Slug (Snai2) to ADM development is not known. Thus, transgenic mice expressing Slug and Kras in acinar cells were generated. Surprisingly, Slug attenuated Kras-induced ADM development, ERK1/2 phosphorylation and proliferation. Co-expression of Slug with Kras also attenuated chronic pancreatitis-induced changes in ADM development and fibrosis. In addition, Slug attenuated TGF-α-induced acinar cell metaplasia to ductal structures and TGF-α-induced expression of ductal markers in ex vivo acinar explant cultures. Significantly, blocking the Rho-associated protein kinase ROCK1/2 in the ex vivo cultures induced expression of ductal markers and reversed the effects of Slug by inducing ductal structures. In addition, blocking ROCK1/2 activity in Slug-expressing Kras mice reversed the inhibitory effects of Slug on ADM, ERK1/2 phosphorylation, proliferation and fibrosis. Overall, these results increase our understanding of the role of Slug in ADM, an early event that can eventually lead to pancreatic cancer development. PMID:27364947

  14. Ductal Injection Does Not Increase the Islet Yield or Function after Cold Storage in a Vascular Perfusion Model

    PubMed Central

    Nakanishi, Wataru; Imura, Takehiro; Inagaki, Akiko; Nakamura, Yasuhiro; Sekiguchi, Satoshi; Fujimori, Keisei; Satomi, Susumu; Goto, Masafumi

    2012-01-01

    Several studies have reported that pancreatic ductal preservation greatly improved the islet yield and function after cold storage. However, these studies were devoid of appropriate controls, such as vascular perfusion, which is routinely performed to preserve organs in the clinical setting. In this study, we created a vascular perfusion model using inbred rats, and investigated the effect of ductal injection on the islet yield and function after cold storage. Rat pancreases after 10 h cold ischemia were classified as follows: without ductal/vascular perfusion; with ductal injection; with vascular perfusion; and with ductal/vascular perfusion. The islet yield, function, viability, release of inflammatory mediators, and pathological changes in the exocrine tissues were assessed in the Hanks' Balanced Salt Solution (HBSS) model. The islet yield was also assesed by introducing University of Wisconsin Solution (UWS) and Histidine-Tryptophan-Ketoglutarate solution (HTK), which are the standard clinical preservation solutions. In the HBSS model, ductal injection and vascular perfusion significantly improved the islet yield compared with the control group. However, ductal injection showed no additional effects on the islet yield, function, viability and suppressing the release of inflammatory mediators when vascular perfusion was performed. Although ductal injection significantly decreased the apoptosis of exocrine cells, no beneficial effect on vacuolation was observed. In contrast, vascular perfusion significantly suppressed vacuolation in the exocrine tissues. Likewise, in the UWS and HTK model, ductal injection and vascular perfusion improved the islet yield compared with the control group. Nevertheless, the combination group showed no additional effects. These data suggest that ductal injection has no additional effect on islet yield and function after cold storage in a vascular perfusion model. We propose that ductal injection can be an effective and simple

  15. Monitoring the progression from intraductal carcinoma to invasive ductal carcinoma based on multiphoton microscopy

    NASA Astrophysics Data System (ADS)

    Wu, Yan; Fu, Fangmeng; Lian, Yuane; Nie, Yuting; Zhuo, Shuangmu; Wang, Chuan; Chen, Jianxin

    2015-09-01

    Intraductal carcinoma is a precancerous lesion of the breast and the immediate precursor of invasive ductal carcinoma. Multiphoton microscopy (MPM) was used to monitor the progression from intraductal carcinoma to invasive ductal carcinoma, which can improve early detection of precursor lesions and halt progression to invasive neoplastic disease. It was found that MPM has the capability to reveal the qualitative changes in features of cells, structure of basement membranes, and architecture of collagens during the development from intraductal carcinoma to invasive ductal carcinoma, as well as the quantitative alterations in nuclear area, circle length of basement membrane, and collagen density. Combined with intra-fiberoptic ductoscopy or transdermal biopsy needle, MPM has the potential to provide immediate histological diagnosis of tumor progression in the field of breast carcinoma.

  16. Immunohistochemistry applied to the differential diagnosis between ductal and lobular carcinoma of the breast.

    PubMed

    de Deus Moura, Rafael; Wludarski, Sheila C L; Carvalho, Filomena M; Bacchi, Carlos E

    2013-01-01

    The distinction between classic lobular and ductal carcinoma, both in situ and invasive, has important therapeutic and management implications. Most ductal and lobular carcinomas are distinguished readily on hematoxylin-eosin-stained sections because of distinct histomorphologic features. In cases with ambiguous morphologic features, however, categorization in one or another type can be a challenge. Several immunohistochemical markers, including epithelial cadherin, p120, β-catenin, and low-molecular-weight and high-molecular-weight cytokeratins among others, have been introduced to help better discriminate between lobular neoplasia and ductal carcinoma. In this critical review of the literature, we comment about the usefulness and the limitations of these markers to improve the accuracy in the differential diagnosis of breast pathology.

  17. Ngn3+ endocrine progenitor cells control the fate and morphogenesis of pancreatic ductal epithelium

    PubMed Central

    Magenheim, Judith; Klein, Allon M.; Stanger, Ben Z.; Ashery-Padan, Ruth; Sosa-Pineda, Beatriz; Gu, Guoqiang; Dor, Yuval

    2013-01-01

    Summary During pancreas development, endocrine and exocrine cells arise from a common multipotent progenitor pool. How these cell fate decisions are coordinated with tissue morphogenesis is poorly understood. Here we have examined ductal morphology, endocrine progenitor cell fate and Notch signaling in Ngn3−/− mice, which do not produce islet cells. Ngn3 deficiency results in reduced branching and enlarged pancreatic duct-like structures, concomitant with Ngn3 promoter activation throughout the ductal epithelium and reduced Notch signaling. Conversely, forced generation of surplus endocrine progenitor cells causes reduced duct caliber and an excessive number of tip cells. Thus, endocrine progenitor cells normally provide a feedback signal to adjacent multipotent ductal progenitor cells that activates Notch signaling, inhibits further endocrine differentiation and promotes proper morphogenesis. These results uncover a novel layer of regulation coordinating pancreas morphogenesis and endocrine/exocrine differentiation, and suggest ways to enhance the yield of beta-cells from stem cells. PMID:21888903

  18. Characterization of Pancreatic Ductal Cell in Human Islet Preparations

    PubMed Central

    Ichii, Hirohito; Miki, Atsushi; Yamamoto, Toshiyuki; Molano, R. Damaris; Barker, Scott; Mita, Atsuyoshi; Rodriguez-Diaz, Rayner; Klein, Dagmar; Pastori, Ricardo; Alejandro, Rodolfo; Inverardi, Luca; Pileggi, Antonello; Ricordi 6, Camillo

    2013-01-01

    Substantial amounts of non-endocrine cells are implanted as part of human islet grafts, and possible influence of non-endocrine cells on clinical islet transplantation outcome has been postulated. There are currently no product release criteria specific for non-endocrine cells due to lack of available methods. Aims of this study were to develop a method for the evaluation of pancreatic ductal cells (PDC) for clinical islet transplantation, and to characterize them regarding phenotype, viability and function. We assessed 161 human islet preparations using laser scanning cytometer (LSC/iCys) for phenotypic analysis of non-endocrine cells and flow cytometer (FACS) for PDC viability. PDC and β-cells obtained from different density fractions during the islet cell purification were compared in terms of viability. Furthermore, we examined PDC ability to produce pro-inflammatory cytokines/chemokines, vascular endothelial growth factor (VEGF) and tissue factor (TF), relevant to islet graft outcome. Phenotypic analysis by LSC/iCys indicated that single staining for CK19 or CA19-9 was not enough for identifying PDC, and that double staining for amylase and CK19 or CA19-9 allowed for quantitative evaluation of acinar cells and PDC content in human islet preparation. PDC showed a significantly higher viability than β-cells (PDC vs. β-cell: 75.5±13.9 and 62.7±18.7 %; p<0.0001). Although β-cells viability was independent from the density, that of PDC was higher as the density from which they were recovered increased. There was no correlation between PDC and β-cells viability (R2=0.0078). PDC sorted from high-density fractions produced significantly higher amount of pro-inflammatory mediators and VEGF, but not TF. PDC isolated from different fractions had different viability and function. The precise characterization and assessment of these cells in addition to β-cells in human islet cell products may be of assistance in understanding their contribution to islet

  19. Outcomes of robotic surgery for pancreatic ductal adenocarcinoma

    PubMed Central

    Zhan, Qian; Deng, Xiaxing; Weng, Yuanchi; Jin, Jiabin; Wu, Zhichong; Li, Hongwei; Shen, Baiyong

    2015-01-01

    Background To explore the effectiveness, safety, and efficacy of the robot-assisted surgery in the radical resection of pancreatic ductal adenocarcinoma (PDAC). Methods The clinical data of 72 patients with PDAC who underwent radical resection using the da Vinci Surgical System from April 2010 to December 2014 were retrospectively analyzed. Results Among these 72 patients, three were converted to conventional laparotomy due to the vascular invasion or due to the difficulties in tissue isolation from the surrounding organs. Among 39 patients who underwent the pancreatoduodenectomy, the average operative time was 395.3±118.8 min, and the mean intra-operative blood loss was 447.3±269.9 mL. Among 31 patients who underwent the distal pancreatectomy (DP), the average operative time was 185.5±74.1 min, and the mean intra-operative blood loss was 267.1±305.3 mL. In two patients who received the middle pancreatectomy (MP), the average operative time was 225 min and mean intra-operative blood loss was 100 mL. Among all the 72 patients, an average of 4.2±2.6 lymph nodes were dissected, with an average hospital stay of 22.6±10.7 days. Complications were observed in 18 patients, which included pancreatic fistula (n=11), bile leak (n=5), anastomotic bleeding (n=2), pancreatic fistula complicated with portal vein thrombosis (n=1), and anastomotic bleeding complicated with acute renal failure (n=1). Except that one patient died due to post-operative bleeding and acute renal failure, all the other patients were cured after conservative treatment. These 72 patients were followed for 1-45 (15.6±5.8) months, during which 10 patients died. Eleven patients suffered from recurrence or metastasis, among which 6 had local recurrence, 4 had liver metastasis, and 1 had ascites accompnaied with incision site tumor metastasis. Conclusions Radical resection of PDAC by robotic surgical system is safe and feasible. It has less surgical trauma and enables faster post-operative recovery, and

  20. Accelerated Partial Breast Irradiation for Pure Ductal Carcinoma in Situ

    SciTech Connect

    Park, Sean S.; Grills, Inga Siiner; Chen, Peter Y.; Kestin, Larry L.; Ghilezan, Michel I.; Wallace, Michelle; Martinez, Alvaro M.; Vicini, Frank A.

    2011-10-01

    Purpose: To report outcomes for ductal carcinoma in situ (DCIS) treated with breast-conserving therapy using accelerated partial breast irradiation (APBI). Methods and Materials: From March 2001 to February 2009, 53 patients with Stage 0 breast cancer were treated with breast conserving surgery and adjuvant APBI. Median age was 62 years. All patients underwent excision with margins negative by {>=}1 mm before adjuvant radiotherapy (RT). A total of 39 MammoSite brachytherapy (MS) patients and 14 three-dimensional conformal external beam RT (3DCRT) patients were treated to the lumpectomy bed alone with 34 Gy and 38.5 Gy, respectively. Of the DCIS cases, 94% were mammographically detected. All patients with calcifications had either specimen radiography or postsurgical mammography confirmation of clearance. Median tumor size was 6 mm, and median margin distance was 5 mm. There were no statistically significant differences according to APBI method for race/ethnicity, tumor detection method, tumor grade, estrogen receptor (ER) status, or use of tamoxifen (p = NS). Recurrence and survival were calculated using the Kaplan-Meier method. Cosmesis was scored by the Harvard criteria. Results: With a median follow-up of 3.6 years (range, 0.4-6.3 years), the overall and cause-specific survival rates were 98% and 100%, respectively. Three-year actuarial ipsilateral breast tumor recurrence was 2%. One failure was observed at the resection bed 11 months post-RT. No other elsewhere breast failures, regional recurrences, or distant metastases were noted. Cosmesis was excellent or good in 92.4% of cases, with no statistically significant differences according to the APBI method (92.3% with MammoSite and 92.8% with 3DCRT; p = 0.649). Conclusions: APBI as part of breast-conserving therapy for pure DCIS was associated with excellent local control and survival rates, with the vast majority of patients having good to excellent cosmesis. This finding supports the recent analysis by the

  1. Diagnosis and management of ductal carcinoma in situ.

    PubMed

    Khan, Amina; Newman, Lisa A

    2004-04-01

    Ductal carcinoma in situ (DCIS) is a preinvasive form of breast cancer that has increased in incidence over the past 25 years, primarily as a result of mammographically detected microcalcifications. Inadequately treated DCIS carries a risk for evolving into the malignant phenotype; however, the magnitude and timeline for this risk are poorly defined. Treatment options include lumpectomy with or without breast irradiation and mastectomy. The overall survival rate is 96% to 98% with any of these strategies, but the risk of local recurrence (LR) is highest after lumpectomy alone. Breast irradiation can reduce this risk from levels in excess of 40% to 10% over a 10-year follow-up period. Approximately 50% of all LR from DCIS are invasive lesions. Therefore, the occurrence of a LR after breast-conserving therapy is a potentially greater threat to the patient with DCIS compared to the patient diagnosed with invasive cancer. In patients diagnosed with invasive cancer, the risk of micrometastatic disease is present from the time of initial diagnosis. In patients with DCIS, the expectation is that a potentially 100% cure rate should be achieved with local therapy alone. Although most DCIS cases complicated by LR will be successfully salvaged with prolonged overall survival, it is critically important to take every precaution that will minimize the risk of locally recurrent disease. Therefore, radiation therapy as an adjunct to lumpectomy is essential. A subset of patients with DCIS with low-volume low-grade disease who can be safely treated by lumpectomy alone has not yet been clearly defined. Prospective studies designed to identify this category are ongoing. Inadequate margin control is the most consistent risk factor for LR that has been reported thus far, but there is no universally accepted definition for what constitutes an optimal negative margin distance. Young age at diagnosis, high nuclear grade, and comedonecrosis are other factors that have been implicated as

  2. A rapid in vivo screen for pancreatic ductal adenocarcinoma therapeutics.

    PubMed

    Ocal, Ozhan; Pashkov, Victor; Kollipara, Rahul K; Zolghadri, Yalda; Cruz, Victoria H; Hale, Michael A; Heath, Blake R; Artyukhin, Alex B; Christie, Alana L; Tsoulfas, Pantelis; Lorens, James B; Swift, Galvin H; Brekken, Rolf A; Wilkie, Thomas M

    2015-10-01

    Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer-related deaths in the United States, and is projected to be second by 2025. It has the worst survival rate among all major cancers. Two pressing needs for extending life expectancy of affected individuals are the development of new approaches to identify improved therapeutics, addressed herein, and the identification of early markers. PDA advances through a complex series of intercellular and physiological interactions that drive cancer progression in response to organ stress, organ failure, malnutrition, and infiltrating immune and stromal cells. Candidate drugs identified in organ culture or cell-based screens must be validated in preclinical models such as KIC (p48(Cre);LSL-Kras(G12D);Cdkn2a(f/f)) mice, a genetically engineered model of PDA in which large aggressive tumors develop by 4 weeks of age. We report a rapid, systematic and robust in vivo screen for effective drug combinations to treat Kras-dependent PDA. Kras mutations occur early in tumor progression in over 90% of human PDA cases. Protein kinase and G-protein coupled receptor (GPCR) signaling activates Kras. Regulators of G-protein signaling (RGS) proteins are coincidence detectors that can be induced by multiple inputs to feedback-regulate GPCR signaling. We crossed Rgs16::GFP bacterial artificial chromosome (BAC) transgenic mice with KIC mice and show that the Rgs16::GFP transgene is a Kras(G12D)-dependent marker of all stages of PDA, and increases proportionally to tumor burden in KIC mice. RNA sequencing (RNA-Seq) analysis of cultured primary PDA cells reveals characteristics of embryonic progenitors of pancreatic ducts and endocrine cells, and extraordinarily high expression of the receptor tyrosine kinase Axl, an emerging cancer drug target. In proof-of-principle drug screens, we find that weanling KIC mice with PDA treated for 2 weeks with gemcitabine (with or without Abraxane) plus inhibitors of Axl signaling

  3. Giant ductal aneurysm in an asymptomatic 4-year-old girl.

    PubMed

    Sachdeva, Ritu; Smith, Clinton; Greenberg, Bruce S; Jaquiss, Robert D B

    2009-03-01

    Ductal aneurysm is a rare but potentially fatal condition. We report the case of an asymptomatic 4-year-old girl who was noted to have a murmur and with further evaluation by echocardiography and computed tomographic angiography was diagnosed with a giant ductal aneurysm. The aneurysm occupied a large space in the mediastinum, compressed the pulmonary arteries, and was in close proximity to the sternum. At surgery, the aneurysm was successfully resected after careful separation from adjacent structures. Because the anterolateral wall of the ascending aorta was noted to be extraordinarily thinned-out, it was replaced with a patch.

  4. Current controversies in the treatment of ductal carcinoma in situ of the breast.

    PubMed

    Franceschini, Gianluca; Terribile, Daniela; Magno, Stefano; Fabbri, Cristina; D'Alba, Pierfrancesco; Chiesa, Federica; Di Leone, Alba; Scafetta, Ilaria; Masetti, Riccardo

    2008-01-01

    The incidence of ductal carcinoma in situ (DCIS), a noninvasive form of breast cancer, has increased markedly in recent decades, and DCIS now accounts for approximately 20% of breast cancers diagnosed by mammography. Laboratory and patient data suggest that DCIS is a precursor lesion for invasive cancer. Controversy exists with regard to the optimal management of DCIS patients. In the past, mastectomy was the primary treatment for patients with DCIS, but as with invasive cancer, breast-conserving surgery has become the standard approach. A mini-review of the management of ductal carcinoma in situ is presented, and the roles and dilemmas of surgery, radiotherapy and endocrine therapy are discussed. PMID:18958961

  5. Influence of ionizing radiation and 7,12-dimethylbenz(a)anthracene on the expression of mammary ductal dysplasia in mice

    SciTech Connect

    Ethier, S.P.

    1982-01-01

    These studies were undertaken to determine if altered growth potential of mammary epithelial cells could be detected in outgrowths derived from monodispersed mammary cells of virgin female BALB/c mice previously exposed to ionizing radiation or 7,12-dimethylbenz(a)anthracene (DMBA). Monodispersed mammary cells were obtained by enzymatic dissociation of mammary tissues of 12-week-old virgin female BALB/c mice. Twenty-four hours prior to cell dissociation, donor animals were exposed to either ..gamma..-ray irradiation or DMBA, while control donors were untreated. Mammary outgrowths were then derived from the donor cells by injecting either 10/sup 5/ or 10/sup 4/ cells into the gland free mammary fat pads of three-week-old virgin female BALB/c mice. In the initial studies all outgrowths were removed 10 weeks after injection of cells. The outgrowths that resulted were examined at the whole mount and histological level and were classified as having a normal ductal architecture or as having ductal dysplasia or alveolar adenosis. Outgrowths exhibiting ductal dysplasia were further classified as having mild or severe epithelial hyperplasia. The data indicated that treatment of donor animals with either ..gamma..-radiation or DMBA could result in an increased incidence of ductal dysplasias over control levels. Further, the incidence of lesions observed in all groups was influenced by the number of cells used to derive the outgrowths in that lesions were more frequent in outgrowths derived from 10/sup 4/ rather than 10/sup 5/ cells. The findings of these experiments indicate that acquisition of altered growth potential by mammary cells that results in expression of ductal dysplasia occurs soon after carcinogen treatment and that deriving mammary outgrowths from dissociated cells results in enhanced expression of these lesions.

  6. A novel approach to ductal spasm during percutaneous device occlusion of patent ductus arteriosus.

    PubMed

    De Decker, Rik; Comitis, George; Thomas, Jenny; van der Merwe, Elmarie; Lawrenson, John

    2016-10-01

    Ductal spasm is a rare yet important complication of device occlusions of patent ductus arteriosus. Spasm may result in failure of the procedure, under-sizing of the device, or embolisation of the implanted device as the spasm resolves after the procedure. We describe a novel protocol that rapidly and completely reversed the spasm in eight prematurely born infants who experienced ductal spasm during cardiac catheterisations for patent ductus arteriosus occlusion. In total, eight infants born between 25 and 34 weeks of gestation presented for transcatheter patent ductus arteriosus occlusion between 13 and 87 months of age. All eight patients experienced ductal spasm either immediately before, during, or soon after induction of anaesthesia or only after entering the ductus arteriosus with a catheter. After detection of the spasm, the anaesthetist, in each case, changed the mode of anaesthesia from inhaled sevoflurane to total intravenous anaesthesia with propofol, reduced the inhaled oxygen fraction to 21%, and initiated a continuous intravenous infusion of prostaglandin E1. The first two steps (total intravenous anaesthesia and FiO2 0.21) resulted in only partial relaxation of the spasm. Complete relaxation was attained after intravenous prostaglandin E1 infusions of only 10-15 minutes' duration. While maintaining this protocol, six ducti were successfully occluded and two were considered to be unsuitable for device occlusion and were referred for surgery. Ductal spasm during transcatheter occlusion may be reliably resolved and the procedure safely completed by a simple anaesthetic protocol, including the continuous infusion of intravenous prostaglandin E1.

  7. A Speculative Role for Stromal Gastrin Signaling in Development and Dissemination of Pancreatic Ductal Adenocarcinoma

    PubMed Central

    Matters, Gail L; Clawson, Gary A

    2013-01-01

    The peptide growth factor gastrin and its receptor, the G-protein coupled cholecystokinin receptor type B (CCKBR), play an integral role in the growth and progression of pancreatic ductal adenocarcinoma (PDAC). Gastrin immunoreactivity is found in the fetal pancreas but its expression is not detected in normal pancreas after birth, except when it is re-expressed in malignant lesions. PMID:25346875

  8. Inflammatory infiltrate in invasive lobular and ductal carcinoma of the breast.

    PubMed Central

    Lee, A. H.; Happerfield, L. C.; Millis, R. R.; Bobrow, L. G.

    1996-01-01

    The significance of inflammation in carcinoma of the breast is controversial. Little attention has been paid to different patterns of inflammation or inflammation associated with different histological types of carcinoma. We have looked at the pattern of inflammation in 123 invasive mammary carcinomas (including 46 lobular), and characterised the inflammatory cells with immunohistochemistry in 21. We found different patterns of inflammation in ductal and lobular carcinoma. Diffuse inflammation was seen more in ductal carcinoma, particularly of high grade, and was predominantly composed of macrophages and T cells. It was associated with necrosis, but the correlation was weak, suggesting that other factors are important. Perilobular inflammation was seen most frequently in lobular and high-grade ductal carcinomas, particularly at the tumour edge. Perivascular inflammation was also largely at the tumour edge, but was not more common in any tumour type. In contrast to the diffuse inflammation, the perivascular and perilobular inflammation was composed of T and B cells. Normal lobules at the tumour edge showed consistent expression of HLA-DR, whereas lobules away from the tumour were negative. A combination of perilobular and perivascular inflammation composed of B and T cells with epithelial expression of HLA-DR mimicking lymphocytic lobulitis was seen more frequently in lobular than ductal carcinoma. Images Figure 1 Figure 2 Figure 3 PMID:8795584

  9. PD2/Paf1 depletion in pancreatic acinar cells promotes acinar-to-ductal metaplasia

    PubMed Central

    Dey, Parama; Rachagani, Satyanarayana; Vaz, Arokia P.; Ponnusamy, Moorthy P.; Batra, Surinder K.

    2014-01-01

    Pancreatic differentiation 2 (PD2), a PAF (RNA Polymerase II Associated Factor) complex subunit, is overexpressed in pancreatic cancer cells and has demonstrated potential oncogenic property. Here, we report that PD2/Paf1 expression was restricted to acinar cells in the normal murine pancreas, but its expression increased in the ductal cells of Pdx1Cre; KrasG12D (KC) mouse model of pancreatic cancer with increasing age, showing highest expression in neoplastic ductal cells of 50 weeks old mice. PD2/Paf1 was specifically expressed in amylase and CK19 double positive metaplastic ducts, representing intermediate structures during pancreatic acinar-to-ductal metaplasia (ADM). Similar PD2/Paf1 expression was observed in murine pancreas that exhibited ADM-like histology upon cerulein challenge. In normal mice, cerulein-mediated inflammation induced a decrease in PD2/Paf1 expression, which was later restored upon recovery of the pancreatic parenchyma. In KC mice, however, PD2/Paf1 mRNA level continued to decrease with progressive dysplasia and subsequent neoplastic transformation. Additionally, knockdown of PD2/Paf1 in pancreatic acinar cells resulted in the abrogation of Amylase, Elastase and Lipase (acinar marker) mRNA levels with simultaneous increase in CK19 and CAII (ductal marker) transcripts. In conclusion, our studies indicate loss of PD2/Paf1 expression during acinar transdifferentiation in pancreatic cancer initiation and PD2/Paf1 mediated regulation of lineage specific markers. PMID:24947474

  10. Grading system for blood vessel tumor emboli of invasive ductal carcinoma of the breast.

    PubMed

    Sugiyama, Michiko; Hasebe, Takahiro; Shimada, Hiroko; Takeuchi, Hideki; Shimizu, Kyoko; Shimizu, Michio; Yasuda, Masanori; Ueda, Shigeto; Shigekawa, Takashi; Osaki, Akihiko; Saeki, Toshiaki

    2015-06-01

    We previously reported that the number of mitotic and apoptotic figures in tumor cells in blood vessel tumor emboli had the greatest significant power for the accurate prediction of the outcome of patients with invasive ductal carcinoma of the breast. The purpose of the present study was to devise a grading system for blood vessel tumor emboli based on the mitotic and apoptotic figures of tumor cells in blood vessel tumor emboli, enabling accurate prediction of the outcome of patients with invasive ductal carcinoma of the breast. We classified 263 invasive ductal carcinomas into the following 3 grades according to the numbers of mitotic and apoptotic figures in tumor cells located in blood vessels within 1 high-power field: grade 0, no blood vessel invasion; grade 1, absence of mitotic figures and presence of any number of apoptotic figures, or 1 mitotic figure and 0 to 2 apoptotic figures; and grade 2, 1 mitotic figure and 3 or more apoptotic figures, or 2 or more mitotic figures and 1 or more apoptotic figures. Multivariate analyses with well-known prognostic factors demonstrated that grade 2 blood vessel tumor emboli significantly increased the hazard ratios for tumor recurrence independent of the nodal status, pathological TNM stage, hormone receptor status, or HER2 status. The presently reported grading system for blood vessel tumor emboli is the strongest histologic factor for accurate prediction of the outcome of patients with invasive ductal carcinoma of the breast.

  11. NOGGIN IS REQUIRED FOR NORMAL LOBE PATTERNING AND DUCTAL BUDDING IN THE MOUSE PROSTATE

    PubMed Central

    Cook, Crist; Vezina, Chad M.; Hicks, Sarah M.; Shaw, Aubie; Yu, Min; Peterson, Richard E.; Bushman, Wade

    2008-01-01

    Mesenchymal expression of the BMP antagonist NOGGIN during prostate development plays a critical role in pre-natal ventral prostate development and opposes BMP4-mediated inhibition of cell proliferation during postnatal ductal development. Morphologic examination of newborn Noggin-/- male fetuses revealed genitourinary anomalies including cryptorchidism, incomplete separation of the hindgut from the urogenital sinus (UGS), absence of the ventral mesenchymal pad and a complete loss of ventral prostate (VP) budding. Examination of lobe-specific marker expression in the E14 Noggin-/- UGS rescued by transplantation under the renal capsule of a male nude mouse confirmed a complete loss of VP determination. More modest effects were observed in the other lobes, including decreased number of ductal buds in the dorsal and lateral prostates of newborn Noggin-/- males. BMP4 and BMP7 have been shown to inhibit ductal budding and outgrowth by negatively regulating epithelial cell proliferation. We show here that NOGGIN can neutralize budding inhibition by BMP4 and rescues branching morphogenesis of BMP4-exposed UGS in organ culture and show that the effects of BMP4 and NOGGIN activities converge on P63+ epithelial cells located at nascent duct tips. Together, these studies show that the BMP-NOGGIN axis regulates patterning of the ventral prostate, regulates ductal budding, and controls proliferation of P63+ epithelial cells in the nascent ducts of developing mouse prostate. PMID:18028901

  12. Nitric oxide alterations following acute ductal constriction in the fetal lamb: a role for superoxide.

    PubMed

    Hsu, Jong-Hau; Oishi, Peter; Wiseman, Dean A; Hou, Yali; Chikovani, Omar; Datar, Sanjeev; Sajti, Eniko; Johengen, Michael J; Harmon, Cynthia; Black, Stephen M; Fineman, Jeffrey R

    2010-06-01

    Acute partial compression of the fetal ductus arteriosus (DA) results in an initial abrupt increase in pulmonary blood flow (PBF), which is followed by a significant reduction in PBF to baseline values over the ensuing 2-4 h. We have previously demonstrated that this potent vasoconstricting response is due, in part, to an endothelin-1 (ET-1)-mediated decrease in nitric oxide synthase (NOS) activity. In addition, in vitro data demonstrate that ET-1 increases superoxide levels in pulmonary arterial smooth muscle cells and that oxidative stress alters NOS activity. Therefore, the objectives of this study were to determine the potential role of superoxide in the alterations of hemodynamics and NOS activity following acute ductal constriction in the late-gestation fetal lamb. Eighteen anesthetized near-term fetal lambs were instrumented, and a lung biopsy was performed. After a 48-h recovery, acute constriction of the DA was performed by inflating a vascular occluder. Polyethylene glycol-superoxide dismutase (PEG-SOD; 1,000-1,500 units/kg, n = 7) or PEG-alone (vehicle control group, n = 5) was injected into the pulmonary artery before ductal constriction. Six animals had a sham operation. In PEG-alone-treated lambs, acute ductal constriction rapidly decreased pulmonary vascular resistance (PVR) by 88%. However, by 4 h, PVR returned to preconstriction baseline. This vasoconstriction was associated with an increase in lung superoxide levels (82%), a decrease in total NOS activity (50%), and an increase in P-eNOS-Thr495 (52%) (P < 0.05). PEG-SOD prevented the increase of superoxide after ductal constriction, attenuated the vasoconstriction, preserved NOS activity, and increased P-eNOS Ser1177 (307%, P < 0.05). Sham procedure induced no changes. These data suggest that an acute decrease in NOS activity that is mediated, in part, by increased superoxide levels, and alterations in the phosphorylation status of the endothelial NOS isoform, underlie the pulmonary vascular

  13. KLF4 Is Essential for Induction of Cellular Identity Change and Acinar-to-Ductal Reprogramming during Early Pancreatic Carcinogenesis.

    PubMed

    Wei, Daoyan; Wang, Liang; Yan, Yongmin; Jia, Zhiliang; Gagea, Mihai; Li, Zhiwei; Zuo, Xiangsheng; Kong, Xiangyu; Huang, Suyun; Xie, Keping

    2016-03-14

    Understanding the molecular mechanisms of tumor initiation has significant impact on early cancer detection and intervention. To define the role of KLF4 in pancreatic ductal adenocarcinoma (PDA) initiation, we used molecular biological analyses and mouse models of klf4 gain- and loss-of-function and mutant Kras. KLF4 is upregulated in and required for acinar-to-ductal metaplasia. Klf4 ablation drastically attenuates the formation of pancreatic intraepithelial neoplasia induced by mutant Kras(G12D), whereas upregulation of KLF4 does the opposite. Mutant KRAS and cellular injuries induce KLF4 expression, and ectopic expression of KLF4 in acinar cells reduces acinar lineage- and induces ductal lineage-related marker expression. These results demonstrate that KLF4 induces ductal identity in PanIN initiation and may be a potential target for prevention of PDA initiation.

  14. Detection of ductal dysplasia in mammary outgrowths derived from carcinogen-treated virgin female BALB/c mice

    SciTech Connect

    Ethier, S.P.; Ullrich, R.L.

    1982-05-01

    These studies were undertaken to determine if altered growth potential of mammary epithelial cells could be detected in outgrowths derived from monodispersed mammary cells of virgin female BALB/c mice previously exposed to ionizing radiation or 7, 12-dimethylbenz(a)anthracene (DMBA). Twenty-four hr prior to cell dissociation, donor animals were exposed to either 100 rads of gamma-ray irradiation, 0.25 mg of DMBA, or 0.075 mg of DMBA. Control donors were untreated. Mammary outgrowths were then derived from these donor cells by injecting either 10(5) or 10(4) cells into the gland-free mammary fat pads of three-week-old virgin female BALB/c mice. Mammary outgrowths were classified either as having a normal ductal architecture or as having ductal dysplasia. Ductal dysplasias were further classified on the basis of an index of severity, which was an arbitrary index based on the number of abnormal ductal structures within each lesion. The data indicated that treatment of donor animals with either gamma-radiation or DMBA increased the frequency of ductal lesions over control levels; however, both the frequency and severity of the lesions depended on the number of cells which were injected into the fat pad. The data indicated that ductal dysplasias were more common and more severe in outgrowths derived 10(4) rather than 10(5) cells. The ductal lesions observed in this study resembled both morphologically and histologically ductal abnormalities which have been associated with the pathogenesis of mammary carcinoma in both rats and mice.

  15. Ductal Breast Carcinoma Metastatic to the Stomach Resembling Primary Linitis Plastica in a Male Patient

    PubMed Central

    Leonardi, Giulia Costanza; Ravaioli, Noemi; De Giglio, Andrea; Brambilla, Marta; Prosperi, Enrico; Ribacchi, Franca; Meacci, Marialuisa; Crinò, Lucio; Maiettini, Daniele; Chiari, Rita; Metro, Giulio

    2016-01-01

    Breast cancer metastases to the gastrointestinal tract are very rare occurrences. Among the histological subtypes of breast cancer, invasive lobular carcinomas have a high capacity of metastasis to uncommon sites including the stomach. Conversely, there has not been sufficient evidence supporting the gastric metastasis of invasive ductal carcinoma. Herein, we report a unique case of metastatic ductal breast carcinoma mimicking primary linitis plastica in a male patient, particularly focusing on the clinical and pathological features of presentation. Moreover, we propose a immunohistochemical panel of selected antibodies including those for cytokeratin 20, cytokeratin 7, estrogen receptor, progesterone receptor, E-cadherin, gross cystic disease fluid protein 15, and GATA binding protein 3 for an accurate differential diagnosis. PMID:27721883

  16. Invasive ductal carcinoma with in situ pattern: how to avoid this diagnostic pitfall?

    PubMed

    Mohan, Narasimhamurthy; Black, Jennifer O; Schwartz, Mary R; Zhai, Qihui Jim

    2016-01-01

    Although the microscopic features of invasion are usually readily recognized, occasionally invasive ductal carcinoma may mimic the pattern of comedo ductal carcinoma in situ (DCIS) by forming large cellular nests with circumscribed borders, but lacking a definitive myoepithelial cell layer. In these cases, the histologic pattern may appear deceptively noninvasive and the absence of a myoepithelial layer can be easily overlooked. We prospectively examined 10 cases of high grade DCIS. P63, smooth muscle actin, muscle specific actin and calponin immunohistochemical stains were used to identify the presence of myoepithelial cells. In our study, 20% of apparent high grade DCIS cases did not exhibit a myoepithelial layer surrounding large, solid nests with comedo necrosis. Since invasion is defined by the absence of a myoepithelial layer, these results suggest that a DCIS-like pattern may actually represent invasive disease in some cases. Immunohistochemical studies may be essential in making this distinction and in avoiding the potential diagnostic pitfall. PMID:27648124

  17. Invasive ductal carcinoma with in situ pattern: how to avoid this diagnostic pitfall?

    PubMed Central

    Mohan, Narasimhamurthy; Black, Jennifer O; Schwartz, Mary R; Zhai, Qihui Jim

    2016-01-01

    Although the microscopic features of invasion are usually readily recognized, occasionally invasive ductal carcinoma may mimic the pattern of comedo ductal carcinoma in situ (DCIS) by forming large cellular nests with circumscribed borders, but lacking a definitive myoepithelial cell layer. In these cases, the histologic pattern may appear deceptively noninvasive and the absence of a myoepithelial layer can be easily overlooked. We prospectively examined 10 cases of high grade DCIS. P63, smooth muscle actin, muscle specific actin and calponin immunohistochemical stains were used to identify the presence of myoepithelial cells. In our study, 20% of apparent high grade DCIS cases did not exhibit a myoepithelial layer surrounding large, solid nests with comedo necrosis. Since invasion is defined by the absence of a myoepithelial layer, these results suggest that a DCIS-like pattern may actually represent invasive disease in some cases. Immunohistochemical studies may be essential in making this distinction and in avoiding the potential diagnostic pitfall.

  18. Invasive Ductal Breast Carcinoma Underneath a Lipoma in a Male Patient

    PubMed Central

    Landero, James; Glick, Bradley P.

    2012-01-01

    Male breast cancer is a rare malignancy and accounts for less than one percent of all cancers in men. The authors describe the case of a 76-year-old Caucasian man with invasive ductal breast carcinoma who presented with a common lipoma. This paper reviews the current literature on epidemiology, risk factors, etiology, different types of breast cancer, clinical presentation, imaging, diagnostic workup, and treatment. PMID:23125888

  19. Frequent PLAG1 gene rearrangements in skin and soft tissue myoepithelioma with ductal differentiation.

    PubMed

    Antonescu, Cristina R; Zhang, Lei; Shao, Sung Yun; Mosquera, Juan-Miguel; Weinreb, Ilan; Katabi, Nora; Fletcher, Christopher D M

    2013-07-01

    A subset of cutaneous and superficial soft tissue myoepithelial (ME) tumors displays a distinct ductal component and closely resembles mixed tumors/pleomorphic adenomas of salivary gland. As PLAG1 and HMGA2 rearrangements are the most common genetic events in pleomorphic adenomas, we sought to investigate if these abnormalities are also present in the skin/soft tissue ME lesions. In contrast, half of the deep-seated soft tissue ME tumors lacking ductal differentiation are known to be genetically unrelated, showing EWSR1 rearrangements. FISH analysis to detect PLAG1 and HMGA2 abnormalities was performed in 35 ME tumors, nine skin and 26 soft tissue, lacking EWSR1 and FUS rearrangements. For the PLAG1-rearranged tumors, FISH and RACE were performed to identify potential fusion partners, including CTNNB1 (beta-catenin) on 3p21 and LIFR (leukemia inhibitory factor receptor) on 5p13. Recurrent PLAG1 rearrangement by FISH was detected in 13 (37%) lesions, including three (33%) in the skin and 10 (38%) in the soft tissue. All were classified as benign and all except one showed abundant tubulo-ductal differentiation (comprising 12/24 [50%] of all tumors with ductal structures). A LIFR-PLAG1 fusion was detected by RACE and then confirmed by FISH in one soft tissue ME tumor with tubular formation. No CTNNB1 or LIFR abnormalities were detected in any of the remaining PLAG1-rearranged tumors. No structural HMGA2 abnormalities were detected in any of the 22 ME lesions tested. A subset of cutaneous and soft tissue ME tumors appears genetically linked to their salivary gland counterparts, displaying frequent PLAG1 gene rearrangements and occasionally LIFR-PLAG1 fusion.

  20. Oral inverted ductal papilloma associated with condyloma acuminata and HPV in an HIV+ patient.

    PubMed

    Infante-Cossio, P; Gonzalo, D H; Hernandez-Gutierrez, J; Borrero-Martin, J J

    2008-12-01

    Oral inverted ductal papillomas are rare benign tumours of minor salivary glands. A case that appeared in a middle-aged HIV+ woman simultaneous to two condyloma acuminata on the lips is described. The presence of human papilloma virus (HPV) 11 DNA was demonstrated in all the samples using polymerase chain reaction. HPV could play an important role in the aetiology and pathogenesis of these lesions in this patient.

  1. MicroRNA analysis of breast ductal fluid in breast cancer patients.

    PubMed

    Do Canto, Luisa Matos; Marian, Catalin; Willey, Shawna; Sidawy, Mary; Da Cunha, Patricia A; Rone, Janice D; Li, Xin; Gusev, Yuriy; Haddad, Bassem R

    2016-05-01

    Recent studies suggest that microRNAs show promise as excellent biomarkers for breast cancer; however there is still a high degree of variability between studies making the findings difficult to interpret. In addition to blood, ductal lavage (DL) and nipple aspirate fluids represent an excellent opportunity for biomarker detection because they can be obtained in a less invasive manner than biopsies and circumvent the limitations of evaluating blood biomarkers with regards to tissue of origin specificity. In this study, we have investigated for the first time, through a real-time PCR array, the expression of 742 miRNAs in the ductal lavage fluid collected from 22 women with unilateral breast tumors. We identified 17 differentially expressed miRNAs between tumor and paired normal samples from patients with ductal breast carcinoma. Most of these miRNAs have various roles in breast cancer tumorigenesis, invasion and metastasis, therapeutic response, or are associated with several clinical and pathological characteristics of breast tumors. Moreover, some miRNAs were also detected in other biological fluids of breast cancer patients such as serum (miR-23b, -133b, -181a, 338-3p, -625), plasma (miR-200a), and breast milk (miR-181a). A systems biology analysis of these differentially expressed miRNAs points out possible pathways and cellular processes previously described as having an important role in breast cancer such as Wnt, ErbB, MAPK, TGF-β, mTOR, PI3K-Akt, p53 signaling pathways. We also observed a difference in the miRNA expression with respect to the histological type of the tumors. In conclusion, our findings suggest that miRNA analysis of breast ductal fluid is feasible and potentially very useful for the detection of breast cancer.

  2. Does pancreatic ductal anatomy play a role in determining outcomes of pancreatic anastomoses?

    PubMed

    Shukla, P J; Sakpal, S V; Maharaj, R

    2011-02-01

    Pancreatoduodenectomy (PD) is the surgical procedure performed for cancers of the head of the pancreas. Despite a substantial reduction in mortality rates following PD, morbidity remains high secondary to major post-operative complications. Post-operative pancreatic fistula (POPF), the commonest major complication following PD, results from the failure of the pancreato-enteric anastomosis. There appears to be a correlation between intrinsic pancreatic features like the texture of the gland and duct size and the outcome of the pancreatic anastomosis. Based on current clinical research data, we propose a new hypothesis called the "pancreatic ductal anatomy" concept. We hypothesize that morphological variations, anomalies or aberrations of the main pancreatic duct play a role in the outcome of the pancreatic anastomosis, irrespective of its type. The consequence of aberrant ductal anatomy is that certain areas of the remnant pancreas remain either undrained or partially drained, or have blocked ductules/ducts. This results in localized obstructive pancreatitis causing an inflammatory reaction which jeopardizes the anastomosis. We also propose two maneuvers which could possibly play a role in predicting potential problems and also planning the surgical resection and reconstruction in order to reduce the incidence of POPF. The first modality is the use of pre-operative magnetic resonance imaging (MRI) of the pancreatic duct, and the second maneuver is the gentle cannulation test of the pancreatic duct with a soft, narrow tube following transection of the pancreatic neck. These factors would alert the surgeon about potential ductal variations and could facilitate the surgical approach.

  3. Expansion and conversion of human pancreatic ductal cells into insulin-secreting endocrine cells.

    PubMed

    Lee, Jonghyeob; Sugiyama, Takuya; Liu, Yinghua; Wang, Jing; Gu, Xueying; Lei, Ji; Markmann, James F; Miyazaki, Satsuki; Miyazaki, Jun-Ichi; Szot, Gregory L; Bottino, Rita; Kim, Seung K

    2013-11-19

    Pancreatic islet β-cell insufficiency underlies pathogenesis of diabetes mellitus; thus, functional β-cell replacement from renewable sources is the focus of intensive worldwide effort. However, in vitro production of progeny that secrete insulin in response to physiological cues from primary human cells has proven elusive. Here we describe fractionation, expansion and conversion of primary adult human pancreatic ductal cells into progeny resembling native β-cells. FACS-sorted adult human ductal cells clonally expanded as spheres in culture, while retaining ductal characteristics. Expression of the cardinal islet developmental regulators Neurog3, MafA, Pdx1 and Pax6 converted exocrine duct cells into endocrine progeny with hallmark β-cell properties, including the ability to synthesize, process and store insulin, and secrete it in response to glucose or other depolarizing stimuli. These studies provide evidence that genetic reprogramming of expandable human pancreatic cells with defined factors may serve as a general strategy for islet replacement in diabetes. DOI: http://dx.doi.org/10.7554/eLife.00940.001.

  4. Coexistence of lobular granulomatous mastitis and ductal carcinoma: a fortuitous association?

    PubMed

    Limaiem, F; Khadhar, A; Hassan, F; Bouraoui, S; Lahmar, A; Mzabi, S

    2013-12-01

    A 77-year-old female patient with a medical history significant for hypertension and epilepsy presented with right breast pain of 6-months duration. Examination revealed a hard sub-areola tender mass with irregular borders associated with mild right nipple retraction. Mammography showed a 2.2 x 2.4 cm stellate mass of the right breast. Ultrasound-guided core biopsies of the tumour were performed. Pathological examination revealed a grade II infiltrating ductal carcinoma. The patient underwent right radical mastectomy with homolateral axillary lymphadenectomy. Histological examination of the surgical specimen revealed grade II infiltrating ductal carcinoma concomitant with granulomatous lobular mastitis. To the best of our knowledge, the coexistence of granulomatous lobular mastitis and ductal carcinoma has been described only twice in the English language literature. The theory that chronic inflammation leads to cancer is well documented. Whether our patient had developed cancer from granulomatous lobular mastitis or otherwise is a matter of debate until more cases are encountered and more research is done in the area of breast cancer pathogenesis with regards to it arising from granulomatous lobular mastitis.

  5. β-cell replacement sources for type 1 diabetes: a focus on pancreatic ductal cells.

    PubMed

    Corritore, Elisa; Lee, Yong-Syu; Sokal, Etienne M; Lysy, Philippe A

    2016-08-01

    Thorough research on the capacity of human islet transplantation to cure type 1 diabetes led to the achievement of 3- to 5-year-long insulin independence in nearly half of transplanted patients. Yet, translation of this technique to clinical routine is limited by organ shortage and the need for long-term immunosuppression, restricting its use to adults with unstable disease. The production of new bona fide β cells in vitro was thus investigated and finally achieved with human pluripotent stem cells (PSCs). Besides ethical concerns about the use of human embryos, studies are now evaluating the possibility of circumventing the spontaneous tumor formation associated with transplantation of PSCs. These issues fueled the search for cell candidates for β-cell engineering with safe profiles for clinical translation. In vivo studies revealed the regeneration capacity of the exocrine pancreas after injury that depends at least partially on facultative progenitors in the ductal compartment. These stimulated subpopulations of pancreatic ductal cells (PDCs) underwent β-cell transdifferentiation through reactivation of embryonic signaling pathways. In vitro models for expansion and differentiation of purified PDCs toward insulin-producing cells were described using cocktails of growth factors, extracellular-matrix proteins and transcription factor overexpression. In this review, we will describe the latest findings in pancreatic β-cell mass regeneration due to adult ductal progenitor cells. We will further describe recent advances in human PDC transdifferentiation to insulin-producing cells with potential for clinical translational studies.

  6. β-cell replacement sources for type 1 diabetes: a focus on pancreatic ductal cells.

    PubMed

    Corritore, Elisa; Lee, Yong-Syu; Sokal, Etienne M; Lysy, Philippe A

    2016-08-01

    Thorough research on the capacity of human islet transplantation to cure type 1 diabetes led to the achievement of 3- to 5-year-long insulin independence in nearly half of transplanted patients. Yet, translation of this technique to clinical routine is limited by organ shortage and the need for long-term immunosuppression, restricting its use to adults with unstable disease. The production of new bona fide β cells in vitro was thus investigated and finally achieved with human pluripotent stem cells (PSCs). Besides ethical concerns about the use of human embryos, studies are now evaluating the possibility of circumventing the spontaneous tumor formation associated with transplantation of PSCs. These issues fueled the search for cell candidates for β-cell engineering with safe profiles for clinical translation. In vivo studies revealed the regeneration capacity of the exocrine pancreas after injury that depends at least partially on facultative progenitors in the ductal compartment. These stimulated subpopulations of pancreatic ductal cells (PDCs) underwent β-cell transdifferentiation through reactivation of embryonic signaling pathways. In vitro models for expansion and differentiation of purified PDCs toward insulin-producing cells were described using cocktails of growth factors, extracellular-matrix proteins and transcription factor overexpression. In this review, we will describe the latest findings in pancreatic β-cell mass regeneration due to adult ductal progenitor cells. We will further describe recent advances in human PDC transdifferentiation to insulin-producing cells with potential for clinical translational studies. PMID:27540464

  7. Expansion and conversion of human pancreatic ductal cells into insulin-secreting endocrine cells

    PubMed Central

    Lee, Jonghyeob; Sugiyama, Takuya; Liu, Yinghua; Wang, Jing; Gu, Xueying; Lei, Ji; Markmann, James F; Miyazaki, Satsuki; Miyazaki, Jun-ichi; Szot, Gregory L; Bottino, Rita; Kim, Seung K

    2013-01-01

    Pancreatic islet β-cell insufficiency underlies pathogenesis of diabetes mellitus; thus, functional β-cell replacement from renewable sources is the focus of intensive worldwide effort. However, in vitro production of progeny that secrete insulin in response to physiological cues from primary human cells has proven elusive. Here we describe fractionation, expansion and conversion of primary adult human pancreatic ductal cells into progeny resembling native β-cells. FACS-sorted adult human ductal cells clonally expanded as spheres in culture, while retaining ductal characteristics. Expression of the cardinal islet developmental regulators Neurog3, MafA, Pdx1 and Pax6 converted exocrine duct cells into endocrine progeny with hallmark β-cell properties, including the ability to synthesize, process and store insulin, and secrete it in response to glucose or other depolarizing stimuli. These studies provide evidence that genetic reprogramming of expandable human pancreatic cells with defined factors may serve as a general strategy for islet replacement in diabetes. DOI: http://dx.doi.org/10.7554/eLife.00940.001 PMID:24252877

  8. Multiple, temporal-specific roles for HNF6 in pancreatic endocrine and ductal differentiation

    PubMed Central

    Zhang, Hongjie; Ables, Elizabeth Tweedie; Pope, Christine F.; Washington, M. Kay; Hipkens, Susan; Means, Anna L.; Path, Gunter; Costa, Robert H.; Seufert, Jochen; Leiter, Andrew B.; Magnuson, Mark A.; Gannon, Maureen

    2009-01-01

    Within the developing pancreas Hepatic Nuclear Factor 6 (HNF6) directly activates the pro-endocrine transcription factor, Ngn3. HNF6 and Ngn3 are each essential for endocrine differentiation and HNF6 is also required for embryonic duct development. Most HNF6−/− animals die as neonates, making it difficult to study later aspects of HNF6 function. Here, we describe, using conditional gene inactivation, that HNF6 has specific functions at different developmental stages in different pancreatic lineages. Loss of HNF6 from Ngn3-expressing cells (HNF6Δendo) resulted in fewer multipotent progenitor cells entering the endocrine lineage, but had no effect on β cell terminal differentiation. Early, pancreas-wide HNF6 inactivation (HNF6Δpanc) resulted in endocrine and ductal defects similar to those described for HNF6 global inactivation. However, all HNF6Δpanc animals survived to adulthood. HNF6Δpanc pancreata displayed increased ductal cell proliferation and metaplasia, as well as characteristics of pancreatitis, including up-regulation of CTGF, MMP7, and p8/Nupr1. Pancreatitis was most likely caused by defects in ductal primary cilia. In addition, expression of Prox1, a known regulator of pancreas development, was decreased in HNF6Δpanc pancreata. These data confirm that HNF6 has both early and late functions in the developing pancreas and is essential for maintenance of Ngn3 expression and proper pancreatic duct morphology. PMID:19766716

  9. β-cell replacement sources for type 1 diabetes: a focus on pancreatic ductal cells

    PubMed Central

    Corritore, Elisa; Lee, Yong-Syu; Sokal, Etienne M.; Lysy, Philippe A.

    2016-01-01

    Thorough research on the capacity of human islet transplantation to cure type 1 diabetes led to the achievement of 3- to 5-year-long insulin independence in nearly half of transplanted patients. Yet, translation of this technique to clinical routine is limited by organ shortage and the need for long-term immunosuppression, restricting its use to adults with unstable disease. The production of new bona fide β cells in vitro was thus investigated and finally achieved with human pluripotent stem cells (PSCs). Besides ethical concerns about the use of human embryos, studies are now evaluating the possibility of circumventing the spontaneous tumor formation associated with transplantation of PSCs. These issues fueled the search for cell candidates for β-cell engineering with safe profiles for clinical translation. In vivo studies revealed the regeneration capacity of the exocrine pancreas after injury that depends at least partially on facultative progenitors in the ductal compartment. These stimulated subpopulations of pancreatic ductal cells (PDCs) underwent β-cell transdifferentiation through reactivation of embryonic signaling pathways. In vitro models for expansion and differentiation of purified PDCs toward insulin-producing cells were described using cocktails of growth factors, extracellular-matrix proteins and transcription factor overexpression. In this review, we will describe the latest findings in pancreatic β-cell mass regeneration due to adult ductal progenitor cells. We will further describe recent advances in human PDC transdifferentiation to insulin-producing cells with potential for clinical translational studies. PMID:27540464

  10. Impaired JNK signaling cooperates with KrasG12D expression to accelerate pancreatic ductal adenocarcinoma

    PubMed Central

    Davies, Clare C.; Harvey, Emma; McMahon, Raymond F.T.; Finegan, Katherine G.; Connor, Frances; Davis, Roger J.; Tuveson, David A.; Tournier, Cathy

    2014-01-01

    The c-Jun N-terminal protein kinase (JNK) and its two direct activators, namely the mitogen-activated protein kinase (MAPK) kinase 4 (MKK4) and MKK7, constitute a signaling node frequently mutated in human pancreatic ductal adenocarcinoma (PDAC). Here we demonstrate the cooperative interaction of endogenous expression of KrasG12D with loss-of-function mutations in mkk4 or both, mkk4 and mkk7 genes in the pancreas. More specifically, impaired JNK signaling in a subpopulation of Pdx1-expressing cells dramatically accelerated the appearance of KrasG12D-induced acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasias, which rapidly progressed to invasive PDAC within 10 weeks of age. Furthermore, inactivation of mkk4/mkk7 compromised acinar regeneration following acute inflammatory stress by locking damaged exocrine cells in a permanently de-differentiated state. Therefore, we propose that JNK signaling exerts its tumor suppressive function in the pancreas by antagonising the metaplastic conversion of acinar cells towards a ductal fate capable of responding to oncogenic stimulation. PMID:24713432

  11. Ductal adenoma of the breast: a lesion which can mimic carcinoma.

    PubMed

    Azzopardi, J G; Salm, R

    1984-09-01

    Twenty-four cases of a solid benign tumour of breast ducts are described, for which we propose the name 'ductal adenoma'. The lesion consists of a single nodule or multiple nodules involving medium size and small ducts, but not major subareolar ducts. It presents as a palpable lump, and is not associated with a nipple discharge. Clinically, radiologically and macroscopically, it can simulate malignancy because of its occurrence in older age groups, frequent microcalcification and the firmness and irregularity of many lesions. Fibrous sclerosis sometimes results in distortion with apparent invasion of surrounding tissue. It can be mistaken for carcinoma both on frozen and paraffin sections. Differentiation into epithelial and myoepithelial cells is the most reliable criterion in the recognition of this lesion as benign. It has microscopic affinities with ductal papilloma, on the one hand, and with salivary-type adenoma, on the other. Ductal adenoma constitutes the third major type of adenoma in the breast, in addition to the already widely recognized nipple adenoma and tubular adenoma.

  12. Ductal papillomas of salivary gland origin: A report of 19 cases and a review of the literature.

    PubMed

    Brannon, R B; Sciubba, J J; Giulani, M

    2001-07-01

    The term ductal papilloma is used to identify a group of 3 rare benign papillary salivary gland tumors known as inverted ductal papilloma, sialadenoma papilliferum, and intraductal papilloma. They represent adenomas with unique papillary features and arise from the salivary gland duct system. We describe the clinical and microscopic features of 19 new cases of ductal papillomas and combine them with 116 cases previously published in the English-language medical literature. These 19 cases were composed of 13 inverted ductal papillomas, 3 sialadenoma papilliferums, and 3 intraductal papillomas. Collectively, these 19 ductal papillomas occurred most commonly in the sixth to eighth decade of life, with an average patient age of 54 years. Men predominated 1.37:1. The sialadenoma papilliferums presented as papillary lesions clinically with all 3 misinterpreted as squamous papillomas by the surgeons. The inverted ductal papillomas and intraductal papillomas appeared as submucosal nodules. The lip and the palate were the most common locations for inverted ductal papilloma and sialadenoma papilliferum, respectively. The sites for the 3 intraductal papillomas were the parotid papilla of the Stensen's duct, the upper lip, and the buccal mucosa. With light microscopy, inverted ductal papillomas appeared to arise from the excretory ducts near the mucosal surface, whereas intraductal papillomas appeared to arise from the excretory ducts at a deeper level. Sialadenoma papilliferum had a more complex histology, with a biphasic growth pattern of exophytic papillary and endophytic components. All 19 cases were treated by surgical excision. Follow-up information was available in only 2 cases, both inverted ductal papillomas. Neither case recurred during a 20-year period. Sialadenoma papilliferum, with a literature-derived recurrence rate of 10% to 15%, seems to assert a more significant biological behavior than inverted ductal papilloma and intraductal papilloma. Our findings justify

  13. [Sentinel lymph node metastasis in patients with ductal breast carcinoma in situ].

    PubMed

    Ruvalcaba-Limón, Eva; de Jesús Garduño-Raya, María; Bautista-Piña, Verónica; Trejo-Martínez, Claudia; Maffuz-Aziz, Antonio; Rodríguez-Cuevas, Sergio

    2014-01-01

    Antecedentes: en pacientes con carcinoma ductal in situ la biopsia de ganglio centinela es motivo de controversia porque se reportan ganglios positivos en 1.4-12.5% debido al carcinoma invasor oculto en la pieza quirúrgica. Objetivo: conocer la frecuencia de metástasis en ganglio centinela en pacientes con carcinoma ductal in situ e identificar las diferencias entre los casos positivos y negativos. Material y métodos: estudio retrospectivo, transversal, analítico de pacientes con carcinoma ductal in situ a quienes se realizó una biopsia de ganglio centinela por requerir mastectomía, tener un tumor palpable, lesión radiológica = 5 cm, inadecuada relación mama-tumor o porque la escisión pudiera afectar el flujo linfático. Resultados: de 168 carcinomas in situ, se incluyeron 50 casos con carcinoma ductal in situ y biopsia de ganglio centinela, de pacientes con edad promedio de 51.6 años, 30 (60%) de ellas asintomáticas. Los signos reportados fueron: nódulo palpable (18%), secreción por el pezón (12%) o ambos (8%). Predominaron las microcalcificaciones (72%), comedonecrosis (62%) y grado histológico -2 (44%) con 28% de receptores hormonales negativos. En el estudio transoperatorio 4 (8%) pacientes tuvieron ganglio centinela positivo y un caso en estudio histopatológico definitivo (60% micrometástasis, 40% macrometástasis), todos con carcinoma invasor en la pieza quirúrgica. Las pacientes con ganglio centinela transoperatorio positivo eran más jóvenes (44.5 vs 51 años), con más tumores palpables (50 vs 23.1%), más grandes (3.5 vs 2 cm), más comedonecrosis (75 vs 60.8%), más indiferenciados (75% vs 39.1%) y menos receptores hormonales (50 vs 73.9%), que las que tenían ganglio centinela negativo, sin que estas diferencias tuvieran significación estadística. Conclusiones: puesto que 1 de cada 12 pacientes con carcinoma ductal in situ tiene afectación ganglionar en el ganglio centinela, se recomienda seguir tomando la biopsia para evitar

  14. Uptake and metabolism of D-glucose in isolated acinar and ductal cells from rat submandibular glands.

    PubMed

    Cetik, Sibel; Rzajeva, Aigun; Hupkens, Emeline; Malaisse, Willy J; Sener, Abdullah

    2014-07-01

    The present study deals with the possible effects of selected environmental agents upon the uptake and metabolism of d-glucose in isolated acinar and ductal cells from the rat submandibular salivary gland. In acinar cells, the uptake of d-[U-(14) C]glucose and its non-metabolised analogue 3-O-[(14) C-methyl]-d-glucose was not affected significantly by phloridzin (0.1 mM) or substitution of extracellular NaCl (115 mM) by an equimolar amount of CsCl, whilst cytochalasin B (20 μM) decreased significantly such an uptake. In ductal cells, both phloridzin and cytochalasin B decreased the uptake of d-glucose and 3-O-methyl-d-glucose. Although the intracellular space was comparable in acinar and ductal cells, the catabolism of d-glucose (2.8 or 8.3 mM) was two to four times higher in ductal cells than in acinar cells. Phloridzin (0.1 mM), ouabain (1.0 mM) and cytochalasin B (20 μM) all impaired d-glucose catabolism in ductal cells. Such was also the case in ductal cells incubated in the absence of extracellular Ca(2+) or in media in which NaCl was substituted by CsCl. It is proposed that the ductal cells in the rat submandibular gland are equipped with several systems mediating the insulin-sensitive, cytochalasin B-sensitive and phloridzin-sensitive transport of d-glucose across the plasma membrane.

  15. Oleic acid and glucose regulate glucagon-like peptide 1 receptor expression in a rat pancreatic ductal cell line

    SciTech Connect

    Zhang, Leshuai W.; McMahon Tobin, Grainne A.; Rouse, Rodney L.

    2012-10-15

    The glucagon-like peptide 1 receptor (GLP1R) plays a critical role in glucose metabolism and has become an important target for a growing class of drugs designed to treat type 2 diabetes. In vitro studies were designed to investigate the effect of the GLP1R agonist, exenatide (Ex4), in “on-target” RIN-5mF (islet) cells as well as in “off-target” AR42J (acinar) and DSL-6A/C1 (ductal) cells in a diabetic environment. Ex4 increased islet cell proliferation but did not affect acinar cells or ductal cells at relevant concentrations. A high caloric, high fat diet is a risk factor for impaired glucose tolerance and type-2 diabetes. An in vitro Oleic acid (OA) model was used to investigate the effect of Ex4 in a high calorie, high fat environment. At 0.1 and 0.4 mM, OA mildly decreased the proliferation of all pancreatic cell types. Ex4 did not potentiate the inhibitory effect of OA on cell proliferation. Akt phosphorylation in response to Ex4 was diminished in OA-treated ductal cells. GLP1R protein detected by western blot was time and concentration dependently decreased after glucose stimulation in OA-treated ductal cells. In ductal cells, OA treatment altered the intracellular localization of GLP1R and its co-localization with early endosome and recycling endosomes. Chloroquine (lysosomal inhibitor), N-acetyl-L-cysteine (reactive oxygen species scavenger) and wortmannin (a phosphatidylinositol-3-kinase inhibitor), fully or partially, rescued GLP1R protein in OA-pretreated, glucose-stimulated ductal cells. The impact of altered regulation on phenotype/function is presently unknown. However, these data suggest that GLP1R regulation in ductal cells can be altered by a high fat, high calorie environment. -- Highlights: ► Exenatide did not inhibit islet, acinar or ductal cell proliferation. ► GLP1R protein decreased after glucose stimulation in oleic acid-treated ductal cells. ► Oleic acid treatment altered localization of GLP1R with early and recycling

  16. Asymptomatic Incidental Ductal Carcinoma in situ in a Male Breast Presenting with Contralateral Gynecomastia

    PubMed Central

    Isley, Laura M.; Leddy, Rebecca J.; Rumboldt, Tihana; Bernard, Jacqueline M.

    2012-01-01

    Ductal carcinoma in situ (DCIS) in males is rare and usually presents with symptoms on the affected side, such as, palpable mass or bloody nipple discharge. Even as DCIS has been reported in conjunction with gynecomastia in the same breast, we report an unusual case of a 62-year-old Caucasian male, with no family history of breast cancer, who presented with symptomatic side gynecomastia, and was incidentally found to have DCIS in a completely asymptomatic left breast. To the best of our knowledge, this case is the first report in literature of asymptomatic, incidentally discovered DCIS in a male patient. PMID:22530182

  17. Re-evaluation of classical prognostic factors in resectable ductal adenocarcinoma of the pancreas

    PubMed Central

    Åkerberg, Daniel; Ansari, Daniel; Andersson, Roland

    2016-01-01

    Pancreatic ductal adenocarcinoma carries a poor prognosis with annual deaths almost matching the reported incidence rates. Surgical resection offers the only potential cure. Yet, even among patients that undergo tumor resection, recurrence rates are high and long-term survival is scarce. Various tumor-related factors have been identified as predictors of survival after potentially curative resection. These factors include tumor size, lymph node disease, tumor grade, vascular invasion, perineural invasion and surgical resection margin. This article will re-evaluate the importance of these factors based on recent publications on the topic, with potential implications for treatment and outcome in patients with pancreatic cancer. PMID:27605878

  18. Oncolytic Activity of Avian Influenza Virus in Human Pancreatic Ductal Adenocarcinoma Cell Lines

    PubMed Central

    Pizzuto, Matteo S.; Silic-Benussi, Micol; Pavone, Silvia; Ciminale, Vincenzo; Capua, Ilaria

    2014-01-01

    ABSTRACT Pancreatic ductal adenocarcinoma (PDA) is the most lethal form of human cancer, with dismal survival rates due to late-stage diagnoses and a lack of efficacious therapies. Building on the observation that avian influenza A viruses (IAVs) have a tropism for the pancreas in vivo, the present study was aimed at testing the efficacy of IAVs as oncolytic agents for killing human PDA cell lines. Receptor characterization confirmed that human PDA cell lines express the alpha-2,3- and the alpha-2,6-linked glycan receptor for avian and human IAVs, respectively. PDA cell lines were sensitive to infection by human and avian IAV isolates, which is consistent with this finding. Growth kinetic experiments showed preferential virus replication in PDA cells over that in a nontransformed pancreatic ductal cell line. Finally, at early time points posttreatment, infection with IAVs caused higher levels of apoptosis in PDA cells than gemcitabine and cisplatin, which are the cornerstone of current therapies for PDA. In the BxPC-3 PDA cell line, apoptosis resulted from the engagement of the intrinsic mitochondrial pathway. Importantly, IAVs did not induce apoptosis in nontransformed pancreatic ductal HPDE6 cells. Using a model based on the growth of a PDA cell line as a xenograft in SCID mice, we also show that a slightly pathogenic avian IAV significantly inhibited tumor growth following intratumoral injection. Taken together, these results are the first to suggest that IAVs may hold promise as future agents of oncolytic virotherapy against pancreatic ductal adenocarcinomas. IMPORTANCE Despite intensive studies aimed at designing new therapeutic approaches, PDA still retains the most dismal prognosis among human cancers. In the present study, we provide the first evidence indicating that avian IAVs of low pathogenicity display a tropism for human PDA cells, resulting in viral RNA replication and a potent induction of apoptosis in vitro and antitumor effects in vivo. These

  19. DNA Aptamer Selected against Pancreatic Ductal Adenocarcinoma for in vivo Imaging and Clinical Tissue Recognition

    PubMed Central

    Wu, Xiaoqiu; Zhao, Zilong; Bai, Huarong; Fu, Ting; Yang, Chao; Hu, Xiaoxiao; Liu, Qiaoling; Champanhac, Carole; Teng, I-Ting; Ye, Mao; Tan, Weihong

    2015-01-01

    In this work, we have developed a truncated DNA aptamer, termed XQ-2d, with high affinity and specificity for pancreatic ductal adenocarcinoma (PDAC). Aptamer XQ-2d selectively binds to PL45 cells with a dissociation constant in the nanomolar range, as determined by its recognition of PL45 tumor cells in mice. Moreover, XQ-2d shows better recognition ratio for 40 tissue sections of clinical PDAC samples (82.5%) compared to the initial cell-SELEX selection library (5%). Therefore, XQ-2d can be considered a promising candidate as a tool for PDAC diagnosis and treatment. PMID:26155314

  20. Re-evaluation of classical prognostic factors in resectable ductal adenocarcinoma of the pancreas.

    PubMed

    Åkerberg, Daniel; Ansari, Daniel; Andersson, Roland

    2016-07-28

    Pancreatic ductal adenocarcinoma carries a poor prognosis with annual deaths almost matching the reported incidence rates. Surgical resection offers the only potential cure. Yet, even among patients that undergo tumor resection, recurrence rates are high and long-term survival is scarce. Various tumor-related factors have been identified as predictors of survival after potentially curative resection. These factors include tumor size, lymph node disease, tumor grade, vascular invasion, perineural invasion and surgical resection margin. This article will re-evaluate the importance of these factors based on recent publications on the topic, with potential implications for treatment and outcome in patients with pancreatic cancer. PMID:27605878

  1. Differences between invasive lobular and invasive ductal carcinoma of the breast: results and therapeutic implications

    PubMed Central

    Barroso-Sousa, Romualdo; Metzger-Filho, Otto

    2016-01-01

    Invasive lobular carcinoma (ILC) is the second most common histologic subtype of breast cancer (BC): ILC differs from invasive ductal carcinoma (IDC) in its clinicopathological characteristics and responsiveness to systemic therapy. From the clinical standpoint, data suggest that ILC derives a distinct benefit from systemic therapy compared to IDC. In addition, comprehensive molecular analyses have been reported for ILCs, confirming that these tumors have specific genomic profiles compared to IDC. Despite these differences, clinical trials and practical clinical guidelines tend to treat BC as a single entity. Here we discuss these clinical and molecular data and their therapeutic implications. PMID:27482285

  2. A benign presentation of primary ductal adenocarcinoma of lacrimal gland: A rare malignancy.

    PubMed

    Lau, Lindfay Laura; Lung, Chong Ka; Ahmad, Syed Shoeb

    2015-11-01

    A 34-year-old patient with a swelling over the upper eyelid for nearly 1 year was seen in our clinic. The history, examination and investigations were suggestive of a benign lacrimal gland tumor. The tumor and lacrimal gland were resected. Subsequent histopathological examination revealed the tumor was a primary ductal adenocarcinoma of the lacrimal gland. This is a very rare tumor with less than half a dozen cases reported so far. This case report is being presented to highlight an unusual presentation of this rare malignancy.

  3. Re-evaluation of classical prognostic factors in resectable ductal adenocarcinoma of the pancreas

    PubMed Central

    Åkerberg, Daniel; Ansari, Daniel; Andersson, Roland

    2016-01-01

    Pancreatic ductal adenocarcinoma carries a poor prognosis with annual deaths almost matching the reported incidence rates. Surgical resection offers the only potential cure. Yet, even among patients that undergo tumor resection, recurrence rates are high and long-term survival is scarce. Various tumor-related factors have been identified as predictors of survival after potentially curative resection. These factors include tumor size, lymph node disease, tumor grade, vascular invasion, perineural invasion and surgical resection margin. This article will re-evaluate the importance of these factors based on recent publications on the topic, with potential implications for treatment and outcome in patients with pancreatic cancer.

  4. Risk of subsequent invasive breast cancer after a diagnosis of ductal carcinoma in situ (DCIS).

    PubMed

    Cheung, Shan; Booth, Mary E; Kearins, Olive; Dodwell, David

    2014-12-01

    Despite surgical removal of ductal carcinoma in situ (DCIS), recurrences still occur. This retrospective cohort study evaluated the risk of invasive recurrence following surgery and investigated factors which may be predictive of recurrence. We specifically investigated invasive recurrence with respect to mode of detection of DCIS. Patients whose DCIS was detected outside of the NHS Breast Screening Programme have a higher risk of subsequent ipsilateral invasive breast cancer than those whose DCIS is detected through screening. There is no significant difference in risk of subsequent contralateral invasive recurrence according to mode of detection.

  5. High-grade adenocarcinoma, (ductal type) arising in unilateral Warthin tumor of the parotid gland.

    PubMed

    Deodhar, Kedar K; Shah, Milap; Chaturvedi, Pankaj

    2011-01-01

    Warthin tumor is a well-recognized benign salivary gland neoplasm consisting of an epithelial as well as a lymphoid component. Malignant transformation in Warthin tumor is rare and its reported incidence is up to 1%. The more common types of carcinomas described in Warthin tumor are the squamous and mucoepidermoid types, with high-grade adenocarcinoma being extremely rare. A high-grade adenocarcinoma (ductal type) arising in the Warthin tumor in a 72-year-old man is presented for its rarity and diagnostic difficulties.

  6. Inverted ductal papilloma of the oral cavity secondary to lower lip trauma. A case report and literature review

    PubMed Central

    Sala-Pérez, Sergi; España-Tost, Antoni; Vidal-Bel, August

    2013-01-01

    Inverted ductal papilloma of the oral cavity is an infrequent benign neoplasm of papillary appearance that originates in the secretory duct of a salivary gland. The etiology is unknown, though some authors have related it to human papillomavirus (HPV) infection. We present the case of a 40-year-old woman with a tumor of the lower lip mucosa. Histopathological study of the lesion diagnosed inverted ductal papilloma of the oral cavity. Human papillomavirus DNA detection and typing based on tumor lesion DNA amplification and posterior hybridization, revealed no presence of viral DNA. The antecedents of trauma reported by the patient could have played an important role in the development of this tumor. Key words:Inverted ductal papilloma, intraductal papilloma, oral papilloma, papillary epidermoid adenoma. PMID:24455058

  7. A Geometrically-Constrained Mathematical Model of Mammary Gland Ductal Elongation Reveals Novel Cellular Dynamics within the Terminal End Bud

    PubMed Central

    Chauviere, Arnaud; Landua, John; Sreekumar, Amulya; Cristini, Vittorio; Rosen, Jeffrey; Lewis, Michael T.

    2016-01-01

    Mathematics is often used to model biological systems. In mammary gland development, mathematical modeling has been limited to acinar and branching morphogenesis and breast cancer, without reference to normal duct formation. We present a model of ductal elongation that exploits the geometrically-constrained shape of the terminal end bud (TEB), the growing tip of the duct, and incorporates morphometrics, region-specific proliferation and apoptosis rates. Iterative model refinement and behavior analysis, compared with biological data, indicated that the traditional metric of nipple to the ductal front distance, or percent fat pad filled to evaluate ductal elongation rate can be misleading, as it disregards branching events that can reduce its magnitude. Further, model driven investigations of the fates of specific TEB cell types confirmed migration of cap cells into the body cell layer, but showed their subsequent preferential elimination by apoptosis, thus minimizing their contribution to the luminal lineage and the mature duct. PMID:27115287

  8. A Geometrically-Constrained Mathematical Model of Mammary Gland Ductal Elongation Reveals Novel Cellular Dynamics within the Terminal End Bud.

    PubMed

    Paine, Ingrid; Chauviere, Arnaud; Landua, John; Sreekumar, Amulya; Cristini, Vittorio; Rosen, Jeffrey; Lewis, Michael T

    2016-04-01

    Mathematics is often used to model biological systems. In mammary gland development, mathematical modeling has been limited to acinar and branching morphogenesis and breast cancer, without reference to normal duct formation. We present a model of ductal elongation that exploits the geometrically-constrained shape of the terminal end bud (TEB), the growing tip of the duct, and incorporates morphometrics, region-specific proliferation and apoptosis rates. Iterative model refinement and behavior analysis, compared with biological data, indicated that the traditional metric of nipple to the ductal front distance, or percent fat pad filled to evaluate ductal elongation rate can be misleading, as it disregards branching events that can reduce its magnitude. Further, model driven investigations of the fates of specific TEB cell types confirmed migration of cap cells into the body cell layer, but showed their subsequent preferential elimination by apoptosis, thus minimizing their contribution to the luminal lineage and the mature duct. PMID:27115287

  9. Inverted ductal papilloma of the oral cavity secondary to lower lip trauma. A case report and literature review.

    PubMed

    Sala-Pérez, Sergi; España-Tost, Antoni; Vidal-Bel, August; Gay-Escoda, Cosme

    2013-04-01

    Inverted ductal papilloma of the oral cavity is an infrequent benign neoplasm of papillary appearance that originates in the secretory duct of a salivary gland. The etiology is unknown, though some authors have related it to human papillomavirus (HPV) infection. We present the case of a 40-year-old woman with a tumor of the lower lip mucosa. Histopathological study of the lesion diagnosed inverted ductal papilloma of the oral cavity. Human papillomavirus DNA detection and typing based on tumor lesion DNA amplification and posterior hybridization, revealed no presence of viral DNA. The antecedents of trauma reported by the patient could have played an important role in the development of this tumor. Key words:Inverted ductal papilloma, intraductal papilloma, oral papilloma, papillary epidermoid adenoma. PMID:24455058

  10. Inverted ductal papilloma of the oral cavity secondary to lower lip trauma. A case report and literature review.

    PubMed

    Sala-Pérez, Sergi; España-Tost, Antoni; Vidal-Bel, August; Gay-Escoda, Cosme

    2013-04-01

    Inverted ductal papilloma of the oral cavity is an infrequent benign neoplasm of papillary appearance that originates in the secretory duct of a salivary gland. The etiology is unknown, though some authors have related it to human papillomavirus (HPV) infection. We present the case of a 40-year-old woman with a tumor of the lower lip mucosa. Histopathological study of the lesion diagnosed inverted ductal papilloma of the oral cavity. Human papillomavirus DNA detection and typing based on tumor lesion DNA amplification and posterior hybridization, revealed no presence of viral DNA. The antecedents of trauma reported by the patient could have played an important role in the development of this tumor. Key words:Inverted ductal papilloma, intraductal papilloma, oral papilloma, papillary epidermoid adenoma.

  11. Effects of large pressure amplitude low frequency noise in the parotid gland perivasculo-ductal connective tissue.

    PubMed

    Oliveira, Pedro; Brito, José; Mendes, João; da Fonseca, Jorge; Águas, Artur; Martins dos Santos, José

    2013-01-01

    Introdução: Em tecidos e órgãos expostos a ruído de baixa frequência de alta amplitude ocorre fibrose na ausência de sinais inflamatórios, que se pensa ser uma resposta protetora. No tecido conjuntivo perivasculo-ductal da glândula parótida seguem artérias, veias e a árvore ductal. Crê-se que o tecido conjuntivo perivasculo-ductal funcione como um estabilizador mecânico do tecido glandular.Material e Métodos: Para quantificar a proliferação de tecido conjuntivo perivasculo-ductal em ratos expostos a ruído de baixafrequência de alta amplitude foram utilizados 60 ratos Wistar igualmente divididos em seis grupos. Um grupo mantido em silêncio, e os restantes 5 expostos a ruído de baixa frequência de alta amplitude continuamente: g1-168h (1 semana); g2-504h (3 semanas); g3-840h (5semanas); g4-1512h (9 semanas) e g5-2184h (13 semanas). Após a exposição, as parótidas foram removidas e o tecido conjuntivo perivasculo-ductal foi medido em todos os grupos. Foi efectuada análise estatística com ANOVA por SPSS 13.0.Resultados: A tendência é um aumento global das áreas do tecido conjuntivo perivasculo-ductal, que se desenvolve de forma linear e significativa com o tempo de exposição (p < 0,001).Discussão: Tem sido sugerido que a resposta biológica à exposição ao ruído de baixa frequência de alta amplitude está associada à necessidade de manter a integridade estrutural. O reforço estrutural seria conseguido através do aumento do tecido conjuntivo perivasculo-ductal.Conclusões: Assim, estes resultados mostram que o tecido conjuntivo perivasculo-ductal aumenta em resposta à exposição ao ruído de baixa frequência de alta amplitude.

  12. Regulation of phospholipase D by muscarinic receptors in rat submandibular ductal cells.

    PubMed

    Pochet, Stéphanie; Métioui, Mourad; Grosfils, Katrina; Gómez-Muñoz, Antonio; Marino, Aida; Dehaye, Jean-Paul

    2003-01-01

    The muscarinic agonist carbachol stimulated phospholipase D (PLD) in rat submandibular gland (RSMG) ductal cells in a time and concentration-dependent manner. This effect was inhibited by chelation of extracellular calcium with ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA). PLD could also be activated by epinephrine and AlF(4)(-), two polyphosphoinositide-specific phospholipase C (PPI-PLC) activators, and by the phorbol ester o-tetradecanoylphorbol 13-acetate (TPA) which activates protein kinase C (PKC). Ionomycin and thapsigargin only slightly increased PLD activity. Ortho-vanadate, a tyrosine phosphatase inhibitor, also stimulated PLD activity. Both carbachol and o-vanadate increased the formation of inositol phosphates and the tyrosine phosphorylation of at least two proteins (55-60 and 120 kDa). Calphostin C (a PKC inhibitor), U73122 (a PPI-PLC inhibitor) and genistein (a tyrosine kinase inhibitor) blocked the activation of PLD, of PLC and the phosphorylation of tyrosyl residues in response to carbachol and vanadate. Taken together, these results suggest that rat submandibular gland ductal cells express a calcium-dependent PLD activity. This enzyme is regulated by carbachol via a PLC-PKC-tyrosine kinase pathway. PMID:12401525

  13. Relationship between Anomalous Pancreaticobiliary Ductal Union and Pathologic Inflammation of Bile Duct in Choledochal Cyst

    PubMed Central

    Park, So Won; Koh, Hong; Oh, Jung-Tak; Han, Seok Joo

    2014-01-01

    Purpose Choledochal cyst is a cystic dilatation of common bile duct. Although the etiology is presently uncertain, anomalous pancreaticobiliary ductal union (APBDU) is thought to be a major etiology of choledochal cyst. In this study, we analyzed the clinical and anatomical characteristics and pathologies of patients diagnosed with choledochal cyst in a single institute for 25 years. Methods A total of 113 patients, diagnosed with choledochal cyst and who received an operation in Severance Children's Hospital from January 1988 to May 2013, were included. Medical records were reviewed, including clinical and demographic data, surgical procedures. Abdominal ultrasonography, magnetic resonance cholangiopancreatography, and intraoperative cholangiography were used as diagnostic tools for evaluation and classification of choledochal cyst and the presence of anomalous pancreaticobiliary ductal union. Todani's classification, and relationship between APBDU and surgical pathology. Results Among 113 patients, 77 patients (68.1%) presented symptoms such as hepatitis, pancreatitis and/or cholecystitis. Eighty three patients (73.5%) had APBDU, and 94 patients (83.2%) showed inflammatory pathologic changes. APBDU, pathologic inflammation, and serological abnormalities such as hepatitis or pancreatitis showed a statistically significant correlation to one another. Conclusion APBDU is thought to be one of the etiologic factors of choledochal cyst. It is related to the inflammatory changes in bile duct that can lead to the cystic dilatation. PMID:25349833

  14. Absence of ductal hyper-keratinization in mouse age-related meibomian gland dysfunction (ARMGD).

    PubMed

    Parfitt, Geraint J; Xie, Yilu; Geyfman, Mikhail; Brown, Donald J; Jester, James V

    2013-11-01

    Meibomian gland dysfunction (MGD) is frequent with aging and is the primary cause of dry eye disease, the most prevalent ocular complaint. We used a novel 3-D reconstruction technique, immunofluorescent computed tomography (ICT), to characterize meibomian gland keratinization and cell proliferation in a mouse model of age-related meibomian gland dysfunction (ARMGD). To visualize the changes associated with ARMGD, 5-month and 2-year old mouse eyelids were 3-D reconstructed by ICT using antibodies to cytokeratin (CK) 1, 5 and 6 and the proliferation marker Ki67. We quantified total gland, ductal and lipid volume from the reconstructions, observing a dramatic decrease in old glands. In young glands, proliferative ductules suggest a potential site of acinar progenitors that were found to be largely absent in aged, atrophic glands. In the aged mouse, we observed an anterior migration of the mucocutaneous junction (MCJ) and an absence of hyper-keratinization with meibomian gland atrophy. Thus, we propose that changes in the MCJ and glandular atrophy through a loss of meibocyte progenitors are most likely responsible for ARMGD and not ductal hyper-keratinization and gland obstruction.

  15. A Self-Folding Hydrogel In Vitro Model for Ductal Carcinoma.

    PubMed

    Kwag, Hye Rin; Serbo, Janna V; Korangath, Preethi; Sukumar, Saraswati; Romer, Lewis H; Gracias, David H

    2016-04-01

    A significant challenge in oncology is the need to develop in vitro models that accurately mimic the complex microenvironment within and around normal and diseased tissues. Here, we describe a self-folding approach to create curved hydrogel microstructures that more accurately mimic the geometry of ducts and acini within the mammary glands, as compared to existing three-dimensional block-like models or flat dishes. The microstructures are composed of photopatterned bilayers of poly (ethylene glycol) diacrylate (PEGDA), a hydrogel widely used in tissue engineering. The PEGDA bilayers of dissimilar molecular weights spontaneously curve when released from the underlying substrate due to differential swelling ratios. The photopatterns can be altered via AutoCAD-designed photomasks so that a variety of ductal and acinar mimetic structures can be mass-produced. In addition, by co-polymerizing methacrylated gelatin (methagel) with PEGDA, microstructures with increased cell adherence are synthesized. Biocompatibility and versatility of our approach is highlighted by culturing either SUM159 cells, which were seeded postfabrication, or MDA-MB-231 cells, which were encapsulated in hydrogels; cell viability is verified over 9 and 15 days, respectively. We believe that self-folding processes and associated tubular, curved, and folded constructs like the ones demonstrated here can facilitate the design of more accurate in vitro models for investigating ductal carcinoma.

  16. Absence of ductal hyper-keratinization in Mouse age-related meibomian gland dysfunction (ARMGD)

    PubMed Central

    Parfitt, Geraint J.; Xie, Yilu; Geyfman, Mikhail; Brown, Donald J.; Jester, James V.

    2013-01-01

    Meibomian gland dysfunction (MGD) is frequent with aging and is the primary cause of dry eye disease, the most prevalent ocular complaint. We used a novel 3-D reconstruction technique, immunofluorescent computed tomography (ICT), to characterize meibomian gland keratinization and cell proliferation in a mouse model of age-related meibomian gland dysfunction (ARMGD). To visualize the changes associated with ARMGD, 5-month and 2-year old mouse eyelids were 3-D reconstructed by ICT using antibodies to cytokeratin (CK) 1, 5 and 6 and the proliferation marker Ki67. We quantified total gland, ductal and lipid volume from the reconstructions, observing a dramatic decrease in old glands. In young glands, proliferative ductules suggest a potential site of acinar progenitors that were found to be largely absent in aged, atrophic glands. In the aged mouse, we observed an anterior migration of the mucocutaneous junction (MCJ) and an absence of hyper-keratinization with meibomian gland atrophy. Thus, we propose that changes in the MCJ and glandular atrophy through a loss of meibocyte progenitors are most likely responsible for ARMGD and not ductal hyper-keratinization and gland obstruction. PMID:24259272

  17. Ductal carcinoma in situ of the breast: the importance of morphologic and molecular interactions.

    PubMed

    Mardekian, Stacey K; Bombonati, Alessandro; Palazzo, Juan P

    2016-03-01

    Ductal carcinoma in situ (DCIS) of the breast is a lesion characterized by significant heterogeneity, in terms of morphology, immunohistochemical staining, molecular signatures, and clinical expression. For some patients, surgical excision provides adequate treatment, but a subset of patients will experience recurrence of DCIS or progression to invasive ductal carcinoma (IDC). Recent years have seen extensive research aimed at identifying the molecular events that characterize the transition from normal epithelium to DCIS and IDC. Tumor epithelial cells, myoepithelial cells, and stromal cells undergo alterations in gene expression, which are most important in the early stages of breast carcinogenesis. Epigenetic modifications, such as DNA methylation, together with microRNA alterations, play a major role in these genetic events. In addition, tumor proliferation and invasion is facilitated by the lesional microenvironment, which includes stromal fibroblasts and macrophages that secrete growth factors and angiogenesis-promoting substances. Characterization of DCIS on a molecular level may better account for the heterogeneity of these lesions and how this manifests as differences in patient outcome and response to therapy. Molecular assays originally developed for assessing likelihood of recurrence in IDC are recently being applied to DCIS, with promising results. In the future, the classification of DCIS will likely incorporate molecular findings along with histologic and immunohistochemical features, allowing for personalized prognostic information and therapeutic options for patients with DCIS. This review summarizes current data regarding the molecular characterization of DCIS and discusses the potential clinical relevance. PMID:26826418

  18. [A case of ductal adenocarcinoma of prostate associated with retroperitoneal multiple cysts].

    PubMed

    Soda, Tetsuji; Fukumoto, Ryo; Hayashi, Tetsuya; Oka, Daizo; Fujimoto, Nobumasa; Koide, Takuo; Akamaru, Yusuke; Kasugai, Tsutomu

    2012-10-01

    A 61-year-old man came to our hospital with a complaint of lower abdominal pain. Computed tomography (CT) and magnetic resonance imaging (MRI) around his abdominal area showed large multiple cysts in the pelvis suggesting a malignant tumor. He showed high levels of serum carbohydrate antigen 19- 9 (CA19-9) and carcinoembryonic antigen (CEA). The complete diagnostic studies, including upper gastrointestinal endoscopy and colonoscopy examinations, failed to demonstrate the presence of alimentary primary tumors. With the diagnosis of cystic tumor in the pelvis, the operation was performed. The cysts adhered firmly to the surrounding organs including bladder and peritonium, which could not be resected completely. A histopathological diagnosis was papillary adenocarcinoma positive for prostate specific antigen (PSA). Because the level of serum PSA was 9.39 ng/ml, prostate biopsy was performed and ductal adenocarcinoma of prostate was revealed. After the operation, the levels of serum CA19-9 and CEA decreased to a normal level. Androgen deprivation therapy (ADT) was started, and the level of PSA was normalized one month later. Ductal adenocarcinoma forming cysts is rare. We reviewed 15 cases reported in the Japanese literature.

  19. PDIA3 and PDIA6 gene expression as an aggressiveness marker in primary ductal breast cancer.

    PubMed

    Ramos, F S; Serino, L T R; Carvalho, C M S; Lima, R S; Urban, C A; Cavalli, I J; Ribeiro, E M S F

    2015-01-01

    Changes in the expression of the protein disulfide isomerase genes PDIA3 and PDIA6 may increase endoplasmic reticulum stress, leading to cellular instability and neoplasia. We evaluated the expression of PDIA3 and PDIA6 in invasive ductal carcinomas. Using reverse transcription-quantitative polymerase chain reaction, we compared the mRNA expression level in 45 samples of invasive ductal carcinoma with that in normal breast samples. Increased expression of the PDIA3 gene in carcinomas (P = 0.0009) was observed. In addition, PDIA3 expression was increased in tumors with lymph node metastasis (P = 0.009) and with grade III (P < 0.02). The PDIA6 gene showed higher expression levels in the presence of lymph node metastasis (U = 99.00, P = 0.0476) and lower expression for negative hormone receptors status (P = 0.0351). Our results suggest that alterations in PDIA3/6 expression levels may be involved in the breast carcinogenic process and should be further investigated as a marker of aggressiveness. PMID:26125904

  20. Preadipocyte factor 1 induces pancreatic ductal cell differentiation into insulin-producing cells.

    PubMed

    Rhee, Marie; Lee, Seung-Hwan; Kim, Ji-Won; Ham, Dong-Sik; Park, Heon-Seok; Yang, Hae Kyung; Shin, Ju-Young; Cho, Jae-Hyoung; Kim, Young-Bum; Youn, Byung-Soo; Sul, Hei Sook; Yoon, Kun-Ho

    2016-01-01

    The preadipocyte factor 1 (Pref-1) is involved in the proliferation and differentiation of various precursor cells. However, the intracellular signaling pathways that control these processes and the role of Pref-1 in the pancreas remain poorly understood. Here, we showed that Pref-1 induces insulin synthesis and secretion via two independent pathways. The overexpression of Pref-1 activated MAPK signaling, which induced nucleocytoplasmic translocation of FOXO1 and PDX1 and led to the differentiation of human pancreatic ductal cells into β-like cells and an increase in insulin synthesis. Concurrently, Pref-1 activated Akt signaling and facilitated insulin secretion. A proteomics analysis identified the Rab43 GTPase-activating protein as a downstream target of Akt. A serial activation of both proteins induced various granular protein syntheses which led to enhanced glucose-stimulated insulin secretion. In a pancreatectomised diabetic animal model, exogenous Pref-1 improved glucose homeostasis by accelerating pancreatic ductal and β-cell regeneration after injury. These data establish a novel role for Pref-1, opening the possibility of applying this molecule to the treatment of diabetes. PMID:27044861

  1. A Self-Folding Hydrogel In Vitro Model for Ductal Carcinoma.

    PubMed

    Kwag, Hye Rin; Serbo, Janna V; Korangath, Preethi; Sukumar, Saraswati; Romer, Lewis H; Gracias, David H

    2016-04-01

    A significant challenge in oncology is the need to develop in vitro models that accurately mimic the complex microenvironment within and around normal and diseased tissues. Here, we describe a self-folding approach to create curved hydrogel microstructures that more accurately mimic the geometry of ducts and acini within the mammary glands, as compared to existing three-dimensional block-like models or flat dishes. The microstructures are composed of photopatterned bilayers of poly (ethylene glycol) diacrylate (PEGDA), a hydrogel widely used in tissue engineering. The PEGDA bilayers of dissimilar molecular weights spontaneously curve when released from the underlying substrate due to differential swelling ratios. The photopatterns can be altered via AutoCAD-designed photomasks so that a variety of ductal and acinar mimetic structures can be mass-produced. In addition, by co-polymerizing methacrylated gelatin (methagel) with PEGDA, microstructures with increased cell adherence are synthesized. Biocompatibility and versatility of our approach is highlighted by culturing either SUM159 cells, which were seeded postfabrication, or MDA-MB-231 cells, which were encapsulated in hydrogels; cell viability is verified over 9 and 15 days, respectively. We believe that self-folding processes and associated tubular, curved, and folded constructs like the ones demonstrated here can facilitate the design of more accurate in vitro models for investigating ductal carcinoma. PMID:26831041

  2. Hepatocyte-Ductal Transdifferentiation Is Mediated by Reciprocal Repression of SOX9 and C/EBPα

    PubMed Central

    O'Neill, Kathy E.; Thowfeequ, Shifaan; Li, Wan-Chun; Eberhard, Daniel; Dutton, James R.; Slack, Jonathan M.W.

    2014-01-01

    Abstract Primary hepatocytes rapidly dedifferentiate when cultured in vitro. We have studied the mechanism of hepatocyte dedifferentiation by using two culture media: one that maintains hepatocytes in a differentiated state and another that allows dedifferentiation. We show that dedifferentiation involves partial transformation of hepatocytes into cells that resemble biliary epithelial cells. Lineage labeling and time-lapse filming confirm that the dedifferentiated cells are derived from hepatocytes and not from contaminating ductal or fibroblastic cells in the original culture. Furthermore, we establish that the conversion of hepatocytes to biliary-like cells is regulated by mutual antagonism of CCAAT/enhancer binding protein alpha (C/EBPα) and SOX9, which have opposing effects on the expression of hepatocyte and ductal genes. Thus, hepatocyte dedifferentiation induces the biliary gene expression program by alleviating C/EBPα-mediated repression of Sox9. We propose that reciprocal antagonism of C/EBPα and SOX9 also operates in the formation of hepatocytes and biliary ducts from hepatoblasts during normal embryonic development. These data demonstrate that reprogramming of differentiated cells can be used to model the acquisition and maintenance of cell fate in vivo. PMID:25153359

  3. Ductal carcinoma in situ of the breast: the importance of morphologic and molecular interactions.

    PubMed

    Mardekian, Stacey K; Bombonati, Alessandro; Palazzo, Juan P

    2016-03-01

    Ductal carcinoma in situ (DCIS) of the breast is a lesion characterized by significant heterogeneity, in terms of morphology, immunohistochemical staining, molecular signatures, and clinical expression. For some patients, surgical excision provides adequate treatment, but a subset of patients will experience recurrence of DCIS or progression to invasive ductal carcinoma (IDC). Recent years have seen extensive research aimed at identifying the molecular events that characterize the transition from normal epithelium to DCIS and IDC. Tumor epithelial cells, myoepithelial cells, and stromal cells undergo alterations in gene expression, which are most important in the early stages of breast carcinogenesis. Epigenetic modifications, such as DNA methylation, together with microRNA alterations, play a major role in these genetic events. In addition, tumor proliferation and invasion is facilitated by the lesional microenvironment, which includes stromal fibroblasts and macrophages that secrete growth factors and angiogenesis-promoting substances. Characterization of DCIS on a molecular level may better account for the heterogeneity of these lesions and how this manifests as differences in patient outcome and response to therapy. Molecular assays originally developed for assessing likelihood of recurrence in IDC are recently being applied to DCIS, with promising results. In the future, the classification of DCIS will likely incorporate molecular findings along with histologic and immunohistochemical features, allowing for personalized prognostic information and therapeutic options for patients with DCIS. This review summarizes current data regarding the molecular characterization of DCIS and discusses the potential clinical relevance.

  4. Multiphoton microscopic imaging of fibrotic focus in invasive ductal carcinoma of the breast

    NASA Astrophysics Data System (ADS)

    Chen, Sijia; Nie, Yuting; Lian, Yuane; Wu, Yan; Fu, Fangmeng; Wang, Chuan; Zhuo, Shuangmu; Chen, Jianxin

    2014-11-01

    During the proliferation of breast cancer, the desmoplastic can evoke a fibrosis response by invading healthy tissue. Fibrotic focus (FF) in invasive ductal carcinoma (IDC) of the breast had been reported to be associated with significantly poorer survival rate than IDC without FF. As an important prognosis indicator, it's difficult to obtain the exact fibrotic information from traditional detection method such as mammography. Multiphoton imaging based on two-photon excited fluorescence (TPEF) and second-harmonic generation (SHG) has been recently employed for microscopic examination of unstained tissue. In this study, multiphoton microscopy (MPM) was used to image the fibrotic focus in invasive ductal carcinoma tissue. The morphology and distribution of collagen in fibrotic focus can be demonstrated by the SHG signal. Variation of collagen between IDC with and without FF will be examined and further characterized, which may be greatly related to the metastasis of breast cancer. Our result suggested that the MPM can be efficient in identifying and locating the fibrotic focus in IDC. Combining with the pathology analysis and other detecting methods, MPM owns potential in becoming an advanced histological tool for detecting the fibrotic focus in IDC and collecting prognosis information, which may guide the subsequent surgery option and therapy procedure for patients.

  5. Loss of heterozygosity in human ductal breast tumors indicates a recessive mutation on chromosome 13

    SciTech Connect

    Lundberg, C.; Skoog, L.; Cavenee, W.K.; Nordenskjoeld, M.

    1987-04-01

    The genotypes at chromosomal loci defined by recombinant DNA probes revealing restriction fragment length polymorphisms were determined in constitutional and tumor tissue from 10 cases of ductal breast cancer: eight premenopausal females and two males. Somatic loss of constitutional heterozygosity was observed at loci on chromosome 13 in primary tumor tissue from three females and one male. In two cases, specific loss of heterozygosity at three distinct genetic loci along the length of the chromosome was observed. In another case, concurrent loss of alleles at loci on chromosomes 2, 13, 14, and 20 was detected, whereas a fourth case showed loss of heterozygosity for chromosomes 5 and 13. In each instance, the data were consistent with loss of one of the homologous chromosomes by mitotic nondisjunction. Analysis of loci on several other chromosomes showed retention of constitutional heterozygosity suggesting the relative specificity of the events. In contrast, similar analyses of other breast cancers, including comedocarcinoma, medullary carcinoma, and juvenile secretory carcinoma, showed no loss of alleles at loci on chromosome 13. These data indicate that the pathogenesis of ductal breast cancer may, in a substantial proportion of cases, involve unmasking of a recessive locus on chromosome 13 and suggest the involvement of such a locus in heritable forms of this disease.

  6. TGF-β1 promotes acinar to ductal metaplasia of human pancreatic acinar cells

    PubMed Central

    Liu, Jun; Akanuma, Naoki; Liu, Chengyang; Naji, Ali; Halff, Glenn A.; Washburn, William K.; Sun, Luzhe; Wang, Pei

    2016-01-01

    Animal studies suggest that pancreatitis-induced acinar-to-ductal metaplasia (ADM) is a key event for pancreatic ductal adenocarcinoma (PDAC) initiation. However, there has not been an adequate system to explore the mechanisms of human ADM induction. We have developed a flow cytometry-based, high resolution lineage tracing method and 3D culture system to analyse ADM in human cells. In this system, well-known mouse ADM inducers did not promote ADM in human cells. In contrast, TGF-β1 efficiently converted human acinar cells to duct-like cells (AD) in a SMAD-dependent manner, highlighting fundamental differences between the species. Functionally, AD cells gained transient proliferative capacity. Furthermore, oncogenic KRAS did not induce acinar cell proliferation, but did sustain the proliferation of AD cells, suggesting that oncogenic KRAS requires ADM-associated-changes to promote PDAC initiation. This ADM model provides a novel platform to explore the mechanisms involved in the development of human pancreatic diseases. PMID:27485764

  7. Symmetrical ethmoidal metastases from ductal carcinoma of the breast, suggesting transcribrosal spread.

    PubMed

    Monserez, D; Vlaminck, S; Kuhweide, R; Casselman, J

    2001-01-01

    Symmetrical ethmoidal metastases from ductal carcinoma of the breast, suggesting transcribrosal spread. While half of breast cancers develop metastases, the appearance of metastatic disease in paranasal sinuses from this origin is very rare. Eighteen other cases were found in the literature, dating from 1939 till now. A case of metastatic breastcancer presenting as a subacute therapy-resistant pansinusitis is described. The perfect symmetry was misleading. Bilateral ethmoidal biopsies were compatible with metastases from a ductal adenocarcinoma. Further investigation revealed meningeal carcinomatosis in the supra-orbital region and locoregional recurrence in the mastectomy scar and axilla. Comparing these 19 cases in chronological order, it was noticed that symptoms at time of diagnosis shift from those of space occupying lesions to those suggestive for sinusitis. This shift could be explained by earlier diagnosis. High index of suspicion is the key to diagnosis. Earlier diagnosis does not result in longer survival since in most cases patients have already widespread disease and die within one year. Most authors mention the role of the vertebral venous plexus in hematogeneous spreading of tumor cells. Another pathway of hematogenous spread is via (occult) lung metastases. This case prompts the hypothesis of transcribrosal spread from meningeal involvement.

  8. Breast ductal carcinoma in situ presenting as recurrent non-puerperal mastitis: case report and literature review.

    PubMed

    Liong, Yee Vonne; Hong, Ga Sze; Teo, Jennifer Gek Choo; Lim, Geok Hoon

    2013-08-07

    Breast ductal carcinoma in situ (DCIS) is a preinvasive form of breast cancer. It typically presents as microcalcifications which are picked up on screening mammogram. We report an atypical case of breast DCIS presenting with recurrent non-puerperal mastitis with a normal mammogram and perform a literature review.

  9. Diet-induced obesity disrupts ductal development in the mammary glands of nonpregnant mice.

    PubMed

    Kamikawa, Akihiro; Ichii, Osamu; Yamaji, Daisuke; Imao, Takeshi; Suzuki, Chiharu; Okamatsu-Ogura, Yuko; Terao, Akira; Kon, Yasuhiro; Kimura, Kazuhiro

    2009-05-01

    Mammary glands develop postnatally in response to the hypothalamic-pituitary-gonadal axis. Obesity-induced changes in the local environment, however, retard mammary gland development during late pregnancy and lactation. To clarify the effects of obesity on fundamental duct development, we compared the mammary glands of nulliparous nonpregnant obese mice fed a high-fat diet with those of lean mice fed a normal diet. Obese mice had enlarged mammary glands, reflecting fat pad size, whereas the ducts in obese mice showed a less dense distribution with less frequent branching. Additionally, the ducts were surrounded by thick collagen layers, and were incompletely lined with myoepithelium. Because leptin receptors were localized in the epithelium region and leptin that was highly expressed in the obese glands suppressed mammary epithelial cell proliferation in vitro, the present results suggest that obesity disrupts mammary ductal development, possibly by remodeling the mammary microenvironment and promoting the expression of such paracrine factors as leptin.

  10. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma.

    PubMed

    Moffitt, Richard A; Marayati, Raoud; Flate, Elizabeth L; Volmar, Keith E; Loeza, S Gabriela Herrera; Hoadley, Katherine A; Rashid, Naim U; Williams, Lindsay A; Eaton, Samuel C; Chung, Alexander H; Smyla, Jadwiga K; Anderson, Judy M; Kim, Hong Jin; Bentrem, David J; Talamonti, Mark S; Iacobuzio-Donahue, Christine A; Hollingsworth, Michael A; Yeh, Jen Jen

    2015-10-01

    Pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease with a 5-year survival rate of 4%. A key hallmark of PDAC is extensive stromal involvement, which makes capturing precise tumor-specific molecular information difficult. Here we have overcome this problem by applying blind source separation to a diverse collection of PDAC gene expression microarray data, including data from primary tumor, metastatic and normal samples. By digitally separating tumor, stromal and normal gene expression, we have identified and validated two tumor subtypes, including a 'basal-like' subtype that has worse outcome and is molecularly similar to basal tumors in bladder and breast cancers. Furthermore, we define 'normal' and 'activated' stromal subtypes, which are independently prognostic. Our results provide new insights into the molecular composition of PDAC, which may be used to tailor therapies or provide decision support in a clinical setting where the choice and timing of therapies are critical. PMID:26343385

  11. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma.

    PubMed

    Moffitt, Richard A; Marayati, Raoud; Flate, Elizabeth L; Volmar, Keith E; Loeza, S Gabriela Herrera; Hoadley, Katherine A; Rashid, Naim U; Williams, Lindsay A; Eaton, Samuel C; Chung, Alexander H; Smyla, Jadwiga K; Anderson, Judy M; Kim, Hong Jin; Bentrem, David J; Talamonti, Mark S; Iacobuzio-Donahue, Christine A; Hollingsworth, Michael A; Yeh, Jen Jen

    2015-10-01

    Pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease with a 5-year survival rate of 4%. A key hallmark of PDAC is extensive stromal involvement, which makes capturing precise tumor-specific molecular information difficult. Here we have overcome this problem by applying blind source separation to a diverse collection of PDAC gene expression microarray data, including data from primary tumor, metastatic and normal samples. By digitally separating tumor, stromal and normal gene expression, we have identified and validated two tumor subtypes, including a 'basal-like' subtype that has worse outcome and is molecularly similar to basal tumors in bladder and breast cancers. Furthermore, we define 'normal' and 'activated' stromal subtypes, which are independently prognostic. Our results provide new insights into the molecular composition of PDAC, which may be used to tailor therapies or provide decision support in a clinical setting where the choice and timing of therapies are critical.

  12. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma

    PubMed Central

    Moffitt, Richard A.; Marayati, Raoud; Flate, Elizabeth L.; Volmar, Keith E.; Loeza, S. Gabriela Herrera; Hoadley, Katherine A.; Rashid, Naim U.; Williams, Lindsay A.; Eaton, Samuel C.; Chung, Alexander H.; Smyla, Jadwiga K.; Anderson, Judy M.; Kim, Hong Jin; Bentrem, David J.; Talamonti, Mark S.; Iacobuzio-Donahue, Christine A.; Hollingsworth, Michael A.; Yeh, Jen Jen

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease with a 5-year survival of 4%. A key hallmark of PDAC is extensive stromal involvement, which makes capturing precise tumor-specific molecular information difficult. Here, we have overcome this problem by applying blind source separation to a diverse collection of PDAC gene expression microarray data, which includes primary, metastatic, and normal samples. By digitally separating tumor, stroma, and normal gene expression, we have identified and validated two tumor-specific subtypes including a “basal-like” subtype which has worse outcome, and is molecularly similar to basal tumors in bladder and breast cancer. Furthermore, we define “normal” and “activated” stromal subtypes which are independently prognostic. Our results provide new insight into the molecular composition of PDAC which may be used to tailor therapies or provide decision support in a clinical setting where the choice and timing of therapies is critical. PMID:26343385

  13. Genetic Diversity of Pancreatic Ductal Adenocarcinoma and Opportunities for Precision Medicine.

    PubMed

    Knudsen, Erik S; O'Reilly, Eileen M; Brody, Jonathan R; Witkiewicz, Agnieszka K

    2016-01-01

    Patients with pancreatic ductal adenocarcinoma (PDA) have a poor prognosis despite new treatments; approximately 7% survive for 5 years. Although there have been advances in systemic, primarily cytotoxic, therapies, it has been a challenge to treat patients with PDA using targeted therapies. Sequence analyses have provided a wealth of information about the genetic features of PDA and have identified potential therapeutic targets. Preclinical and early-phase clinical studies have found specific pathways could be rationally targeted; it might also be possible to take advantage of the genetic diversity of PDAs to develop therapeutic agents. The genetic diversity and instability of PDA cells have long been thought of as obstacles to treatment, but are now considered exploitable features. We review the latest findings in pancreatic cancer genetics and the promise of targeted approaches in PDA therapy.

  14. BAG3 promotes pancreatic ductal adenocarcinoma growth by activating stromal macrophages

    PubMed Central

    Rosati, Alessandra; Basile, Anna; D'Auria, Raffaella; d'Avenia, Morena; De Marco, Margot; Falco, Antonia; Festa, Michelina; Guerriero, Luana; Iorio, Vittoria; Parente, Roberto; Pascale, Maria; Marzullo, Liberato; Franco, Renato; Arra, Claudio; Barbieri, Antonio; Rea, Domenica; Menichini, Giulio; Hahne, Michael; Bijlsma, Maarten; Barcaroli, Daniela; Sala, Gianluca; di Mola, Fabio Francesco; di Sebastiano, Pierluigi; Todoric, Jelena; Antonucci, Laura; Corvest, Vincent; Jawhari, Anass; Firpo, Matthew A; Tuveson, David A; Capunzo, Mario; Karin, Michael; De Laurenzi, Vincenzo; Turco, Maria Caterina

    2015-01-01

    The incidence and death rate of pancreatic ductal adenocarcinoma (PDAC) have increased in recent years, therefore the identification of novel targets for treatment is extremely important. Interactions between cancer and stromal cells are critically involved in tumour formation and development of metastasis. Here we report that PDAC cells secrete BAG3, which binds and activates macrophages, inducing their activation and the secretion of PDAC supporting factors. We also identify IFITM-2 as a BAG3 receptor and show that it signals through PI3K and the p38 MAPK pathways. Finally, we show that the use of an anti-BAG3 antibody results in reduced tumour growth and prevents metastasis formation in three different mouse models. In conclusion, we identify a paracrine loop involved in PDAC growth and metastatic spreading, and show that an anti-BAG3 antibody has therapeutic potential. PMID:26522614

  15. Ductal carcinoma in situ in a benign phyllodes tumor of breast: A rare presentation.

    PubMed

    Ghosh, Prithwijit; Saha, Kaushik

    2014-07-01

    Phyllodes tumor (PT) is an uncommon tumor of female breast. The tumor clinically, radiologically, cytologically as well as histologically can mimic fibroadenoma which is a common tumor of fibroepithelial group. Ductal carcinoma in situ (DCIS) in the epithelial component of PT is very rare. We report a rare case of intermediate grade DCIS arising in a benign PT in a 42-year-old lady. The patient presented with a small nodule in right breast along with serosanguineous discharge from nipple. Ultrasonography and cytology failed to distinguish between fibroadenoma and PT. Histopathological examination following wide local excision displayed the biphasic tumor comprising of benign looking cellular stroma and epithelial lining. It also demonstrated the foci of intermediate grade DCIS without any invasive component. Considering the clinicoradiological profile along with histopathological features, the diagnosis of DCIS in a benign PT of breast was made. PMID:25097439

  16. A review of the management of ductal carcinoma in situ following breast conserving surgery.

    PubMed

    Boxer, M M; Delaney, G P; Chua, B H

    2013-12-01

    Ductal carcinoma in situ (DCIS) is a heterogeneous, pre-malignant disease accounting for 10-20% of all new breast tumours. Evidence shows a statistically significant local control benefit for adjuvant radiotherapy (RT) following breast conserving surgery (BCS) for all patients. The baseline recurrence risk of individual patients varies according to clinical-pathological criteria and in selected patients, omission of RT may be considered, following a discussion with the patient. The role of adjuvant endocrine therapy remains uncertain. Ongoing studies are attempting to define subgroups of patients who are at sufficiently low risk of recurrence that RT may be safely omitted; investigating RT techniques and dose fractionation schedules; and defining the role of endocrine therapy. Future directions in the management of patients with DCIS will include investigation of prognostic and predictive biomarkers to inform individualised therapy tailored to the risk of recurrence.

  17. Monitoring morphological alterations during invasive ductal breast carcinoma progression using multiphoton microscopy.

    PubMed

    Wu, Yan; Fu, Fangmeng; Lian, Yuane; Chen, Jianxin; Wang, Chuan; Nie, Yuting; Zheng, Liqin; Zhuo, Shuangmu

    2015-04-01

    Morphological alteration of cells and matrices is critical for tumor initiation and progression. Monitoring these alterations during tumor progression is vitally important for making real-time histological diagnoses of tumor staging. In this study, 20 pairs of normal and cancerous human breast tissues were imaged by multiphoton microscopy (MPM), and nuclear area and collagen density were quantified by LSM 5 software (version 3.2). Comparison of MPM images from normal breast tissue with low- and high-grade invasive ductal carcinoma (IDC) lesions clearly showed changes in both cellular features and extracellular matrix architecture during IDC development. Moreover, analysis of nuclear area and collagen density established a quantitative link between these two morphological features and progression of IDC. Present results demonstrated that MPM can provide both qualitative and quantitative evaluations of tumor progression. With additional development, this technique has the potential to make real-time histological diagnoses of tumor staging and guide development of efficacious clinical therapies.

  18. Differentiating fibroadenoma and ductal carcinoma in situ from normal breast tissue by multiphoton microscopy

    NASA Astrophysics Data System (ADS)

    Nie, Yuting; Wu, Yan; Lian, Yuane; Fu, Fangmeng; Wang, Chuan; Chen, Jianxin

    2014-09-01

    Fibroadenoma (FA) is the most common benign tumor of the female breast and several studies have reported that women with it have increased risk of breast cancer. While the ductal carcinoma in situ (DCIS) is a very early form of breast cancer. Thus, early detections of FA and DCIS are critical for improving breast tumor outcome and survival. In this paper, we use multiphoton microscopy (MPM) to obtain the high-contrast images of fresh, unfixed, unstained human breast specimens (normal breast tissue, FA and DCIS). Our results show that MPM has the ability to identify the characteristics of FA and DCIS including changes of duct architecture and collagen morphology. These results are consistent with the histological results. With the advancement of MPM, the technique has potential ability to serve as a real-time noninvasive imaging tool for early detection of breast tumor.

  19. [Clinical-biological differences between invasive ductal carcinomas and breast lobular carcinomas. Preliminary results].

    PubMed

    Ruibal, A; Núñez, M I; del Río, M f; Arias, J; Martínez, M I; Rabadán, J; Tejerina, A

    1999-01-01

    In order to know the biological differences between both histological types, we have analyzed some clinical and biological parameters in tissues of women having infiltrating carcinomas (247 ductal (IDCs) 17 and lobular (ILCs) of the breast. Our preliminary results led us to suggest the following. 1) In negative axillary lymph node involvement (N-) patients, ILCs were more frequently associated with diploidy and the existence of multiple foci; likewise, they had higher pS2 cytosolic levels than IDC; 2) in N+ patients, ILC were associated with multicentricity and had higher concentrations of progesterone receptors and 3) these findings could help to explain us the clinical and biological peculiarities, as well as, the clinical outcome of both histological types. PMID:10352319

  20. Obstructive Sleep Apnea and Pathological Characteristics of Resected Pancreatic Ductal Adenocarcinoma

    PubMed Central

    Dal Molin, Marco; Brant, Aaron; Blackford, Amanda L.; Griffin, James F.; Shindo, Koji; Barkley, Thomas; Rezaee, Neda; Hruban, Ralph H.; Wolfgang, Christopher L.; Goggins, Michael

    2016-01-01

    Background Prospective studies have identified obstructive sleep apnea (OSA) as a risk factor for increased overall cancer incidence and mortality. The potential role of OSA in the risk or progression of specific cancers is not well known. We hypothesized that pathological differences in pancreatic cancers from OSA cases compared to non-OSA cases would implicate OSA in pancreatic cancer progression. Methods We reviewed the medical records of 1031 patients who underwent surgical resection without neoadjuvant therapy for pancreatic ductal adenocarcinoma (PDAC) at Johns Hopkins Hospital between 2003 and 2014 and compared the TNM classification of their cancer and their overall survival by patient OSA status. Results OSA cases were significantly more likely than non-OSA cases to have lymph node-negative tumors (37.7% vs. 21.8%, p = 0.004). Differences in the prevalence of nodal involvement of OSA vs. non-OSA cases were not associated with differences in other pathological characteristics such as tumor size, tumor location, resection margin status, vascular or perineural invasion, or other comorbidities more common to OSA cases (BMI, smoking, diabetes). A logistic regression model found that a diagnosis of OSA was an independent predictor of lymph node status (hazard ratio, 0.051, p = 0.038). Patients with OSA had similar overall survival compared to those without OSA (HR, 0.89, (0.65–1.24), p = 0.41). Conclusion The observed pathological differences between OSA-associated and non-OSA-associated pancreatic cancers supports the hypothesis that OSA can influence the pathologic features of pancreatic ductal adenocarcinoma. PMID:27732623

  1. Stromal ETS2 Regulates Chemokine Production and Immune Cell Recruitment during Acinar-to-Ductal Metaplasia.

    PubMed

    Pitarresi, Jason R; Liu, Xin; Sharma, Sudarshana M; Cuitiño, Maria C; Kladney, Raleigh D; Mace, Thomas A; Donohue, Sydney; Nayak, Sunayana G; Qu, Chunjing; Lee, James; Woelke, Sarah A; Trela, Stefan; LaPak, Kyle; Yu, Lianbo; McElroy, Joseph; Rosol, Thomas J; Shakya, Reena; Ludwig, Thomas; Lesinski, Gregory B; Fernandez, Soledad A; Konieczny, Stephen F; Leone, Gustavo; Wu, Jinghai; Ostrowski, Michael C

    2016-09-01

    Preclinical studies have suggested that the pancreatic tumor microenvironment both inhibits and promotes tumor development and growth. Here we establish the role of stromal fibroblasts during acinar-to-ductal metaplasia (ADM), an initiating event in pancreatic cancer formation. The transcription factor V-Ets avian erythroblastosis virus E26 oncogene homolog 2 (ETS2) was elevated in smooth muscle actin-positive fibroblasts in the stroma of pancreatic ductal adenocarcinoma (PDAC) patient tissue samples relative to normal pancreatic controls. LSL-Kras(G12D/+); LSL-Trp53(R172H/+); Pdx-1-Cre (KPC) mice showed that ETS2 expression initially increased in fibroblasts during ADM and remained elevated through progression to PDAC. Conditional ablation of Ets-2 in pancreatic fibroblasts in a Kras(G12D)-driven mouse ADM model decreased the amount of ADM events. ADMs from fibroblast Ets-2-deleted animals had reduced epithelial cell proliferation and increased apoptosis. Surprisingly, fibroblast Ets-2 deletion significantly altered immune cell infiltration into the stroma, with an increased CD8+ T-cell population, and decreased presence of regulatory T cells (Tregs), myeloid-derived suppressor cells, and mature macrophages. The mechanism involved ETS2-dependent chemokine ligand production in fibroblasts. ETS2 directly bound to regulatory sequences for Ccl3, Ccl4, Cxcl4, Cxcl5, and Cxcl10, a group of chemokines that act as potent mediators of immune cell recruitment. These results suggest an unappreciated role for ETS2 in fibroblasts in establishing an immune-suppressive microenvironment in response to oncogenic Kras(G12D) signaling during the initial stages of tumor development. PMID:27659014

  2. A study on biliary ductal system and bile fistula in the American alligator, Alligator mississippiensis.

    PubMed

    Xu, G; Elsey, R M; Lance, V A; Javors, B; Chen, T S; Salen, G; Tint, G S

    1997-12-15

    The anomalous arrangement of bile ducts in the Crocodylia has not been fully appreciated. A clear understanding of biliary anatomy is necessary in order to create complete bile drainage in these reptiles. The object of this study was to clarify the anatomy of the bile ductal system and to establish total bile fistulas in the American alligator, Alligator mississippiensis. Bile duct anatomy was studied in 104 juvenile alligators, and bile fistulas were constructed in seven alligators. In 93 out of 104 (89%) of the juveniles dissected there was an interconnection between the right and left hepatic duct before the right hepatic duct emptied into the gallbladder. The left hepatic duct then entered the duodenum independently of the cystic duct which drained the gallbladder directly into the duodenum. In 8% of the animals, the left hepatic duct did not enter the duodenum but joined with the right duct, forming a common hepatic duct that emptied into the gallbladder. In 3% of the cases, the right hepatic duct emptied into the gallbladder, while the left duct had no communication with the right hepatic duct and drained separately into the duodenum. This arrangement of bile ducts is similar to that seen in birds and reflects the common ancestry of crocodiles and birds. In other reptiles, the biliary system shows much more variability and is different from the alligator. In five of seven alligators in which total biliary diversion was attempted, the biliary catheter remained in place and stayed patent from 2-7 weeks. Bile flow was extremely low (1.5-2.5 ml/24 h) when compared to that of mammals (80-100 ml/24 h). This study demonstrates the variable nature of the biliary ductal system in Alligator mississippiensis and suggest a method for constructing an effective total bile fistula in these animals.

  3. Expressions of Matrix Metalloproteinases 2, 7, and 9 in Carcinogenesis of Pancreatic Ductal Adenocarcinoma

    PubMed Central

    Januszewska, Joanna; Sidorkiewicz, Iwona; Niewiński, Andrzej; Lewczuk, Łukasz; Kędra, Bogusław; Guzińska-Ustymowicz, Katarzyna

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal disease, usually diagnosed in an advanced stage which gives a slight chance of recovery. Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that participate in tissue remodeling and stimulate neovascularization and inflammatory response. The aim of the study was to evaluate the expression of MMP-2, MMP-7, and MMP-9 in normal ducts, tumor pancreatic adenocarcinoma cells, and peritumoral stroma in correlation with clinicohistopathological parameters. The study material was obtained from 29 patients with pancreatic ductal adenocarcinoma. The expressions of MMP-2, MMP-7, and MMP-9 were performed by immunohistochemical technique. Microvessel density (MVD) was visualized by special immunostaining. The expressions of MMP-2, MMP-7, and MMP-9 were mainly observed in tumor cells and peritumoral stroma. MMP-2 expression in cancer cells was correlated with female gender, stronger inflammation, and histopathological type of cancer (R = 0.460, p = 0.013; R = 0.690, p = 0.0001; R = −0.440, p = 0.005, resp.). The expression of MMP-7 in tumor cells was found to positively correlate with the presence of necrosis and negatively correlate with MVD (R = 0.402, p = 0.031; R = −0.682, p = 0.000). We also showed that positive MMP-9 expression in tumor cells was associated with MVD (R = 0.368, p = 0.084); however, it was not statistically significant. Our results demonstrate that MMP-2, MMP-7, and MMP-9 expressions correlate with various morphological features of the PDAC tumor such as inflammation, necrosis, and formation of the new blood vessels. PMID:27429508

  4. Interstitial Pressure in Pancreatic Ductal Adenocarcinoma Is Dominated by a Gel-Fluid Phase.

    PubMed

    DuFort, Christopher C; DelGiorno, Kathleen E; Carlson, Markus A; Osgood, Ryan J; Zhao, Chunmei; Huang, Zhongdong; Thompson, Curtis B; Connor, Robert J; Thanos, Christopher D; Scott Brockenbrough, J; Provenzano, Paolo P; Frost, Gregory I; Michael Shepard, H; Hingorani, Sunil R

    2016-05-10

    Elevated interstitial fluid pressure can present a substantial barrier to drug delivery in solid tumors. This is particularly true of pancreatic ductal adenocarcinoma, a highly lethal disease characterized by a robust fibroinflammatory response, widespread vascular collapse, and hypoperfusion that together serve as primary mechanisms of treatment resistance. Free-fluid pressures, however, are relatively low in pancreatic ductal adenocarcinoma and cannot account for the vascular collapse. Indeed, we have shown that the overexpression and deposition in the interstitium of high-molecular-weight hyaluronan (HA) is principally responsible for generating pressures that can reach 100 mmHg through the creation of a large gel-fluid phase. By interrogating a variety of tissues, tumor types, and experimental model systems, we show that an HA-dependent fluid phase contributes substantially to pressures in many solid tumors and has been largely unappreciated heretofore. We investigated the relative contributions of both freely mobile fluid and gel fluid to interstitial fluid pressure by performing simultaneous, real-time fluid-pressure measurements with both the classical wick-in-needle method (to estimate free-fluid pressure) and a piezoelectric pressure catheter transducer (which is capable of capturing pressures associated with either phase). We demonstrate further that systemic treatment with pegylated recombinant hyaluronidase (PEGPH20) depletes interstitial HA and eliminates the gel-fluid phase. This significantly reduces interstitial pressures and leaves primarily free fluid behind, relieving the barrier to drug delivery. These findings argue that quantifying the contributions of free- and gel-fluid phases to hydraulically transmitted pressures in a given cancer will be essential to designing the most appropriate and effective strategies to overcome this important and frequently underestimated resistance mechanism. PMID:27166818

  5. [Functional distinction of secreting pools of the pancreas and participation of the pancreatic ductal system in the development of the pancreatic secret properties].

    PubMed

    Korot'ko, G F; Voskanian, S E; Gladkiĭ, E Iu; Makarova, T M; Bulgakov, V A

    2002-08-01

    Acute experiments on dogs with separate secretion of the pancreatic enzymes, either stimulated or inhibited, from two lobes of pancreas, and investigation into the character of kinetics of the secretion from 5-7 ductal pools of the pancreas showed the functional specifics, with the device of ductal valves and microdepot of a secret of the pancreas ductal system playing an important role. The conclusion is made that the final secret of pancreas removed to the duodenum is a product of a secret-motor activation of non-equipotentional microregions of the gland, being the components of an intervisceral dynamical mosaic.

  6. Classifying the Progression of Ductal Carcinoma from Single-Cell Sampled Data via Integer Linear Programming: A Case Study.

    PubMed

    Catanzaro, Daniele; Shackney, Stanley E; Schaffer, Alejandro A; Schwartz, Russell

    2016-01-01

    Ductal Carcinoma In Situ (DCIS) is a precursor lesion of Invasive Ductal Carcinoma (IDC) of the breast. Investigating its temporal progression could provide fundamental new insights for the development of better diagnostic tools to predict which cases of DCIS will progress to IDC. We investigate the problem of reconstructing a plausible progression from single-cell sampled data of an individual with synchronous DCIS and IDC. Specifically, by using a number of assumptions derived from the observation of cellular atypia occurring in IDC, we design a possible predictive model using integer linear programming (ILP). Computational experiments carried out on a preexisting data set of 13 patients with simultaneous DCIS and IDC show that the corresponding predicted progression models are classifiable into categories having specific evolutionary characteristics. The approach provides new insights into mechanisms of clonal progression in breast cancers and helps illustrate the power of the ILP approach for similar problems in reconstructing tumor evolution scenarios under complex sets of constraints.

  7. Sentinel lymph node biopsy in clinically detected ductal carcinoma in situ

    PubMed Central

    Al-Ameer, Ahmed Yahia; Al Nefaie, Sahar; Al Johani, Badria; Anwar, Ihab; Al Tweigeri, Taher; Tulbah, Asma; Alshabanah, Mohmmed; Al Malik, Osama

    2016-01-01

    AIM: To study the indications for sentinel lymph node biopsy (SLNB) in clinically-detected ductal carcinoma in situ (CD-DCIS). METHODS: A retrospective analysis of 20 patients with an initial diagnosis of pure DCIS by an image-guided core needle biopsy (CNB) between June 2006 and June 2012 was conducted at King Faisal Specialist Hospital. The accuracy of performing SLNB in CD-DCIS, the rate of sentinel and non-sentinel nodal metastasis, and the histologic underestimation rate of invasive cancer at initial diagnosis were analyzed. The inclusion criteria were a preoperative diagnosis of pure DCIS with no evidence of invasion. We excluded any patient with evidence of microinvasion or invasion. There were two cases of mammographically detected DCIS and 18 cases of CD-DCIS. All our patients were diagnosed by an image-guided CNB except two patients who were diagnosed by fine needle aspiration (FNA). All patients underwent breast surgery, SLNB, and axillary lymph node dissection (ALND) if the SLN was positive. RESULTS: Twenty patients with an initial diagnosis of pure DCIS underwent SLNB, 2 of whom had an ALND. The mean age of the patients was 49.7 years (range, 35-70). Twelve patients (60%) were premenopausal and 8 (40%) were postmenopausal. CNB was the diagnostic procedure for 18 patients, and 2 who were diagnosed by FNA were excluded from the calculation of the underestimation rate. Two out of 20 had a positive SLNB and underwent an ALND and neither had additional non sentinel lymph node metastasis. Both the sentinel visualization rate and the intraoperative sentinel identification rate were 100%. The false negative rate was 0%. Only 2 patients had a positive SLNB (10%) and neither had additional metastasis following an ALND. After definitive surgery, 3 patients were upstaged to invasive ductal carcinoma (3/18 = 16.6%) and 3 other patients were upstaged to DCIS with microinvasion (3/18 = 16.6%). Therefore the histologic underestimation rate of invasive disease was 33

  8. Hypoxia inducible BHLHB2 is a novel and independent prognostic marker in pancreatic ductal adenocarcinoma

    SciTech Connect

    Wang, Weibin; Reiser-Erkan, Carolin; Michalski, Christoph W.; Raggi, Matthias C.; Quan, Liao; Yupei, Zhao; Friess, Helmut; Erkan, Mert; Kleeff, Joerg

    2010-10-22

    Research highlights: {yields} The expression and function of BHLHB2 (DEC1/SHARP2) in pancreatic cancer is unknown. {yields} Hypoxia and serum starvation induces BHLHB2 expression in pancreatic ductal adenocarcinoma. {yields} BHLHB2 inhibition in pancreatic cancer cell line SU86.86 increases ED50 of gemcitabine 2.8-fold. {yields} BHLHB2 is an independent prognostic factor in multivariable cox analysis with a hazard ratio of 2:4. -- Abstract: Aims: The cyclic adenosine monophosphate-inducible basic helix-loop-helix (bHLH) domain containing class-B2 transcriptional factor BHLHB2 is differentially expressed in a number of human malignancies. In the present study, the expression, regulation, functions and prognostic impact of BHLHB2 in pancreatic cancer were investigated. Methods: Expression analyses were carried out in tissues of the normal pancreas (n = 10) and pancreatic ductal adenocarcinoma (n = 77) as well as in eight pancreatic cancer cell lines using quantitative RT-PCR, semiquantitative immunohistochemistry, and immunoblot analyses. In vitro functional experiments were conducted using siRNA transfection, hypoxia, serum starvation, apoptosis induction with gemcitabine and actinomycin-D, and invasion assays. Survival analysis was performed using the Kaplan-Meier method. Prognostic factors were determined in a multivariable analysis using a Cox proportional hazards model. Results: BHLHB2 mRNA and protein expressions were strongly induced by hypoxia and by serum starvation in pancreatic cancer cell lines. BHLHB2 silencing with RNAi had no significant effects on growth and invasion but increased apoptosis resistance against gemcitabine by reducing caspace-3 cleavage. In BHLHB2 silenced cells the ED50 of gemcitabine increased from 13.95 {+-} 1.353 to 38.70 {+-} 5.262 nM (p < 0.05). Ex vivo, the weak/absent nuclear staining in normal pancreatic ducts and acinar cells was replaced by moderate to strong nuclear/cytoplasmic staining in PanIN lesions and pancreatic cancer

  9. High resolution 3D MRI of mouse mammary glands with intra-ductal injection of contrast media.

    PubMed

    Markiewicz, Erica; Fan, Xiaobing; Mustafi, Devkumar; Zamora, Marta; Roman, Brian B; Jansen, Sanaz A; Macleod, Kay; Conzen, Suzanne D; Karczmar, Gregory S

    2015-01-01

    The purpose of this study was to use high resolution three-dimensional (3D) magnetic resonance imaging (MRI) to study mouse mammary gland ductal architecture based on intra-ductal injection of contrast agents. Female FVB/N mice age 12-20 weeks (n=12), were used in this study. A 34G, 45° tip Hamilton needle with a 25μL Hamilton syringe was inserted into the tip of the nipple. Approximately 20-25μL of a Gadodiamide/Trypan blue/saline solution was injected slowly over one minute into the nipple and duct. To prevent washout of contrast media from ducts due to perfusion, and maximize the conspicuity of ducts on MRI, mice were sacrificed one minute after injection. High resolution 3D T1-weighted images were acquired on a 9.4T Bruker scanner after sacrifice to eliminate motion artifacts and reduce contrast media leakage from ducts. Trypan blue staining was well distributed throughout the ductal tree. MRI showed the mammary gland ductal structure clearly. In spoiled gradient echo T1-weighted images, the signal-to-noise ratio of regions identified as enhancing mammary ducts following contrast injection was significantly higher than that of muscle (p<0.02) and significantly higher than that of contralateral mammary ducts that were not injected with contrast media (p<0.0001). The methods described here could be adapted for injection of specialized contrast agents to measure metabolism or target receptors in normal ducts and ducts with in situ cancers.

  10. A comparison study of pancreatic acinar cell carcinoma with ductal adenocarcinoma using computed tomography in Chinese patients

    PubMed Central

    Wang, Qingbing; Wang, Xiaolin; Guo, Rongfang; Li, Guoping

    2016-01-01

    Pancreatic acinar cell carcinoma (ACC) is a rare tumor that is difficult to diagnose preoperatively. The aim of this study was to evaluate and describe the computed tomography (CT) features of ACC and compare the results with pancreatic ductal adenocarcinoma (DAC) for improving preoperative diagnosis. The control group consisted of 34 patients with DAC collected from the pathology electronic database. The CT imaging from nine patients with pathologically confirmed ACC was retrospectively reviewed. Two radiologists independently assessed the tumor location, size, texture, and enhancement patterns. We found that 64.3% (9/14) of ACC tumors were homogeneous and 35.7% (5/14) had necrosis. The percentage of common bile duct and pancreatic ductal dilation was 14.3% (2/14) and 7.1% (1/14), respectively. The mean size of ACC was 50.1±24.2 mm. The mean attenuation of ACC was 35.4±3.9 Hounsfield unit (HU) before enhancement, 73.1±42.9 HU in arterial phase, and 71.8±15.6 HU in port venous phase. It is difficult to distinguish ACC from DAC preoperatively only based on CT findings. However, compared with DAC, we found that ACC tumors are likely to be larger and contain more heterogeneous intratumoral necrotic hypovascular regions, and less pancreatic ductal and common biliary dilation. PMID:27660464

  11. A comparison study of pancreatic acinar cell carcinoma with ductal adenocarcinoma using computed tomography in Chinese patients

    PubMed Central

    Wang, Qingbing; Wang, Xiaolin; Guo, Rongfang; Li, Guoping

    2016-01-01

    Pancreatic acinar cell carcinoma (ACC) is a rare tumor that is difficult to diagnose preoperatively. The aim of this study was to evaluate and describe the computed tomography (CT) features of ACC and compare the results with pancreatic ductal adenocarcinoma (DAC) for improving preoperative diagnosis. The control group consisted of 34 patients with DAC collected from the pathology electronic database. The CT imaging from nine patients with pathologically confirmed ACC was retrospectively reviewed. Two radiologists independently assessed the tumor location, size, texture, and enhancement patterns. We found that 64.3% (9/14) of ACC tumors were homogeneous and 35.7% (5/14) had necrosis. The percentage of common bile duct and pancreatic ductal dilation was 14.3% (2/14) and 7.1% (1/14), respectively. The mean size of ACC was 50.1±24.2 mm. The mean attenuation of ACC was 35.4±3.9 Hounsfield unit (HU) before enhancement, 73.1±42.9 HU in arterial phase, and 71.8±15.6 HU in port venous phase. It is difficult to distinguish ACC from DAC preoperatively only based on CT findings. However, compared with DAC, we found that ACC tumors are likely to be larger and contain more heterogeneous intratumoral necrotic hypovascular regions, and less pancreatic ductal and common biliary dilation.

  12. Monoclonal antibody BrE-3 participation in a multivariate prognostic model for infiltrating ductal carcinoma of the breast.

    PubMed

    Chan, C M; Baratta, F S; Ozzello, L; Ceriani, R L

    1994-01-01

    Monoclonal antibody (MoAb) BrE-3, an anti-human milk fat globule (HMFG) MoAb, is used here as a novel prognostic indicator for survival and relapse time in patients with infiltrating ductal carcinoma of the breast. A scoring system (4-Score method) was developed to this effect that measured, in a statistically reliable fashion, the level of expression of the epitope for MoAb BrE-3 in the cytoplasm and membranes of breast carcinoma cells in paraffin-embedded sections. In univariate analysis, data obtained by the 4-Score Method as well as data from traditional prognostic indicators (tumor size, axillary node status, and grade of differentiation) were found to be associated with patient survival and relapse. In multivariate analysis, using a Cox proportional hazards regression model, levels of expression of BrE-3 epitope plus tumor size and axillary node status were weighted and combined in an Individual Linear Composite Prognostic Score (ILCPS) that had a high level of association with survival and relapse time in this sample model of patients with infiltrating ductal carcinoma of the breast. This level of association was found to be higher than the level of association for any other combination of traditional or 4-Score method variables. The level of expression of BrE-3 significantly adds to the prognostic capacity of traditional prognostic markers for infiltrating ductal carcinoma of the breast. PMID:7981443

  13. Association between dynamic contrast enhanced MRI imaging features and WHO histopathological grade in patients with invasive ductal breast cancer

    PubMed Central

    HUANG, JUAN; YU, JIANQUN; PENG, YULAN

    2016-01-01

    The present study aimed to investigate the dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) and World Health Organization (WHO) histopathological grade in patients with invasive ductal breast cancer. A retrospective analysis on the results of DCE-MRI of 92 patients, who were diagnosed with invasive ductal breast cancer following surgery or biopsy, and these results were correlated with WHO histopathological grade. The statistical analysis demonstrated that the tumor size, shape and characteristics of early enhancement were associated with the WHO histopathological grade: The larger the lesion's long diameter, the higher the WHO histopathological grade; the WHO histopathological grades of round and oval masses were relatively lower, while those of lobulated and irregular masses were higher; and tumors with heterogeneous and ring-like enhancement exhibited higher WHO histopathological grades, while those of homogeneous enhancement were lower. The lesion's margin shape was not associated with the WHO histopathological grade. The present study demonstrates that features of DCE-MRI and WHO histopathological grade in patients with invasive ductal breast cancer are correlated, and these MRI features could be used to evaluate the biological behavior and prognosis of lesions. PMID:27123145

  14. Role of YAP and TAZ in pancreatic ductal adenocarcinoma and in stellate cells associated with cancer and chronic pancreatitis.

    PubMed

    Morvaridi, Susan; Dhall, Deepti; Greene, Mark I; Pandol, Stephen J; Wang, Qiang

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is characterized by a fibrotic and inflammatory microenvironment that is formed primarily by activated, myofibroblast-like, stellate cells. Although the stellate cells are thought to contribute to tumorigenesis, metastasis and drug resistance of PDAC, the signaling events involved in activation of the stellate cells are not well defined. Functioning as transcription co-factors, Yes-associated protein (YAP) and its homolog transcriptional co-activator with PDZ-binding motif (TAZ) modulate the expression of genes involved in various aspects of cellular functions, such as proliferation and mobility. Using human tissues we show that YAP and TAZ expression is restricted to the centroacinar and ductal cells of normal pancreas, but is elevated in cancer cells. In particular, YAP and TAZ are expressed at high levels in the activated stellate cells of both chronic pancreatitis and PDAC patients as well as in the islets of Langerhans in chronic pancreatitis tissues. Of note, YAP is up regulated in both acinar and ductal cells following induction of acute and chronic pancreatitis in mice. These findings indicate that YAP and TAZ may play a critical role in modulating pancreatic tissue regeneration, neoplastic transformation, and stellate cell functions in both PDAC and pancreatitis. PMID:26567630

  15. Role of YAP and TAZ in pancreatic ductal adenocarcinoma and in stellate cells associated with cancer and chronic pancreatitis

    PubMed Central

    Morvaridi, Susan; Dhall, Deepti; Greene, Mark I.; Pandol, Stephen J.; Wang, Qiang

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is characterized by a fibrotic and inflammatory microenvironment that is formed primarily by activated, myofibroblast-like, stellate cells. Although the stellate cells are thought to contribute to tumorigenesis, metastasis and drug resistance of PDAC, the signaling events involved in activation of the stellate cells are not well defined. Functioning as transcription co-factors, Yes-associated protein (YAP) and its homolog transcriptional co-activator with PDZ-binding motif (TAZ) modulate the expression of genes involved in various aspects of cellular functions, such as proliferation and mobility. Using human tissues we show that YAP and TAZ expression is restricted to the centroacinar and ductal cells of normal pancreas, but is elevated in cancer cells. In particular, YAP and TAZ are expressed at high levels in the activated stellate cells of both chronic pancreatitis and PDAC patients as well as in the islets of Langerhans in chronic pancreatitis tissues. Of note, YAP is up regulated in both acinar and ductal cells following induction of acute and chronic pancreatitis in mice. These findings indicate that YAP and TAZ may play a critical role in modulating pancreatic tissue regeneration, neoplastic transformation, and stellate cell functions in both PDAC and pancreatitis. PMID:26567630

  16. Quantitative changes of collagen in human normal breast tissue and invasive ductal carcinoma using nonlinear optical microscopy

    NASA Astrophysics Data System (ADS)

    Li, Weiqiang; Wu, Yan; Lian, Yuane; Fu, Fangmeng; Wang, Chuan; Zhuo, Shuangmu; Chen, Jianxin

    2014-11-01

    Multiphoton microscopy (MPM) imaging of collagen plays a key role in noninvasive diagnosis of human tissue. During the experiment, we observed an interesting phenomenon which two-photon excited fluorescence (TPEF) signal of collagen in human invasive ductal carcinoma of breast tissue becomes much weaker than the normal breast tissue, but the second harmonic generation (SHG) signal of collagen does not get an obvious change . In order to explain the phenomena,this paper emphasizes on the intensity of TPEF and SHG signal from collagen in human invasive ductal carcinoma of breast tissues and normal breast tissue. Further, we respectively obtain the intensity spectral information from collagen in the above two tissues with all parameter unaltered. Our quantitative results show that the intensity of TPEF from collagen in human invasive ductal carcinoma of breast tissue is much lower than the intensity of TPEF from collagen in normal breast tissue. According to the theoretic analysis, it was concluded that the intensity of TPEF declined due to the reduction of the quantum yield when the collagen was intruded by cancer cells. However, the invasion of cancer cells has no effect on decisive factor of SHG. Our theoretical analysis brings more detailed information about intensity of SHG and TPEF from collagen in the above two tissues.

  17. A comparison study of pancreatic acinar cell carcinoma with ductal adenocarcinoma using computed tomography in Chinese patients.

    PubMed

    Wang, Qingbing; Wang, Xiaolin; Guo, Rongfang; Li, Guoping

    2016-01-01

    Pancreatic acinar cell carcinoma (ACC) is a rare tumor that is difficult to diagnose preoperatively. The aim of this study was to evaluate and describe the computed tomography (CT) features of ACC and compare the results with pancreatic ductal adenocarcinoma (DAC) for improving preoperative diagnosis. The control group consisted of 34 patients with DAC collected from the pathology electronic database. The CT imaging from nine patients with pathologically confirmed ACC was retrospectively reviewed. Two radiologists independently assessed the tumor location, size, texture, and enhancement patterns. We found that 64.3% (9/14) of ACC tumors were homogeneous and 35.7% (5/14) had necrosis. The percentage of common bile duct and pancreatic ductal dilation was 14.3% (2/14) and 7.1% (1/14), respectively. The mean size of ACC was 50.1±24.2 mm. The mean attenuation of ACC was 35.4±3.9 Hounsfield unit (HU) before enhancement, 73.1±42.9 HU in arterial phase, and 71.8±15.6 HU in port venous phase. It is difficult to distinguish ACC from DAC preoperatively only based on CT findings. However, compared with DAC, we found that ACC tumors are likely to be larger and contain more heterogeneous intratumoral necrotic hypovascular regions, and less pancreatic ductal and common biliary dilation. PMID:27660464

  18. [Synchronous and ipsilateral invasive ductal carcinoma of the breast occurring near a phyllodes tumor - a case report].

    PubMed

    Nagashima, Saki; Sakurai, Kenichi; Suzuki, Shuhei; Sakagami, Masashi; Enomoto, Katsuhisa; Amano, Sadao; Koshinaga, Tsugumichi

    2014-11-01

    We report 2 cases of invasive ductal carcinoma of the breast occurring near a phyllodes tumor. The first case was ofa 58- year-old woman who had a tumor in her right breast and visited our hospital. Following a core needle biopsy (CNB), a malignant phyllodes tumor was diagnosed. We performed a lumpectomy for the phyllodes tumor, with 1.5-cm surgical margins. Pathological diagnosis of the resected specimen confirmed the malignant phyllodes tumor. A ductal carcinoma in situ (DCIS) was also discovered near the phyllodes tumor. The second case was of another 58-year-old woman who had a big tumor in her right breast and visited our hospital. CNB resulted in pathological diagnosis ofa benign phyllodes tumor. The tumor was removed by a lumpectomy with 1.5-cm surgical margins. The pathological diagnosis from the resected specimen was borderline phyllodes tumor with invasive ductal carcinoma in the proximity. In both cases, DCIS could not have been diagnosed preoperatively. PMID:25731391

  19. Scribble Modulates the MAPK/Fra1 Pathway to Disrupt Luminal and Ductal Integrity and Suppress Tumour Formation in the Mammary Gland

    PubMed Central

    Godde, Nathan J.; Sheridan, Julie M.; Smith, Lorey K.; Pearson, Helen B.; Britt, Kara L.; Galea, Ryan C.; Yates, Laura L.; Visvader, Jane E.; Humbert, Patrick O.

    2014-01-01

    Polarity coordinates cell movement, differentiation, proliferation and apoptosis to build and maintain complex epithelial tissues such as the mammary gland. Loss of polarity and the deregulation of these processes are critical events in malignant progression but precisely how and at which stage polarity loss impacts on mammary development and tumourigenesis is unclear. Scrib is a core polarity regulator and tumour suppressor gene however to date our understanding of Scrib function in the mammary gland has been limited to cell culture and transplantation studies of cell lines. Utilizing a conditional mouse model of Scrib loss we report for the first time that Scrib is essential for mammary duct morphogenesis, mammary progenitor cell fate and maintenance, and we demonstrate a critical and specific role for Scribble in the control of the early steps of breast cancer progression. In particular, Scrib-deficiency significantly induced Fra1 expression and basal progenitor clonogenicity, which resulted in fully penetrant ductal hyperplasia characterized by high cell turnover, MAPK hyperactivity, frank polarity loss with mixing of apical and basolateral membrane constituents and expansion of atypical luminal cells. We also show for the first time a role for Scribble in mammalian spindle orientation with the onset of mammary hyperplasia being associated with aberrant luminal cell spindle orientation and a failure to apoptose during the final stage of duct tubulogenesis. Restoring MAPK/Fra1 to baseline levels prevented Scrib-hyperplasia, whereas persistent Scrib deficiency induced alveolar hyperplasia and increased the incidence, onset and grade of mammary tumours. These findings, based on a definitive genetic mouse model provide fundamental insights into mammary duct maturation and homeostasis and reveal that Scrib loss activates a MAPK/Fra1 pathway that alters mammary progenitor activity to drive premalignancy and accelerate tumour progression. PMID:24852022

  20. Sports-induced blood sugar utilization prevents development of pancreatic ductal adenocarcinoma.

    PubMed

    Lu, Jinkui; Yin, Xiaojian; Jiang, Jiazhen

    2015-02-01

    Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor of extremely high lethality in humans. Pancreatic intraepithelial neoplasia (PanIN) is the predominant precancerous lesion for PDAC and is frequently detected in the normal and inflamed pancreas. However, only a few of PanIN eventually progress into PDAC. Thus, understanding of the regulation of PanIN-to-PDAC conversion appears to be critical for prevention of the occurrence of PDAC. Here, we evaluated the effect of sports on the progression of PanIN into PDAC in an established mouse PDAC model (Ptf1a-Cre; K-ras fx/fx). We found that swimming (3 min twice per day) since 12 weeks of age significantly decreased the incidence of the development of PDAC in these PanIN-baring mice at 24 weeks of age. Moreover, swimming significantly decreased fasting blood sugar and improved glucose response in these mice, compared to the control. Furthermore, implantation of insulin pellets into the mice not only reduced fasting blood sugar and improved glucose response, but also significantly reduced the incidence of development of PDAC, which mimicked the effect of swimming. Taken together, our study suggests that sports-induced blood sugar utilization may prevent development of PDAC.

  1. Pancreatic Ductal Perfusion at Organ Procurement Enhances Islet Yield in Human Islet Isolation

    PubMed Central

    Shimoda, Masayuki; Kanak, Mazhar A.; Shahbazov, Rauf; Kunnathodi, Faisal; Lawrence, Michael C.; Naziruddin, Bashoo; Levy, Marlon F.

    2015-01-01

    Objective Pancreas preservation is a major factor influencing the results of islet cell transplantation. This study evaluated the effects of two different solutions for pancreatic ductal perfusion (PDP) at organ procurement. Methods Eighteen human pancreases were assigned to three groups: non-PDP (control), PDP with ET-Kyoto solution, and PDP with cold storage/purification stock solution. Pancreatic islets were isolated according to the modified Ricordi method. Results No significant differences in donor characteristics, including cold ischemia time, were observed between the three groups. All islet isolations in the PDP groups had >400,000 IEQ in total islet yield post-purification, a significant increase when compared with the control (P = 0.04 and <0.01). The islet quality assessments—including an in vivo diabetic nude mice assay and the response of high-mobility group box protein 1 to cytokine stimulation—also showed no significant differences. The proportion of TUNEL-positive cells showing apoptosis in islets in the PDP groups was significantly lower than in the control group (P < 0.05). Conclusion Both ET-Kyoto solution and cold storage/purification stock solution are suitable for PDP and consistently resulted in isolation success. Further studies with a larger number of pancreas donors should be done to compare the effects of the PDP solutions. PMID:25058879

  2. High expression of WISP-1 correlates with poor prognosis in pancreatic ductal adenocarcinoma.

    PubMed

    Yang, Jian-Yu; Yang, Min-Wei; Huo, Yan-Miao; Liu, Wei; Liu, De-Jun; Li, Jiao; Zhang, Jun-Feng; Hua, Rong; Sun, Yong-Wei

    2015-01-01

    WNT1 inducible signaling pathway protein 1 (WISP-1) is a member of the CCN family of growth factors and reported to possess an important role in tumorigenesis by triggering downstream events via integrin signaling. However, the exact role of WISP-1 in cancer remains unclear. In this study, we examined the expression pattern of WISP-1 at both mRNA and protein levels and evaluated the prognostic value of WISP-1 in pancreatic ductal adenocarcinoma (PDA). Expression of WISP-1 at mRNA level was upregulated in 17/24 tumor tissues compared to the matched adjacent non-tumor tissues and the result was confirmed by western blotting at protein level. Immunohistochemical staining of 194 pairs of PDA specimens suggested that high expression of WISP-1 is strongly correlated with clinical stage (P=0.003), T classification (P=0.008) and liver metastasis (P=0.012). Consistently, Kaplan-Meier survival curves indicated that patients with high expression of WISP-1 had a shorter survival time independent of clinical stage and lymphatic metastasis status. Moreover, univariate and multivariate analysis confirmed WISP-1 expression, age, classification and liver metastasis as independent prognostic factors for overall survival of PDA patients. Taken together, these results suggest that WISP-1 may serve as a potential prognostic biomarker for PDA.

  3. MicroRNA in pancreatic ductal adenocarcinoma and its precursor lesions

    PubMed Central

    Hernandez, Yasmin G; Lucas, Aimee L

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is the 4th deadliest cancer in the United States, due to its aggressive nature, late detection, and resistance to chemotherapy. The majority of PDAC develops from 3 precursor lesions, pancreatic intraepithelial lesions (PanIN), intraductual papillary mucinous neoplasm (IPMN), and mucinous cystic neoplasm. Early detection and surgical resection can increase PDAC 5-year survival rate from 6% for Stage IV to 50% for Stage I. To date, there are no reliable biomarkers that can detect PDAC. MicroRNAs (miRNA) are small noncoding RNAs (18-25 nucleotides) that regulate gene expression by affecting translation of messenger RNA (mRNA). A large body of evidence suggests that miRNAs are dysregulated in various types of cancers. MiRNA has been profiled as a potential biomarker in pancreatic tumor tissue, blood, cyst fluid, stool, and saliva. Four miRNA biomarkers (miR-21, miR-155, miR-196, and miR-210) have been consistently dysregulated in PDAC. MiR-21, miR-155, and miR-196 have also been dysregulated in IPMN and PanIN lesions suggesting their use as early biomarkers of this disease. In this review, we explore current knowledge of miRNA sampling, miRNA dysregulation in PDAC and its precursor lesions, and advances that have been made in using miRNA as a biomarker for PDAC and its precursor lesions. PMID:26798434

  4. Overview of the randomized trials of radiotherapy in ductal carcinoma in situ of the breast.

    PubMed

    Correa, C; McGale, P; Taylor, C; Wang, Y; Clarke, M; Davies, C; Peto, R; Bijker, N; Solin, L; Darby, S

    2010-01-01

    Individual patient data were available for all four of the randomized trials that began before 1995, and that compared adjuvant radiotherapy vs no radiotherapy following breast-conserving surgery for ductal carcinoma in situ (DCIS). A total of 3729 women were eligible for analysis. Radiotherapy reduced the absolute 10-year risk of any ipsilateral breast event (ie, either recurrent DCIS or invasive cancer) by 15.2% (SE 1.6%, 12.9% vs 28.1% 2 P <.00001), and it was effective regardless of the age at diagnosis, extent of breast-conserving surgery, use of tamoxifen, method of DCIS detection, margin status, focality, grade, comedonecrosis, architecture, or tumor size. The proportional reduction in ipsilateral breast events was greater in older than in younger women (2P < .0004 for difference between proportional reductions; 10-year absolute risks: 18.5% vs 29.1% at ages <50 years, 10.8% vs 27.8% at ages ≥ 50 years) but did not differ significantly according to any other available factor. Even for women with negative margins and small low-grade tumors, the absolute reduction in the 10-year risk of ipsilateral breast events was 18.0% (SE 5.5, 12.1% vs 30.1%, 2P = .002). After 10 years of follow-up, there was, however, no significant effect on breast cancer mortality, mortality from causes other than breast cancer, or all-cause mortality. PMID:20956824

  5. [CRITICAL VIEWPOINT ON THE CURRENT APPROACH OF LOCALIZED PANCREATIC DUCTAL ADENOCARCINOMA].

    PubMed

    Van Daele, D; Martinive, P; Loly, C; Polus, M; Collignon, J; Gast, P; Louis, E; Van Laethem, J-L

    2015-11-01

    Surgical resection followed by chemotherapy is the actual standard of care for localized, deemed resectable, pancreatic ductal adenocarcinoma. Despite a better selection of surgical candidates and the actual performance of expert teams, the proportion of patients with a prolonged survival has not been ameliorated during the last three decades. The morphological determinants of resectability are the subject of limitations. In the future, only a better understanding of the biological process, an earlier diagnosis of purely localized disease and more efficient systemic therapies may lead to a better prognosis. Meanwhile, taking into account the prognostic factors associated with a lower chance of cure is currently a matter of debate. The optimal therapeutic sequence, being a surgery-first or a neoadjuvant approach is controversial. The theoretical advantages of preoperative chemotherapy eventually associated with chemo-radiation are demonstrated in other tumours and applicable to pancreatic cancer without any excess of operative mortality, early progression rates and, on the contrary with positive survival data. The completion rates of multi-modal therapy are in favour of the preoperative approach, which also gives the opportunity to select the best candidates for surgical resection.

  6. Ballistic penetration test results for Ductal and ultra-high performance concrete samples.

    SciTech Connect

    Reinhart, William Dodd; Thornhill, Tom Finley, III

    2010-03-01

    This document provides detailed test results of ballistic impact experiments performed on several types of high performance concrete. These tests were performed at the Sandia National Laboratories Shock Thermodynamic Applied Research Facility using a 50 caliber powder gun to study penetration resistance of concrete samples. This document provides test results for ballistic impact experiments performed on two types of concrete samples, (1) Ductal{reg_sign} concrete is a fiber reinforced high performance concrete patented by Lafarge Group and (2) ultra-high performance concrete (UHPC) produced in-house by DoD. These tests were performed as part of a research demonstration project overseen by USACE and ERDC, at the Sandia National Laboratories Shock Thermodynamic Applied Research (STAR) facility. Ballistic penetration tests were performed on a single stage research powder gun of 50 caliber bore using a full metal jacket M33 ball projectile with a nominal velocity of 914 m/s (3000 ft/s). Testing was observed by Beverly DiPaolo from ERDC-GSL. In all, 31 tests were performed to achieve the test objectives which were: (1) recovery of concrete test specimens for post mortem analysis and characterization at outside labs, (2) measurement of projectile impact velocity and post-penetration residual velocity from electronic and radiographic techniques and, (3) high-speed photography of the projectile prior to impact, impact and exit of the rear surface of the concrete construct, and (4) summarize the results.

  7. Developing in vitro models of human ductal carcinoma in situ from primary tissue explants.

    PubMed

    Brown, Daniel D; Dabbs, David J; Lee, Adrian V; McGuire, Kandace P; Ahrendt, Gretchen M; Bhargava, Rohit; Davidson, Nancy E; Brufsky, Adam M; Johnson, Ronald R; Oesterreich, Steffi; McAuliffe, Priscilla F

    2015-09-01

    Because there are currently no reliable predictors for progression of ductal carcinoma in situ (DCIS) to invasive disease, nearly all patients receive comprehensive therapy, leading to over-treatment in many cases. Few in vitro models for studying DCIS progression have been developed. We report here the successful culture and expansion of primary DCIS from surgical specimens using a conditional reprogramming protocol. Patients with percutaneous core-needle biopsy demonstrating DCIS were enrolled in a tissue banking protocol after informed consent was received. Fresh tissue was taken from lumpectomy or mastectomy specimens, mechanically and enzymatically dissociated, cultured in medium conditioned by irradiated mouse fibroblasts and supplemented with rho-associated protein kinase (ROCK) inhibitor, and characterized by immunocytochemistry. Out of 33 DCIS cases, 58% (19) were expanded for up to 2 months in culture, and 42% (14) were frozen immediately after mechanical dissociation for future growth. The cultures are almost exclusively composed of cytokeratin 8- and EpCAM-positive luminal and cytokeratin 14-, cytokeratin 5-, and p63-positive basal mammary epithelial cells, suggesting maintenance of heterogeneity in vitro. Furthermore, as assessed by luminal and basal marker expression, these cells retain their cellular identities both in the "conditionally reprogrammed" proliferative state and after conditioned media and ROCK inhibitor withdrawal. When grown to 100 % confluency, the cultures organize into luminal and basal layers as well as luminal compartments surrounded by basal cells. Primary cultures of DCIS derived directly from patient tissues can be generated and may serve as in vitro models for the study of DCIS.

  8. Selective Reoperation for Locally Recurrent or Metastatic Pancreatic Ductal Adenocarcinoma Following Primary Pancreatic Resection

    PubMed Central

    Thomas, Ryan M.; Truty, Mark J.; Nogueras-Gonzalez, Graciela M.; Fleming, Jason B.; Vauthey, Jean-Nicolas; Pisters, Peter W. T.; Lee, Jeffrey E.; Rice, David C.; Hofstetter, Wayne L.; Wolff, Robert A.; Varadhachary, Gauri R.; Wang, Huamin

    2013-01-01

    Background Resection of certain recurrent malignancies can prolong survival, but resection of recurrent pancreatic ductal adenocarcinoma is typically contraindicated because of poor outcomes. Methods All patients from 1992 to 2010 with recurrent pancreatic cancer after intended surgical cure were retrospectively evaluated. Clinicopathologic features were compared from patients who did and did not undergo subsequent reoperation with curative intent to identify factors associated with prolonged survival. Results Twenty-one of 426 patients (5 %) with recurrent pancreatic cancer underwent potentially curative reoperation for solitary local-regional (n=7) or distant (n=14) recurrence. The median disease-free interval after initial resection among reoperative patients was longer for those with lung or local-regional recurrence (52.4 and 41.1 months, respectively) than for those with liver recurrence (7.6 months, p=0.006). The median interval between reoperation and second recurrence was longer in patients with lung recurrence (median not reached) than with liver or local-regional recurrence (6 and 9 months, respectively, p=0.023). Reoperative patients with an initial disease-free interval >20 months had a longer median survival than those who did not (92.3 versus 31.3 months, respectively; p=0.033). Conclusion Patients with a solitary pulmonary recurrence of pancreatic cancer after a prolonged disease-free interval should be considered for reoperation, as they are more likely to benefit from resection versus other sites of solitary recurrence. PMID:22644446

  9. Differential roles of cyclin D1 and D3 in pancreatic ductal adenocarcinoma

    PubMed Central

    2010-01-01

    Background The cyclin D1 (CCND1) and cyclin D3 (CCND3) are frequently co-overexpressed in pancreatic ductal adenocarcinoma (PDAC). Here we examine their differential roles in PDAC. Results CCND1 and CCND3 expression were selectively suppressed by shRNA in PDAC cell lines with expression levels of equal CCND1 and CCND3 (BxPC3), enhanced CCND1 (HPAC) or enhanced CCND3 (PANC1). Suppression of cell proliferation was greater with CCND3 than CCND1 downregulation. CCND3 suppression led to a reduced level of phosphorylated retinoblastoma protein (Ser795p-Rb/p110) and resulted in decreased levels of cyclin A mRNA and protein. A global gene expression analysis identified deregulated genes in D1- or D3-cyclin siRNA-treated PANC1 cells. The downregulated gene targets in CCND3 suppressed cells were significantly enriched in cell cycle associated processes (p < 0.005). In contrast, focal adhesion/actin cytoskeleton, MAPK and NF B signaling appeared to characterize the target genes and their interacting proteins in CCND1 suppressed PANC1 cells. Conclusions Our results suggest that CCND3 is the primary driver of the cell cycle, in cooperation with CCND1 that integrates extracellular mitogenic signaling. We also present evidence that CCND1 plays a role in tumor cell migration. The results provide novel insights for common and differential targets of CCND1 and CCND3 overexpression during pancreatic duct cell carcinogenesis. PMID:20113529

  10. Anomalous arrangement of the pancreatobiliary ductal system in patients with a choledochal cyst.

    PubMed

    Todani, T; Watanabe, Y; Fujii, T; Uemura, S

    1984-05-01

    An anomalous arrangement of the pancreatobiliary ductal system is usually observed in patients with a congenital choledochal cyst and is represented by a long common channel distal to the pancreatobiliary junction. According to the angle of the pancreatobiliary junction, anomalous junctions can be classified into four groups: right angle, acute angle, complex union, and normal union (presented here in the order of their incidence). The right-angle type tends to have cystic dilatation of the choledochus, whereas the acute-angle type generally has cylindrical dilatation. However, the grade and length of the stenosis on the distal part of the choledochus tend to determine the type of choledochal cyst. Cystic dilatation is usually observed in patients with high-grade and long stenosis, whereas cylindrical dilatation is seen in those with low-grade and short stenosis. Patients with an acute angle junction seem to only suffer from abdominal pain, and those in the complex union group tend to have jaundice and an abdominal tumor. A high amylase level in the bile within the cyst is observed frequently. In patients with obstructive jaundice, however, the amylase level is usually not elevated, because pancreatic juice cannot enter the choledochus.

  11. Long-term Survival after Resection of HER2+ Infiltrating Ductal Carcinoma Metastasis to the Brainstem.

    PubMed

    Awad, Al-Wala; Zaidi, Hasan A; Awad, Al-Homam; Spetzler, Robert

    2016-01-01

    The central nervous system is a common site of metastatic spread from neoplasms in distant organs, including breast, bone, and lung. The decision to surgically treat these metastatic lesions is often challenging, especially in the setting of systemic disease or when eloquent brain regions are involved. Treating metastatic disease in the brainstem can be technically difficult, and in many institutions, considered a contraindication to surgical intervention, given the relatively high risk of new postoperative neurological deficits. Herein, we report a case of metastatic ductal carcinoma of the breast with spread to the pontine-medullary junction that was treated with aggressive surgical resection and chronic hormonal therapy. After surgical excision of the brainstem lesion, the patient remained asymptomatic and was maintained on trastuzumab therapy over a 10-year follow-up period, with no radiographic or clinical evidence of recurrent disease. To our knowledge, this is the first report of a patient treated for a solitary metastasis to the brainstem with long-term survival. PMID:26929889

  12. Morphometric grading of invasive ductal breast cancer. I. Thresholds for nuclear grade.

    PubMed Central

    Kronqvist, P.; Kuopio, T.; Collan, Y.

    1998-01-01

    We analysed 170 histological samples of invasive ductal breast cancer from years 1988-91 by computerized nuclear morphometry, to find objective and quantitative thresholds for nuclear grade. Based on Kaplan-Meier curves reflecting survival and recurrence of disease and univariate analysis by Cox's regression, optimal thresholds were determined for features related to nuclear size and size variation. In our material, with mean follow-up time of 5 years 9 months, the determined thresholds for nuclear profile area (32 microm2 and 47 microm2), nuclear diameter (6.4 microm and 7.4 microm) and mean shortest nuclear axis (4.8 microm and 6.4 microm) best separated the cases with favourable, intermediate and unfavourable course of disease. In this material from the era of mammography and adjuvant therapy, the mean shortest nuclear axis was found to be a significant prognostic factor, with a risk ratio (RR) exceeded only by that of tumour size (RRs 2.9- and 3.5-fold respectively). The results suggest that morphometric grading criteria can be developed for application in Bloom-Richardson grading and in the Nottingham Prognostic Index. PMID:9743304

  13. Analysis of long non-coding RNA expression profiles in pancreatic ductal adenocarcinoma.

    PubMed

    Fu, Xue-Liang; Liu, De-Jun; Yan, Ting-Ting; Yang, Jian-Yu; Yang, Min-Wei; Li, Jiao; Huo, Yan-Miao; Liu, Wei; Zhang, Jun-Feng; Hong, Jie; Hua, Rong; Chen, Hao-Yan; Sun, Yong-Wei

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive and lethal malignancies. Long non-coding RNAs (lncRNAs) are a novel class of non-protein-coding transcripts that have been implicated in cancer biogenesis and prognosis. By repurposing microarray probes, we herein analysed the lncRNA expression profiles in two public PDAC microarray datasets and identified 34 dysregulated lncRNAs in PDAC. In addition, the expression of 6 selected lncRNAs was confirmed in Ren Ji cohort and pancreatic cell lines, and their association with 80 PDAC patients' clinicopathological features and prognosis was investigated. Results indicated that AFAP1-AS1, UCA1 and ENSG00000218510 might be involved in PDAC progression and significantly associated with overall survival of PDAC. UCA1 and ENSG00000218510 expression status may serve as independent prognostic biomarkers for overall survival of PDAC. Gene set enrichment analysis (GSEA) analysis suggested that high AFAP1-AS1, UCA1 and low ENSG00000218510 expression were correlated with several tumorigenesis related pathways. Functional experiments demonstrated that AFAP1-AS1 and UCA1 were required for efficient invasion and/or proliferation promotion in PDAC cell lines, while ENSG00000218510 acted the opposite. Our findings provide novel information on lncRNAs expression profiles which might be beneficial to the precise diagnosis, subcategorization and ultimately, the individualized therapy of PDAC. PMID:27628540

  14. An angiopoietin-like protein 2 autocrine signaling promotes EMT during pancreatic ductal carcinogenesis.

    PubMed

    Carbone, Carmine; Piro, Geny; Fassan, Matteo; Tamburrino, Anna; Mina, Maria Mihaela; Zanotto, Marco; Chiao, Paul J; Bassi, Claudio; Scarpa, Aldo; Tortora, Giampaolo; Melisi, Davide

    2015-05-30

    The identification of the earliest molecular events responsible for the metastatic dissemination of pancreatic ductal adenocarcinoma (PDAC) remains critical for early detection, prevention, and treatment interventions. In this study, we hypothesized that an autocrine signaling between Angiopoietin-like Protein (ANGPTL)2 and its receptor leukocyte immunoglobulin-like receptor B2 (LILRB2) might be responsible for the epithelial-to-mesenchymal transition (EMT) and, the early metastatic behavior of cells in pancreatic preneoplastic lesions.We demonstrated that the sequential activation of KRAS, expression of HER2 and silencing of p16/p14 are sufficient to progressively and significantly increase the secretion of ANGPTL2, and the expression of LILRB2. Silencing the expression of ANGPTL2 reverted EMT and reduced migration in these cell lines. Blocking ANGPTL2 receptor LILRB2 in KRAS, and KRAS/HER2/p16p14shRNA LILRB2- expressing cells reduced ANGPTL2-induced cell proliferation and invasion. An increasingly significant overexpression of ANGPTL2 was observed in in a series of 68 different human PanIN and 27 PDAC lesions if compared with normal pancreatic parenchyma.These findings showed that the autocrine signaling of ANGPTL2 and its receptor LILRB2 plays key roles in sustaining EMT and the early metastatic behavior of cells in pancreatic preneoplastic lesions supporting the potential role of ANGPTL2 for early detection, metastasis prevention, and treatment in PDAC.

  15. Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors

    PubMed Central

    Daemen, Anneleen; Peterson, David; Sahu, Nisebita; McCord, Ron; Du, Xiangnan; Liu, Bonnie; Kowanetz, Katarzyna; Hong, Rebecca; Moffat, John; Gao, Min; Boudreau, Aaron; Mroue, Rana; Corson, Laura; O’Brien, Thomas; Qing, Jing; Sampath, Deepak; Merchant, Mark; Yauch, Robert; Manning, Gerard; Settleman, Jeffrey; Hatzivassiliou, Georgia; Evangelista, Marie

    2015-01-01

    Although targeting cancer metabolism is a promising therapeutic strategy, clinical success will depend on an accurate diagnostic identification of tumor subtypes with specific metabolic requirements. Through broad metabolite profiling, we successfully identified three highly distinct metabolic subtypes in pancreatic ductal adenocarcinoma (PDAC). One subtype was defined by reduced proliferative capacity, whereas the other two subtypes (glycolytic and lipogenic) showed distinct metabolite levels associated with glycolysis, lipogenesis, and redox pathways, confirmed at the transcriptional level. The glycolytic and lipogenic subtypes showed striking differences in glucose and glutamine utilization, as well as mitochondrial function, and corresponded to differences in cell sensitivity to inhibitors of glycolysis, glutamine metabolism, lipid synthesis, and redox balance. In PDAC clinical samples, the lipogenic subtype associated with the epithelial (classical) subtype, whereas the glycolytic subtype strongly associated with the mesenchymal (QM-PDA) subtype, suggesting functional relevance in disease progression. Pharmacogenomic screening of an additional ∼200 non-PDAC cell lines validated the association between mesenchymal status and metabolic drug response in other tumor indications. Our findings highlight the utility of broad metabolite profiling to predict sensitivity of tumors to a variety of metabolic inhibitors. PMID:26216984

  16. Elevated expression of CTHRC1 predicts unfavorable prognosis in patients with pancreatic ductal adenocarcinoma

    PubMed Central

    Liu, Wei; Fu, Xue-Liang; Yang, Jian-Yu; Yang, Min-Wei; Tao, Ling-Ye; Liu, De-Jun; Huo, Yan-Miao; Zhang, Jun-Feng; Hua, Rong; Sun, Yong-Wei

    2016-01-01

    Collagen triple helix repeat containing-1 (CTHRC1), a secreted protein, has been demonstrated as an oncogene in many types of human cancers including pancreatic ductal adenocarcinoma (PDAC). However, little is known about the prognostic value of CTHRC1 in PDAC. In current study, we investigated the expression pattern and underlying clinical significance of CTHRC1 in PDAC. Data from public PDAC microarray datasets, real-time PCR and immunohistochemistry demonstrated that CTHRC1 expression was dramatically increased in PDAC compared with normal tissues at both mRNA and protein level, which was consistent with previous studies. Analysis of its correlation with clinicopathological parameters indicated that high protein expression level of CTHRC1 was significantly associated with lymph node metastasis, vascular invasion and perineural invasion. Kaplan-Meier survival analysis showed that patients with higher CTHRC1 expression exhibited a remarkably shorter overall survival in four different PDAC patient cohorts. Importantly, univariable and multivariable Cox regression analysis revealed that CTHRC1 protein expression level was a significant and independent prognostic factor for overall survival rate of PDAC patients. Together, these data suggested that CTHRC1 is an unfavorable biomarker of prognosis in PDAC and may serve as a potential therapeutic candidate for PDAC treatment. PMID:27648368

  17. An angiopoietin-like protein 2 autocrine signaling promotes EMT during pancreatic ductal carcinogenesis

    PubMed Central

    Carbone, Carmine; Piro, Geny; Fassan, Matteo; Tamburrino, Anna; Mina, Maria Mihaela; Zanotto, Marco; Chiao, Paul J; Bassi, Claudio; Scarpa, Aldo; Tortora, Giampaolo; Melisi, Davide

    2015-01-01

    The identification of the earliest molecular events responsible for the metastatic dissemination of pancreatic ductal adenocarcinoma (PDAC) remains critical for early detection, prevention, and treatment interventions. In this study, we hypothesized that an autocrine signaling between Angiopoietin-like Protein (ANGPTL)2 and its receptor leukocyte immunoglobulin-like receptor B2 (LILRB2) might be responsible for the epithelial-to-mesenchymal transition (EMT) and, the early metastatic behavior of cells in pancreatic preneoplastic lesions. We demonstrated that the sequential activation of KRAS, expression of HER2 and silencing of p16/p14 are sufficient to progressively and significantly increase the secretion of ANGPTL2, and the expression of LILRB2. Silencing the expression of ANGPTL2 reverted EMT and reduced migration in these cell lines. Blocking ANGPTL2 receptor LILRB2 in KRAS, and KRAS/HER2/p16p14shRNA LILRB2- expressing cells reduced ANGPTL2-induced cell proliferation and invasion. An increasingly significant overexpression of ANGPTL2 was observed in in a series of 68 different human PanIN and 27 PDAC lesions if compared with normal pancreatic parenchyma. These findings showed that the autocrine signaling of ANGPTL2 and its receptor LILRB2 plays key roles in sustaining EMT and the early metastatic behavior of cells in pancreatic preneoplastic lesions supporting the potential role of ANGPTL2 for early detection, metastasis prevention, and treatment in PDAC. PMID:25360865

  18. Metabonomic changes from pancreatic intraepithelial neoplasia to pancreatic ductal adenocarcinoma in tissues from rats.

    PubMed

    Wen, Shi; Li, Zhishui; Feng, Jianghua; Bai, Jianxi; Lin, Xianchao; Huang, Heguang

    2016-06-01

    Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors and is difficult to diagnose in the early phase. This study was aimed at obtaining the metabolic profiles and characteristic metabolites of pancreatic intraepithelial neoplasia (PanIN) and PDAC tissues from Sprague-Dawley (SD) rats to establish metabonomic methods used in the early diagnosis of PDAC. In the present study, the animal models were established by embedding 7,12-dimethylbenzanthracene (DMBA) in the pancreas of SD rats to obtain PanIN and PDAC tissues. After the preprocessing of tissues, (1) H nuclear magnetic resonance (NMR) spectroscopy combined with multivariate and univariate statistical analysis was applied to identify the potential metabolic signatures and the corresponding metabolic pathways. Pattern recognition models were successfully established and differential metabolites, including glucose, amino acids, carboxylic acids and coenzymes, were screened out. Compared with the control, the trends in the variation of several metabolites were similar in both PanIN and PDAC. Kynurenate and methionine levels were elevated in PanIN but decreased in PDAC, thus, could served as biomarkers to distinguish PanIN from PDAC. Our results suggest that NMR-based techniques combined with multivariate statistical analysis can distinguish the metabolic differences among PanIN, PDAC and normal tissues, and, therefore, present a promising approach for physiopathologic metabolism investigations and early diagnoses of PDAC. PMID:27019331

  19. MUC16 contributes to the metastasis of pancreatic ductal adenocarcinoma through focal adhesion mediated signaling mechanism

    PubMed Central

    Chugh, Seema; Rachagani, Satyanarayana; Lakshmanan, Imayavaramban; Gupta, Suprit; Seshacharyulu, Parthasarathy; Smith, Lynette M.; Ponnusamy, Moorthy P.; Batra, Surinder K.

    2016-01-01

    MUC16, a heavily glycosylated type-I transmembrane mucin is overexpressed in several cancers including pancreatic ductal adenocarcinoma (PDAC). Previously, we have shown that MUC16 is significantly overexpressed in human PDAC tissues. However, the functional consequences and its role in PDAC is poorly understood. Here, we show that MUC16 knockdown decreases PDAC cell proliferation, colony formation and migration in vitro. Also, MUC16 knockdown decreases the tumor formation and metastasis in orthotopic xenograft mouse model. Mechanistically, immunoprecipitation and immunofluorescence analyses confirms MUC16 interaction with galectin-3 and mesothelin in PDAC cells. Adhesion assay displayed decreased cell attachment of MUC16 knockdown cells with recombinant galectin-1 and galectin-3 protein. Further, CRISPR/Cas9-mediated MUC16 knockout cells show decreased tumor-associated carbohydrate antigens (T and Tn) in PDAC cells. Importantly, carbohydrate antigens were decreased in the region that corresponds to MUC16 and suggests for the decreased MUC16-galectin interactions. Co-immunoprecipitation also revealed a novel interaction between MUC16 and FAK in PDAC cells. Interestingly, we observed decreased expression of mesenchymal and increased expression of epithelial markers in MUC16-silenced cells. Additionally, MUC16 loss showed a decreased FAK-mediated Akt and ERK/MAPK activation. Altogether, these findings suggest that MUC16-focal adhesion signaling may play a critical role in facilitating PDAC growth and metastasis. PMID:27382435

  20. Imbalanced expression of Tif1γ inhibits pancreatic ductal epithelial cell growth

    PubMed Central

    Ligr, Martin; Wu, Xinyu; Daniels, Garrett; Zhang, David; Wang, Huamin; Hajdu, Cristina; Wang, Jinhua; Pan, Ruimin; Pei, Zhiheng; Zhang, Lanjing; Melis, Marcovalerio; Pincus, Matthew R; Saunders, John K; Lee, Peng; Xu, Ruliang

    2014-01-01

    Transcriptional intermediary factor 1 gamma (Tif1γ) (Ectodermin/PTC7/RFG7/TRIM33) is a transcriptional cofactor with an important role in the regulation of the TGFβ pathway. It has been suggested that it competes with Smad2/Smad3 for binding to Smad4, or alternatively that it may target Smad4 for degradation, although its role in carcinogenesis is unclear. In this study, we showed that Tif1γ interacts with Smad1/Smad4 complex in vivo, using both yeast two-hybrid and coimmunoprecipitation assays. We demonstrated that Tif1γ inhibits transcriptional activity of the Smad1/Smad4 complex through its PHD domain or bromo-domainin pancreatic cells by luciferase assay. Additionally, there is a dynamic inverse relationship between the levels of Tif1γ and Smad4 in benign and malignant pancreatic cell lines. Overexpression of Tif1γ resulted in decreased level of Smad4. Both overexpression and knockdown of Tif1γ resulted in growth inhibition in both benign and cancerous pancreatic cell lines, attributable to a G2-phase cell cycle arrest, but only knockdown of Tif1γ reduces tumor cell invasiveness in vitro. Our study demonstrated that imbalanced expression of Tif1γ results in inhibition of pancreatic ductal epithelial cell growth. In addition, knockdown of Tif1γ may inhibit tumor invasion. These data suggest that Tif1γ might serve as a potential therapeutic target for pancreatic cancer. PMID:24959375

  1. Efficacy of Contrast-enhanced Harmonic Endoscopic Ultrasonography in the Diagnosis of Pancreatic Ductal Carcinoma

    PubMed Central

    Uekitani, Toshiyuki; Kaino, Seiji; Harima, Hirofumi; Suenaga, Shigeyuki; Sen-yo, Manabu; Sakaida, Isao

    2016-01-01

    Background/Aims: Distinguishing pancreatic ductal carcinoma (DC) from other pancreatic masses remains challenging. This study aims at evaluating the efficacy of contrast-enhanced harmonic endoscopic ultrasonography (CEH-EUS) in the diagnosis of DC. Patients and Methods: Forty-nine patients with solid pancreatic mass lesions underwent CEH-EUS. EUS (B-mode) was used to evaluate the inner echoes, distributions, and borders of the masses. The vascular patterns of the masses were evaluated with CEH-EUS at 30–50 s (early phase) and 70–90 s (late phase) after the administration of Sonazoid®. Results: The final diagnoses included DCs (37), mass-forming pancreatitis (6), endocrine neoplasms (3), a solid pseudopapillary neoplasm (1), a metastatic carcinoma (1), and an acinar cell carcinoma (1). The sensitivity, specificity, and accuracy of the diagnoses of DC in hypoechoic masses using EUS (B-mode) were 89.2%, 16.7%, and 71.4%, respectively. The sensitivity, specificity, and accuracy for the diagnosis of DC in hypovascular masses using CEH-EUS were 73.0%, 91.7%, and 77.6% in the early phase and 83.8%, 91.7%, and 85.7% in the late phase, respectively. Conclusions: CEH-EUS for the diagnosis of DC is superior to EUS. CEH-EUS in the late phase was particularly efficacious in the diagnosis of DC. PMID:27184637

  2. Identification of novel vascular projections with cellular trafficking abilities on the microvasculature of pancreatic ductal adenocarcinoma

    PubMed Central

    Wu, Yanhua; Wei, Youheng; Fang, Yuan; Han, Xu; Li, Jianang; Zhou, Ping; Yi, Qing; Maitra, Anirban; Liu, Jun O; Tuveson, David A.; Lou, Wenhui; Yu, Long

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a nearly lethal neoplasm. It is a remarkably stroma-rich, vascular-poor, hypoperfused tumor, which prevents efficient drug delivery. Paradoxically, the neoplastic cells have robust glucose uptake, suggesting the microvasculature has adopted an alternative method for nutrient uptake and cellular trafficking. Using an adapted thick tumor section immunostaining and 3-dimensional (3D) construction imaging method in human tissue samples, we identified an undiscovered feature of the mature and angiostatic microvasculature in advanced PDAC tumors; long, “hairy”-like projections on the basal surface of microvessels that we refer to as “basal microvilli”. Functionally, these basal microvilli have an actin-rich cytoskeleton, endocytic and exocytic properties, and they contain glucose transporter-1 (GLUT-1) positive vesicles. Clinically, as was demonstrated by PET-CT, the tumor microvasculature with the longest and the most abundant basal microvilli positively correlated with the high glucose uptake of the PDAC tumor itself. In addition, these basal microvilli were found in regions of the tumor with low GLUT-1 expression, suggesting their presence could be dependent upon the glucose concentrations in the tumor milieu. Altogether, these basal microvilli mark a novel, pathological feature of the PDAC tumor microvasculature. Because these basal microvilli are pathological features with endo- and exocytic properties, they may provide a non-conventional method for cellular trafficking in PDAC tumors. PMID:25561062

  3. Analysis of long non-coding RNA expression profiles in pancreatic ductal adenocarcinoma

    PubMed Central

    Fu, Xue-Liang; Liu, De-Jun; Yan, Ting-Ting; Yang, Jian-Yu; Yang, Min-Wei; Li, Jiao; Huo, Yan-Miao; Liu, Wei; Zhang, Jun-Feng; Hong, Jie; Hua, Rong; Chen, Hao-Yan; Sun, Yong-Wei

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive and lethal malignancies. Long non-coding RNAs (lncRNAs) are a novel class of non-protein-coding transcripts that have been implicated in cancer biogenesis and prognosis. By repurposing microarray probes, we herein analysed the lncRNA expression profiles in two public PDAC microarray datasets and identified 34 dysregulated lncRNAs in PDAC. In addition, the expression of 6 selected lncRNAs was confirmed in Ren Ji cohort and pancreatic cell lines, and their association with 80 PDAC patients’ clinicopathological features and prognosis was investigated. Results indicated that AFAP1-AS1, UCA1 and ENSG00000218510 might be involved in PDAC progression and significantly associated with overall survival of PDAC. UCA1 and ENSG00000218510 expression status may serve as independent prognostic biomarkers for overall survival of PDAC. Gene set enrichment analysis (GSEA) analysis suggested that high AFAP1-AS1, UCA1 and low ENSG00000218510 expression were correlated with several tumorigenesis related pathways. Functional experiments demonstrated that AFAP1-AS1 and UCA1 were required for efficient invasion and/or proliferation promotion in PDAC cell lines, while ENSG00000218510 acted the opposite. Our findings provide novel information on lncRNAs expression profiles which might be beneficial to the precise diagnosis, subcategorization and ultimately, the individualized therapy of PDAC. PMID:27628540

  4. Simultaneous targeting of 5-LOX-COX and EGFR blocks progression of pancreatic ductal adenocarcinoma

    PubMed Central

    Rao, Chinthalapally V.; Janakiram, Naveena B.; Madka, Venkateshwar; Devarkonda, Vishal; Brewer, Misty; Biddick, Laura; Lightfoot, Stan; Steele, Vernon E.; Mohammed, Altaf

    2015-01-01

    Cyclooxygenase-2 (COX-2), 5-Lipoxygenase (5-LOX), and epidermal growth factor receptor (EGRF) are over-expressed in human pancreatic ductal adenocarcinoma (PDAC). Using next-generation sequencing (NGS) analysis, we show significant increase in COX-2, 5-LOX, and EGFR expression during PDAC progression. Targeting complementary pathways will achieve better treatment efficacy than a single agent high-dose strategy that could increase risk of side effects and tumor resistance. To target COX-2, 5-LOX, and EGFR simultaneously, we tested effects of licofelone (dual 5-LOX-COX inhibitor), and gefitinib (EGFR inhibitor), individually and in combination, on pancreatic intraepithelial neoplasms (PanINs) and their progression to PDAC using genetically engineered mice. Individually, licofelone (L) and gefitinib (G) significantly inhibited incidence of PDAC in male (72% L, 90% G, p < 0.0001) and female (90% L, 85% G, p < 0.0001) mice. The combination drug treatment produced complete inhibition of PDAC in both genders. Pancreata of mice receiving combination treatment showed significantly fewer Dclk1-positive cancer stem-like cells, inhibition of COX-2, 5-LOX, PCNA, EGFR and β-catenin expression (p < 0.05–0.0002), increased p21 expression. Significant changes in tumor immune responses and desmoplastic reaction was observed by NGS analysis in combination treatment (p < 0.05). In summary, early simultaneous targeting of 5-LOX-COX- and EGFR pathways may provide additive inhibitory effects leading to complete suppression of PDAC. PMID:26429877

  5. Quantitative Proteomic Analysis of Differentially Expressed Protein Profiles Involved in Pancreatic Ductal Adenocarcinoma

    PubMed Central

    Kuo, Kung-Kai; Kuo, Chao-Jen; Chiu, Chiang-Yen; Liang, Shih-Shin; Huang, Chun-Hao; Chi, Shu-Wen; Tsai, Kun-Bow; Chen, Chiao-Yun; Hsi, Edward; Cheng, Kuang-Hung; Chiou, Shyh-Horng

    2016-01-01

    Objectives The aim of this study was to identify differentially expressed proteins among various stages of pancreatic ductal adenocarcinoma (PDAC) by shotgun proteomics using nano-liquid chromatography coupled tandem mass spectrometry and stable isotope dimethyl labeling. Methods Differentially expressed proteins were identified and compared based on the mass spectral differences of their isotope-labeled peptide fragments generated from protease digestion. Results Our quantitative proteomic analysis of the differentially expressed proteins with stable isotope (deuterium/hydrogen ratio, ≥2) identified a total of 353 proteins, with at least 5 protein biomarker proteins that were significantly differentially expressed between cancer and normal mice by at least a 2-fold alteration. These 5 protein biomarker candidates include α-enolase, α-catenin, 14-3-3 β, VDAC1, and calmodulin with high confidence levels. The expression levels were also found to be in agreement with those examined by Western blot and histochemical staining. Conclusions The systematic decrease or increase of these identified marker proteins may potentially reflect the morphological aberrations and diseased stages of pancreas carcinoma throughout progressive developments leading to PDAC. The results would form a firm foundation for future work concerning validation and clinical translation of some identified biomarkers into targeted diagnosis and therapy for various stages of PDAC. PMID:26262590

  6. Amplified centrosomes may underlie aggressive disease course in pancreatic ductal adenocarcinoma

    PubMed Central

    Mittal, Karuna; Ogden, Angela; Reid, Michelle D; Rida, Padmashree CG; Varambally, Sooryanarayana; Aneja, Ritu

    2015-01-01

    Centrosome amplification (CA), the presence of centrosomes that are abnormally numerous or enlarged, is a well-established driver of tumor initiation and progression associated with poor prognosis across a diversity of malignancies. Pancreatic ductal adenocarcinoma (PDAC) carries one of the most dismal prognoses of all cancer types. A majority of these tumors are characterized by numerical and structural centrosomal aberrations, but it is unknown how CA contributes to the disease and patient outcomes. In this study, we sought to determine whether CA was associated with worse clinical outcomes, poor prognostic indicators, markers of epithelial-mesenchymal transition (EMT), and ethnicity in PDAC. We also evaluated whether CA could precipitate more aggressive phenotypes in a panel of cultured PDAC cell lines. Using publicly available microarray data, we found that increased expression of genes whose dysregulation promotes CA was associated with worse overall survival and increased EMT marker expression in PDAC. Quantitative analysis of centrosomal profiles in PDAC cell lines and tissue sections uncovered varying levels of CA, and the expression of CA markers was associated with the expression of EMT markers. We induced CA in PDAC cells and found that CA empowered them with enhanced invasive and migratory capabilities. In addition, we discovered that PDACs from African American (AA) patients exhibited a greater extent of both numerical and structural CA than PDACs from European American (EA) patients. Taken together, these findings suggest that CA may fuel a more aggressive disease course in PDAC patients. PMID:26151406

  7. Warburg metabolism in tumor-conditioned macrophages promotes metastasis in human pancreatic ductal adenocarcinoma.

    PubMed

    Penny, Hweixian Leong; Sieow, Je Lin; Adriani, Giulia; Yeap, Wei Hseun; See Chi Ee, Peter; San Luis, Boris; Lee, Bernett; Lee, Terence; Mak, Shi Ya; Ho, Ying Swan; Lam, Kong Peng; Ong, Choon Kiat; Huang, Ruby Y J; Ginhoux, Florent; Rotzschke, Olaf; Kamm, Roger D; Wong, Siew Cheng

    2016-08-01

    Patients with pancreatic ductal adenocarcinoma (PDAC) face a clinically intractable disease with poor survival rates, attributed to exceptionally high levels of metastasis. Epithelial-to-mesenchymal transition (EMT) is pronounced at inflammatory foci within the tumor; however, the immunological mechanisms promoting tumor dissemination remain unclear. It is well established that tumors exhibit the Warburg effect, a preferential use of glycolysis for energy production, even in the presence of oxygen, to support rapid growth. We hypothesized that the metabolic pathways utilized by tumor-infiltrating macrophages are altered in PDAC, conferring a pro-metastatic phenotype. We generated tumor-conditioned macrophages in vitro, in which human peripheral blood monocytes were cultured with conditioned media generated from normal pancreatic or PDAC cell lines to obtain steady-state and tumor-associated macrophages (TAMs), respectively. Compared with steady-state macrophages, TAMs promoted vascular network formation, augmented extravasation of tumor cells out of blood vessels, and induced higher levels of EMT. TAMs exhibited a pronounced glycolytic signature in a metabolic flux assay, corresponding with elevated glycolytic gene transcript levels. Inhibiting glycolysis in TAMs with a competitive inhibitor to Hexokinase II (HK2), 2-deoxyglucose (2DG), was sufficient to disrupt this pro-metastatic phenotype, reversing the observed increases in TAM-supported angiogenesis, extravasation, and EMT. Our results indicate a key role for metabolic reprogramming of tumor-infiltrating macrophages in PDAC metastasis, and highlight the therapeutic potential of using pharmacologics to modulate these metabolic pathways. PMID:27622062

  8. Elevated expression of CTHRC1 predicts unfavorable prognosis in patients with pancreatic ductal adenocarcinoma.

    PubMed

    Liu, Wei; Fu, Xue-Liang; Yang, Jian-Yu; Yang, Min-Wei; Tao, Ling-Ye; Liu, De-Jun; Huo, Yan-Miao; Zhang, Jun-Feng; Hua, Rong; Sun, Yong-Wei

    2016-01-01

    Collagen triple helix repeat containing-1 (CTHRC1), a secreted protein, has been demonstrated as an oncogene in many types of human cancers including pancreatic ductal adenocarcinoma (PDAC). However, little is known about the prognostic value of CTHRC1 in PDAC. In current study, we investigated the expression pattern and underlying clinical significance of CTHRC1 in PDAC. Data from public PDAC microarray datasets, real-time PCR and immunohistochemistry demonstrated that CTHRC1 expression was dramatically increased in PDAC compared with normal tissues at both mRNA and protein level, which was consistent with previous studies. Analysis of its correlation with clinicopathological parameters indicated that high protein expression level of CTHRC1 was significantly associated with lymph node metastasis, vascular invasion and perineural invasion. Kaplan-Meier survival analysis showed that patients with higher CTHRC1 expression exhibited a remarkably shorter overall survival in four different PDAC patient cohorts. Importantly, univariable and multivariable Cox regression analysis revealed that CTHRC1 protein expression level was a significant and independent prognostic factor for overall survival rate of PDAC patients. Together, these data suggested that CTHRC1 is an unfavorable biomarker of prognosis in PDAC and may serve as a potential therapeutic candidate for PDAC treatment. PMID:27648368

  9. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular-fibrosis and tumor progression

    PubMed Central

    Laklai, Hanane; Miroshnikova, Yekaterina A.; Pickup, Michael W.; Collisson, Eric A.; Kim, Grace E.; Barrett, Alex S.; Hill, Ryan C.; Lakins, Johnathon N.; Schlaepfer, David D.; Mouw, Janna K.; LeBleu, Valerie S.; Roy, Nilotpal; Novitskiy, Sergey V.; Johansen, Julia S.; Poli, Valeria; Kalluri, Raghu; Iacobuzio-Donahue, Christine A.; Wood, Laura D.; Hebrok, Matthias; Hansen, Kirk; Moses, Harold L.; Weaver, Valerie M.

    2016-01-01

    Fibrosis compromises pancreatic ductal carcinoma (PDAC) treatment and contributes to patient mortality yet anti-stromal therapies are controversial. We found that human PDACs with impaired epithelial transforming growth factor β (TGF-β) signaling have elevated epithelial Stat3 activity and develop a stiffer, matricellular-enriched fibrosis associated with high epithelial tension and shorter patient survival. In several Kras-driven mouse models, both the loss of TGF-β signaling and elevated β1-integrin mechanosignaling engaged a positive feedback loop whereby Stat3 signaling promotes tumor progression by increasing matricellular fibrosis and tissue tension. In contrast, epithelial Stat3 ablation attenuated tumor progression by reducing the stromal stiffening and epithelial contractility induced by loss of TGF-β signaling. In PDAC patient biopsies, higher matricellular protein and activated Stat3 associated with SMAD4 mutation and shorter survival. The findings implicate epithelial tension and matricellular fibrosis in the aggressiveness of SMAD4 mutant pancreatic tumors, and highlight Stat3 and mechanics as key drivers of this phenotype. PMID:27089513

  10. Invasive ductal breast carcinoma detector that is robust to image magnification in whole digital slides.

    PubMed

    Balazsi, Matthew; Blanco, Paula; Zoroquiain, Pablo; Levine, Martin D; Burnier, Miguel N

    2016-04-01

    Invasive ductal breast carcinomas (IDBCs) are the most frequent and aggressive subtypes of breast cancer, affecting a large number of Canadian women every year. Part of the diagnostic process includes grading the cancerous tissue at the microscopic level according to the Nottingham modification of the Scarff-Bloom-Richardson system. Although reliable, there exists a growing interest in automating the grading process, which will provide consistent care for all patients. This paper presents a solution for automatically detecting regions expressing IDBC in images of microscopic tissue, or whole digital slides. This represents the first stage in a larger solution designed to automatically grade IDBC. The detector first tessellated whole digital slides, and image features were extracted, such as color information, local binary patterns, and histograms of oriented gradients. These were presented to a random forest classifier, which was trained and tested using a database of 66 cases diagnosed with IDBC. When properly tuned, the detector balanced accuracy, F1 score, and Dice's similarity coefficient were 88.7%, 79.5%, and 0.69, respectively. Overall, the results seemed strong enough to integrate our detector into a larger solution equipped with components that analyze the cancerous tissue at higher magnification, automatically producing the histopathological grade. PMID:27226977

  11. Overview of the randomized trials of radiotherapy in ductal carcinoma in situ of the breast.

    PubMed

    Correa, C; McGale, P; Taylor, C; Wang, Y; Clarke, M; Davies, C; Peto, R; Bijker, N; Solin, L; Darby, S

    2010-01-01

    Individual patient data were available for all four of the randomized trials that began before 1995, and that compared adjuvant radiotherapy vs no radiotherapy following breast-conserving surgery for ductal carcinoma in situ (DCIS). A total of 3729 women were eligible for analysis. Radiotherapy reduced the absolute 10-year risk of any ipsilateral breast event (ie, either recurrent DCIS or invasive cancer) by 15.2% (SE 1.6%, 12.9% vs 28.1% 2 P <.00001), and it was effective regardless of the age at diagnosis, extent of breast-conserving surgery, use of tamoxifen, method of DCIS detection, margin status, focality, grade, comedonecrosis, architecture, or tumor size. The proportional reduction in ipsilateral breast events was greater in older than in younger women (2P < .0004 for difference between proportional reductions; 10-year absolute risks: 18.5% vs 29.1% at ages <50 years, 10.8% vs 27.8% at ages ≥ 50 years) but did not differ significantly according to any other available factor. Even for women with negative margins and small low-grade tumors, the absolute reduction in the 10-year risk of ipsilateral breast events was 18.0% (SE 5.5, 12.1% vs 30.1%, 2P = .002). After 10 years of follow-up, there was, however, no significant effect on breast cancer mortality, mortality from causes other than breast cancer, or all-cause mortality.

  12. A Multicenter Trial Defining a Serum Protein Signature Associated with Pancreatic Ductal Adenocarcinoma

    PubMed Central

    Gerdtsson, Anna S.; Malats, Núria; Säll, Anna; Real, Francisco X.; Porta, Miquel; Skoog, Petter; Persson, Helena; Wingren, Christer; Borrebaeck, Carl A. K.

    2015-01-01

    Background. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with rapid tumor progression and poor prognosis. This study was motivated by the lack of sensitive and specific PDAC biomarkers and aimed to identify a diagnostic, serum protein signature for PDAC. Methods. To mimic a real life test situation, a multicenter trial comprising a serum sample cohort, including 338 patients with either PDAC or other pancreatic diseases (OPD) and controls with nonpancreatic conditions (NPC), was analyzed on 293-plex recombinant antibody microarrays targeting immunoregulatory and cancer-associated antigens. Results. Serum samples collected from different hospitals were analyzed and showed that (i) sampling from five different hospitals could not be identified as a preanalytical variable and (ii) a multiplexed biomarker signature could be identified, utilizing up to 10 serum markers that could discriminate PDAC from controls, with sensitivities and specificities in the 91–100% range. The first protein profiles associated with the location of the primary tumor in the pancreas could also be identified. Conclusions. The results demonstrate that robust enough serum signatures could be identified in a multicenter trial, potentially contributing to the development of a multiplexed biomarker immunoassay for improved PDAC diagnosis. PMID:26587286

  13. Genetic ablation of Smoothened in pancreatic fibroblasts increases acinar-ductal metaplasia.

    PubMed

    Liu, Xin; Pitarresi, Jason R; Cuitiño, Maria C; Kladney, Raleigh D; Woelke, Sarah A; Sizemore, Gina M; Nayak, Sunayana G; Egriboz, Onur; Schweickert, Patrick G; Yu, Lianbo; Trela, Stefan; Schilling, Daniel J; Halloran, Shannon K; Li, Maokun; Dutta, Shourik; Fernandez, Soledad A; Rosol, Thomas J; Lesinski, Gregory B; Shakya, Reena; Ludwig, Thomas; Konieczny, Stephen F; Leone, Gustavo; Wu, Jinghai; Ostrowski, Michael C

    2016-09-01

    The contribution of the microenvironment to pancreatic acinar-to-ductal metaplasia (ADM), a preneoplastic transition in oncogenic Kras-driven pancreatic cancer progression, is currently unclear. Here we show that disruption of paracrine Hedgehog signaling via genetic ablation of Smoothened (Smo) in stromal fibroblasts in a Kras(G12D) mouse model increased ADM. Smo-deleted fibroblasts had higher expression of transforming growth factor-α (Tgfa) mRNA and secreted higher levels of TGFα, leading to activation of EGFR signaling in acinar cells and increased ADM. The mechanism involved activation of AKT and noncanonical activation of the GLI family transcription factor GLI2. GLI2 was phosphorylated at Ser230 in an AKT-dependent fashion and directly regulated Tgfa expression in fibroblasts lacking Smo Additionally, Smo-deleted fibroblasts stimulated the growth of Kras(G12D)/Tp53(R172H) pancreatic tumor cells in vivo and in vitro. These results define a non-cell-autonomous mechanism modulating Kras(G12D)-driven ADM that is balanced by cross-talk between Hedgehog/SMO and AKT/GLI2 pathways in stromal fibroblasts. PMID:27633013

  14. Comparative evaluation of cancer stem cell markers in normal pancreas and pancreatic ductal adenocarcinoma.

    PubMed

    Vizio, Barbara; Mauri, Francesco A; Prati, Adriana; Trivedi, Pritesh; Giacobino, Alice; Novarino, Anna; Satolli, Maria Antonietta; Ciuffreda, Libero; Camandona, Michele; Gasparri, Guido; Bellone, Graziella

    2012-01-01

    Chemoresistance and self-renewal of cancer stem cells (CSC), found in many tumors including pancreatic ductal adenocarcinoma (PDAC), are believed to underlie tumor mass regrowth. The distribution of cells carrying the putative stem-cell markers CD133, Nestin, Notch1-4, Jagged1 and 2, ABCG2 and aldehyde dehydrogenase (ALDH1) was assessed immunohistochemically using PDAC and normal pancreas tissue microarrays. The immunoreactivity was semi-quantitatively graded against the normal pancreas and was correlated with the differentiation grade and disease stage. No statistical significant differences were found between normal pancreas and PDAC in the expression of Nestin, Notch1, 3 and 4, ABCG2 or ALDH1. Notch2 and Jagged1 and 2 expression were increased in PDAC. CD133-positive cells were above-normal in PDAC, but the difference was not statistically significant. Nestin, Notch1-4, Jagged1, ABCG2 and ALDH1 immunostaining scores were not correlated with tumor grade or disease stage. CD133 and Notch2 expression was significantly inversely correlated with tumor grade, but not disease stage. Notch3 immunostaining positively correlated with tumor stage, but not with differentiation grade. Jagged2 protein expression correlated inversely with disease stage, but not with tumor grade. From the clinical standpoint, improved delineation of the tumor CSC signature, putatively responsible for tumor initiation and recurrence after initial response to chemotherapy, may offer novel therapeutic targets for this highly lethal cancer.

  15. Identifying three different architectural subtypes of mammary ductal carcinoma in situ using multiphoton microscopy

    NASA Astrophysics Data System (ADS)

    Wu, Yan; Fu, Fangmeng; Lian, Yuane; Nie, Yuting; Zhuo, shuangmu; Wang, Chuan; Chen, Jianxin

    2015-10-01

    Ductal carcinoma in situ (DCIS) is often considered as the precursor of invasive breast cancer, and the risk of DCIS progression to IBC has been estimated based on the evaluation of pathological features, among which the architectural subtype is the most common one. In this study, multiphoton microscopy (MPM) is applied to identify three different architectural subtypes of DCIS (solid, cribriform and comedo). It is found that MPM has the capability to visualize the proliferating pattern of tumor cells, the presence of intraluminal necrosis and the morphology of basement membrane, which are all taken into account in subtyping DCIS. In addition, MPM also can be used to quantify the cellular metabolism, for quantitatively identifying tumor staging during tumor progression. This result highlights the potential of MPM as an advanced technique to assess the pathological characters of the breast tumor in real-time and reflect the degree of tumor progression in vivo, by integrating into the intra-fiberoptic ductoscopy or transdermal biopsy needle.

  16. Prenatal programming of pulmonary hypertension induced by chronic hypoxia or ductal ligation in sheep

    PubMed Central

    2013-01-01

    Abstract Pulmonary hypertension of the newborn is caused by a spectrum of functional and structural abnormalities of the cardiopulmonary circuit. The existence of multiple etiologies and an incomplete understanding of the mechanisms of disease progression have hindered the development of effective therapies. Animal models offer a means of gaining a better understanding of the fundamental basis of the disease. To that effect, a number of experimental animal models are being used to generate pulmonary hypertension in the fetus and newborn. In this review, we compare the mechanisms associated with pulmonary hypertension caused by two such models: in utero ligation of the ductus arteriosus and chronic perinatal hypoxia in sheep fetuses and newborns. In this manner, we make direct comparisons between ductal ligation and chronic hypoxia with respect to the associated mechanisms of disease, since multiple studies have been performed with both models in a single species. We present evidence that the mechanisms associated with pulmonary hypertension are dependent on the type of stress to which the fetus is subjected. Such an analysis allows for a more thorough evaluation of the disease etiology, which can help focus clinical treatments. The final part of the review provides a clinical appraisal of current treatment strategies and lays the foundation for developing individualized therapies that depend on the causative factors. PMID:25006393

  17. The Proteomes of Human Parotid and Submandibular/Sublingual Gland Salivas Collected as the Ductal Secretions

    PubMed Central

    Denny, Paul; Hagen, Fred K.; Hardt, Markus; Liao, Lujian; Yan, Weihong; Arellanno, Martha; Bassilian, Sara; Bedi, Gurrinder S.; Boontheung, Pinmannee; Cociorva, Daniel; Delahunty, Claire M.; Denny, Trish; Dunsmore, Jason; Faull, Kym F.; Gilligan, Joyce; Gonzalez-Begne, Mireya; Halgand, Frédéric; Hall, Steven C.; Han, Xuemei; Henson, Bradley; Hewel, Johannes; Hu, Shen; Jeffrey, Sherry; Jiang, Jiang; Loo, Joseph A.; Ogorzalek Loo, Rachel R.; Malamud, Daniel; Melvin, James E.; Miroshnychenko, Olga; Navazesh, Mahvash; Niles, Richard; Park, Sung Kyu; Prakobphol, Akraporn; Ramachandran, Prasanna; Richert, Megan; Robinson, Sarah; Sondej, Melissa; Souda, Puneet; Sullivan, Mark A.; Takashima, Jona; Than, Shawn; Wang, Jianghua; Whitelegge, Julian P.; Witkowska, H. Ewa; Wolinsky, Lawrence; Xie, Yongming; Xu, Tao; Yu, Weixia; Ytterberg, Jimmy; Wong, David T.; Yates, John R.; Fisher, Susan J.

    2009-01-01

    Saliva is a body fluid with important functions in oral and general health. A consortium of three research groups catalogued the proteins in human saliva collected as the ductal secretions: 1166 identifications—914 in parotid and 917 in submandibular/sublingual saliva—were made. The results showed that a high proportion of proteins that are found in plasma and/or tears are also present in saliva along with unique components. The proteins identified are involved in numerous molecular processes ranging from structural functions to enzymatic/catalytic activities. As expected, the majority mapped to the extracellular and secretory compartments. An immunoblot approach was used to validate the presence in saliva of a subset of the proteins identified by mass spectrometric approaches. These experiments focused on novel constituents and proteins for which the peptide evidence was relatively weak. Ultimately, information derived from the work reported here and related published studies can be used to translate blood-based clinical laboratory tests into a format that utilizes saliva. Additionally, a catalogue of the salivary proteome of healthy individuals allows future analyses of salivary samples from individuals with oral and systemic diseases, with the goal of identifying biomarkers with diagnostic and/or prognostic value for these conditions; another possibility is the discovery of therapeutic targets. PMID:18361515

  18. The proteomes of human parotid and submandibular/sublingual gland salivas collected as the ductal secretions.

    PubMed

    Denny, Paul; Hagen, Fred K; Hardt, Markus; Liao, Lujian; Yan, Weihong; Arellanno, Martha; Bassilian, Sara; Bedi, Gurrinder S; Boontheung, Pinmannee; Cociorva, Daniel; Delahunty, Claire M; Denny, Trish; Dunsmore, Jason; Faull, Kym F; Gilligan, Joyce; Gonzalez-Begne, Mireya; Halgand, Frédéric; Hall, Steven C; Han, Xuemei; Henson, Bradley; Hewel, Johannes; Hu, Shen; Jeffrey, Sherry; Jiang, Jiang; Loo, Joseph A; Ogorzalek Loo, Rachel R; Malamud, Daniel; Melvin, James E; Miroshnychenko, Olga; Navazesh, Mahvash; Niles, Richard; Park, Sung Kyu; Prakobphol, Akraporn; Ramachandran, Prasanna; Richert, Megan; Robinson, Sarah; Sondej, Melissa; Souda, Puneet; Sullivan, Mark A; Takashima, Jona; Than, Shawn; Wang, Jianghua; Whitelegge, Julian P; Witkowska, H Ewa; Wolinsky, Lawrence; Xie, Yongming; Xu, Tao; Yu, Weixia; Ytterberg, Jimmy; Wong, David T; Yates, John R; Fisher, Susan J

    2008-05-01

    Saliva is a body fluid with important functions in oral and general health. A consortium of three research groups catalogued the proteins in human saliva collected as the ductal secretions: 1166 identifications--914 in parotid and 917 in submandibular/sublingual saliva--were made. The results showed that a high proportion of proteins that are found in plasma and/or tears are also present in saliva along with unique components. The proteins identified are involved in numerous molecular processes ranging from structural functions to enzymatic/catalytic activities. As expected, the majority mapped to the extracellular and secretory compartments. An immunoblot approach was used to validate the presence in saliva of a subset of the proteins identified by mass spectrometric approaches. These experiments focused on novel constituents and proteins for which the peptide evidence was relatively weak. Ultimately, information derived from the work reported here and related published studies can be used to translate blood-based clinical laboratory tests into a format that utilizes saliva. Additionally, a catalogue of the salivary proteome of healthy individuals allows future analyses of salivary samples from individuals with oral and systemic diseases, with the goal of identifying biomarkers with diagnostic and/or prognostic value for these conditions; another possibility is the discovery of therapeutic targets.

  19. Proteomic profiling of 13 paired ductal infiltrating breast carcinomas and non-tumoral adjacent counterparts.

    PubMed

    Pucci-Minafra, Ida; Cancemi, Patrizia; Marabeti, Maria Rita; Albanese, Nadia Ninfa; Di Cara, Gianluca; Taormina, Pietra; Marrazzo, Antonio

    2007-01-01

    According to recent statistics, breast cancer remains one of the leading causes of death among women in Western countries. Breast cancer is a complex and heterogeneous disease, presently classified into several subtypes according to their cellular origin. Among breast cancer histotypes, infiltrating ductal carcinoma represents the most common and potentially aggressive form. Despite the current progress achieved in early cancer detection and treatment, including the new generation of molecular therapies, there is still need for identification of multiparametric biomarkers capable of discriminating between cancer subtypes and predicting cancer progression for personalized therapies. One established step in this direction is the proteomic strategy, expected to provide enough information on breast cancer profiling. To this aim, in the present study we analyzed 13 breast cancer tissues and their matched non-tumoral tissues by 2-DE. Collectively, we identified 51 protein spots, corresponding to 34 differentially expressed proteins, which may represent promising candidate biomarkers for molecular-based diagnosis of breast cancer and for pattern discovery. The relevance of these proteins as factors contributing to breast carcinogenesis is discussed. PMID:21136615

  20. Basaloid ductal carcinoma in situ arising in salivary gland metaplasia of the breast: a case report.

    PubMed

    Jang, Eun Jeong; Kang, Su Hwan; Bae, Young Kyung

    2014-01-01

    Salivary gland metaplasia is a newly recognized, adenosis-like lesion which could not be classified according to known categories of adenosis of the breast. We report a case of basaloid ductal carcinoma in situ (DCIS) arising in a background of salivary gland metaplasia in a 49-year old woman who visited our hospital for a right breast mass. Breast ultrasonography showed a multi-lobulating mixed hypoechoic and isoechoic mass measuring 2.9 cm in size at the periareolar area. Histologically, the lesion showed a well-defined DCIS with basaloid tumor cells and central comedo-type necrosis surrounded by salivary gland metaplasia composed of glands or ducts not specific to the breast, ducts with cribriform proliferation of luminal epithelial cells, and ducts with varying degrees of proliferation of basaloid cells including solid nests of basaloid cells. Salivary gland metaplasia is a most unusual lesion of the breast characterized by salivary gland-type acini and ducts with various proliferations of luminal and basaloid cells, and accompanied by malignant tumor of basal cell type.

  1. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression.

    PubMed

    Laklai, Hanane; Miroshnikova, Yekaterina A; Pickup, Michael W; Collisson, Eric A; Kim, Grace E; Barrett, Alex S; Hill, Ryan C; Lakins, Johnathon N; Schlaepfer, David D; Mouw, Janna K; LeBleu, Valerie S; Roy, Nilotpal; Novitskiy, Sergey V; Johansen, Julia S; Poli, Valeria; Kalluri, Raghu; Iacobuzio-Donahue, Christine A; Wood, Laura D; Hebrok, Matthias; Hansen, Kirk; Moses, Harold L; Weaver, Valerie M

    2016-05-01

    Fibrosis compromises pancreatic ductal carcinoma (PDAC) treatment and contributes to patient mortality, yet antistromal therapies are controversial. We found that human PDACs with impaired epithelial transforming growth factor-β (TGF-β) signaling have high epithelial STAT3 activity and develop stiff, matricellular-enriched fibrosis associated with high epithelial tension and shorter patient survival. In several KRAS-driven mouse models, both the loss of TGF-β signaling and elevated β1-integrin mechanosignaling engaged a positive feedback loop whereby STAT3 signaling promotes tumor progression by increasing matricellular fibrosis and tissue tension. In contrast, epithelial STAT3 ablation attenuated tumor progression by reducing the stromal stiffening and epithelial contractility induced by loss of TGF-β signaling. In PDAC patient biopsies, higher matricellular protein and activated STAT3 were associated with SMAD4 mutation and shorter survival. The findings implicate epithelial tension and matricellular fibrosis in the aggressiveness of SMAD4 mutant pancreatic tumors and highlight STAT3 and mechanics as key drivers of this phenotype.

  2. The impact of surgery on ductal carcinoma in situ outcomes: the use of mastectomy.

    PubMed

    Hwang, E Shelley

    2010-01-01

    Mastectomy has been the historical mainstay of treatment for ductal carcinoma in situ (DCIS), but over time, there have been significant changes in its use for preinvasive breast cancer. Although there was an early reduction in mastectomy rates for DCIS with the introduction of breast-conserving surgery, in some groups, the rates of both mastectomy and contralateral mastectomy for DCIS have increased in recent years. Due to advances in breast cancer screening as well as improvements in breast reconstruction, mastectomy will continue to be an important and acceptable treatment option. Recurrence is rare following mastectomy for DCIS. Nevertheless, there remains a need to follow patients for in-breast, nodal, or contralateral breast events, which can occur long after the index DCIS has been treated. Since up to 70% of women with newly diagnosed DCIS have disease that can be managed with breast-conserving surgery, patient counseling is imperative to ensure the best use of this option for DCIS, given that mastectomy does not significantly impact survival in this setting. PMID:20956829

  3. Radiation induces genomic instability and mammary ductal dysplasia in Atm heterozygous mice

    NASA Technical Reports Server (NTRS)

    Weil, M. M.; Kittrell, F. S.; Yu, Y.; McCarthy, M.; Zabriskie, R. C.; Ullrich, R. L.

    2001-01-01

    Ataxia-telangiectasia (AT) is a genetic syndrome resulting from the inheritance of two defective copies of the ATM gene that includes among its stigmata radiosensitivity and cancer susceptibility. Epidemiological studies have demonstrated that although women with a single defective copy of ATM (AT heterozygotes) appear clinically normal, they may never the less have an increased relative risk of developing breast cancer. Whether they are at increased risk for radiation-induced breast cancer from medical exposures to ionizing radiation is unknown. We have used a murine model of AT to investigate the effect of a single defective Atm allele, the murine homologue of ATM, on the susceptibility of mammary epithelial cells to radiation-induced transformation. Here we report that mammary epithelial cells from irradiated mice with one copy of Atm truncated in the PI-3 kinase domain were susceptible to radiation-induced genomic instability and generated a 10% incidence of dysplastic mammary ducts when transplanted into syngenic recipients, whereas cells from Atm(+/+) mice were stable and formed only normal ducts. Since radiation-induced ductal dysplasia is a precursor to mammary cancer, the results indicate that AT heterozygosity increases susceptibility to radiogenic breast cancer in this murine model system.

  4. A case of renal cell carcinoma metastasizing to invasive ductal breast carcinoma.

    PubMed

    Chen, Tai-Di; Lee, Li-Yu

    2014-02-01

    Tumor-to-tumor metastasis is an uncommon but well-documented phenomenon. We present a case of a clear cell renal cell carcinoma (RCC) metastasizing to an invasive ductal carcinoma (IDC) of the breast. A 74-year-old woman with a past history of clear cell RCC status after radical nephrectomy underwent right modified radical mastectomy for an enlarging breast mass 3 years after nephrectomy. Histological examination revealed a small focus with distinct morphological features similar to clear cell RCC encased in the otherwise typical IDC. Immunohistochemical studies showed that this focus was positive for CD10 and vimentin, in contrast to the surrounding IDC, which was negative for both markers and positive for Her2/neu. Based on the histological and immunohistochemical features, the patient was diagnosed with metastasis of clear cell RCC to the breast IDC. To the best of our knowledge, this is the first reported case of a breast neoplasm as the recipient tumor in tumor-to-tumor metastasis. PMID:24530247

  5. Role of HGF in epithelial–stromal cell interactions during progression from benign breast disease to ductal carcinoma in situ

    PubMed Central

    2013-01-01

    Introduction Basal-like and luminal breast cancers have distinct stromal–epithelial interactions, which play a role in progression to invasive cancer. However, little is known about how stromal–epithelial interactions evolve in benign and pre-invasive lesions. Methods To study epithelial–stromal interactions in basal-like breast cancer progression, we cocultured reduction mammoplasty fibroblasts with the isogenic MCF10 series of cell lines (representing benign/normal, atypical hyperplasia, and ductal carcinoma in situ). We used gene expression microarrays to identify pathways induced by coculture in premalignant cells (MCF10DCIS) compared with normal and benign cells (MCF10A and MCF10AT1). Relevant pathways were then evaluated in vivo for associations with basal-like subtype and were targeted in vitro to evaluate effects on morphogenesis. Results Our results show that premalignant MCF10DCIS cells express characteristic gene expression patterns of invasive basal-like microenvironments. Furthermore, while hepatocyte growth factor (HGF) secretion is upregulated (relative to normal, MCF10A levels) when fibroblasts are cocultured with either atypical (MCF10AT1) or premalignant (MCF10DCIS) cells, only MCF10DCIS cells upregulated the HGF receptor MET. In three-dimensional cultures, upregulation of HGF/MET in MCF10DCIS cells induced morphological changes suggestive of invasive potential, and these changes were reversed by antibody-based blocking of HGF signaling. These results are relevant to in vivo progression because high expression of a novel MCF10DCIS-derived HGF signature was correlated with the basal-like subtype, with approximately 86% of basal-like cancers highly expressing the HGF signature, and because high expression of HGF signature was associated with poor survival. Conclusions Coordinated and complementary changes in HGF/MET expression occur in epithelium and stroma during progression of pre-invasive basal-like lesions. These results suggest that

  6. Does contrast-enhanced ultrasound reveal tumor angiogenesis in pancreatic ductal carcinoma? A prospective study.

    PubMed

    Nishida, Mutsumi; Koito, Kazumitsu; Hirokawa, Naoki; Hori, Masakazu; Satoh, Taishi; Hareyama, Masato

    2009-02-01

    The purpose of this study is to evaluate tumor vascularity of pancreatic carcinoma noninvasively by contrast-enhanced ultrasound (US) and clarify the diagnostic value of tumor vascularity in subjects with nonresectable advanced pancreatic carcinoma. The study was approved by our institutional review board and written informed consent was obtained from all subjects. Twenty-seven subjects with advanced pancreatic ductal carcinoma were treated by chemoradiotherapy. Contrast-enhanced US, US guided biopsies and dynamic computed tomography (CT) were performed before and after the therapy. We assigned the intratumoral enhancement pattern of US as an enhanced ultrasound (EU) score, from 1 to 4, according to the degree of enhancement area. Intratumoral microvessel density (IMD) and average vessel diameter (AVD) were calculated by means of CD 34 immunostaining. Vascular endothelial growth factor (VEGF) staining was graded on a scale of 1 to 3. EU scores before chemoradiotherapy were compared with IMD, AVD, VEGF, histological grading and hepatic metastasis. After the therapy, local treatment response was evaluated by dynamic CT calculating the maximum area of the tumor, by comparing it with its size in pre- therapy. Subjects who had at least a 50% or more decrease of tumor size lasting more than 4 wk were estimated as partial response (PR), more than a 50% of increase progressive disease (PD) and if neither PR nor PD criteria were met, they were classified as stabled disease (SD). Next, EU scores were compared with IMD, AVD, VEGF and treatment response. Statistically significant differences were evaluated by Pearson's correlation, post-hoc, Spearman's rank correlation, Wilcoxon rank sum and Student's t-test. A p < 0.05 was defined as being statistically significant. Before the therapy, the EU score and IMD were significantly correlated (r = 0.50, p < 0.02), as was VEGF (r = 0.45, p < 0.05). The EU score and AVD were negatively correlated (r = - 0.56, p < 0.02). Significant

  7. Texture analysis for survival prediction of pancreatic ductal adenocarcinoma patients with neoadjuvant chemotherapy

    NASA Astrophysics Data System (ADS)

    Chakraborty, Jayasree; Langdon-Embry, Liana; Escalon, Joanna G.; Allen, Peter J.; Lowery, Maeve A.; O'Reilly, Eileen M.; Do, Richard K. G.; Simpson, Amber L.

    2016-03-01

    Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in the United States. The five-year survival rate for all stages is approximately 6%, and approximately 2% when presenting with distant disease.1 Only 10-20% of all patients present with resectable disease, but recurrence rates are high with only 5 to 15% remaining free of disease at 5 years. At this time, we are unable to distinguish between resectable PDAC patients with occult metastatic disease from those with potentially curable disease. Early classification of these tumor types may eventually lead to changes in initial management including the use of neoadjuvant chemotherapy or radiation, or in the choice of postoperative adjuvant treatments. Texture analysis is an emerging methodology in oncologic imaging for quantitatively assessing tumor heterogeneity that could potentially aid in the stratification of these patients. The present study derives several texture-based features from CT images of PDAC patients, acquired prior to neoadjuvant chemotherapy, and analyzes their performance, individually as well as in combination, as prognostic markers. A fuzzy minimum redundancy maximum relevance method with leave-one-image-out technique is included to select discriminating features from the set of extracted features. With a naive Bayes classifier, the proposed method predicts the 5-year overall survival of PDAC patients prior to neoadjuvant therapy and achieves the best results in terms of the area under the receiver operating characteristic curve of 0:858 and accuracy of 83:0% with four-fold cross-validation techniques.

  8. Management of pancreaticobiliary disease using a new intra-ductal endoscope: The Texas experience

    PubMed Central

    Fishman, Douglas S; Tarnasky, Paul R; Patel, Sandeep N; Raijman, Isaac

    2009-01-01

    AIM: To evaluate a new single-operator mini-endoscope, Spyglass®, for its performance, feasibility and safety in the management of pancreaticobiliary disease. METHODS: In a multicenter retrospective analysis of patients undergoing intraductal endoscopy, we evaluated 128 patients (71 men, mean age 57.6 years). Indications were therapeutic (TX) in 72 (56%) and diagnostic (DX) in 56 (44%). RESULTS: Peroral endoscopy was performed in 121 and percutaneous in seven. TX indications included CBD stones in 41, PD stones in six, and biliary strictures in 25. DX indications included abnormal LFT’s in 15, abnormal imaging in 38 and cholangiocarcinoma staging in three. Visualization of the stone(s) was considered good in 31, fair in six, and poor in four. Advancement of the electrohydraulic lithotripsy probe was not possible in three patients and proper targeting of the lesion was partial in four patients. A holmium laser was used successfully in three patients. Ductal clearance was achieved in 37 patients after one procedure and in four patients after two procedures. Diagnosis of biliary strictures was modified in 20/29 and confirmed to be malignant in 10/23. Of the modified patients, no diagnosis was available in 17. Spyglass® demonstrated malignancy in 8/17 and non-malignancy in nine. Suspected pathology by imaging studies and abnormal LFT’s was modified in 43/63 (66%). Staging of cholangiocarcinoma demonstrated multicentric cholangiocarcinoma in 2/3. There was no morbidity associated with the use of Spyglass®. CONCLUSION: Spyglass Spyscope® is a first generation, single operator miniature endoscope that can evaluate and treat various biliary and pancreatic tract diseases. PMID:19294765

  9. Resolution of Novel Pancreatic Ductal Adenocarcinoma Subtypes by Global Phosphotyrosine Profiling.

    PubMed

    Humphrey, Emily S; Su, Shih-Ping; Nagrial, Adnan M; Hochgräfe, Falko; Pajic, Marina; Lehrbach, Gillian M; Parton, Robert G; Yap, Alpha S; Horvath, Lisa G; Chang, David K; Biankin, Andrew V; Wu, Jianmin; Daly, Roger J

    2016-08-01

    Comprehensive characterization of signaling in pancreatic ductal adenocarcinoma (PDAC) promises to enhance our understanding of the molecular aberrations driving this devastating disease, and may identify novel therapeutic targets as well as biomarkers that enable stratification of patients for optimal therapy. Here, we use immunoaffinity-coupled high-resolution mass spectrometry to characterize global tyrosine phosphorylation patterns across two large panels of human PDAC cell lines: the ATCC series (19 cell lines) and TKCC series (17 cell lines). This resulted in the identification and quantification of over 1800 class 1 tyrosine phosphorylation sites and the consistent segregation of both PDAC cell line series into three subtypes with distinct tyrosine phosphorylation profiles. Subtype-selective signaling networks were characterized by identification of subtype-enriched phosphosites together with pathway and network analyses. This revealed that the three subtypes characteristic of the ATCC series were associated with perturbations in signaling networks associated with cell-cell adhesion and epithelial-mesenchyme transition, mRNA metabolism, and receptor tyrosine kinase (RTK) signaling, respectively. Specifically, the third subtype exhibited enhanced tyrosine phosphorylation of multiple RTKs including the EGFR, ERBB3 and MET. Interestingly, a similar RTK-enriched subtype was identified in the TKCC series, and 'classifier' sites for each series identified using Random Forest models were able to predict the subtypes of the alternate series with high accuracy, highlighting the conservation of the three subtypes across the two series. Finally, RTK-enriched cell lines from both series exhibited enhanced sensitivity to the small molecule EGFR inhibitor erlotinib, indicating that their phosphosignature may provide a predictive biomarker for response to this targeted therapy. These studies highlight how resolution of subtype-selective signaling networks can provide a

  10. Preoperative cognitive function predicts survival in patients with resectable pancreatic ductal adenocarcinoma

    PubMed Central

    Baekelandt, Bart M.G.; Hjermstad, Marianne J.; Nordby, Tom; Fagerland, Morten W.; Kure, Elin H.; Heiberg, Turid; Buanes, Trond; Labori, Knut J.

    2015-01-01

    Background The purpose of this prospective study was to evaluate whether pre-surgery health-related quality of life (HRQoL) and subjectively rated symptom scores are prognostic factors for survival in patients with resectable pancreatic ductal adenocarcinoma (PDAC). Methods Patients undergoing pancreatic resection for PDAC completed the Edmonton Symptom Assessment System (ESAS) and the EORTC QLQ-C30 and QLQ-PAN26 questionnaires preoperatively. Patient, tumor and treatment characteristics, recurrence and survival were registered. Results Sixty-six consecutive patients underwent R0/R1 resection for PDAC. Baseline ESAS and EORTC questionnaire compliance was 44/66 (67%) with no statistically significant differences between compliers (n = 44) and non-compliers (n = 22) when comparing clinicopathological parameters and survival. Univariable analyses showed that three symptoms (nausea, dry mouth, cognitive function) and two clinicopathological factors (CA 19-9 > 400 U/ml, lymph node ratio > 0.1) were significantly associated with shorter survival (p < 0.05). In multivariable analysis, cognitive function was the only independent predictor for survival: hazard ratio = 0.35 (95%CI 0.13–0.93) for high vs low cognitive function. Median survival times for patients with high and low cognitive function were 21 and 10 months, respectively (p < 0.001). Conclusion Presurgery cognitive function is a significant independent predictor of survival in patients with resectable PDAC. Thus, presurgery patient reported outcomes may provide as strong prognostic information as clinicopathological factors. PMID:27017164

  11. Interfacing polymeric scaffolds with primary pancreatic ductal adenocarcinoma cells to develop 3D cancer models

    PubMed Central

    Ricci, Claudio; Mota, Carlos; Moscato, Stefania; D’Alessandro, Delfo; Ugel, Stefano; Sartoris, Silvia; Bronte, Vincenzo; Boggi, Ugo; Campani, Daniela; Funel, Niccola; Moroni, Lorenzo; Danti, Serena

    2014-01-01

    We analyzed the interactions between human primary cells from pancreatic ductal adenocarcinoma (PDAC) and polymeric scaffolds to develop 3D cancer models useful for mimicking the biology of this tumor. Three scaffold types based on two biocompatible polymeric formulations, such as poly(vinyl alcohol)/gelatin (PVA/G) mixture and poly(ethylene oxide terephthalate)/poly(butylene terephthalate) (PEOT/PBT) copolymer, were obtained via different techniques, namely, emulsion and freeze-drying, compression molding followed by salt leaching, and electrospinning. In this way, primary PDAC cells interfaced with different pore topographies, such as sponge-like pores of different shape and size or nanofiber interspaces. The aim of this study was to investigate the influence played by the scaffold architecture over cancerous cell growth and function. In all scaffolds, primary PDAC cells showed good viability and synthesized tumor-specific metalloproteinases (MMPs) such as MMP-2, and MMP-9. However, only sponge-like pores, obtained via emulsion-based and salt leaching-based techniques allowed for an organized cellular aggregation very similar to the native PDAC morphological structure. Differently, these cell clusters were not observed on PEOT/PBT electrospun scaffolds. MMP-2 and MMP-9, as active enzymes, resulted to be increased in PVA/G and PEOT/PBT sponges, respectively. These findings suggested that spongy scaffolds supported the generation of pancreatic tumor models with enhanced aggressiveness. In conclusion, primary PDAC cells showed diverse behaviors while interacting with different scaffold types that can be potentially exploited to create stage-specific pancreatic cancer models likely to provide new knowledge on the modulation and drug susceptibility of MMPs. PMID:25482337

  12. Axillary evaluation and lymphedema in women with ductal carcinoma in situ.

    PubMed

    Coromilas, Ellie J; Wright, Jason D; Huang, Yongmei; Feldman, Sheldon; Neugut, Alfred I; Hillyer, Grace Clarke; Chen, Ling; Hershman, Dawn L

    2016-07-01

    Axillary evaluation in women with ductal carcinoma in situ (DCIS) is increasing; however, this may introduce additional morbidity with unclear benefit. Our objective was to examine the morbidity and mortality associated with axillary evaluation in DCIS. We conducted a retrospective cohort study of 10,504 women aged 65-90 years with DCIS who underwent breast conserving surgery between 2002 and 2012 using SEER-Medicare database. Patients were categorized by receipt of axillary evaluation with either sentinel lymph node biopsy (SLNB) or axillary node dissection (ALND). We determined the incidence of lymphedema treatment as defined by diagnostic and procedural codes, as well as 10-year breast cancer-specific and all-cause mortality. 18.3 % of those treated with BCS and 69.4 % of those treated with mastectomy had an axillary evaluation. One year after treatment, 8.2 % of women who had an axillary evaluation developed lymphedema, compared to 5.9 % of those who did not. In a multivariable Cox proportional hazard model, the incidence of lymphedema was higher among those who underwent axillary evaluation (HR 1.22, 95 % CI 1.04-1.45). Overall 10-year breast cancer-specific survival was similar between both groups (HR 0.83, 95 % CI 0.40-1.74). Only 44 (0.40 %) women died of breast cancer; receipt of axillary evaluation did not alter overall survival. Axillary evaluation is commonly performed in women with DCIS, especially those undergoing mastectomy. However, women who receive an axillary evaluation have higher rates of lymphedema, without breast cancer-specific or overall survival benefit. Efforts should be made to determine the population of women with DCIS who benefit from this procedure.

  13. Identification of genes and pathways associated with pancreatic ductal adenocarcinoma by bioinformatics analyses

    PubMed Central

    LONG, JIN; ZHANG, ZHONGBO; LIU, ZHE; XU, YUANHONG; GE, CHUNLIN

    2016-01-01

    This study aimed to explore the underlying genes and pathways associated with pancreatic ductal adenocarcinoma (PDAC) by bioinformatics analyses. Gene expression profile GSE43795 was downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) between six PDAC and five non-neoplastic pancreatic tissue samples were analyzed using the limma package. Gene ontology (GO) and pathway enrichment analyses of DEGs were performed, followed by functional annotation and protein-protein interaction (PPI) network construction. Finally, the sub-network was identified and pathway enrichment analysis was performed on the contained DEGs. A total of 374 downregulated and 559 upregulated DEGs were identified. The downregulated DEGs were enriched in GO terms associated with digestion and transport and pathways related to metabolism, while the upregulated DEGs were enriched in GO terms associated with the cell cycle and mitosis and pathways associated with the occurrence of cancer including the cell cycle pathway. Following functional annotation, the oncogene pituitary tumor-transforming 1 (PTTG1) was upregulated. In the PPI network and sub-network, cell division cycle 20 (CDC20) and BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B) were hub genes with high connectivity degrees. Additionally, DEGs in the sub-network including cyclin B1 (CCNB1) were mainly enriched in the cell cycle and p53 signaling pathways. In conclusion, the cell cycle and p53 signaling pathways may play significant roles in PDAC, and DEGs including CDC20, BUB1B, CCNB1 and PTTG1 may be potential targets for PDAC diagnosis and treatment. PMID:26893748

  14. Outcomes in Patients Treated With Mastectomy for Ductal Carcinoma In Situ

    SciTech Connect

    Owen, Dawn; Tyldesley, Scott; Alexander, Cheryl; Speers, Caroline; Truong, Pauline; Nichol, Alan; Wai, Elaine S.

    2013-03-01

    Purpose: To examine, in a large, population-based cohort of women, the risk factors for recurrence after mastectomy for pure ductal carcinoma in situ (DCIS) and to identify which patients may benefit from postmastectomy radiation therapy. Methods and Materials: Data were analyzed for 637 subjects with pure DCIS, diagnosed between January 1990 and December 1999, treated initially with mastectomy. Locoregional relapse (LRR), breast cancer-specific survival, and overall survival were described using the Kaplan-Meier method. Reported risk factors for LRR (age, margins, size, Van Nuys Prognostic Index, grade, necrosis, and histologic subtype) were analyzed by univariate (log-rank) and multivariate (Cox modeling) methods. Results: Median follow-up was 12.0 years. Characteristics of the cohort were median age 55 years, 8.6% aged ≤40 years, 30.5% tumors >4 cm, 42.5% grade 3 histology, 37.7% multifocal disease, and 4.9% positive margins. At 10 years, LRR was 1.0%, breast cancer-specific survival was 98.0%, and overall survival was 90.3%. All recurrences (n=12) involved ipsilateral chest wall disease, with the majority being invasive disease (11 of 12). None of the 12 patients with recurrence died of breast cancer; all were successfully salvaged (median follow-up of 4.4 years). Ten-year LRR was higher with age ≤40 years (7.5% vs 1.5%; P=.003). Conclusion: Mastectomy provides excellent locoregional control for DCIS. Routine use of postmastectomy radiation therapy is not justified. Young age (≤40 years) predicts slightly higher LRR, but possibly owing to the small number of cases with multiple risk factors for relapse, a subgroup with a high risk of LRR (ie, approximately 15%) was not identified.

  15. Prospective Multicenter Trial Evaluating Balloon-Catheter Partial-Breast Irradiation for Ductal Carcinoma in Situ

    SciTech Connect

    Abbott, Andrea M.; Portschy, Pamela R.; Lee, Chung; Le, Chap T.; Han, Linda K.; Washington, Tara; Kinney, Michael; Bretzke, Margit; Tuttle, Todd M.

    2013-11-01

    Purpose: To determine outcomes of accelerated partial-breast irradiation (APBI) with MammoSite in the treatment of ductal carcinoma in situ (DCIS) after breast-conserving surgery. Methods and Materials: We conducted a prospective, multicenter trial between 2003 and 2009. Inclusion criteria included age >18 years, core needle biopsy diagnosis of DCIS, and no prior breast cancer history. Patients underwent breast-conserving surgery plus MammoSite placement. Radiation was given twice daily for 5 days for a total of 34 Gy. Patients were evaluated for development of toxicities, cosmetic outcome, and ipsilateral breast tumor recurrence (IBTR). Results: A total of 41 patients (42 breasts) completed treatment in the study, with a median follow up of 5.3 years. Overall, 28 patients (68.3%) experienced an adverse event. Skin changes and pain were the most common adverse events. Cosmetic outcome at 6 months was judged excellent/good by 100% of physicians and by 96.8% of patients. At 12 months, 86.7% of physicians and 92.3% of patients rated the cosmetic outcome as excellent/good. Overall, 4 patients (9.8%) developed an IBTR (all DCIS), with a 5-year actuarial rate of 11.3%. All IBTRs were outside the treatment field. Among patients with IBTRs, the mean time to recurrence was 3.2 years. Conclusions: Accelerated partial-breast irradiation using MammoSite seems to provide a safe and cosmetically acceptable outcome; however, the 9.8% IBTR rate with median follow-up of 5.3 years is concerning. Prospective randomized trials are necessary before routine use of APBI for DCIS can be recommended.

  16. Evaluation of automated breast volume scanner for breast conservation surgery in ductal carcinoma in situ

    PubMed Central

    Huang, Anqian; Zhu, Luoxi; Tan, Yanjuan; Liu, Jian; Xiang, Jingjing; Zhu, Qingqing; Bao, Lingyun

    2016-01-01

    The present is a retrospective study examining the use of automated breast volume scanner (ABVS) for guiding breast conservation surgery in ductal carcinoma in situ (DCIS). A total of 142 patients with pathologically confirmed DCIS were initially included in the study. The patients underwent preoperative examination by conventional ultrasound and by ABVS. The BI-RADS category system was used to identify benign and malignant lesions, after which breast conservation surgery was performed, and the therapeutic effects were compared. DCIS lesions were found in each quadrant of the breasts. Typical symptoms included: Duct ectasia and filling in 23 cases, mass (mainly solid, occasionally cystic, with or without calcification) in 38 cases, hypoechoic area (with or without calcification) in 33 cases, calcifications (simple) in 23 cases, and architectural distortion in 17 cases. In addition, 110 cases (82.1%) were detected as grade ≥4 according to the BI-RADS category, and 92 cases (68.7%) were considered malignant lesions following conventional ultrasound scanning. The detection rate of ABVS was significantly higher than that of conventional ultrasound (χ2=268.000, P<0.001). The average tumor diameter was 2.5±0.8 cm using ABVS and 2.0±0.9 cm using conventional ultrasound (the former being significantly higher than the latter; t=6.325, P=0.034). Eight patients (5.6%) had recurrences of the cancer, and the tumor diameter in the 8 patients was significantly larger using ABVS as compared to conventional ultrasound. In the diagnosis of DCIS, ABVS was superior to conventional ultrasound scanner in guiding breast conservation surgery and predicting recurrence. However, large-scale studies are required for confirmation of the findings.

  17. Interfacing polymeric scaffolds with primary pancreatic ductal adenocarcinoma cells to develop 3D cancer models.

    PubMed

    Ricci, Claudio; Mota, Carlos; Moscato, Stefania; D'Alessandro, Delfo; Ugel, Stefano; Sartoris, Silvia; Bronte, Vincenzo; Boggi, Ugo; Campani, Daniela; Funel, Niccola; Moroni, Lorenzo; Danti, Serena

    2014-01-01

    We analyzed the interactions between human primary cells from pancreatic ductal adenocarcinoma (PDAC) and polymeric scaffolds to develop 3D cancer models useful for mimicking the biology of this tumor. Three scaffold types based on two biocompatible polymeric formulations, such as poly(vinyl alcohol)/gelatin (PVA/G) mixture and poly(ethylene oxide terephthalate)/poly(butylene terephthalate) (PEOT/PBT) copolymer, were obtained via different techniques, namely, emulsion and freeze-drying, compression molding followed by salt leaching, and electrospinning. In this way, primary PDAC cells interfaced with different pore topographies, such as sponge-like pores of different shape and size or nanofiber interspaces. The aim of this study was to investigate the influence played by the scaffold architecture over cancerous cell growth and function. In all scaffolds, primary PDAC cells showed good viability and synthesized tumor-specific metalloproteinases (MMPs) such as MMP-2, and MMP-9. However, only sponge-like pores, obtained via emulsion-based and salt leaching-based techniques allowed for an organized cellular aggregation very similar to the native PDAC morphological structure. Differently, these cell clusters were not observed on PEOT/PBT electrospun scaffolds. MMP-2 and MMP-9, as active enzymes, resulted to be increased in PVA/G and PEOT/PBT sponges, respectively. These findings suggested that spongy scaffolds supported the generation of pancreatic tumor models with enhanced aggressiveness. In conclusion, primary PDAC cells showed diverse behaviors while interacting with different scaffold types that can be potentially exploited to create stage-specific pancreatic cancer models likely to provide new knowledge on the modulation and drug susceptibility of MMPs.

  18. Predictors of Recurrent Ductal Carcinoma In Situ after Breast-Conserving Surgery

    PubMed Central

    Kim, Jung Yeon; Kang, Guhyun; Kim, Hyun-Jung; Gwak, Geumhee; Shin, Young-Joo

    2016-01-01

    Purpose Local recurrence is a major concern in patients who have undergone surgery for ductal carcinoma in situ (DCIS). The present study assessed whether the expression levels of hormone receptors, human epidermal growth factor receptor 2 (HER2), and Ki-67, as well as resection margin status, tumor grade, age at diagnosis, and adjuvant hormonal therapy and radiotherapy (RT) are associated with recurrence in women with DCIS. Methods In total, 111 patients with DCIS were included in the present study. The invasive and noninvasive recurrence events were recorded. The clinicopathological features; resection margins; administration of hormonal therapy and RT; expression statuses of estrogen receptor (ER), progesterone receptor (PR), and HER2; Ki-67 expression; and molecular subtypes were evaluated. Logistic regression analysis was performed to examine the risk factors for recurrence. Results Recurrence was noted in 27 of 111 cases (24.3%). Involvement of resection margins, low tumor grade, high Ki-67 expression, and RT were independently associated with an increase in the recurrence rate (p<0.05, Pearson chi-square test). The recurrence rate was not significantly associated with patient age; ER, PR, and HER2 statuses; molecular subtype; and hormonal therapy. Conclusion The results of the present study suggested that the involvement of resection margins, low tumor grade, high Ki-67 index, and the absence of adjuvant RT were independently associated with increased recurrence in patients with DCIS. Future studies should be conducted in a larger cohort of patients to further improve the identification of patients at high-risk for DCIS recurrence. PMID:27382395

  19. A Molecular Portrait of High-Grade Ductal Carcinoma In Situ

    PubMed Central

    Abba, Martin C.; Gong, Ting; Lu, Yue; Lee, Jaeho; Zhong, Yi; Lacunza, Ezequiel; Butti, Matias; Takata, Yoko; Gaddis, Sally; Shen, Jianjun; Estecio, Marcos R.; Sahin, Aysegul A.; Aldaz, C. Marcelo

    2016-01-01

    Ductal carcinoma in situ (DCIS) is a noninvasive precursor lesion to invasive breast carcinoma. We still have no understanding on why only some DCIS lesions evolve to invasive cancer whereas others appear not to do so during the life span of the patient. Here, we performed full exome (tumor vs. matching normal), transcriptome, and methylome analysis of 30 pure high-grade DCIS (HG-DCIS) and 10 normal breast epithelial samples. Sixty-two percent of HG-DCIS cases displayed mutations affecting cancer driver genes or potential drivers. Mutations were observed affecting PIK3CA (21% of cases), TP53 (17%), GATA3 (7%), MLL3 (7%) and single cases of mutations affecting CDH1, MAP2K4, TBX3, NF1, ATM, and ARID1A. Significantly, 83% of lesions displayed numerous large chromosomal copy number alterations, suggesting they might precede selection of cancer driver mutations. Integrated pathway-based modeling analysis of RNA-seq data allowed us to identify two DCIS subgroups (DCIS-C1 and DCIS-C2) based on their tumor-intrinsic subtypes, proliferative, immune scores, and in the activity of specific signaling pathways. The more aggressive DCIS-C1 (highly proliferative, basal-like, or ERBB2+) displayed signatures characteristic of activated Treg cells (CD4+/CD25+/FOXP3+) and CTLA4+/CD86+ complexes indicative of a tumor-associated immunosuppressive phenotype. Strikingly, all lesions showed evidence of TP53 pathway inactivation. Similarly, ncRNA and methylation profiles reproduce changes observed postinvasion. Among the most significant findings, we observed upregulation of lncRNA HOTAIR in DCIS-C1 lesions and hypermethylation of HOXA5 and SOX genes. We conclude that most HG-DCIS lesions, in spite of representing a preinvasive stage of tumor progression, displayed molecular profiles indistinguishable from invasive breast cancer. PMID:26249178

  20. A Six-Gene Signature Predicts Survival of Patients with Localized Pancreatic Ductal Adenocarcinoma

    PubMed Central

    Stratford, Jeran K.; Bentrem, David J.; Anderson, Judy M.; Fan, Cheng; Volmar, Keith A.; Marron, J. S.; Routh, Elizabeth D.; Caskey, Laura S.; Samuel, Jonathan C.; Der, Channing J.; Thorne, Leigh B.; Calvo, Benjamin F.; Kim, Hong Jin; Talamonti, Mark S.; Iacobuzio-Donahue, Christine A.; Hollingsworth, Michael A.; Perou, Charles M.; Yeh, Jen Jen

    2010-01-01

    Background Pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease. For patients with localized PDAC, surgery is the best option, but with a median survival of less than 2 years and a difficult and prolonged postoperative course for most, there is an urgent need to better identify patients who have the most aggressive disease. Methods and Findings We analyzed the gene expression profiles of primary tumors from patients with localized compared to metastatic disease and identified a six-gene signature associated with metastatic disease. We evaluated the prognostic potential of this signature in a training set of 34 patients with localized and resected PDAC and selected a cut-point associated with outcome using X-tile. We then applied this cut-point to an independent test set of 67 patients with localized and resected PDAC and found that our signature was independently predictive of survival and superior to established clinical prognostic factors such as grade, tumor size, and nodal status, with a hazard ratio of 4.1 (95% confidence interval [CI] 1.7–10.0). Patients defined to be high-risk patients by the six-gene signature had a 1-year survival rate of 55% compared to 91% in the low-risk group. Conclusions Our six-gene signature may be used to better stage PDAC patients and assist in the difficult treatment decisions of surgery and to select patients whose tumor biology may benefit most from neoadjuvant therapy. The use of this six-gene signature should be investigated in prospective patient cohorts, and if confirmed, in future PDAC clinical trials, its potential as a biomarker should be investigated. Genes in this signature, or the pathways that they fall into, may represent new therapeutic targets. Please see later in the article for the Editors' Summary PMID:20644708

  1. Genome and transcriptome delineation of two major oncogenic pathways governing invasive ductal breast cancer development

    PubMed Central

    Aswad, Luay; Yenamandra, Surya Pavan; Ow, Ghim Siong; Grinchuk, Oleg; Ivshina, Anna V.; Kuznetsov, Vladimir A.

    2015-01-01

    Invasive ductal carcinoma (IDC) is a major histo-morphologic type of breast cancer. Histological grading (HG) of IDC is widely adopted by oncologists as a prognostic factor. However, HG evaluation is highly subjective with only 50%–85% inter-observer agreements. Specifically, the subjectivity in the assignment of the intermediate grade (histologic grade 2, HG2) breast cancers (comprising ~50% of IDC cases) results in uncertain disease outcome prediction and sub-optimal systemic therapy. Despite several attempts to identify the mechanisms underlying the HG classification, their molecular bases are poorly understood. We performed integrative bioinformatics analysis of TCGA and several other cohorts (total 1246 patients). We identified a 22-gene tumor aggressiveness grading classifier (22g-TAG) that reflects global bifurcation in the IDC transcriptomes and reclassified patients with HG2 tumors into two genetically and clinically distinct subclasses: histological grade 1-like (HG1-like) and histological grade 3-like (HG3-like). The expression profiles and clinical outcomes of these subclasses were similar to the HG1 and HG3 tumors, respectively. We further reclassified IDC into low genetic grade (LGG = HG1+HG1-like) and high genetic grade (HGG = HG3-like+HG3) subclasses. For the HG1-like and HG3-like IDCs we found subclass-specific DNA alterations, somatic mutations, oncogenic pathways, cell cycle/mitosis and stem cell-like expression signatures that discriminate between these tumors. We found similar molecular patterns in the LGG and HGG tumor classes respectively. Our results suggest the existence of two genetically-predefined IDC classes, LGG and HGG, driven by distinct oncogenic pathways. They provide novel prognostic and therapeutic biomarkers and could open unique opportunities for personalized systemic therapies of IDC patients. PMID:26474389

  2. Rates of Second Malignancies After Definitive Local Treatment for Ductal Carcinoma In Situ of the Breast

    SciTech Connect

    Shaitelman, Simona F.; Grills, Inga S.; Kestin, Larry L.; Ye Hong; Nandalur, Sirisha; Huang Jiayi; Vicini, Frank A.

    2011-12-01

    Purpose: We analyzed the risk of second malignancies developing in patients with ductal carcinoma in situ (DCIS) undergoing surgery and radiotherapy (S+RT) vs. surgery alone. Methods and Materials: The S+RT cohort consisted of 256 women treated with breast-conserving therapy at William Beaumont Hospital. The surgery alone cohort consisted of 2,788 women with DCIS in the regional Surveillance, Epidemiology, and End Results database treated during the same time period. A matched-pair analysis was performed in which each S+RT patient was randomly matched with 8 surgery alone patients (total of 2,048 patients). Matching criteria included age {+-} 2 years. The rates of second malignancies were analyzed overall and as contralateral breast vs. non-breast cancers and by organ system. Results: Median follow-up was 13.7 years for the S+RT cohort and 13.3 years for the surgery alone cohort. The overall 10-/15-year rates of second malignancies among the S+RT and surgery alone cohorts were 14.2%/24.2% and 16.4%/22.6%, respectively (p = 0.668). The 15-year second contralateral breast cancer rate was 14.2% in the S+RT cohort and 10.3% in the surgery alone cohort (p = 0.439). The 15-year risk of a second non-breast malignancy was 14.2% for the S+RT cohort and 13.4% for the surgery alone cohort (p = 0.660). When analyzed by organ system, the 10- and 15-year rates of second malignancies did not differ between the S+RT and surgery alone cohorts for pulmonary, gastrointestinal, central nervous system, gynecologic, genitourinary, lymphoid, sarcomatoid, head and neck, or unknown primary tumors. Conclusions: Compared with surgery alone, S+RT is not associated with an overall increased risk of second malignancies in women with DCIS.

  3. Stromal galectin-1 expression is associated with long-term survival in resectable pancreatic ductal adenocarcinoma

    PubMed Central

    Chen, Ru; Pan, Sheng; Ottenhof, NIki A.; de Wilde, Roeland F.; Wolfgang, Christopher L.; Lane, Zhaoli; Post, Jane; Bronner, Mary P.; Willmann, Jürgen K.; Maitra, Anirban; Brentnall, Teresa A.

    2012-01-01

    The overall 5 year survival rate for pancreatic ductal adenocarcinoma (i.e., PDAC) is a dismal 5%, although patients that have undergone surgical resection have a somewhat better survival rate of up to 20%. Very long-term survivors of PDAC (defined as patients with ≥ 10 year survival following apparently curative resection), on the other hand, are considerably less frequent. The molecular characteristics of very long-term survivors (VLTS) are poorly understood, but might provide novel insights into prognostication for this disease. In this study, a panel of five VLTS and stage-matched short-term survivors (STS, defined as disease-specific mortality within 14 months of resection) were identified, and quantitative proteomics was applied to comparatively profile tumor tissues from both cohorts. Differentially expressed proteins were identified in cancers from VLTS vs. STS patients. Specifically, the expression of galectin-1 was 2-fold lower in VLTS compared with STS tumors. Validation studies were performed by immunohistochemistry (IHC) in two additional cohorts of resected PDAC, including: 1) an independent cohort of VLTS and 2) a panel of sporadic PDAC with a considerable range of overall survival following surgery. Immunolabeling analysis confirmed that significantly lower expression of stromal galectin-1 was associated with VLTS (p = 0.02) and also correlated with longer survival in sporadic, surgically-treated PDAC cases (hazard ratio = 4.9, p = 0.002). The results from this study provide new insights to better understand the role of galectin-1 in PDAC survival, and might be useful for rendering prognostic information, and developing more effective therapeutic strategies aimed at improving survival. PMID:22785208

  4. Systemic Inflammatory Response and Elevated Tumour Markers Predict Worse Survival in Resectable Pancreatic Ductal Adenocarcinoma

    PubMed Central

    Salmiheimo, Aino; Mustonen, Harri; Stenman, Ulf-Håkan; Puolakkainen, Pauli; Kemppainen, Esko; Seppänen, Hanna; Haglund, Caj

    2016-01-01

    Background Estimation of the prognosis of resectable pancreatic ductal adenocarcinoma (PDAC) currently relies on tumour-related factors such as resection margins and on lymph-node ratio (LNR) both inconveniently available only postoperatively. Our aim was to assess the accuracy of preoperative laboratory data in predicting PDAC prognosis. Methods Collection of laboratory and clinical data was retrospective from 265 consecutive patients undergoing surgery for PDAC at Helsinki University Hospital. Cancer-specific survival assessment utilized Kaplan-Meier analysis, and independent associations between factors were by the Cox regression model. Results During follow-up, 76% of the patients died of PDAC, with a median survival time of 19.6 months. In univariate analysis, CRP, albumin, CEA, and CA19-9 were significantly associated with postoperative cancer-specific survival. In multivariate analysis, taking into account age, gender, LNR, resection margins, tumour status, and adjuvant chemotherapy, the preoperative biomarkers independently associated with adverse prognosis were hypoalbuminemia (< 36 g/L, hazard ratio (HR) 1.56, 95% confidence interval (CI) 1.10–2.19, p = 0.011), elevated CRP (> 5 mg/L, HR 1.44, 95% CI 1.03–2.02, p = 0.036), CEA (> 5 μg/L, HR 1.60, 95% CI 1.07–2.53, p = 0.047), and CA19-9 (≥555 kU/L, HR 1.91, 95% CI 1.18–3.08, p = 0.008). Conclusion For patients with resectable PDAC, preoperative CRP, along with albumin and tumour markers, is useful for predicting prognosis. PMID:27632196

  5. Expression of SATB1 protein in the ductal breast carcinoma tissue microarrays - preliminary study.

    PubMed

    Kobierzycki, Christopher; Wojnar, Andrzej; Dziegiel, Piotr

    2013-01-01

    Special AT-rich sequence-binding protein 1 (SATB1) is a nuclear matrix protein which interacts with specific regions of DNA, ensuring its proper organization and function in the cell. The expression of SATB1 was primarily found in thymocytes, but its increased levels were observed in various types of cancers. However, the knowledge of the function and application possibilities of this protein is still limited. The aim of this study was to investigate the expression of SATB1 protein using immunohistochemistry and tissue microarray (TMA) technique and determine its possible relationship with the proliferative marker Ki-67, estrogen a (ER) and progesterone (PR) receptors as well as grade of histological malignancy (G). The study was performed on material of 48 archival invasive ductal breast cancers (IDC). The TMAs were prepared with the use of 0.6 mm diameter punches. Immunohistochemical reactions were carried out using antibodies against Ki-67, ER, PR and SATB1 proteins. The intensity of the nuclear reaction was evaluated using a light microscope and computer-assisted image analysis. Expression of Ki-67 and SATB1 protein was observed in 89.58% and 31.25% of cancer cases, respectively. 62.5% of tumors were classified as ER-positive, and 47.92% as PR-positive. Statistical analysis showed a moderate positive correlation between Ki-67 and SATB1 expression (r = 0.291, p = 0.045 independently on the receptor status, and r = 0.392, p = 0.032 in ER-negative tumors). The expression of the Ki-67 antigen increased with higher grade of histological malignancy (G). The results suggest that SATB1 protein may play an indirect role in the cell proliferation and should be evaluated in relation to the other markers. Further studies concerning determination of its role in cancer progression and metastasis, in terms of application as therapeutic target and prognostic marker, are recommended.

  6. Expression of melatonin receptor MT1 in cells of human invasive ductal breast carcinoma.

    PubMed

    Jablonska, Karolina; Pula, Bartosz; Zemla, Agata; Owczarek, Tomasz; Wojnar, Andrzej; Rys, Janusz; Ambicka, Aleksandra; Podhorska-Okolow, Marzena; Ugorski, Maciej; Dziegiel, Piotr

    2013-04-01

    In humans, two main types of membrane melatonin receptors have been identified, MT1 and MT2. Expression of MT1 in neoplastic cells seems to increase the efficacy of melatonin's oncostatic activity. The purpose of this study was to determine the distribution and the intensity of MT1 expression in breast cancer cells and to correlate it with clinicopathological factors. Immunohistochemical studies (IHC) were conducted on 190 cases of invasive ductal breast carcinomas (IDC) and molecular studies were performed on 29 cases of frozen tumor fragments and selected breast cancer cell lines. Most of the studied tumors manifested a membranous/cytoplasmic IHC expression of MT1. In IDC, the MT1 expression was higher than in fibrocystic breast disease. MT1 expression was higher in estrogen receptor positive (ER+) and HER2 positive (HER2+) tumors. Triple negative tumors (TN) manifested the lowest MT1 expression level. The lowest MT1 protein expression level was noted in the TN breast cancer cell line MDA-MB-231 compared with ER+ cell lines MCF-7 and SK-BR-3. MT1 mRNA expression was negatively correlated with the malignancy grade of the studied IDC cases. Moreover, higher MT1 expression was associated with patients' longer overall survival (OS) in the group of ER+ breast cancers and treated with tamoxifen. Multivariate analysis indicated that MT1 was an independent prognostic factor in the ER+ tumors for OS and event-free survival in the ER+ tumors. The results of this study may point to a potential prognostic and therapeutic significance of MT1 in IDC.

  7. Ductal Plate Malformation in the Liver of Boxer Dogs: Clinical and Histological Features.

    PubMed

    Pillai, S; Center, S A; McDonough, S P; Demarco, J; Pintar, J; Henderson, A K; Cooper, J; Bolton, T; Sharpe, K; Hill, S; Benedict, A G; Haviland, R

    2016-05-01

    Ductal plate malformations (DPMs) represent developmental biliary disorders with a wide phenotypic spectrum. This study characterizes DPM in 30 Boxer dogs. Median age was 1.5 (range, 0.3-10.0) years, with 12 dogs <1 year. Clinical features included increased serum levels of liver enzymes (28), gastrointestinal signs (16), poor body condition (14), abdominal effusion (9), and hepatic encephalopathy (2). Additional malformations included gallbladder atresia (8), atrophied left liver (2), absent quadrate lobe with left-displaced gallbladder (1), portal vasculature atresia (left liver, 1), intrahepatic portosystemic shunt (1), and complex intrahepatic arteriovenous malformation (1). All dogs had portal tracts dimensionally expanded by a moderate-to-severe multiple small bile duct phenotype embedded in abundant extracellular matrix; 80% displayed variable portal-to-portal bridging. Quantitative analysis confirmed significantly increased fibrillar collagen and a 3-fold increased portal tract area relative to 6 Boxer and 10 non-Boxer controls. Biliary phenotype was dominated by tightly formed CK19-positive ductules, typically 10 to 15 μm in diameter, with 3 to >30 profiles per portal tract, reduced luminal apertures, and negative Ki-67 immunoreactivity. CK19-positive biliary epithelium intersected directly with zone 1 hepatocytes as a signature feature when considered with other DPM characteristics. Phenotypic variation included a multiple small bile duct phenotype (all dogs), predominantly thin-walled sacculated ducts (4), well-formed saccular ducts (4), and sacculated segmental, interlobular, and intralobular ducts (Caroli malformation, 2 dogs, one with bridging portal fibrosis). Histologic evidence of portal venous hypoperfusion accompanied increased biliary profiles in every case. We propose that this spectrum of disorders be referred to as DPM with appropriate modifiers to characterize the unique phenotypes.

  8. Evaluation of automated breast volume scanner for breast conservation surgery in ductal carcinoma in situ

    PubMed Central

    Huang, Anqian; Zhu, Luoxi; Tan, Yanjuan; Liu, Jian; Xiang, Jingjing; Zhu, Qingqing; Bao, Lingyun

    2016-01-01

    The present is a retrospective study examining the use of automated breast volume scanner (ABVS) for guiding breast conservation surgery in ductal carcinoma in situ (DCIS). A total of 142 patients with pathologically confirmed DCIS were initially included in the study. The patients underwent preoperative examination by conventional ultrasound and by ABVS. The BI-RADS category system was used to identify benign and malignant lesions, after which breast conservation surgery was performed, and the therapeutic effects were compared. DCIS lesions were found in each quadrant of the breasts. Typical symptoms included: Duct ectasia and filling in 23 cases, mass (mainly solid, occasionally cystic, with or without calcification) in 38 cases, hypoechoic area (with or without calcification) in 33 cases, calcifications (simple) in 23 cases, and architectural distortion in 17 cases. In addition, 110 cases (82.1%) were detected as grade ≥4 according to the BI-RADS category, and 92 cases (68.7%) were considered malignant lesions following conventional ultrasound scanning. The detection rate of ABVS was significantly higher than that of conventional ultrasound (χ2=268.000, P<0.001). The average tumor diameter was 2.5±0.8 cm using ABVS and 2.0±0.9 cm using conventional ultrasound (the former being significantly higher than the latter; t=6.325, P=0.034). Eight patients (5.6%) had recurrences of the cancer, and the tumor diameter in the 8 patients was significantly larger using ABVS as compared to conventional ultrasound. In the diagnosis of DCIS, ABVS was superior to conventional ultrasound scanner in guiding breast conservation surgery and predicting recurrence. However, large-scale studies are required for confirmation of the findings. PMID:27698816

  9. Differential Patterns of Allelic Loss in Estrogen Receptor-Positive Infiltrating Lobular and Ductal Breast Cancer

    PubMed Central

    Loo, L.W.M.; Ton, C.; Wang, Y.-W.; Grove, D.I.; Bouzek, H.; Vartanian, N.; Lin, M.-G.; Yuan, X.; Lawton, T.L.; Daling, J.R.; Malone, K.E.; Li, C.I.; Hsu, L.; Porter, P.L.

    2009-01-01

    The two main histological types of infiltrating breast cancer, lobular (ILC) and the more common ductal (IDC) carcinoma are morphologically and clinically distinct. To assess the molecular alterations associated with these breast cancer subtypes, we conducted a whole-genome study of 166 archival estrogen receptor (ER)-positive tumors (89 IDC and 77 ILC) using the Affymetrix GeneChip® Mapping 10K Array to identify sites of loss of heterozygosity (LOH) that either distinguished, or were shared by, the two phenotypes. We found single nucleotide polymorphisms (SNPs) of high-frequency LOH (>50%) common to both ILC and IDC tumors predominately in 11q, 16q, and 17p. Overall, IDC had a slightly higher frequency of LOH events across the genome than ILC (fractional allelic loss = 0.186 and 0.156). By comparing the average frequency of LOH by chromosomal arm, we found IDC tumors with significantly (P < 0.05) higher frequency of LOH on 3p, 5q, 8p, 9p, 20p, and 20q than ILC tumors. We identified additional chromosomal arms differentiating the subtypes when tumors were stratified by tumor size, mitotic rate, or DNA content. Of 5,754 informative SNPs (>25% informativity), we identified 78 and 466 individual SNPs with a higher frequency of LOH (P < 0.05) in ILC and IDC tumors, respectively. Hierarchical clustering of these 544 SNPs grouped tumors into four major groups based on their patterns of LOH and retention of heterozygosity. LOH in chromosomal arms 8p and 5q was common in higher grade IDC tumors, whereas ILC and low-grade IDC grouped together by virtue of LOH in 16q. PMID:18720524

  10. Increased serum carbohydrate antigen 19-9 in relapsed ductal breast carcinoma.

    PubMed

    Papantoniou, Vassilios; Tsiouris, Spyridon; Koutsikos, John; Ptohis, Nikolaos; Lazaris, Dimitrios; Zerva, Cherry

    2006-01-01

    Increased serum carbohydrate antigen (CA) 19-9 is a quite uncommon manifestation of breast cancer both on early disease and on relapse. A 53-year-old woman with invasive ductal breast carcinoma underwent left-sided mastectomy. Two years later she palpated a subcutaneous mass at the mastectomy scar, arousing suspicion of local relapse. Surgery and histopathology revealed infiltration by breast adenocarcinoma and she was treated with chemotherapy. At that time serum tumor markers, carcinoembryonic antigen (CEA) and CA 15-3 were within normal range. Over the next six months she displayed an increase of serum CEA while serum CA 15-3 remained within normal range. In an attempt to search for a second neoplasm possibly of gastrointestinal (GI) origin, abdominal computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance cholangio-pancreatography (MRCP), endoscopy of the upper GI tract and colonoscopy were performed, as well as measurement of serum CA 19-9. While no indication of a GI neoplasm was detected, she displayed an over 10-fold increase of serum CA 19-9. The patient had also an X-ray mammography and technetium-99m hexakis-2-methoxyisobutylisonitrile ((99m)Tc-MIBI) scintimammography (SM). Whilst mammography was negative for contralateral disease recurrence, SM was suggestive of axillary lymph node involvement. Axillary lymph node dissection confirmed an extensive metastatic infiltration of these nodes by breast adenocarcinoma. Three months later serum CA 19-9 and CEA became normal. The interest of this case lies on the unexpected high serum CA 19-9 values found in a breast relapsed adenocarcinoma and in the important contribution of SM in diagnosing the axillary lymph node metastatic infiltration. PMID:16617392

  11. Resistance of cyclooxygenase-2 expressing pancreatic ductal adenocarcinoma cells against γδ T cell cytotoxicity

    PubMed Central

    Gonnermann, Daniel; Oberg, Hans-Heinrich; Kellner, Christian; Peipp, Matthias; Sebens, Susanne; Kabelitz, Dieter; Wesch, Daniela

    2015-01-01

    The prostaglandin (PG) synthetase cyclooxygenase 2 (Cox-2) promotes tumorigenesis, tumor progression, and metastasis in a variety of human cancer entities including pancreatic ductal adenocarcinoma (PDAC). In this study, we demonstrate that in PDAC cells such as Colo357 cells, enhanced Cox-2 expression and increased release of the Cox-2 metabolite prostaglandin E2 (PGE2) promotes resistance against γδ T cell-mediated lysis. Co-culture with activated γδ T cells induced an upregulation of Cox-2 expression in Colo357 cells, and thereby an enhanced PGE2 release, in response to tumor necrosis factor α (TNFα) secretion from γδ T cells. The PGE2-mediated inhibition of γδ T cell cytotoxicity against Cox-2-expressing PDAC cells can be partially overcome by Cox-2 inhibitors. Our results show that differences between PDAC cells in regards to sensitivity to γδ T-cell cytotoxicity can be due to distinct levels of Cox-2 expression associated with varying amounts of PGE2 release. While γδ T cell cytotoxicity against PDAC cells expressing low levels of Cox-2 can be effectively enhanced by tribody [(Her2)2×Vγ9] with specificity for Vγ9 T cell receptor and HER-2/neu on PDAC cells, a combination of tribody [(Her2)2×Vγ9] and Cox-2 inhibitor is necessary to induce complete lysis of Cox-2 high expressing Colo357. In conclusion, our results suggest that the application of tribody [(Her2)2×Vγ9] that enhances γδ T-cell cytotoxicity and Cox-2 inhibitors that overcome PGE2-mediated resistance of PDAC cells to the cytotoxic activity of γδ T cells might offer a promising combined immunotherapy for pancreatic cancer. PMID:25949900

  12. A High Ductal Flow Velocity Is Associated with Successful Pharmacological Closure of Patent Ductus Arteriosus in Infants 22–27 Weeks Gestational Age

    PubMed Central

    Olsson, Karl Wilhelm; Jonzon, Anders; Sindelar, Richard

    2012-01-01

    Objective. To identify factors affecting closure of patent ductus arteriosus (PDA) in newborn infants born at 22–27 weeks gestational age (GA) during pharmacological treatment with cyclooxygenase inhibitors. Method. Infants born at 22–27 weeks of GA between January 2006 and December 2009 who had been treated pharmacologically for PDA were identified retrospectively. Medical records were assessed for clinical, ventilatory, and outcome parameters. Echocardiographic examinations during treatment were reviewed. Results. Fifty-six infants were included in the study. Overall success rate of ductal closure with pharmacological treatment was 52%. Infants whose PDA was successfully closed had a higher GA (25 + 4 weeks versus 24 + 3 weeks; P = 0.047), and a higher pretreatment left to right maximal ductal flow velocity (1.6 m/s versus 1.1 m/s; P = 0.023). Correcting for GA, preeclampsia, antenatal steroids, and age at start of treatment, a higher maximal ductal flow velocity was still associated with successful ductal closure (OR 3.04; P = 0.049). Conclusion. Maximal ductal flow velocity was independently associated with success of PDA treatment. PMID:23316351

  13. Ploidy differences between hormone- and chemical carcinogen-induced rat mammary neoplasms: comparison to invasive human ductal breast cancer.

    PubMed

    Li, Jonathan J; Papa, Dan; Davis, Marilyn F; Weroha, S John; Aldaz, C Marcelo; El-Bayoumy, Karam; Ballenger, Jodi; Tawfik, Ossama; Li, Sara Antonia

    2002-01-01

    To ascertain differences between solely hormone- and chemical carcinogen-induced murine mammary gland tumors (MGTs), a direct comparison of their ploidy status was assessed. Nuclear image cytometry (NIC) was used to evaluate ploidy in ductal carcinoma in situ (DCIS) and MGTs induced solely by 17beta-estradiol (E(2)) in female A-strain Copenhagen Irish hooded gene rats (ACI) and E(2) plus testosterone propionate in male Noble rats. These results were compared to ploidy data from primary MGTs induced by two synthetic carcinogens, 7,12-dimethylbenz[a]antracene and nitrosomethylurea in female Brown Lewis Norway rats and an environmental carcinogen, 6-nitrochrysene, in female Sprague-Dawley rats. Both DCIS and primary MGTs induced solely by hormones were highly aneuploid (> 84%), whereas MGTs induced by either synthetic or environmental carcinogens were primarily diploid (> 85%). Examination of 76 metaphase plates obtained from eight individual E(2)-induced ACI female rat MGTs revealed the following consistent chromosome alterations: gains in chromosomes 7, 11, 12, 13, 19, and 20 and loss of chromosome 12. On Southern blot analysis, six of nine ACI female rat primary E(2)-induced MGTs (66%) exhibited amplified copy numbers (range: 3.4-6.9 copies) of the c-myc gene. Fluorescence in situ hybridization (FISH) analysis of these MGTs revealed specific fluorescent hybridization signals for c-myc (7q33) on all three homologs of a trisomy in chromosome 7. NIC analysis of 140 successive nonfamilial sporadic invasive human ductal breast cancers (BCs) showed an aneuploid frequency of 61%, while 31 DCISs revealed a 71% aneuploid frequency. These results clearly demonstrate that the female ACI rat E(2)-induced MGTs more closely resemble invasive human DCIS and ductal BC in two pertinent aspects: they are highly aneuploid compared with chemical carcinogen-induced MGTs and exhibit a high frequency of c-myc amplification. PMID:11807958

  14. Ductal carcinoma in situ in core needle biopsies and its association with extensive in situ component in the surgical specimen

    PubMed Central

    2012-01-01

    Background We evaluated the presence of ductal carcinoma in situ (DCIS) in core needle biopsies (CNB) from invasive ductal lesions. Methods Retrospective study, which analyzed 90 cases of invasive ductal carcinoma lesions. The percentage of DCIS was quantified in each specimens obtained from CNB, which were compared to the surgical specimens. CNB and surgical specimens were evaluated by the same pathologist, and the percentage of DCIS in CNB was evaluated (percentage) and divided into categories. We considered the following parameters regarding the amount of DCIS: 1 = 0; 2 = 1 for 5%; 3 = 6 for 24%; 4 = 25 for 50%; 5 = 51 for 75% and 6 = 76 for 99%. The number of fragments and the histological pattern of DCIS was found. Results We found the following results regarding the distribution of the percentage of DCIS in the CNB: 1 = 63.3%; 2 = 12.2%; 3 = 12.2%; 4 = 5.6%; 5 = 1.1% and 6 = 5.6%. The logistic regression analysis showed that CNB percentages above 45% reflected the presence of DCIS in the surgical specimen in 100% of the cases (p < 0.001), with a specificity of 100%, accuracy of 83.3% and false positive rate of 0% (p <0.001). Conclusion There is direct relationship between extensive intraductal component in the surgical specimen when the core biopsy shows 45% or more of the DCI or microinvasive in the material examined. PMID:22715888

  15. Correlation between Ultrasound Findings of Tumor Margin and Clinicopathological Findings in Patients with Invasive Ductal Carcinoma of the Breast

    PubMed Central

    Sannomiya, Naoko; Hattori, Yuiko; Ueda, Naoyuki; Kamida, Akira; Koyanagi, Yuki; Nagira, Haruki; Ikunishi, Saeko; Shimabayashi, Kenta; Hashimoto, Yuki; Murata, Aya; Sato, Kengo; Hirooka, Yumi; Hosoya, Keiko; Ishiguro, Kiyosuke; Murata, Yoko; Hirooka, Yasuaki

    2016-01-01

    Background Breast ultrasound findings regarding tumor margins are crucial in judging whether a tumor is malignant or benign. However, the relationships between the margins and clinicopathological characteristics remain largely unknown. In this study, we examined the clinicopathological characteristics of patients with invasive ductal carcinoma whose ultrasound images showed either well-defined and rough or indistinct margins. Methods Of all consecutive patients diagnosed with invasive ductal carcinoma at the Division of Breast and Endocrine Surgery of Tottori University Hospital from January 2012 to December 2014, 122 patients whose ultrasound images showed either “well-defined and rough” or “indistinct” tumor margins were included in this study. Mammography and ultrasound images taken at the initial examination were reviewed. Patients were divided into two groups based on ultrasound findings of the tumor margins: the “well-defined and rough group” and the “indistinct group.” The relationships among ultrasound findings, mammography findings and clinicopathological findings were investigated in the two groups. Results The well-defined and rough group was more likely to contain solid-tubular carcinoma, while the indistinct group was more likely to contain scirrhous carcinoma. The MIB-1 index was higher in the well-defined and rough group than in the indistinct group. Additionally, the proportion of patients with nuclear grade 3, estrogen receptor-negative/progesterone receptor-negative, and triple-negative breast cancer was greater in the well-defined and rough group than in the indistinct group. Conclusion Invasive ductal carcinomas with well-defined and rough margins on ultrasound were likely to be malignant and proliferative than those with indistinct margins. PMID:27493488

  16. Ductal constriction during dexamethasone treatment in an anti-SSA-antibody-exposed fetus with signs of myocardial inflammation.

    PubMed

    Talemal, Lauren; Olivieri, Laura; Krishnan, Anita

    2016-06-01

    This report describes the clinical course and multi-modality imaging findings in an anti-SSA-antibody-exposed fetus with suspected myocardial inflammation. Postnatal cardiac MRI - using fast acquisition, free-breathing with feed-and-swaddle technique - was used to evaluate for myocardial fibrosis/inflammation. This is the first published report, to our knowledge, of ductal constriction temporally associated with oral dexamethasone therapy in an anti-SSA-antibody-exposed fetus and of the use of this unique postnatal MRI protocol in this setting. PMID:27087593

  17. Patterns of reduced nipple aspirate fluid production and ductal lavage cellularity in women at high risk for breast cancer

    PubMed Central

    Higgins, Susan A; Matloff, Ellen T; Rimm, David L; Dziura, James; Haffty, Bruce G; King, Bonnie L

    2005-01-01

    Introduction Nipple aspiration is a noninvasive technique for obtaining breast fluids from the duct openings of the nipple for the evaluation of abnormalities associated with breast cancer. Nipple aspirate fluid (NAF) can be elicited from 48 to 94% of healthy women, and its production has been linked to an increased relative risk for breast cancer development. NAF production has been used in studies to guide the selection of ducts for ductal lavage, a procedure in which ducts are cannulated and flushed with saline to collect cells. In a previous multicenter trial to evaluate intraductal approaches in women at high-risk for breast cancer, NAF production was observed in 84% of the subjects. However, we observed a significantly lower proportion of fluid-yielding subjects in a similar series of high-risk women. The purpose of the present study was to identify variables associated with this reduction. Method Nipple aspiration was performed on 33 high-risk women (defined as having a 5-year Gail model index of more than 1.7, a personal or family history of breast cancer, and/or a BRCA1 or BRCA2 germline mutation) to identify ductal orifices for lavage procedures. Lavage was performed on all fluid-yielding ducts and on nine non-fluid-yielding ducts. Results Fluid-yielding ducts were identified in 12 of 33 (36%) of the subjects in the present series, compared with 16 of 19 (84%) of the subjects undergoing identical procedures at our facility during a multicenter trial (P = 0.001). Reduced NAF yields were associated with postmenopausal status (P = 0.02), BRCA germline mutations (P = 0.004), and risk reduction therapies, including bilateral salpingo-oophorectomy (BSO) and/or selective estrogen receptor modulators (SERMs; P = 0.009). All nine (100%) of the ductal lavage specimens collected from non-fluidyielding ducts were acellular, in comparison with 3 of 13 specimens from fluid-yielding ducts (P < .001). Conclusion Analysis of high-risk women in the present series revealed

  18. miRNAs As Diagnostic and Prognostic Biomarkers in Pancreatic Ductal Adenocarcinoma and Its Precursor Lesions: A Review

    PubMed Central

    Alemar, Bárbara; Gregório, Cleandra; Ashton-Prolla, Patricia

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDAC), a rare but lethal tumor, is difficult to diagnose without performing an invasive procedure. miRNAs are known to be deregulated in PDAC patients, and recent studies have shown that they can be used as diagnostic and prognostic of the disease. The detection of miRNAs in samples acquired through minimally or noninvasive procedures, such as serum, plasma, and saliva, can have a positive impact on the clinical management of these patients. This article is a comprehensive review of the major studies that have evaluated the expression of miRNAs as biomarkers in pancreatic cancer and its premalignant lesions. PMID:26688661

  19. Integration of transcript expression, copy number and LOH analysis of infiltrating ductal carcinoma of the breast

    PubMed Central

    2010-01-01

    Background A major challenge in the interpretation of genomic profiling data generated from breast cancer samples is the identification of driver genes as distinct from bystander genes which do not impact tumorigenesis. One way to assess the relative importance of alterations in the transcriptome profile is to combine parallel analyses that assess changes in the copy number alterations (CNAs). This integrated analysis permits the identification of genes with altered expression that map within specific chromosomal regions which demonstrate copy number alterations, providing a mechanistic approach to identify the 'driver genes'. Methods We have performed whole genome analysis of CNAs using the Affymetrix 250K Mapping array on 22 infiltrating ductal carcinoma samples (IDCs). Analysis of transcript expression alterations was performed using the Affymetrix U133 Plus2.0 array on 16 IDC samples. Fourteen IDC samples were analyzed using both platforms and the data integrated. We also incorporated data from loss of heterozygosity (LOH) analysis to identify genes showing altered expression in LOH regions. Results Common chromosome gains and amplifications were identified at 1q21.3, 6p21.3, 7p11.2-p12.1, 8q21.11 and 8q24.3. A novel amplicon was identified at 5p15.33. Frequent losses were found at 1p36.22, 8q23.3, 11p13, 11q23, and 22q13. Over 130 genes were identified with concurrent increases or decreases in expression that mapped to these regions of copy number alterations. LOH analysis revealed three tumors with whole chromosome or p arm allelic loss of chromosome 17. Genes were identified that mapped to copy neutral LOH regions. LOH with accompanying copy loss was detected on Xp24 and Xp25 and genes mapping to these regions with decreased expression were identified. Gene expression data highlighted the PPARα/RXRα Activation Pathway as down-regulated in the tumor samples. Conclusion We have demonstrated the utility of the application of integrated analysis using high

  20. Improved Outcomes of Breast-Conserving Therapy for Patients With Ductal Carcinoma in Situ

    SciTech Connect

    Halasz, Lia M.; Sreedhara, Meera; Bellon, Jennifer R.; Punglia, Rinaa S.; Wong, Julia S.; Harris, Jay R.

    2012-03-15

    Purpose: Patients treated for ductal carcinoma in situ (DCIS) with breast-conserving surgery (BCS) and radiation therapy (RT) at our center from 1976 to 1990 had a 15% actuarial 10-year local recurrence (LR) rate. Since then, improved mammographic and pathologic evaluation and greater attention to achieving negative margins may have resulted in a lower risk of LR. In addition, clinical implications of hormone receptor and HER-2 status in DCIS remain unclear. We sought to determine the following: LR rates with this more modern approach; the relation between LR and HER-2 status; and clinical and pathologic factors associated with HER-2{sup +} DCIS. Methods and Materials: We studied 246 consecutive patients who underwent BCS and RT for DCIS from 2001 to 2007. Of the patients, 96 (39%) were Grade III and the median number of involved tissue blocks was 3. Half underwent re-excision and 222 (90%) had negative margins (>2 mm). All received whole-breast RT (40-52 Gy) and 99% (244) received a tumor bed boost (8-18 Gy). Routine estrogen receptor (ER), progesterone receptor (PR), and HER-2 immunohistochemistry was instituted in 2003. Results: With median follow-up of 58 months, there were no LRs. Seven patients (3%) developed contralateral breast cancer (4 invasive and 3 in situ). Among 163 patients with immunohistochemistry, 124 were ER/PR{sup +}HER-2{sup -}, 27 were ER/PR{sup +}HER-2{sup +}, 6 were ER{sup -}/PR{sup -}HER-2{sup +}, and 6 were ER{sup -}/PR{sup -}HER-2{sup -}. On univariable analysis, HER-2{sup +}was significantly associated with Grade III, ER{sup -}/PR{sup -}, central necrosis, comedo subtype, more extensive DCIS, and postmenopausal status. On multivariable analysis, Grade III and postmenopausal status remained significantly associated with HER-2{sup +}. Conclusions: In an era of mammographically identified DCIS, larger excisions, widely negative margins and the use of a tumor bed boost, we observed no LR regardless of ER/PR/HER-2 status. Factors associated

  1. Five Year Outcome of 145 Patients With Ductal Carcinoma In Situ (DCIS) After Accelerated Breast Radiotherapy

    SciTech Connect

    Ciervide, Raquel; Dhage, Shubhada; Guth, Amber; Shapiro, Richard L.; Axelrod, Deborah M.; Roses, Daniel F.; Formenti, Silvia C.

    2012-06-01

    Background: Accelerated whole-breast radiotherapy (RT) with tumor bed boost in the treatment of early invasive breast cancer has demonstrated equivalent local control and cosmesis when compared with standard RT. Its efficacy in the treatment of ductal carcinoma in situ (DCIS) remains unknown. Methods and Materials: Patients treated for DCIS with lumpectomy and negative margins were eligible for 2 consecutive hypofractionated whole-breast RT clinical trials. The first trial (New York University [NYU] 01-51) prescribed to the whole breast 42 Gy (2.8 Gy in 15 fractions) and the second trial (NYU 05-181) 40.5 Gy (2.7 Gy in 15 fractions) with an additional daily boost of 0.5 Gy to the surgical cavity. Results: Between 2002 and 2009, 145 DCIS patients accrued, 59 to the first protocol and 86 to the second trial. Median age was 56 years and 65% were postmenopausal at the time of treatment. Based on optimal sparing of normal tissue, 79% of the patients were planned and treated prone and 21% supine. At 5 years' median follow-up (60 months; range 2.6-105.5 months), 6 patients (4.1%) experienced an ipsilateral breast recurrence in all cases of DCIS histology. In 3/6 patients, recurrence occurred at the original site of DCIS and in the remaining 3 cases outside the original tumor bed. New contralateral breast cancers arose in 3 cases (1 DCIS and 2 invasive carcinomas). Cosmetic self-assessment at least 2 years after treatment is available in 125 patients: 91% reported good-to-excellent and 9% reported fair-to-poor outcomes. Conclusions: With a median follow-up of 5 years, the ipsilateral local recurrence rate is 4.1%, comparable to that reported from the NSABP (National Surgical Adjuvant Breast and Bowel Project) trials that employed 50 Gy in 25 fractions of radiotherapy for DCIS. There were no invasive recurrences. These results provide preliminary evidence that accelerated hypofractionated external beam radiotherapy is a viable option for DCIS.

  2. Is Radiation Indicated in Patients With Ductal Carcinoma In Situ and Close or Positive Mastectomy Margins?

    SciTech Connect

    Chan, Linda W.; Rabban, Joseph; Hwang, E. Shelley; Bevan, Alison; Alvarado, Michael; Ewing, Cheryl; Esserman, Laura; Fowble, Barbara

    2011-05-01

    Purpose: Resection margin status is one of the most significant factors for local recurrence in patients with ductal carcinoma in situ (DCIS) treated with breast-conserving surgery with or without radiation. However, its impact on chest wall recurrence in patients treated with mastectomy is unknown. The purpose of this study was to determine chest wall recurrence rates in women with DCIS and close (<5 mm) or positive mastectomy margins in order to evaluate the potential role of radiation therapy. Methods and Materials: Between 1985 and 2005, 193 women underwent mastectomy for DCIS. Fifty-five patients had a close final margin, and 4 patients had a positive final margin. Axillary surgery was performed in 17 patients. Median follow-up was 8 years. Formal pathology review was conducted to measure and verify margin status. Nuclear grade, architectural pattern, and presence or absence of necrosis was recorded. Results: Median pathologic size of the DCIS in the mastectomy specimen was 4.5 cm. Twenty-two patients had DCIS of >5 cm or diffuse disease. Median width of the close final margin was 2 mm. Nineteen patients had margins of <1 mm. One of these 59 patients experienced a chest wall recurrence with regional adenopathy, followed by distant metastases 2 years following skin-sparing mastectomy. The DCIS was high-grade, 4 cm, with a 5-mm deep margin. A second patient developed an invasive cancer in the chest wall 20 years after her mastectomy for DCIS. This cancer was considered a new primary site arising in residual breast tissue. Conclusions: The risk of chest wall recurrence in this series of patients is 1.7% for all patients and 3.3% for high-grade DCIS. One out of 20 (5%) patients undergoing skin sparing or total skin-sparing mastectomy experienced a chest wall recurrence. This risk of a chest wall recurrence appears sufficiently low not to warrant a recommendation for postmastectomy radiation therapy for patients with margins of <5 mm. There were too few patients

  3. Automatic detection of invasive ductal carcinoma in whole slide images with convolutional neural networks

    NASA Astrophysics Data System (ADS)

    Cruz-Roa, Angel; Basavanhally, Ajay; González, Fabio; Gilmore, Hannah; Feldman, Michael; Ganesan, Shridar; Shih, Natalie; Tomaszewski, John; Madabhushi, Anant

    2014-03-01

    This paper presents a deep learning approach for automatic detection and visual analysis of invasive ductal carcinoma (IDC) tissue regions in whole slide images (WSI) of breast cancer (BCa). Deep learning approaches are learn-from-data methods involving computational modeling of the learning process. This approach is similar to how human brain works using different interpretation levels or layers of most representative and useful features resulting into a hierarchical learned representation. These methods have been shown to outpace traditional approaches of most challenging problems in several areas such as speech recognition and object detection. Invasive breast cancer detection is a time consuming and challenging task primarily because it involves a pathologist scanning large swathes of benign regions to ultimately identify the areas of malignancy. Precise delineation of IDC in WSI is crucial to the subsequent estimation of grading tumor aggressiveness and predicting patient outcome. DL approaches are particularly adept at handling these types of problems, especially if a large number of samples are available for training, which would also ensure the generalizability of the learned features and classifier. The DL framework in this paper extends a number of convolutional neural networks (CNN) for visual semantic analysis of tumor regions for diagnosis support. The CNN is trained over a large amount of image patches (tissue regions) from WSI to learn a hierarchical part-based representation. The method was evaluated over a WSI dataset from 162 patients diagnosed with IDC. 113 slides were selected for training and 49 slides were held out for independent testing. Ground truth for quantitative evaluation was provided via expert delineation of the region of cancer by an expert pathologist on the digitized slides. The experimental evaluation was designed to measure classifier accuracy in detecting IDC tissue regions in WSI. Our method yielded the best quantitative

  4. Mucinous carcinoma of the breast is genomically distinct from invasive ductal carcinomas of no special type.

    PubMed

    Lacroix-Triki, Magali; Suarez, Paula H; MacKay, Alan; Lambros, Maryou B; Natrajan, Rachael; Savage, Kay; Geyer, Felipe C; Weigelt, Britta; Ashworth, Alan; Reis-Filho, Jorge S

    2010-11-01

    Mucinous carcinomas are a rare entity accounting for up to 2% of all breast cancers, which have been shown to display a gene expression profile distinct from that of invasive ductal carcinomas of no special type (IDC-NSTs). Here, we have defined the genomic aberrations that are characteristic of this special type of breast cancer and have investigated whether mucinous carcinomas might constitute a genomic entity distinct from IDC-NSTs. Thirty-five pure and 11 mixed mucinous breast carcinomas were assessed by immunohistochemistry using antibodies against oestrogen receptor (ER), progesterone receptor, HER2, Ki67, cyclin D1, cortactin, Bcl-2, p53, E-cadherin, basal markers, neuroendocrine markers, and WT1. Fifteen pure mucinous carcinomas and 30 grade- and ER-matched IDC-NSTs were microdissected and subjected to high-resolution microarray-based comparative genomic hybridization (aCGH). In addition, the distinct components of seven mixed mucinous carcinomas were microdissected separately and subjected to aCGH. Pure mucinous carcinomas consistently expressed ER (100%), lacked HER2 expression (97.1%), and showed a relatively low level of genetic instability. Unsupervised hierarchical cluster analysis revealed that pure mucinous carcinomas were homogeneous and preferentially clustered together, separately from IDC-NSTs. They less frequently harboured gains of 1q and 16p and losses of 16q and 22q than grade- and ER-matched IDC-NSTs, and no pure mucinous carcinoma displayed concurrent 1q gain and 16q loss, a hallmark genetic feature of low-grade IDC-NSTs. Finally, both components of all but one mixed mucinous carcinoma displayed similar patterns of genetic aberrations and preferentially clustered together with pure mucinous carcinomas on unsupervised clustering analysis. Our results demonstrate that mucinous carcinomas are more homogeneous between themselves at the genetic level than IDC-NSTs. Both components of mixed mucinous tumours are remarkably similar at the

  5. Zinc presence in invasive ductal carcinoma of the breast and its correlation with oestrogen receptor status

    NASA Astrophysics Data System (ADS)

    Farquharson, M. J.; Al-Ebraheem, A.; Geraki, K.; Leek, R.; Jubb, A.; Harris, A. L.

    2009-07-01

    Zinc is known to play an important role in many cellular processes, and the levels of zinc are controlled by specific transporters from the ZIP (SLC39A) influx transporter group and the ZnT (SLC30A) efflux transporter group. The distribution of zinc was measured in 59 samples of invasive ductal carcinoma of breast using synchrotron radiation micro probe x-ray fluorescence facilities. The samples were formalin fixed paraffin embedded tissue micro arrays (TMAs) enabling a high throughput of samples and allowing us to correlate the distribution of trace metals with tumour cell distribution and, for the first time, important biological variables. The samples were divided into two classes, 34 oestrogen receptor positive (ER+ve) and 25 oestrogen receptor negative (ER-ve) based on quantitative immunohistochemistry assessment. The overall levels of zinc (i.e. in tumour and surrounding tissue) in the ER+ve samples were on average 60% higher than those in the ER-ve samples. The zinc levels were higher in the ER+ve tumour areas compared to the ER-ve tumour areas with the mean levels in the ER+ve samples being approximately 80% higher than the mean ER-ve levels. However, the non-tumour tissue regions of the samples contained on average the same levels of zinc in both types of breast cancers. The relative levels of zinc in tumour areas of the tissue were compared with levels in areas of non-tumour surrounding tissue. There was a significant increase in zinc in the tumour regions of the ER+ve samples compared to the surrounding regions (P < 0.001) and a non-significant increase in the ER-ve samples. When comparing the increase in zinc in the tumour regions expressed as a percentage of the surrounding non-tumour tissue zinc level in the same sample, a significant difference between the ER+ve and ER-ve samples was found (P < 0.01).

  6. MSX2 in pancreatic tumor development and its clinical application for the diagnosis of pancreatic ductal adenocarcinoma

    PubMed Central

    Satoh, Kennichi; Hamada, Shin; Shimosegawa, Tooru

    2012-01-01

    MSX2, a member of the homeobox genes family, is demonstrated to be the downstream target for ras signaling pathway and is expressed in a variety of carcinoma cells, suggesting its relevance to the development of ductal pancreatic tumors since pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary-mucinous neoplasia (IPMN) harbor frequent K-ras gene mutations. Recent studies revealed the roles of MSX2 in the development of carcinoma of various origins including pancreas. Among gastrointestinal tumors, PDAC is one of the most malignant. PDAC progresses rapidly to develop metastatic lesions, frequently by the time of diagnosis, and these tumors are usually resistant to conventional chemotherapy and radiation therapy. The molecular mechanisms regulating the aggressive behavior of PDAC still remain to be clarified. On the other hand, IPMN of the pancreas is distinct from PDAC because of its intraductal growth in the main pancreatic duct or secondary branches with rare invasion and metastasis to distant organs. However, recent evidence indicated that once IPMN showed stromal invasion, it progresses like PDAC. Therefore, it is important to determin how IPMN progresses to malignant phenotype. In this review, we focus on the involvement of MSX2 in the enhancement of malignant behavior in PDAC and IPMN, and further highlight the clinical approach to differentiate PDAC from chronic pancreatitis by evaluating MSX2 expression level. PMID:23162473

  7. KrasG12D induces EGFR-MYC cross signaling in murine primary pancreatic ductal epithelial cells

    PubMed Central

    Diersch, Sandra; Wirth, Matthias; Schneeweis, Christian; Jörs, Simone; Geisler, Fabian; Siveke, Jens T.; Rad, Roland; Schmid, Roland M.; Saur, Dieter; Rustgi, Anil K.; Reichert, Maximilian; Schneider, Günter

    2015-01-01

    Epidermal growth factor receptor (EGFR) signaling has a critical role in oncogenic Kras-driven pancreatic carcinogenesis. However, the downstream targets of this signaling network are largely unknown. We developed a novel model system utilizing murine primary pancreatic ductal epithelial cells (PDECs), genetically engineered to allow time-specific expression of oncogenic KrasG12D from the endogenous promoter. We show that primary PDECs are susceptible to KrasG12D-driven transformation and form pancreatic ductal adenocarcinomas (PDAC) in vivo after Cdkn2a inactivation. In addition, we demonstrate that activation of KrasG12D induces an EGFR signaling loop to drive proliferation. Interestingly, pharmacological inhibition of EGFR fails to decrease KrasG12D-activated ERK or PI3K signaling. Instead our data provide novel evidence that EGFR signaling is needed to activate the oncogenic and pro-proliferative transcription factor c-MYC. EGFR and c-MYC have been shown to be essential for pancreatic carcinogenesis. Importantly, our data link both pathways and thereby, explain the crucial role of EGFR for KrasG12D-driven carcinogenesis in the pancreas. PMID:26592448

  8. Collision of Ductal Carcinoma In Situ of Anogenital Mammary-like Glands and Vulvar Sarcomatoid Squamous Cell Carcinoma.

    PubMed

    Tran, Tien A N; Deavers, Michael T; Carlson, J Andrew; Malpica, Anais

    2015-09-01

    A spectrum of invasive adenocarcinomas presumably arising from the anogenital mammary-like glands of the vulva has been reported. Even rarer are the cases of pure ductal carcinoma in situ that originated from these unique glandular structures. Herein, we report an 81-yr-old woman presented with an invasive well-differentiated squamous cell carcinoma of the vulva. Unexpectedly, the underlying dermis demonstrated a cystically dilated structure that displayed a layer of malignant squamous cells in the periphery, and a second centrally located population of neoplastic cells exhibiting glandular differentiation. In addition, a spindle and pleomorphic malignant cell population consistent with a sarcomatoid carcinoma was identified around the cystic structure. Scattered benign anogenital mammary-like glands were present in the adjacent dermis. The histologic and immunohistochemical findings were consistent with those of vulvar squamous cell carcinoma that has undergone sarcomatoid transformation after spreading in a pagetoid fashion into an underlying focus of ductal carcinoma in situ of anogenital mammary-like gland origin.

  9. Identification of the boundary between normal breast tissue and invasive ductal carcinoma during breast-conserving surgery using multiphoton microscopy

    NASA Astrophysics Data System (ADS)

    Deng, Tongxin; Nie, Yuting; Lian, Yuane; Wu, Yan; Fu, Fangmeng; Wang, Chuan; Zhuo, Shuangmu; Chen, Jianxin

    2014-11-01

    Breast-conserving surgery has become an important way of surgical treatment for breast cancer worldwide nowadays. Multiphoton microscopy (MPM) has the ability to noninvasively visualize tissue architectures at the cellular level using intrinsic fluorescent molecules in biological tissues without the need for fluorescent dye. In this study, MPM is used to image the microstructures of terminal duct lobular unit (TDLU), invasive ductal carcinoma and the boundary region between normal and cancerous breast tissues. Our study demonstrates that MPM has the ability to not only reveal the morphological changes of the cuboidal epithelium, basement membrane and interlobular stroma but also identify the boundary between normal breast tissue and invasive ductal carcinoma, which correspond well to the Hematoxylin and Eosin (H and E) images. Predictably, MPM can monitor surgical margins in real time and provide considerable accuracy for resection of breast cancerous tissues intraoperatively. With the development of miniature, real-time MPM imaging technology, MPM should have great application prospects during breast-conserving surgery.

  10. β2-adrenergic receptor signaling promotes pancreatic ductal adenocarcinoma (PDAC) progression through facilitating PCBP2-dependent c-myc expression.

    PubMed

    Wan, Chunhua; Gong, Chen; Zhang, Haifeng; Hua, Lu; Li, Xiaohong; Chen, Xudong; Chen, Yinji; Ding, Xiaoling; He, Song; Cao, Wei; Wang, Yingying; Fan, Shaoqing; Xiao, Ying; Zhou, Guoxiong; Shen, Aiguo

    2016-04-01

    The β2-adrenergic receptor (β2-AR) plays a crucial role in pancreatic ductal adenocarcinoma (PDAC) progression. In this report, we identified poly(rC)-binding protein 2 (PCBP2) as a novel binding partner for β2-AR using immunoprecipitation-mass spectrometry (IP-MS) approach. The association between β2-AR and PCBP2 was verified using reciprocal immunoprecipitation. Importantly, we found significant interaction and co-localization of the two proteins in the presence of β2-AR agonist in Panc-1 and Bxpc3 PDAC cells. β2-AR-induced recruitment of PCBP2 led to augmented protein level of c-myc in PDAC cells, likely as a result of enhanced internal ribosome entry segment (IRES)-mediated translation of c-myc. The activation of β2-AR accelerated cell proliferation and colony formation, while knockdown of PCBP2 or c-myc restrained the effect. Furthermore, overexpression of PCBP2 was observed in human PDAC cell lines and tissue specimens compared to the normal pancreatic ductal epithelial cells and the non-cancerous tissues respectively. Overexpression of β2-AR and PCBP2 was associated with advanced tumor stage and significantly worsened prognosis in patients with PDAC. Our results elucidate a new molecular mechanism by which β2-AR signaling facilitates PDAC progression through triggering PCBP2-dependent c-myc expression. PMID:26803058

  11. MicroRNAs in stool samples as potential screening biomarkers for pancreatic ductal adenocarcinoma cancer.

    PubMed

    Yang, Jian-Yu; Sun, Yong-Wei; Liu, De-Jun; Zhang, Jun-Feng; Li, Jiao; Hua, Rong

    2014-01-01

    Pancreatic ductal adenocarcinoma (PDAC) accounts for approximately 90-95% exocrine malignant tumors of the pancreas. The high prevalence of metastasis and the difficulty of early diagnosis lead to a dismal prognosis. MicroRNAs (miRNAs) play a critical role in extensive biological processes. The purpose of this study was to evaluate the feasibility of stool miRNAs as novel biomarker for PDAC screening. MiRNAs were extracted from clinical specimens which included cancer and matched adjacent benign pancreatic tissues of 30 PDAC patients, pancreatic juice of 20 from the 30 PDAC patients and 10 chronic pancreatitis (CP) patients, stool samples of the 30 PDAC patients, the 10 CP patients and 15 healthy volunteers. Relative expression of a panel of 5 dysregulated miRNAs (miR-21, miR-155, miR-196a, miR-216 and miR-217) was analyzed with qRT-PCR. Receiver operating characteristic curve (ROC) analysis was performed to assess the diagnosing value of stool miRNAs in PDAC patients. The study showed that our methods of extracting and detecting miRNAs from pancreatic juice and stool specimens had high reproducibility. Compared to matched adjacent benign pancreatic tissues and pancreatic juice of CP patients, the expression of miR-21 (P = 0.0021 and P = 0.0027) as well as miR-155 (P = 0.0087 and P = 0.0067) was significantly higher and the expression of miR-216 (P < 0.0001 and P = 0.0044) was significantly lower in primary tumor tissues and pancreatic juice of PDAC patients. PDAC patients had a significantly higher stool miR-21 and miR-155 (P = 0.0049 and P = 0.0112) and lower miR-216 level (P = 0.0002) compared to normal controls. The same results were obtained in the expression levels of stool miR-21, miR-155 and miR-216 between PDAC and CP patients (P = 0.0337, P = 0.0388 and P = 0.0117, respectively). Receiver operating characteristic (ROC) analysis by using stool miRNAs expression indicated that combination of miR-21 and miR-155 had best sensitivity of 93.33% while the

  12. Incremental Value of Secretin-Enhanced Magnetic Resonance Cholangiopancreatography in Detecting Ductal Communication in a Population with High Prevalence of Small Pancreatic Cysts

    PubMed Central

    Rastegar, Neda; Matteoni-Athayde, Luciana G.; Eng, John; Takahashi, Naoki; Tamm, Eric P.; Mortele, Koenraad J.; Syngal, Sapna; Margolis, Daniel; Lennon, Anne Marie; Wolfgang, Christopher L.; Fishman, Elliot K.; Hruban, Ralph H.; Goggins, Michael; Canto, Marcia I.; Kamel, Ihab R.

    2016-01-01

    Purpose We investigated the incremental diagnostic yield of S-MRCP in a population with high prevalence of small pancreatic cysts. Methods Standard MRCP protocol was performed with and without secretin using 1.5 T unites in subjects undergoing pancreatic screening because of a strong family history of pancreatic cancer as part of the multicenter Cancer of the Pancreas Screening-3 trial (CAPS 3). All studies were reviewed prospectively by two independent readers who recorded the presence and number of pancreatic cysts, the presence of visualized ductal communication before and after secretin, and the degree of confidence in the diagnoses. Result Of 202 individuals enrolled (mean age 56 years, 46% males), 93 (46%) had pancreatic cysts detected by MRCP, and 64 of the 93 had pre-and post-secretin MRCP images available for comparison. Data from the 128 readings show that 6 (6/128 = 4.7%) had ductal communication visualized only on the secretin studies compared to pre-secretin studies (odds ratio 1.28, p = 0.04). In addition, there was a statistically significant increase in confidence in reporting ductal communication after secretin compared to before secretin (p <0.0005). Conclusion At 1.5 T MRI, the use of secretin can improve the visualization of ductal communication of cystic pancreatic lesions. PMID:25619503

  13. Elevated NCX1 and NCKX4 expression in the patent postnatal ductus arteriosus of ductal-dependent congenital heart disease patients.

    PubMed

    Hong, Haifa; Xia, Yu; Sun, Yanjun; Ye, Lincai; Liu, Jinfen; Bai, Jie; Zhang, Haibo

    2015-04-01

    Patency of the ductus arteriosus (DA) after birth is essential in ductal-dependent congenital heart disease. The Na(+)/Ca(2+) exchanger (NCX) has been demonstrated to play a key role in regulating vascular tone. The potassium-dependent Na(+)/Ca(2+) exchanger (NCKX) is a related family of NCX depending on the K(+) gradients which triggers DA constriction. The present study investigated the comparative expression of NCX and NCKX between a constricted DA and patent DA in human ductal-dependant congenital heart disease. Human DAs, which were patent (n = 10, age = 20.2 ± 4.3 days) or constricted (n = 10, age = 18.3 ± 3.9 days), were excised during surgery from neonates with ductal-dependent congenital heart disease. Western blotting analysis, real-time quantitative polymerase chain reaction analysis and immunofluorescence studies were performed to detect the protein and mRNA levels of NCX1, NCKX3, and NCKX4. The expressions of NCX1 and NCKX4 were significantly higher in the patent DA group at both the protein and mRNA levels, and expression was localized to the smooth muscle layer. These findings indicate that NCX1 and NCKX4 are up-regulated in human postnatal patent DAs and may represent potential therapeutic targets for maintaining DA patency in ductal-dependent congenital heart disease.

  14. Correlation of HER2 overexpression with gene amplification and its relation to chromosome 17 aneuploidy: a 5-year experience with invasive ductal and lobular carcinomas.

    PubMed

    Nassar, Aziza; Khoor, Andras; Radhakrishnan, Reshmitha; Radhakrishnan, Anu; Cohen, Cynthia

    2014-01-01

    The HER2 oncogene shows expression or amplification, or both, in approximately 15% to 20% of breast cancers and has been associated with poor prognosis and a response to trastuzumab therapy. HER2 gene status determines the eligibility of breast cancer patients for trastuzumab therapy and a large fraction (41-56%) of these patients respond to targeted therapy. Several studies have related the increased expression of HER2 to an increased copy number of chromosome 17, rather than amplification of the HER2 gene. We compared the results of immunohistochemistry and fluorescence in situ hybridization in both invasive ductal and invasive lobular carcinomas, to determine the frequency of chromosome 17 aneuploidy associated with discordant results. In total, 390 invasive ductal carcinomas and 180 invasive lobular carcinomas diagnosed from January 2000 to December 2005 were included in the study only if results were available for immunohistochemistry (HercepTest; DAKO, Carpinteria, California) and fluorescence in situ hybridization (PathVysion HER2 DNA Probe Kit; Abbott Laboratories, Des Plaines, Illinois). Tumors classified as invasive ductal carcinomas were graded according to the Bloom-Richardson grading system. Correlation between the results of immunohistochemistry and fluorescence in situ hybridization was performed for all categories. Among invasive ductal carcinomas, 29% (115/390) showed chromosome 17 aneuploidy, mostly associated with grade 3/HER2 2+ (45%) or grade 2/HER2 3+ (55%) that were not amplified. Also, 34% (12/35) of invasive lobular carcinomas showed chromosome 17 aneuploidy; approximately one-third of these cases were HER2 2+ (33%) and HER2 3+ (37%) that were not amplified. Discordance between the results of immunohistochemistry and fluorescence in situ hybridization in both ductal and lobular carcinomas is largely associated with chromosome 17 aneuploidy.

  15. The phosphorylation status of VASP at serine 322 can be predictive for aggressiveness of invasive ductal carcinoma

    PubMed Central

    Borges, Sahra; Geiger, Xochiquetzal; Storz, Peter

    2015-01-01

    Vasodilator-stimulated phosphoprotein (VASP) signaling is critical for dynamic actin reorganization processes that define the motile phenotype of cells. Here we show that VASP is generally highly expressed in normal breast tissue and breast cancer. We also show that the phosphorylation status of VASP at S322 can be predictive for breast cancer progression to an aggressive phenotype. Our data indicate that phosphorylation at S322 is gradually decreased from normal breast to DCIS, luminal/ER+, HER2+ and basal-like/TN phenotypes. Similarly, the expression levels of PKD2, the kinase that phosphorylates VASP at this site, are decreased in invasive ductal carcinoma samples of all three groups. Overall, the phosphorylation status of this residue may serve as an indicator of aggressiveness of breast tumors. PMID:26336132

  16. Combining in Vitro Diagnostics with in Vivo Imaging for Earlier Detection of Pancreatic Ductal Adenocarcinoma: Challenges and Solutions.

    PubMed

    Laeseke, Paul F; Chen, Ru; Jeffrey, R Brooke; Brentnall, Teresa A; Willmann, Jürgen K

    2015-12-01

    Pancreatic ductal adenocarcinoma (PDAC) is the fourth-leading cause of cancer-related death in the United States and is associated with a dismal prognosis, particularly when diagnosed at an advanced stage. Overall survival is significantly improved if PDAC is detected at an early stage prior to the onset of symptoms. At present, there is no suitable screening strategy for the general population. Available diagnostic serum markers are not sensitive or specific enough, and clinically available imaging modalities are inadequate for visualizing early-stage lesions. In this article, the role of currently available blood biomarkers and imaging tests for the early detection of PDAC will be reviewed. Also, the emerging biomarkers and molecularly targeted imaging agents being developed to improve the specificity of current imaging modalities for PDAC will be discussed. A strategy incorporating blood biomarkers and molecularly targeted imaging agents could lead to improved screening and earlier detection of PDAC in the future. (©) RSNA, 2015. PMID:26599925

  17. Psychosocial distress affecting patients with ductal carcinoma in situ compared to patients with early invasive breast cancer.

    PubMed

    Sanders, Judith Brown; Loftin, Adam; Seda, Julia S; Ehlenbeck, Chris

    2014-12-01

    Psychological distress in patients with a diagnosis of ductal carcinoma in situ (DCIS) or early invasive breast cancer (EIBC) can emanate from perceived risk of recurrence and is accompanied by perceived risk of death from the diseases. These factors can impart a lower quality of life that can result in poorer health outcomes. In addition, inaccurate risk perceptions can have an effect on decision making, psychosocial outcomes, and subsequent health behaviors. The purpose of this study is to assess patients with DCIS and EIBC and their perceived risk of recurrence and perceived risk of dying, and evaluate their outlook for the future, the degree of social support from spouses and significant others of patients who have been diagnosed with DCIS and EIBC, and the relationship to the patient's perceived risk perception of recurrence and dying from the diseases.

  18. Identification of lesion subtypes in biopsies of ductal carcinoma in situ of the breast using biomarker ratio imaging microscopy.

    PubMed

    Clark, Andrea J; Petty, Howard R

    2016-01-01

    Although epidemiological studies propose aggressive and non-aggressive forms of ductal carcinoma in situ (DCIS), they cannot be identified with conventional histopathology. We now report a retrospective study of human biopsy samples using biomarker ratio imaging microscopy (BRIM). Using BRIM, micrographs of biomarkers whose expression correlates with breast cancer aggressiveness are divided by micrographs of biomarkers whose expression negatively correlates with aggressiveness to create computed micrographs reflecting aggressiveness. The biomarker pairs CD44/CD24, N-cadherin/E-cadherin, and CD74/CD59 stratified DCIS samples. BRIM identified subpopulations of DCIS lesions with ratiometric properties resembling either benign fibroadenoma or invasive carcinoma samples. Our work confirms the existence of distinct subpopulations of DCIS lesions, which will likely have utility in breast cancer research and clinical practice. PMID:27247112

  19. Next-Generation Sequencing: A powerful tool for the discovery of molecular markers in breast ductal carcinoma in situ

    PubMed Central

    Kaur, Hitchintan; Mao, Shihong; Shah, Seema; Gorski, David H.; Krawetz, Stephen A.; Sloane, Bonnie F.; Mattingly, Raymond R.

    2013-01-01

    Mammographic screening leads to frequent biopsies and concomitant overdiagnosis of breast cancer, particularly ductal carcinoma in situ (DCIS). Some DCIS lesions rapidly progress to invasive carcinoma whereas others remain indolent. Because we cannot yet predict which lesions will not progress, all DCIS is regarded as malignant, and many women are overtreated. Thus, there is a pressing need for a panel of molecular markers in addition to the current clinical and pathologic factors to provide prognostic information. Genomic technologies such as microarrays have made major contributions to defining sub-types of breast cancer. Next-generation sequencing (NGS) modalities offer unprecedented depth of expression analysis through revealing transcriptional boundaries, mutations, rare transcripts and alternative splice variants. NGS approaches are just beginning to be applied to DCIS. Here, we review the applications and challenges of NGS in discovering novel potential therapeutic targets and candidate biomarkers in the premalignant progression of breast cancer. PMID:23477556

  20. Mammographycally occult high grade ductal carcinoma in situ (DCIS) as second primary breast cancer, detected with MRI: a case report

    PubMed Central

    Zebic-Sinkovec, Marta; Kadivec, Maksimiljan; Podobnik, Gasper; Skof, Erik; Snoj, Marko

    2010-01-01

    Background Contralateral breast cancer (CLB) is the most common second primary breast cancer in patients diagnosed with breast cancer. The majority of patients harbouring CLB tumours develop the invasive disease. Almost all invasive carcinomas are believed to begin as ductal carcinoma in situ (DCIS) lesions. The sensitivity of MRI for DCIS is much higher than that of mammography. Case report We report the case of a woman who was treated with breast conserving therapy 10 years ago. At that time the invasive medullary carcinoma was diagnosed in the left breast. Ten years later mammographically occult DCIS was diagnosed with MRI-guided core biopsy in contralateral breast. Conclusions There might be a potential role of MRI screening as part of an annual follow-up for patients diagnosed with breast cancer. PMID:22933920

  1. Subtotal resection of the head of the pancreas combined with ductal obliteration of the distal pancreas in chronic pancreatitis.

    PubMed Central

    Kerremans, R P; Penninckx, F M; De Groote, J; Fevery, J

    1987-01-01

    Subtotal resection of the head of the pancreas combined with duct obliteration of the distal pancreas by prolamine was performed in 12 selected patients who had chronic alcohol-induced pancreatitis with most destruction in the proximal pancreas. The main indication for operation was intractable pain. There was no postoperative mortality but morbidity was high when no pancreaticojejunostomy was constructed. After a follow-up period of 32 months, lasting pain relief was obtained in 10 patients; pseudocyst formation occurred in three patients; calcification of the distal pancreas, absent before operation, was demonstrated in four of six patients; six of 11 nondiabetic patients became hyperglycemic either abruptly (1 patient) or progressively (5 patients); quality of life improved in most patients. This procedure preserves the stomach, duodenum, spleen, distal pancreas and common bile duct if possible. However, pancreatic ductal obliteration with prolamine does not prevent relapses of chronic pancreatitis. PMID:3827358

  2. Combining in Vitro Diagnostics with in Vivo Imaging for Earlier Detection of Pancreatic Ductal Adenocarcinoma: Challenges and Solutions.

    PubMed

    Laeseke, Paul F; Chen, Ru; Jeffrey, R Brooke; Brentnall, Teresa A; Willmann, Jürgen K

    2015-12-01

    Pancreatic ductal adenocarcinoma (PDAC) is the fourth-leading cause of cancer-related death in the United States and is associated with a dismal prognosis, particularly when diagnosed at an advanced stage. Overall survival is significantly improved if PDAC is detected at an early stage prior to the onset of symptoms. At present, there is no suitable screening strategy for the general population. Available diagnostic serum markers are not sensitive or specific enough, and clinically available imaging modalities are inadequate for visualizing early-stage lesions. In this article, the role of currently available blood biomarkers and imaging tests for the early detection of PDAC will be reviewed. Also, the emerging biomarkers and molecularly targeted imaging agents being developed to improve the specificity of current imaging modalities for PDAC will be discussed. A strategy incorporating blood biomarkers and molecularly targeted imaging agents could lead to improved screening and earlier detection of PDAC in the future. (©) RSNA, 2015.

  3. Identification of lesion subtypes in biopsies of ductal carcinoma in situ of the breast using biomarker ratio imaging microscopy

    PubMed Central

    Clark, Andrea J.; Petty, Howard R.

    2016-01-01

    Although epidemiological studies propose aggressive and non-aggressive forms of ductal carcinoma in situ (DCIS), they cannot be identified with conventional histopathology. We now report a retrospective study of human biopsy samples using biomarker ratio imaging microscopy (BRIM). Using BRIM, micrographs of biomarkers whose expression correlates with breast cancer aggressiveness are divided by micrographs of biomarkers whose expression negatively correlates with aggressiveness to create computed micrographs reflecting aggressiveness. The biomarker pairs CD44/CD24, N-cadherin/E-cadherin, and CD74/CD59 stratified DCIS samples. BRIM identified subpopulations of DCIS lesions with ratiometric properties resembling either benign fibroadenoma or invasive carcinoma samples. Our work confirms the existence of distinct subpopulations of DCIS lesions, which will likely have utility in breast cancer research and clinical practice. PMID:27247112

  4. The phosphorylation status of VASP at serine 322 can be predictive for aggressiveness of invasive ductal carcinoma.

    PubMed

    Döppler, Heike; Bastea, Ligia; Borges, Sahra; Geiger, Xochiquetzal; Storz, Peter

    2015-10-01

    Vasodilator-stimulated phosphoprotein (VASP) signaling is critical for dynamic actin reorganization processes that define the motile phenotype of cells. Here we show that VASP is generally highly expressed in normal breast tissue and breast cancer. We also show that the phosphorylation status of VASP at S322 can be predictive for breast cancer progression to an aggressive phenotype. Our data indicate that phosphorylation at S322 is gradually decreased from normal breast to DCIS, luminal/ER+, HER2+ and basal-like/TN phenotypes. Similarly, the expression levels of PKD2, the kinase that phosphorylates VASP at this site, are decreased in invasive ductal carcinoma samples of all three groups. Overall, the phosphorylation status of this residue may serve as an indicator of aggressiveness of breast tumors. PMID:26336132

  5. p21(WAF1) (/Cip1) limits senescence and acinar-to-ductal metaplasia formation during pancreatitis.

    PubMed

    Grabliauskaite, Kamile; Hehl, Adrian B; Seleznik, Gitta M; Saponara, Enrica; Schlesinger, Kathryn; Zuellig, Richard A; Dittmann, Anja; Bain, Martha; Reding, Theresia; Sonda, Sabrina; Graf, Rolf

    2015-02-01

    Trans-differentiation of pancreatic acinar cells into ductal-like lesions, a process defined as acinar-to-ductal metaplasia (ADM), is observed in the course of organ regeneration following pancreatitis. In addition, ADM is found in association with pre-malignant PanIN lesions and correlates with an increased risk of pancreatic adenocarcinoma (PDAC). Human PDAC samples show down-regulation of p21(WAF1) (/Cip1) , a key regulator of cell cycle and cell differentiation. Here we investigated whether p21 down-regulation is implicated in controlling the early events of acinar cell trans-differentiation and ADM formation. p21-mediated regulation of ADM formation and regression was analysed in vivo during the course of cerulein-induced pancreatitis, using wild-type (WT) and p21-deficient (p21(-/-) ) mice. Biochemical and immunohistochemical methods were used to evaluate disease progression over 2 weeks of the disease and during a recovery phase. We found that p21 was strongly up-regulated in WT acinar cells during pancreatitis, while it was absent in ADM areas, suggesting that p21 down-regulation is associated with ADM formation. In support of this hypothesis, p21(-/-) mice showed a significant increase in number and size of metaplasia. In addition, p21 over-expression in acinar cells reduced ADM formation in vitro, suggesting that the protein regulates the metaplastic transition in a cell-autonomous manner. p21(-/-) mice displayed increased expression and relocalization of β-catenin both during pancreatitis and in the subsequent recovery phase. Finally, loss of p21 was accompanied by increased DNA damage and development of senescence. Our findings are consistent with a gate-keeper role of p21 in acinar cells to limit senescence activation and ADM formation during pancreatic regeneration. PMID:25212177

  6. p21(WAF1) (/Cip1) limits senescence and acinar-to-ductal metaplasia formation during pancreatitis.

    PubMed

    Grabliauskaite, Kamile; Hehl, Adrian B; Seleznik, Gitta M; Saponara, Enrica; Schlesinger, Kathryn; Zuellig, Richard A; Dittmann, Anja; Bain, Martha; Reding, Theresia; Sonda, Sabrina; Graf, Rolf

    2015-02-01

    Trans-differentiation of pancreatic acinar cells into ductal-like lesions, a process defined as acinar-to-ductal metaplasia (ADM), is observed in the course of organ regeneration following pancreatitis. In addition, ADM is found in association with pre-malignant PanIN lesions and correlates with an increased risk of pancreatic adenocarcinoma (PDAC). Human PDAC samples show down-regulation of p21(WAF1) (/Cip1) , a key regulator of cell cycle and cell differentiation. Here we investigated whether p21 down-regulation is implicated in controlling the early events of acinar cell trans-differentiation and ADM formation. p21-mediated regulation of ADM formation and regression was analysed in vivo during the course of cerulein-induced pancreatitis, using wild-type (WT) and p21-deficient (p21(-/-) ) mice. Biochemical and immunohistochemical methods were used to evaluate disease progression over 2 weeks of the disease and during a recovery phase. We found that p21 was strongly up-regulated in WT acinar cells during pancreatitis, while it was absent in ADM areas, suggesting that p21 down-regulation is associated with ADM formation. In support of this hypothesis, p21(-/-) mice showed a significant increase in number and size of metaplasia. In addition, p21 over-expression in acinar cells reduced ADM formation in vitro, suggesting that the protein regulates the metaplastic transition in a cell-autonomous manner. p21(-/-) mice displayed increased expression and relocalization of β-catenin both during pancreatitis and in the subsequent recovery phase. Finally, loss of p21 was accompanied by increased DNA damage and development of senescence. Our findings are consistent with a gate-keeper role of p21 in acinar cells to limit senescence activation and ADM formation during pancreatic regeneration.

  7. Association between ALDH1+/CD133+ stem-like cells and tumor angiogenesis in invasive ductal breast carcinoma

    PubMed Central

    LV, XINQUAN; WANG, YINGZI; SONG, YIMIN; PANG, XIA; LI, HUIXIANG

    2016-01-01

    The growth and metastasis of tumors is dependent on angiogenesis; however, the association between tumor stem cells (TSCs) and tumor angiogenesis remains to be elucidated. The present study aimed to investigate the expression of the TSC markers aldehyde dehydrogenase 1 (ALDH1) and cluster of differentiation 133 (CD133) in invasive ductal breast carcinoma, and identify their correlation with tumor angiogenesis. Stem-like cells from the breast tissue of 120 patients, who were diagnosed with invasive ductal breast carcinoma at The First Affiliated Hospital of Zhengzhou University (Zhengzhou, Henan, China) between January 2009 and December 2010, were collected by surgical resection and analyzed using immunohistochemical double staining. The expression of the vascular markers CD34, CD105 and vascular endothelial growth factor (VEGF) were determined using single staining. Overall, 25.83% (31/120) of the specimens contained a large number of ALDH1+/CD133+ stem-like cells (ALDH1+/CD133+ tumor). ALDH1+/CD133+ expression is associated with microvessel density, VEGF-positive rate and estrogen receptor expression (P<0.05); however, ALDH1+/CD133+ expression was not associated with age, tumor diameter, lymph node metastasis, histological classification, progesterone receptor expression or human epidermal growth factor receptor 2 expression (P>0.05). The ALDH1+/CD133+ tumor phenotype and expression of VEGF were identified to be correlated in the present study (P=0.020). The present study revealed a close association between breast cancer TSC markers, including ALDH1 and CD133, and tumor angiogenesis. The results of the present study may provide a novel target and treatment strategy for future studies investigating tumor growth and metastasis. PMID:26998072

  8. Primary ductal adenocarcinoma of the lacrimal gland, associated with abundant intracytoplasmic lumens containing some eosinophilic hyaline globules: cytological, histological and ultrastructural findings.

    PubMed

    Min, Kyueng-Whan; Park, Hyung Kyu; Kim, Wook Youn; Kim, Wan-Seop; Lim, So Dug; Han, Hye Seung; Hwang, Tae Sook

    2014-10-01

    A primary ductal adenocarcinoma (PDA) of the lacrimal gland is a rare distinct subtype of an epithelial tumor arising in the lacrimal gland. PDA is the counterpart of salivary duct carcinoma (SDC) resembling an invasive ductal carcinoma (IDC) of the breast. In our case, PDA revealed histopathological and immunohistochemical results corresponding to SDC. Interestingly, the tumor cells showed intracytoplasmic vacuoles containing dense eosinophilic hyaline globules at light microscopy. Ultrastructurally, the tumor cells exhibited microvilli-lined intracytoplasmic lumen containing homogenous electron-dense secretory products. A previous study demonstrated that numerous intracytoplasmic lumens of tumor cells are favored breast malignant tumor, similar to the histopathology of PDA, rather than benign lesion. This characteristic finding may be meaningful to diagnose high grade epithelial tumors including PDA.

  9. Development and Evaluation of a Prediction Model for Underestimated Invasive Breast Cancer in Women with Ductal Carcinoma In Situ at Stereotactic Large Core Needle Biopsy

    PubMed Central

    Diepstraten, Suzanne C. E.; van de Ven, Stephanie M. W. Y.; Pijnappel, Ruud M.; Peeters, Petra H. M.; van den Bosch, Maurice A. A. J.; Verkooijen, Helena M.; Elias, Sjoerd G.

    2013-01-01

    Background We aimed to develop a multivariable model for prediction of underestimated invasiveness in women with ductal carcinoma in situ at stereotactic large core needle biopsy, that can be used to select patients for sentinel node biopsy at primary surgery. Methods From the literature, we selected potential preoperative predictors of underestimated invasive breast cancer. Data of patients with nonpalpable breast lesions who were diagnosed with ductal carcinoma in situ at stereotactic large core needle biopsy, drawn from the prospective COBRA (Core Biopsy after RAdiological localization) and COBRA2000 cohort studies, were used to fit the multivariable model and assess its overall performance, discrimination, and calibration. Results 348 women with large core needle biopsy-proven ductal carcinoma in situ were available for analysis. In 100 (28.7%) patients invasive carcinoma was found at subsequent surgery. Nine predictors were included in the model. In the multivariable analysis, the predictors with the strongest association were lesion size (OR 1.12 per cm, 95% CI 0.98-1.28), number of cores retrieved at biopsy (OR per core 0.87, 95% CI 0.75-1.01), presence of lobular cancerization (OR 5.29, 95% CI 1.25-26.77), and microinvasion (OR 3.75, 95% CI 1.42-9.87). The overall performance of the multivariable model was poor with an explained variation of 9% (Nagelkerke’s R2), mediocre discrimination with area under the receiver operating characteristic curve of 0.66 (95% confidence interval 0.58-0.73), and fairly good calibration. Conclusion The evaluation of our multivariable prediction model in a large, clinically representative study population proves that routine clinical and pathological variables are not suitable to select patients with large core needle biopsy-proven ductal carcinoma in situ for sentinel node biopsy during primary surgery. PMID:24147085

  10. A Pilot Study of Ultrasound-Guided Cryoablation of Invasive Ductal Carcinomas up to 15 mm With MRI Follow-Up and Subsequent Surgical Resection

    PubMed Central

    Poplack, Steven P.; Levine, Gary M.; Henry, Lisa; Wells, Wendy A.; Heinemann, F. Scott; Hanna, Cheryl M.; Deneen, Daniel R.; Tosteson, Tor D.; Barth, Richard J.

    2016-01-01

    OBJECTIVE The purpose of this study was to evaluate the effectiveness of ultrasound-guided cryoablation in treating small invasive ductal carcinoma and to assess the role of contrast-enhanced (CE) MRI in determining the outcome of cryoablation. SUBJECTS AND METHODS Twenty consecutive participants with invasive ductal carcinomas up to 15 mm, with limited or no ductal carcinoma in situ (DCIS), underwent ultrasound-guided cryoablation. Preablation mammography, ultrasound, and CE-MRI were performed to assess eligibility. Clinical status was evaluated at 1 day, 7–10 days, and 2 weeks after ablation. CE-MRI was performed 25–40 days after ablation, followed by surgical resection within 5 days. RESULTS Ultrasound-guided cryoablation was uniformly technically successful, and postablation clinical status was good to excellent in all participants. Cryoablation was not clinically successful in 15% (three of 20 patients). Three participants had residual cancer at the periphery of the cryoablation site. Two participants had viable nonmalignant tissue within the central zone of cryoablation-induced necrosis. Postablation CE-MRI had a sensitivity of 0% (0/3) and specificity of 88% (15/17). The predictive value of negative findings on CE-MRI was 83% (15/18). Correlations between cancer characteristics, cryoablation procedural variables, postablation CE-MRI findings, and surgical specimen features were not statistically significant. There were also no significant differences in participants with or without residual cancer. CONCLUSION In our pilot experience, ultrasound-guided cryoablation of invasive ductal carcinomas up to 15 mm has a clinical failure rate of 15% but is technically feasible and well tolerated by patients. The majority of cryoablation failures are manifest as DCIS outside the cryoablation field. Postablation CE-MRI does not reliably predict cryoablation outcome. PMID:25905948

  11. Successful Salvage Chemotherapy with FOLFIRINOX for Recurrent Mixed Acinar Cell Carcinoma and Ductal Adenocarcinoma of the Pancreas in an Adolescent Patient

    PubMed Central

    Pfrommer, Sarah; Weber, Achim; Dutkowski, Philipp; Schäfer, Niklaus G.; Müllhaupt, Beat; Bourquin, Jean-Pierre; Breitenstein, Stefan; Pestalozzi, Bernhard C.; Stenner, Frank; Renner, Christoph; D'Addario, Giannicola; Graf, Hans-Jörg; Knuth, Alexander; Clavien, Pierre-Alain; Samaras, Panagiotis

    2013-01-01

    Pancreatic tumors are rare in children and adolescents. Here, we report the case of a 15-year-old boy who presented with a mixed acinar cell carcinoma/ductal adenocarcinoma with blastomatous components. He received multimodal treatment including various chemotherapy regimens and multistep surgery including liver transplantation. Introduction of FOLFIRINOX after relapse repeatedly achieved a durable metabolic and clinical response with good quality of life. PMID:24163668

  12. Successful Salvage Chemotherapy with FOLFIRINOX for Recurrent Mixed Acinar Cell Carcinoma and Ductal Adenocarcinoma of the Pancreas in an Adolescent Patient.

    PubMed

    Pfrommer, Sarah; Weber, Achim; Dutkowski, Philipp; Schäfer, Niklaus G; Müllhaupt, Beat; Bourquin, Jean-Pierre; Breitenstein, Stefan; Pestalozzi, Bernhard C; Stenner, Frank; Renner, Christoph; D'Addario, Giannicola; Graf, Hans-Jörg; Knuth, Alexander; Clavien, Pierre-Alain; Samaras, Panagiotis

    2013-01-01

    Pancreatic tumors are rare in children and adolescents. Here, we report the case of a 15-year-old boy who presented with a mixed acinar cell carcinoma/ductal adenocarcinoma with blastomatous components. He received multimodal treatment including various chemotherapy regimens and multistep surgery including liver transplantation. Introduction of FOLFIRINOX after relapse repeatedly achieved a durable metabolic and clinical response with good quality of life. PMID:24163668

  13. Analysis of morphological and functional maturation of neoislets generated in vitro from pancreatic ductal cells and their suitability for islet banking and transplantation.

    PubMed

    Katdare, M R; Bhonde, R R; Parab, P B

    2004-07-01

    The pancreatic ductal stem cells are known to differentiate into islets of Langerhans; however, their yield is limited and the islet population is not defined. Therefore, the aims of the present study were to improvise a methodology for obtaining large numbers of islets in vitro and to characterize their morphological and functional status for islet cell banking and transplantation. Pancreatic ductal epithelial cell cultures were set in serum-free medium. Monolayers of epithelial cells in culture gave rise to islet-like clusters within 3-4 weeks. The identity of neoislets was confirmed by dithizone staining and analysis of the gene expression for endocrine markers by reverse transcriptase-polymerase chain reaction (RT-PCR). The islet population obtained was analysed by image analysis and insulin secretion in response to secretagogues. The cellular extracts from neoislets were immunoreactive to anti-insulin antibody and expressed insulin, glucagon, GLUT-2, PDX-1 and Reg-1 genes. The islets generated within 3-4 weeks exhibited a mixed population of large- and small-sized islets with clear cut dichotomy in the pattern of their insulin secretion in response to L-arginine and glucose. These neoislets maintained their structural and functional integrity on cryopreservation and transplantation indicating their suitability for islet cell banking. Thus, the present study describes an improved method for obtaining a constant supply of large numbers of islets from pancreatic ductal stem cell cultures. The newly generated islets undergo functional maturation indicating their suitability for transplantation.

  14. Impact of Boost Radiation in the Treatment of Ductal Carcinoma In Situ: A Population-Based Analysis

    SciTech Connect

    Rakovitch, Eileen; Narod, Steven A.; Nofech-Moses, Sharon; Hanna, Wedad; Thiruchelvam, Deva; Saskin, Refik; Taylor, Carole; Tuck, Alan; Youngson, Bruce; Miller, Naomi; Done, Susan J.; Sengupta, Sandip; Elavathil, Leela; Jani, Prashant A.; Bonin, Michel; Metcalfe, Stephanie; Paszat, Lawrence

    2013-07-01

    Purpose: To report the outcomes of a population of women with ductal carcinoma in situ (DCIS) treated with breast-conserving surgery and radiation and to evaluate the independent effect of boost radiation on the development of local recurrence. Methods and Materials: All women diagnosed with DCIS and treated with breast-conserving surgery and radiation therapy in Ontario from 1994 to 2003 were identified. Treatments and outcomes were identified through administrative databases and validated by chart review. The impact of boost radiation on the development of local recurrence was determined using survival analyses. Results: We identified 1895 cases of DCIS that were treated by breast-conserving surgery and radiation therapy; 561 patients received boost radiation. The cumulative 10-year rate of local recurrence was 13% for women who received boost radiation and 12% for those who did not (P=.3). The 10-year local recurrence-free survival (LRFS) rate among women who did and who did not receive boost radiation was 88% and 87%, respectively (P=.27), 94% and 93% for invasive LRFS (P=.58), and was 95% and 93% for DCIS LRFS (P=.31). On multivariable analyses, boost radiation was not associated with a lower risk of local recurrence (hazard ratio = 0.82, 95% confidence interval 0.59-1.15) (P=.25). Conclusions: Among a population of women treated with breast-conserving surgery and radiation for DCIS, additional (boost) radiation was not associated with a lower risk of local or invasive recurrence.

  15. Expression of genes responsible for the repair of mispaired bases of the DNA (MLH1) in invasive ductal breast carcinoma.

    PubMed

    Milanović, Rudolf; Stanec, Sanda; Stanec, Mladen; Korusić, Andelko; Husedzinović, Ino; Razumović, Jasminka Jakić

    2013-09-01

    Breast cancer is a heterogeneous group of diseases determined and distinguished by cellular type, gene expression and clinical signs and symptoms. Identification of histological and biological markers is of great value in predicting the progression of tumor growth and anticipating the expected response to various treatment options. Due to a high degree of cell proliferation in breast tumors and high genetic instability of these tumors, as a consequence of defective DNA repair mechanisms, chemotherapy as a treatment option often renders very successful results. During our scientific research we wanted to determine the involvement of the genetic polymorphisms of DNA mismatch repair system (MLH1 gene) and the subsequent development of breast carcinoma. This study included 108 patients who were surgically treated for invasive breast cancer at the Department of Plastic, Reconstructive and Aesthetic Surgery, University Hospital "Dubrava". The expression of the MLH1 gene was determined by immunohistochemical methods. The results showed that 82.9% of tumor cells expressed the MLH1 gene. Analysis of survival rate for patients with invasive ductal breast cancer showed a statistically significant (p = 0.043) correlation with the expression of MLH1 genes. The overall five year survival rate of our patients was 78.7%. These results indicate that there is a possible involvement of MLH1 gene in the progression and development of breast cancer.

  16. Health behavior change following a diagnosis of ductal carcinoma in situ: An opportunity to improve health outcomes.

    PubMed

    Berkman, Amy M; Trentham-Dietz, Amy; Dittus, Kim; Hart, Vicki; Vatovec, Christine M; King, John G; James, Ted A; Lakoski, Susan G; Sprague, Brian L

    2015-11-01

    Ductal carcinoma in situ (DCIS) is a non-invasive breast cancer that comprises approximately 20% of new breast cancer diagnoses. DCIS is predominantly detected by screening mammography prior to the development of any clinical symptoms. Prognosis following a DCIS diagnosis is excellent, due to both the availability of effective treatments and the frequently benign nature of the disease. However, a DCIS diagnosis and its treatment have psychological and physical impacts that often lead to adverse changes in health-related behaviors, including changes in physical activity, body weight, alcohol intake, and smoking, which may represent a greater threat to the woman's overall health than the DCIS itself. Depending on age at diagnosis, women diagnosed with DCIS are 3-13 times more likely to die from non-breast cancer related causes, such as cardiovascular disease, than from breast cancer. Thus, the maintenance and improvement of healthy behaviors that influence a variety of outcomes after diagnosis may warrant increased attention during DCIS management. This may also represent an important opportunity to promote the adoption of healthy behaviors, given that DCIS carries the psychological impact of a cancer diagnosis but also a favorable prognosis. Particular focus is needed to address these issues in vulnerable patient subgroups with pre-existing higher rates of unhealthy behaviors and demonstrated health disparities. PMID:25858806

  17. Slit2 and netrin 1 act synergistically as adhesive cues to generate tubular bi-layers during ductal morphogenesis.

    PubMed

    Strickland, Phyllis; Shin, Grace C; Plump, Andrew; Tessier-Lavigne, Marc; Hinck, Lindsay

    2006-03-01

    Development of many organs, including the mammary gland, involves ductal morphogenesis. Mammary ducts are bi-layered tubular structures comprising an outer layer of cap/myoepithelial cells (MECs) and an inner layer of luminal epithelial cells (LECs). Slit2 is expressed by cells in both layers, with secreted SLIT2 broadly distributed throughout the epithelial compartment. By contrast, Robo1 is expressed specifically by cap/MECs. Loss-of-function mutations in Slit2 and Robo1 yield similar phenotypes, characterized by disorganized end buds (EBs) reminiscent of those present in Ntn1(-/-) glands, suggesting that SLIT2 and NTN1 function in concert during mammary development. Analysis of Slit2(-/-);Ntn1(-/-) glands demonstrates an enhanced phenotype that extends through the ducts and is characterized by separated cell layers and occluded lumens. Aggregation assays show that Slit2(-/-);Ntn1(-/-) cells, in contrast to wild-type cells, do not form bi-layered organoids, a defect rescued by addition of SLIT2. NTN1 has no effect alone, but synergistically enhances this rescue. Thus, our data establish a novel role for SLIT2 as an adhesive cue, acting in parallel with NTN1 to generate cell boundaries along ducts during bi-layered tube formation.

  18. Invasive ductal carcinoma within borderline phyllodes tumor with lymph node metastases: A case report and review of the literature

    PubMed Central

    WU, DI; ZHANG, HAIPENG; GUO, LIANG; YAN, XU; FAN, ZHIMIN

    2016-01-01

    Phyllodes tumor (PT) is a rare type of biphasic fibroepithelial neoplasm that may coexist with a breast tumor in rare cases. In the current study, a 52-year-old female presented with a left breast lump. Mammography and sonographic examination results suggested a diagnosis of malignant tumor. Histological analysis revealed a borderline PT with invasive ductal carcinoma (IDC) within the tumor. Due to the presence of a single micrometastasis in three of the sentinel lymph nodes, the patient underwent modified radical mastectomy. The excised tumor contained triple negative breast cancer; therefore, postoperative treatment included six cycles of chemotherapy and 25 cycles of radiotherapy. The patient exhibited no recurrence and no metastatic disease at the 23-month follow-up examination. Thus, the present study discussed the case of a female patient that presented with IDC within borderline PT and reviewed the literature on this rare type of neoplasm. Various types of breast carcinoma have been identified to coexist with PT in different masses; however, no standard therapeutic regimen has been established for the coexistence of PT and breast cancer in the same mass. The present study indicates that determination of an appropriate treatment strategy predominantly depends on the characteristics of the individual breast tumor. PMID:27073506

  19. Targeting the mRNA-binding protein HuR impairs malignant characteristics of pancreatic ductal adenocarcinoma cells

    PubMed Central

    Jimbo, Masaya; Blanco, Fernando F.; Screnci, Brad A.; Cosma, Gabriela L.; Alexeev, Vitali; Gonye, Gregory E.; Yeo, Charles J.; Sawicki, Janet A.; Winter, Jordan M.; Brody, Jonathan R.

    2015-01-01

    Post-transcriptional regulation is a powerful mediator of gene expression, and can rapidly alter the expression of numerous transcripts involved in tumorigenesis. We have previously shown that the mRNA-binding protein HuR (ELAVL1) is elevated in human pancreatic ductal adenocarcinoma (PDA) specimens compared to normal pancreatic tissues, and its cytoplasmic localization is associated with increased tumor stage. To gain a better insight into HuR’s role in PDA biology and to assess it as a candidate therapeutic target, we altered HuR expression in PDA cell lines and characterized the resulting phenotype in preclinical models. HuR silencing by short hairpin and small interfering RNAs significantly decreased cell proliferation and anchorage-independent growth, as well as impaired migration and invasion. In comparison, HuR overexpression increased migration and invasion, but had no significant effects on cell proliferation and anchorage-independent growth. Importantly, two distinct targeted approaches to HuR silencing showed marked impairment in tumor growth in mouse xenografts. NanoString nCounter® analyses demonstrated that HuR regulates core biological processes, highlighting that HuR inhibition likely thwarts PDA viability through post-transcriptional regulation of diverse signaling pathways (e.g. cell cycle, apoptosis, DNA repair). Taken together, our study suggests that targeted inhibition of HuR may be a novel, promising approach to the treatment of PDA. PMID:26314962

  20. Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell- and patient-derived tumor organoids.

    PubMed

    Huang, Ling; Holtzinger, Audrey; Jagan, Ishaan; BeGora, Michael; Lohse, Ines; Ngai, Nicholas; Nostro, Cristina; Wang, Rennian; Muthuswamy, Lakshmi B; Crawford, Howard C; Arrowsmith, Cheryl; Kalloger, Steve E; Renouf, Daniel J; Connor, Ashton A; Cleary, Sean; Schaeffer, David F; Roehrl, Michael; Tsao, Ming-Sound; Gallinger, Steven; Keller, Gordon; Muthuswamy, Senthil K

    2015-11-01

    There are few in vitro models of exocrine pancreas development and primary human pancreatic adenocarcinoma (PDAC). We establish three-dimensional culture conditions to induce the differentiation of human pluripotent stem cells into exocrine progenitor organoids that form ductal and acinar structures in culture and in vivo. Expression of mutant KRAS or TP53 in progenitor organoids induces mutation-specific phenotypes in culture and in vivo. Expression of TP53(R175H) induces cytosolic SOX9 localization. In patient tumors bearing TP53 mutations, SOX9 was cytoplasmic and associated with mortality. We also define culture conditions for clonal generation of tumor organoids from freshly resected PDAC. Tumor organoids maintain the differentiation status, histoarchitecture and phenotypic heterogeneity of the primary tumor and retain patient-specific physiological changes, including hypoxia, oxygen consumption, epigenetic marks and differences in sensitivity to inhibition of the histone methyltransferase EZH2. Thus, pancreatic progenitor organoids and tumor organoids can be used to model PDAC and for drug screening to identify precision therapy strategies.

  1. Identification and characterization of the gene expression profiles for protein coding and non-coding RNAs of pancreatic ductal adenocarcinomas

    PubMed Central

    Gutiérrez, María Laura; Corchete, Luis; Teodosio, Cristina; Sarasquete, María Eugenia; Abad, María del Mar; Iglesias, Manuel; Esteban, Carmen

    2015-01-01

    Significant advances have been achieved in recent years in the identification of the genetic and the molecular alterations of pancreatic ductal adenocarcinoma (PDAC). Despite this, at present the understanding of the precise mechanisms involved in the development and malignant transformation of PDAC remain relatively limited. Here, we evaluated for the first time, the molecular heterogeneity of PDAC tumors, through simultaneous assessment of the gene expression profile (GEP) for both coding and non-coding genes of tumor samples from 27 consecutive PDAC patients. Overall, we identified a common GEP for all PDAC tumors, characterized by an increased expression of genes involved in PDAC cell proliferation, local invasion and metastatic capacity, together with a significant alteration of the early steps of the cellular immune response. At the same time, we confirm and extend on previous observations about the genetic complexity of PDAC tumors as revealed by the demonstration of two clearly distinct and unique GEPs (e.g. epithelial-like vs. mesenchymal-like) reflecting the alteration of different signaling pathways involved in the oncogenesis and progression of these tumors. Our results also highlight the potential role of the immune system microenvironment in these tumors, with potential diagnostic and therapeutic implications. PMID:26053098

  2. SOX2 functions as a molecular rheostat to control the growth, tumorigenicity and drug responses of pancreatic ductal adenocarcinoma cells

    PubMed Central

    Wuebben, Erin L.; Wilder, Phillip J.; Cox, Jesse L.; Grunkemeyer, James A.; Caffrey, Thomas; Hollingsworth, Michael A.; Rizzino, Angie

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a highly deadly malignancy. Expression of the stem cell transcription factor SOX2 increases during progression of PDAC. Knockdown of SOX2 in PDAC cell lines decreases growth in vitro; whereas, stable overexpression of SOX2 in one PDAC cell line reportedly increases growth in vitro. Here, we reexamined the role of SOX2 in PDAC cells, because inducible SOX2 overexpression in other tumor cell types inhibits growth. In this study, four PDAC cell lines were engineered for inducible overexpression of SOX2 or inducible knockdown of SOX2. Remarkably, inducible overexpression of SOX2 in PDAC cells inhibits growth in vitro and reduces tumorigenicity. Additionally, inducible knockdown of SOX2 in PDAC cells reduces growth in vitro and in vivo. Thus, growth and tumorigenicity of PDAC cells is highly dependent on the expression of optimal levels of SOX2 – a hallmark of molecular rheostats. We also determined that SOX2 alters the responses of PDAC cells to drugs used in PDAC clinical trials. Increasing SOX2 reduces growth inhibition mediated by MEK and AKT inhibitors; whereas knockdown of SOX2 further reduces growth when PDAC cells are treated with these inhibitors. Thus, targeting SOX2, or its mode of action, could improve the treatment of PDAC. PMID:27145457

  3. Suppression of pancreatic ductal adenocarcinoma growth by intratumoral delivery of attenuated Salmonella typhimurium using a dual fluorescent live tracking system

    PubMed Central

    Zhou, Sujin; Zhao, Zhenggang; Lin, Yan; Gong, Sijia; Li, Fanghong; Pan, Jinshun; Li, Xiaoxi; Gao, Zhuo; Zhao, Allan Z.

    2016-01-01

    ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) has the poorest prognosis among all malignancies and is resistant to almost all current therapies. Attenuated Salmonella typhimurium strain VNP20009 has been deployed as powerful anticancer agent in a variety of animal cancer models, and previous phase 1 clinical trials have proven its safety profiles. However, thus far, little is known about its effect on PDAC. Here, we established CFPAC-1 cell lines expressing an mKate2 protein and thus emitting far-red fluorescence in the subsequent xenograft implant. VNP20009 strain was further engineered to carry a luciferase cDNA, which catalyzes the light-emitting reaction to allow the observation of salmonella distribution and accumulation within tumor with live imaging. Using such VNP20009 strain and intratumoral delivery, we could reduce the growth of pancreatic cancer by inducing apoptosis and severe necrosis in a dosage dependent manner. Consistent with this finding, intratumoral delivery of VNP20009 also increase caspase-3 activity and the expression of Bax protein. In summary, we revealed that VNP20009 is a promising bacterial agent for the treatment of PDAC, and that we have established a dual fluorescent imaging system as a valuable tool for noninvasive live imaging of solid tumor and engineered bacterial drug. PMID:27089121

  4. Lysyl oxidase family activity promotes resistance of pancreatic ductal adenocarcinoma to chemotherapy by limiting the intratumoral anticancer drug distribution.

    PubMed

    Le Calvé, Benjamin; Griveau, Audrey; Vindrieux, David; Maréchal, Raphaël; Wiel, Clotilde; Svrcek, Magali; Gout, Johann; Azzi, Lamia; Payen, Léa; Cros, Jérôme; de la Fouchardière, Christelle; Dubus, Pierre; Guitton, Jérôme; Bartholin, Laurent; Bachet, Jean-Baptiste; Bernard, David

    2016-05-31

    Solid tumors often display chemotherapy resistance. Pancreatic ductal adenocarcinoma (PDAC) is the archetype of resistant tumors as current chemotherapies are inefficient. The tumor stroma and extracellular matrix (ECM) are key contributors to PDAC aggressiveness and to limiting the efficacy of chemotherapy. Lysyl oxidase (LOX) family members mediate collagen cross-linking and thus promote ECM stiffening. Our data demonstrate increased LOX, LOXL1, and LOXL2 expression in PDAC, and that the level of fibrillar collagen, which is directly dependent of LOX family activity, is an independent predictive biomarker of adjuvant "Gemcitabine-based chemotherapy" benefit. Experimentally in mice, increased LOX family activity through LOXL2 promotes chemoresistance. This effect of LOX family activity seems to be due to decreased gemcitabine intra-tumoral diffusion. This observation might be explained by increased fibrillar collagen and decreased vessel size observed in tumors with increased LOX family activity. In conclusion, our data support that LOX family activity is both a novel target to improve chemotherapy as well as a novel biomarker to predict gemcitabine benefit in PDAC. Beyond the PDAC, it is possible that targeting LOX family activity might improve efficacy of chemotherapies against different kinds of solid tumors.

  5. High ROR2 expression in tumor cells and stroma is correlated with poor prognosis in pancreatic ductal adenocarcinoma

    PubMed Central

    Huang, Jianfei; Fan, Xiangjun; Wang, Xudong; Lu, Yuhua; Zhu, Huijun; Wang, Wei; Zhang, Shu; Wang, Zhiwei

    2015-01-01

    RTK-like orphan receptor 2 (ROR2) is overexpressed in several cancers and has tumorigenic activity. However, the expression of ROR2 and its functional and prognostic significance have yet to be evaluated in pancreatic ductal adenocarcinoma (PDAC). Quantitative real-time polymerase chain reaction was used to characterize the expression of ROR2 mRNA in PDAC, corresponding peritumoral tissues, and PDAC cell lines. Immunohistochemical analysis with tissue microarrays was used to evaluate ROR2 expression in PDAC and to investigate the relationship of this expression to clinicopathological factors and prognosis. The expression of ROR2 mRNA and protein was significantly higher in PDAC than in normal pancreatic tissues. High cytoplasmic ROR2 expression in cancer cells was significantly associated with a primary tumor, distant metastasis, and TNM stage, and high stromal ROR2 expression was significantly associated with regional lymph node metastasis and TNM stage. The Kaplan–Meier method and Cox regression analyses showed that high ROR2 expression in tumor cytoplasm or stromal cells was significantly associated with malignant attributes and reduced survival in PDAC. We present strong evidence that ROR2 could be used as an indicator of poor prognosis and could represent a novel therapeutic target for PDAC. PMID:26259918

  6. Clinical and prognostic significance of serum transforming growth factor-beta1 levels in patients with pancreatic ductal adenocarcinoma

    PubMed Central

    Zhao, J.; Liang, Y.; Yin, Q.; Liu, S.; Wang, Q.; Tang, Y.; Cao, C.

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate of 5%. Biomarkers for the early detection of pancreatic cancer are urgently needed. Transforming growth factor-beta1 (TGF-β1) is elevated in the tissues and plasma of patients with PDAC. However, no studies systemically report prognostic significance of plasma TGF-β1 levels in PDAC. In the present study, we assessed the prognostic significance of serum TGF-β levels in patients with PDAC. TGF-β levels were determined in serum from 146 PDAC patients, and 58 patients with benign pancreatic conditions. Regression models were used to correlate TGF-β levels to gender, age, stage, class, and metastasis. Survival analyses were performed using multivariate Cox models. Serum levels of TGF-β1 distinguished PDAC from benign pancreatic conditions (P<0.001) and healthy control subjects (P<0.001). Serum levels of TGF-β also distinguished tumor stage (P=0.002) and lymph node metastasis (P=0.001). High serum levels of TGF-β1 were significantly correlated with reduced patient survival. Multivariate analysis revealed that TGF-β1, lymph node metastasis and tumor stage were independent factors for PDAC survival. Our results indicate that serum TGF-β1 may be used as a potential prognostic marker for PDAC. PMID:27464025

  7. Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma.

    PubMed

    Mazur, Pawel K; Herner, Alexander; Mello, Stephano S; Wirth, Matthias; Hausmann, Simone; Sánchez-Rivera, Francisco J; Lofgren, Shane M; Kuschma, Timo; Hahn, Stephan A; Vangala, Deepak; Trajkovic-Arsic, Marija; Gupta, Aayush; Heid, Irina; Noël, Peter B; Braren, Rickmer; Erkan, Mert; Kleeff, Jörg; Sipos, Bence; Sayles, Leanne C; Heikenwalder, Mathias; Heßmann, Elisabeth; Ellenrieder, Volker; Esposito, Irene; Jacks, Tyler; Bradner, James E; Khatri, Purvesh; Sweet-Cordero, E Alejandro; Attardi, Laura D; Schmid, Roland M; Schneider, Guenter; Sage, Julien; Siveke, Jens T

    2015-10-01

    Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers and shows resistance to any therapeutic strategy used. Here we tested small-molecule inhibitors targeting chromatin regulators as possible therapeutic agents in PDAC. We show that JQ1, an inhibitor of the bromodomain and extraterminal (BET) family of proteins, suppresses PDAC development in mice by inhibiting both MYC activity and inflammatory signals. The histone deacetylase (HDAC) inhibitor SAHA synergizes with JQ1 to augment cell death and more potently suppress advanced PDAC. Finally, using a CRISPR-Cas9-based method for gene editing directly in the mouse adult pancreas, we show that de-repression of p57 (also known as KIP2 or CDKN1C) upon combined BET and HDAC inhibition is required for the induction of combination therapy-induced cell death in PDAC. SAHA is approved for human use, and molecules similar to JQ1 are being tested in clinical trials. Thus, these studies identify a promising epigenetic-based therapeutic strategy that may be rapidly implemented in fatal human tumors. PMID:26390243

  8. Outcomes after breast conservation treatment with radiation in women with ductal carcinoma in situ and prior nonbreast malignancy.

    PubMed

    Shah, Deepika N; Vapiwala, Neha; Solin, Lawrence J

    2009-01-01

    Management of ductal carcinoma in situ (DCIS) of the breast is controversial, as not all patients progress to invasive carcinoma. This report analyzes the outcomes after breast conservation treatment (BCT) with radiation in patients with DCIS following prior malignancy at another anatomic site. The study cohort was comprised of 14 women with DCIS who were treated between 1978 and 2003. The median age at diagnosis of DCIS was 54 years (mean 56; range 37-78) and for the prior nonbreast malignancy was 44 years (mean 47; range 27-76). All patients underwent breast conservation surgery followed by whole breast radiation and tumor bed boost. The median and mean follow-up times after treatment of DCIS were 8.0 and 9.1 years, respectively (range 2-18). The median and mean interval period between the prior malignancy and DCIS was 6.0 and 8.2 years, respectively (range 1-30). There was one (7%) local failure, two (14%) contralateral breast cancers, and one (7%) death from breast cancer that occurred 7 years after BCT following contralateral invasive breast cancer. In this cohort of 14 patients treated for DCIS of the breast after a prior nonbreast malignancy, treatment for DCIS resulted in a high rate of local control and should be considered for curative intent.

  9. Cardiac morbidity and mortality in women with ductal carcinoma in situ of the breast treated with breast conservation therapy.

    PubMed

    Park, Catherine K; Li, Xiaohong; Starr, Jason; Harris, Eleanor E R

    2011-01-01

    Left-sided breast irradiation has been associated with increased risk of cardiac morbidity and mortality in some studies. This study examines the cardiac toxicity of irradiation in left- versus right-sided patients with ductal carcinoma in situ (DCIS). The medical records of 129 patients with DCIS treated with breast conservation therapy (BCT) at the Moffitt Cancer Center from 1986 to 2002 were reviewed and data regarding subsequent breast cancer and cardiac events were recorded. There were 59 left-sided and 70 right-sided patients treated. Mean age was 55 years. At 8 years, there was no significant difference observed between right- and left-sided breast cancer patients in the development of coronary artery disease, myocardial infarction, congestive heart failure, arrhythmia, valvular disease, cardiomyopathy, or cardiac-related death. Among those patients with left-sided breast cancer, 13.5% of patients developed a cardiovascular event compared to 7% of right-sided patients (p = 0.25). The overall survival at 8 years was 96% and the relapse-free survival was 85%. There were no significant differences in cardiac mortality or morbidity between right- and left-sided DCIS patients treated with BCT. Longer follow-up will be required to ascertain whether late events are more prevalent in left-sided patients.

  10. Targeting the mRNA-binding protein HuR impairs malignant characteristics of pancreatic ductal adenocarcinoma cells.

    PubMed

    Jimbo, Masaya; Blanco, Fernando F; Huang, Yu-Hung; Telonis, Aristeidis G; Screnci, Brad A; Cosma, Gabriela L; Alexeev, Vitali; Gonye, Gregory E; Yeo, Charles J; Sawicki, Janet A; Winter, Jordan M; Brody, Jonathan R

    2015-09-29

    Post-transcriptional regulation is a powerful mediator of gene expression, and can rapidly alter the expression of numerous transcripts involved in tumorigenesis. We have previously shown that the mRNA-binding protein HuR (ELAVL1) is elevated in human pancreatic ductal adenocarcinoma (PDA) specimens compared to normal pancreatic tissues, and its cytoplasmic localization is associated with increased tumor stage. To gain a better insight into HuR's role in PDA biology and to assess it as a candidate therapeutic target, we altered HuR expression in PDA cell lines and characterized the resulting phenotype in preclinical models. HuR silencing by short hairpin and small interfering RNAs significantly decreased cell proliferation and anchorage-independent growth, as well as impaired migration and invasion. In comparison, HuR overexpression increased migration and invasion, but had no significant effects on cell proliferation and anchorage-independent growth. Importantly, two distinct targeted approaches to HuR silencing showed marked impairment in tumor growth in mouse xenografts. NanoString nCounter® analyses demonstrated that HuR regulates core biological processes, highlighting that HuR inhibition likely thwarts PDA viability through post-transcriptional regulation of diverse signaling pathways (e.g. cell cycle, apoptosis, DNA repair). Taken together, our study suggests that targeted inhibition of HuR may be a novel, promising approach to the treatment of PDA.

  11. Ascl3 expression marks a progenitor population of both acinar and ductal cells in mouse salivary glands.

    PubMed

    Bullard, Tara; Koek, Laurie; Roztocil, Elisa; Kingsley, Paul D; Mirels, Lily; Ovitt, Catherine E

    2008-08-01

    Ascl3, also know as Sgn1, is a member of the mammalian achaete scute (Mash) gene family of transcription factors, which have been implicated in cell fate specification and differentiation. In the mouse salivary gland, expression of Ascl3 is restricted to a subset of duct cells. Salivary gland function depends on the secretory acinar cells, which are responsible for saliva formation, and duct cells, which modify the saliva and conduct it to the oral cavity. The salivary gland ducts are also the putative site of progenitor cells in the adult gland. Using a Cre recombinase-mediated reporter system, we followed the fate of Ascl3-expressing cells after the introduction of an EGFP-Cre expression cassette into the Ascl3 locus by homologous recombination. Lineage tracing shows that these cells are progenitors of both acinar and ductal cell types in all three major salivary glands. In the differentiated progeny, expression of Ascl3 is down-regulated. These data directly demonstrate a progenitor-progeny relationship between duct cells and the acinar cell compartment, and identify a population of multipotent progenitor cells, marked by expression of Ascl3, which is capable of generating both gland cell types. We conclude that Ascl3-expressing cells contribute to the maintenance of the adult salivary glands.

  12. Lysyl oxidase family activity promotes resistance of pancreatic ductal adenocarcinoma to chemotherapy by limiting the intratumoral anticancer drug distribution

    PubMed Central

    Le Calvé, Benjamin; Maréchal, Raphaël; Wiel, Clotilde; Svrcek, Magali; Gout, Johann; Azzi, Lamia; Payen, Léa; Cros, Jérôme; de la Fouchardière, Christelle; Dubus, Pierre; Guitton, Jérôme; Bartholin, Laurent; Bachet, Jean-Baptiste; Bernard, David

    2016-01-01

    Solid tumors often display chemotherapy resistance. Pancreatic ductal adenocarcinoma (PDAC) is the archetype of resistant tumors as current chemotherapies are inefficient. The tumor stroma and extracellular matrix (ECM) are key contributors to PDAC aggressiveness and to limiting the efficacy of chemotherapy. Lysyl oxidase (LOX) family members mediate collagen cross-linking and thus promote ECM stiffening. Our data demonstrate increased LOX, LOXL1, and LOXL2 expression in PDAC, and that the level of fibrillar collagen, which is directly dependent of LOX family activity, is an independent predictive biomarker of adjuvant “Gemcitabine-based chemotherapy” benefit. Experimentally in mice, increased LOX family activity through LOXL2 promotes chemoresistance. This effect of LOX family activity seems to be due to decreased gemcitabine intra-tumoral diffusion. This observation might be explained by increased fibrillar collagen and decreased vessel size observed in tumors with increased LOX family activity. In conclusion, our data support that LOX family activity is both a novel target to improve chemotherapy as well as a novel biomarker to predict gemcitabine benefit in PDAC. Beyond the PDAC, it is possible that targeting LOX family activity might improve efficacy of chemotherapies against different kinds of solid tumors. PMID:27050073

  13. Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma

    PubMed Central

    Mazur, Pawel K; Herner, Alexander; Mello, Stephano S; Wirth, Matthias; Hausmann, Simone; Sánchez-Rivera, Francisco J; Lofgren, Shane M; Kuschma, Timo; Hahn, Stephan A; Vangala, Deepak; Trajkovic-Arsic, Marija; Gupta, Aayush; Heid, Irina; Noël, Peter B; Braren, Rickmer; Erkan, Mert; Kleeff, Jörg; Sipos, Bence; Sayles, Leanne C; Heikenwalder, Mathias; Heßmann, Elisabeth; Ellenrieder, Volker; Esposito, Irene; Jacks, Tyler; Bradner, James E; Khatri, Purvesh; Sweet-Cordero, E Alejandro; Attardi, Laura D; Schmid, Roland M; Schneider, Guenter; Sage, Julien; Siveke, Jens T

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers and shows resistance to any therapeutic strategy used. Here we tested small-molecule inhibitors targeting chromatin regulators as possible therapeutic agents in PDAC. We show that JQ1, an inhibitor of the bromodomain and extraterminal (BET) family of proteins, suppresses PDAC development in mice by inhibiting both MYC activity and inflammatory signals. The histone deacetylase (HDAC) inhibitor SAHA synergizes with JQ1 to augment cell death and more potently suppress advanced PDAC. Finally, using a CRISPR-Cas9–based method for gene editing directly in the mouse adult pancreas, we show that de-repression of p57 (also known as KIP2 or CDKN1C) upon combined BET and HDAC inhibition is required for the induction of combination therapy–induced cell death in PDAC. SAHA is approved for human use, and molecules similar to JQ1 are being tested in clinical trials. Thus, these studies identify a promising epigenetic-based therapeutic strategy that may be rapidly implemented in fatal human tumors. PMID:26390243

  14. Sp1 and COX2 expression is positively correlated with a poor prognosis in pancreatic ductal adenocarcinoma

    PubMed Central

    Han, Ting; Zhuo, Meng; Zhou, Yangyang; Wang, Lei; Wang, Yi; Jiao, Feng; Wang, Liwei

    2016-01-01

    Previous studies showed that celecoxib, a cyclooxygenase-2 (COX2) inhibitor, can inhibit angiogenesis and metastasis of pancreatic ductal adenocarcinoma (PDAC) via the suppression of specificity protein 1 (Sp1). In this study, we investigated the prognostic value of Sp1 and COX2 in 88 PDAC patients. Our study showed there was a positive correlation between Sp1 and COX2 expression (P=0.001) by using the Spearman's rank test. Pearson Chi-square test revealed that Sp1 and COX2 expression were positively associated with lymph node metastasis (P<0.05, both). In addition, the Kaplan–Meier analysis showed that patients with Sp1- or COX2-positive expression exhibited poorer overall survival (OS) than those with Sp1- or COX2-negative expression (P<0.05, all). Most importantly, Sp1- and COX2-negative patients had the best OS (P=0.01). In multivariate analysis, Sp1 expression (P=0.03), COX2 expression (P=0.04), and nuclear grade (P=0.009) were found to be independent predictors for OS. Moreover, we confirmed that Sp1 could upregulate the expression of COX2 in PDAC cell lines by western blot analysis, and both are of important prognostic value in PDAC. PMID:27057636

  15. Low expression of nucleus accumbens-associated protein 1 predicts poor prognosis for patients with pancreatic ductal adenocarcinoma.

    PubMed

    Nishi, Takeshi; Maruyama, Riruke; Urano, Takeshi; Nakayama, Naomi; Kawabata, Yasunari; Yano, Seiji; Yoshida, Manabu; Nakayama, Kentaro; Miyazaki, Kohji; Takenaga, Keizo; Tanaka, Tsuneo; Tajima, Yoshitsugu

    2012-12-01

    Nucleus accumbens-associated protein 1 (NAC1) is overexpressed in various carcinomas including ovarian, cervical, breast, and pancreatic carcinomas. High expression of NAC1 is considered to have adverse effects on prognosis through negative regulation of growth arrest and DNA-damage-inducible 45-γ interacting protein 1 (GADD45GIP1) in ovarian and cervical carcinomas. In the present study, the expression of NAC1 in pancreatic ductal adenocarcinoma (PDA) was measured using immunohistochemistry and computer-assisted image analysis in order to investigate its correlation with various clinicopathological parameters and prognosis. Patients with low-NAC1 PDA had worse overall survival (P = 0.0010) and a shorter disease-free survival (P = 0.0036) than patients with high-NAC1 PDA. This was a clinical effect opposite to that reported in ovarian and cervical carcinomas. Furthermore, knockdown of NAC1 in pancreatic carcinoma cell lines did not increase expression of the GADD45GIP1 protein. These results indicate that the gene(s) regulated by NAC1 vary depending on the types of carcinoma or originating tissue, and that low expression of NAC1 predicts poor prognosis for patients with PDA.

  16. CYP3A5 mediates basal and acquired therapy resistance in different subtypes of pancreatic ductal adenocarcinoma

    PubMed Central

    Noll, Elisa M.; Eisen, Christian; Stenzinger, Albrecht; Espinet, Elisa; Muckenhuber, Alexander; Klein, Corinna; Vogel, Vanessa; Klaus, Bernd; Nadler, Wiebke; Rösli, Christoph; Lutz, Christian; Kulke, Michael; Engelhardt, Jan; Zickgraf, Franziska M.; Espinosa, Octavio; Schlesner, Matthias; Jiang, Xiaoqi; Kopp-Schneider, Annette; Neuhaus, Peter; Bahra, Marcus; Sinn, Bruno V.; Eils, Roland; Giese, Nathalia A.; Hackert, Thilo; Strobel, Oliver; Werner, Jens; Büchler, Markus W.; Weichert, Wilko; Trumpp, Andreas; Sprick, Martin R.

    2016-01-01

    Although subtypes of pancreatic ductal adenocarcinoma (PDAC) were described, this malignancy is clinically still treated as a single disease. Here, we present patient-derived models representing the full spectrum of previously identified quasi-mesenchymal (QM-PDA), classical and exocrine-like PDAC subtypes, and identify two markers—HNF1A and KRT81—that enable stratification of tumors into different subtypes by immunohistochemistry. Individuals bearing tumors of these subtypes show significant differences in overall survival and their tumors differ in drug sensitivity, with the exocrine-like subtype being resistant to tyrosine kinase inhibitors and paclitaxel. Cytochrome P450 3A5 (CYP3A5) metabolizes these compounds in tumors of the exocrine-like subtype, and pharmacological or shRNA-mediated CYP3A5 inhibition sensitizes tumor cells to these drugs. Whereas hepatocyte nuclear factor 4 alpha (HNF4A) controls basal expression of CYP3A5, drug-induced CYP3A5 upregulation is mediated by the nuclear receptor NR1I2. CYP3A5 also contributes to acquired drug resistance in QM-PDA and classical PDAC, and is highly expressed in several additional malignancies. These findings designate CYP3A5 as predictor of therapy response and as a tumor cell-autonomous detoxification mechanism that must be overcome to prevent drug resistance. PMID:26855150

  17. Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer.

    PubMed

    Saloman, Jami L; Albers, Kathryn M; Li, Dongjun; Hartman, Douglas J; Crawford, Howard C; Muha, Emily A; Rhim, Andrew D; Davis, Brian M

    2016-03-15

    Pancreatic ductal adenocarcinoma (PDAC) is characterized by an exuberant inflammatory desmoplastic response. The PDAC microenvironment is complex, containing both pro- and antitumorigenic elements, and remains to be fully characterized. Here, we show that sensory neurons, an under-studied cohort of the pancreas tumor stroma, play a significant role in the initiation and progression of the early stages of PDAC. Using a well-established autochthonous model of PDAC (PKC), we show that inflammation and neuronal damage in the peripheral and central nervous system (CNS) occurs as early as the pancreatic intraepithelial neoplasia (PanIN) 2 stage. Also at the PanIN2 stage, pancreas acinar-derived cells frequently invade along sensory neurons into the spinal cord and migrate caudally to the lower thoracic and upper lumbar regions. Sensory neuron ablation by neonatal capsaicin injection prevented perineural invasion (PNI), astrocyte activation, and neuronal damage, suggesting that sensory neurons convey inflammatory signals from Kras-induced pancreatic neoplasia to the CNS. Neuron ablation in PKC mice also significantly delayed PanIN formation and ultimately prolonged survival compared with vehicle-treated controls (median survival, 7.8 vs. 4.5 mo; P = 0.001). These data establish a reciprocal signaling loop between the pancreas and nervous system, including the CNS, that supports inflammation associated with oncogenic Kras-induced neoplasia. Thus, pancreatic sensory neurons comprise an important stromal cell population that supports the initiation and progression of PDAC and may represent a potential target for prevention in high-risk populations.

  18. The management of ductal intraepithelial neoplasia (DIN): open controversies and guidelines of the Istituto Europeo di Oncologia (IEO), Milan, Italy.

    PubMed

    Farante, Gabriel; Zurrida, Stefano; Galimberti, Viviana; Veronesi, Paolo; Curigliano, Giuseppe; Luini, Alberto; Goldhirsch, Aron; Veronesi, Umberto

    2011-07-01

    The management of ductal intraepithelial neoplasia (DIN) has substantially changed over the past 30 years, as its incidence has increased (from 2-3% to more than 20%), mainly due to the widespread use of mammography screening. This article describes not only the more widespread theoretical concepts on DIN but also the differences in the practical applications of the theory between different countries, different oncology specialists, and different cancer centers. Papers related to the international multicentre-randomized trials and retrospective studies were analyzed. We include articles and papers published between 1993 and 2010 related to patients with DIN, and abstracts and reports from MEDLINE and other sources were indentified. The standard of care for DIN consists of (a) breast conservative surgery (mastectomy is still indicated in large lesions--masses or microcalcifications--in about 30% of cases); (b) radiotherapy (RT) after conservative surgery, and (c) medical treatment in estrogen receptors-positive patients. However, most studies have shown significant differences between theory and practical application. Moreover, there are differences regarding (a) the indications of sentinel lymph node biopsy, (b) the definition and identification of low-risk DIN subgroups that can avoid RT and tamoxifen, and (c) the research into new alternative drugs in adjuvant medical therapy. A general agreement on the best management of DIN does not exist as yet. New large trials are needed in order to define the best management of DIN patients which is (in most respects) still complex and controversial.

  19. Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell and patient-derived tumor organoids

    PubMed Central

    Huang, Ling; Holtzinger, Audrey; Jagan, Ishaan; BeGora, Michael; Lohse, Ines; Ngai, Nicholas; Nostro, Cristina; Wang, Rennian; Muthuswamy, Lakshmi B.; Crawford, Howard C.; Arrowsmith, Cheryl; Kalloger, Steve E.; Renouf, Daniel J.; Connor, Ashton A; Cleary, Sean; Schaeffer, David F.; Roehrl, Michael; Tsao, Ming-Sound; Gallinger, Steven; Keller, Gordon; Muthuswamy, Senthil K.

    2016-01-01

    There are few in vitro models of exocrine pancreas development and primary human pancreatic adenocarcinoma (PDAC). We establish three-dimensional culture conditions to induce the differentiation of human pluripotent stem cells (PSCs) into exocrine progenitor organoids that form ductal and acinar structures in culture and in vivo. Expression of mutant KRAS or TP53 in progenitor organoids induces mutation-specific phenotypes in culture and in vivo. Expression of TP53R175H induced cytosolic SOX9 localization. In patient tumors bearing TP53 mutations, SOX9 was cytoplasmic and associated with mortality. Culture conditions are also defined for clonal generation of tumor organoids from freshly resected PDAC. Tumor organoids maintain the differentiation status, histoarchitecture, phenotypic heterogeneity of the primary tumor, and retain patient-specific physiologic changes including hypoxia, oxygen consumption, epigenetic marks, and differential sensitivity to EZH2 inhibition. Thus, pancreatic progenitor organoids and tumor organoids can be used to model PDAC and for drug screening to identify precision therapy strategies. PMID:26501191

  20. CYP3A5 mediates basal and acquired therapy resistance in different subtypes of pancreatic ductal adenocarcinoma.

    PubMed

    Noll, Elisa M; Eisen, Christian; Stenzinger, Albrecht; Espinet, Elisa; Muckenhuber, Alexander; Klein, Corinna; Vogel, Vanessa; Klaus, Bernd; Nadler, Wiebke; Rösli, Christoph; Lutz, Christian; Kulke, Michael; Engelhardt, Jan; Zickgraf, Franziska M; Espinosa, Octavio; Schlesner, Matthias; Jiang, Xiaoqi; Kopp-Schneider, Annette; Neuhaus, Peter; Bahra, Marcus; Sinn, Bruno V; Eils, Roland; Giese, Nathalia A; Hackert, Thilo; Strobel, Oliver; Werner, Jens; Büchler, Markus W; Weichert, Wilko; Trumpp, Andreas; Sprick, Martin R

    2016-03-01

    Although subtypes of pancreatic ductal adenocarcinoma (PDAC) have been described, this malignancy is clinically still treated as a single disease. Here we present patient-derived models representing the full spectrum of previously identified quasi-mesenchymal (QM-PDA), classical and exocrine-like PDAC subtypes, and identify two markers--HNF1A and KRT81--that enable stratification of tumors into different subtypes by using immunohistochemistry. Individuals with tumors of these subtypes showed substantial differences in overall survival, and their tumors differed in drug sensitivity, with the exocrine-like subtype being resistant to tyrosine kinase inhibitors and paclitaxel. Cytochrome P450 3A5 (CYP3A5) metabolizes these compounds in tumors of the exocrine-like subtype, and pharmacological or short hairpin RNA (shRNA)-mediated CYP3A5 inhibition sensitizes tumor cells to these drugs. Whereas hepatocyte nuclear factor 4, alpha (HNF4A) controls basal expression of CYP3A5, drug-induced CYP3A5 upregulation is mediated by the nuclear receptor NR1I2. CYP3A5 also contributes to acquired drug resistance in QM-PDA and classical PDAC, and it is highly expressed in several additional malignancies. These findings designate CYP3A5 as a predictor of therapy response and as a tumor cell-autonomous detoxification mechanism that must be overcome to prevent drug resistance. PMID:26855150

  1. Annexin A8 Identifies a Subpopulation of Transiently Quiescent c-Kit Positive Luminal Progenitor Cells of the Ductal Mammary Epithelium

    PubMed Central

    Iglesias, Juan Manuel; Cairney, Claire J.; Ferrier, Roderick K.; McDonald, Laura; Soady, Kelly; Kendrick, Howard; Pringle, Marie-Anne; Morgan, Reginald O.; Martin, Finian; Smalley, Matthew J.; Blyth, Karen; Stein, Torsten

    2015-01-01

    We have previously shown that Annexin A8 (ANXA8) is strongly associated with the basal-like subgroup of breast cancers, including BRCA1-associated breast cancers, and poor prognosis; while in the mouse mammary gland AnxA8 mRNA is expressed in low-proliferative isolated pubertal mouse mammary ductal epithelium and after enforced involution, but not in isolated highly proliferative terminal end buds (TEB) or during pregnancy. To better understand ANXA8’s association with this breast cancer subgroup we established ANXA8’s cellular distribution in the mammary gland and ANXA8’s effect on cell proliferation. We show that ANXA8 expression in the mouse mammary gland was strong during pre-puberty before the expansion of the rudimentary ductal network and was limited to a distinct subpopulation of ductal luminal epithelial cells but was not detected in TEB or in alveoli during pregnancy. Similarly, during late involution its expression was found in the surviving ductal epithelium, but not in the apoptotic alveoli. Double-immunofluorescence (IF) showed that ANXA8 positive (+ve) cells were ER-alpha negative (−ve) and mostly quiescent, as defined by lack of Ki67 expression during puberty and mid-pregnancy, but not terminally differentiated with ∼15% of ANXA8 +ve cells re-entering the cell cycle at the start of pregnancy (day 4.5). RT-PCR on RNA from FACS-sorted cells and double-IF showed that ANXA8+ve cells were a subpopulation of c-kit +ve luminal progenitor cells, which have recently been identified as the cells of origin of basal-like breast cancers. Over expression of ANXA8 in the mammary epithelial cell line Kim-2 led to a G0/G1 arrest and suppressed Ki67 expression, indicating cell cycle exit. Our data therefore identify ANXA8 as a potential mediator of quiescence in the normal mouse mammary ductal epithelium, while its expression in basal-like breast cancers may be linked to ANXA8’s association with their specific cells of origin. PMID:25803307

  2. Outcomes of Low-Risk Ductal Carcinoma In Situ in Southeast Asian Women Treated With Breast Conservation Therapy

    SciTech Connect

    Wong, Fuh Yong; Wang, Fuqiang; Chen, John Ju; Tan, Chiew Har; Tan, Puay Hoon

    2014-04-01

    Purpose: To examine the outcomes of Southeast Asian (SEA) women with low-risk ductal carcinoma in situ (DCIS) treated with breast-conserving surgery (BCS) and adjuvant radiation therapy. Methods and Materials: Retrospective chart reviews of patients treated with BCS for DCIS from 1995 to 2011 were performed. Patients meeting the selection criteria from Eastern Cooperative Oncology Group 5194 were included. Most patients received adjuvant radiation therapy (RT) consisting of whole-breast RT delivered to 50 Gy followed by a 10-Gy boost to the tumor bed. Results: Of 744 patients with pathologic diagnosis of pure DCIS identified, 273 met the selection criteria: low-intermediate grade (LIG), n=219; high grade (HG), n=54. Median follow-up for these patients was 60 months. There were 8 ipsilateral breast tumor recurrences (IBTRs) in total, 7 of which were DCIS. The estimated actuarial IBTR rates at 5 and 10 years for the entire cohort are 1.8% and 4.3%, respectively. Of the 219 patients with LIG DCIS, 210 received RT and 9 did not. There were 7 IBTRs in LIG DCIS, 2 among the 9 patients who did not receive RT. The IBTR rates in LIG DCIS at 5 and 10 years are 2.3% and 4.2%, respectively. All patients with HG DCIS received RT. There was only 1 IBTR occurring beyond 5 years, giving an estimated IBTR rate of 4.5% at 10 years. Conclusions: SEA women with screen-detected DCIS have exceedingly low rates of IBTR after BCS, comparable to that observed in reports of similar patients with low-risk DCIS treated with adjuvant radiation.

  3. Phenotypic Drift as a Cause for Intratumoral Morphological Heterogeneity of Invasive Ductal Breast Carcinoma Not Otherwise Specified

    PubMed Central

    Zavyalova, Marina V.; Tashireva, Lubov A.; Gerashchenko, Tatiana S.; Litviakov, Nikolay V.; Skryabin, Nikolay A.; Vtorushin, Sergey V.; Telegina, Nadezhda S.; Slonimskaya, Elena M.; Cherdyntseva, Nadezhda V.; Perelmuter, Vladimir M.

    2013-01-01

    Abstract Invasive ductal carcinoma (IDC) not otherwise specified (NOS), the most common type of breast cancer, demonstrates great intratumoral morphological heterogeneity, which encompasses the presence of different types of morphological structures—tubular, trabecular, solid, and alveolar structures and discrete groups of tumor cells, the origins of which remain unclear at present. In this study of 162 IDC NOS patients, we investigated whether the distribution of different types of morphological structures is related to the basic clinicopathological parameters of IDC NOS. Our results showed that in patients with only one type of tumor structure, the presence of any one of the five types was equally probable; however, cases with two types of structures were more likely to contain trabecular structures than the other four types. The development of intratumoral morphological heterogeneity was not associated with menopausal status, tumor size, histological grade, hematogenic metastasis, or recurrence. However, the number of different types of morphological structures was significantly higher in luminal tumors than in triple-negative tumors. An increase in the frequency of lymph node metastasis correlated with the increased number of different types of structures in breast tumors; however, in contrast to premenopausal patients, this association was explained by the presence of alveolar structures in postmenopausal women. In addition, we showed a significant decrease in the numbers of positive lymph nodes in tumors with high numbers of morphological variants. The frequency of lymph node metastases and the number of positive nodes were generally independent features and formed by different mechanisms. Based on the evidence, the term “phenotypic drift” has been designated as the basis for the development of intratumoral morphological heterogeneity of IDC NOS. PMID:23593567

  4. Carboxylesterase 2 as a Determinant of Response to Irinotecan and Neoadjuvant FOLFIRINOX Therapy in Pancreatic Ductal Adenocarcinoma

    PubMed Central

    Capello, Michela; Lee, Minhee; Wang, Hong; Babel, Ingrid; Katz, Matthew H.; Fleming, Jason B.; Maitra, Anirban; Wang, Huamin; Tian, Weihua; Taguchi, Ayumu

    2015-01-01

    Background: Serine hydrolases (SHs) are among the largest classes of enzymes in humans and play crucial role in many pathophysiological processes of cancer. We have undertaken a comprehensive proteomic analysis to assess the differential expression and cellular localization of SHs, which uncovered distinctive expression of Carboxylesterase 2 (CES2), the most efficient carboxyl esterase in activating the prodrug irinotecan into SN-38, in pancreatic ductal adenocarcinoma (PDAC). We therefore assessed the extent of heterogeneity in CES2 expression in PDAC and its potential relevance to irinotecan based therapy. Methods: CES2 expression in PDAC and paired nontumor tissues was evaluated by immunohistochemistry. CES2 activity was assessed by monitoring the hydrolysis of the substrate p-NPA and correlated with irinotecan IC50 values by means of Pearson’s correlation. Kaplan-Meier and Cox regression analyses were applied to assess the association between overall survival and CES2 expression in patients who underwent neoadjuvant FOLFIRINOX treatment. All statistical tests were two-sided. Results: Statistically significant overexpression of CES2, both at the mRNA and protein levels, was observed in PDAC compared with paired nontumor tissue (P < .001), with 48 of 118 (40.7%) tumors exhibiting high CES2 expression. CES2 activity in 11 PDAC cell lines was inversely correlated with irinotecan IC50 values (R = -0.68, P = .02). High CES2 expression in tumor tissue was associated with longer overall survival in resectable and borderline resectable patients who underwent neoadjuvant FOLFIRINOX treatment (hazard ratio = 0.14, 95% confidence interval = 0.04 to 0.51, P = .02). Conclusion: Our findings suggest that CES2 expression and activity, by mediating the intratumoral activation of irinotecan, is a contributor to FOLFIRINOX sensitivity in pancreatic cancer and CES2 assessment may define a subset of patients likely to respond to irinotecan based therapy. PMID:26025324

  5. Study of Clinical Survival and Gene Expression in a Sample of Pancreatic Ductal Adenocarcinoma by Parsimony Phylogenetic Analysis.

    PubMed

    Nalbantoglu, Sinem; Abu-Asab, Mones; Tan, Ming; Zhang, Xuemin; Cai, Ling; Amri, Hakima

    2016-07-01

    Pancreatic ductal adenocarcinoma (PDAC) is one of the rapidly growing forms of pancreatic cancer with a poor prognosis and less than 5% 5-year survival rate. In this study, we characterized the genetic signatures and signaling pathways related to survival from PDAC, using a parsimony phylogenetic algorithm. We applied the parsimony phylogenetic algorithm to analyze the publicly available whole-genome in silico array analysis of a gene expression data set in 25 early-stage human PDAC specimens. We explain here that the parsimony phylogenetics is an evolutionary analytical method that offers important promise to uncover clonal (driver) and nonclonal (passenger) aberrations in complex diseases. In our analysis, parsimony and statistical analyses did not identify significant correlations between survival times and gene expression values. Thus, the survival rankings did not appear to be significantly different between patients for any specific gene (p > 0.05). Also, we did not find correlation between gene expression data and tumor stage in the present data set. While the present analysis was unable to identify in this relatively small sample of patients a molecular signature associated with pancreatic cancer prognosis, we suggest that future research and analyses with the parsimony phylogenetic algorithm in larger patient samples are worthwhile, given the devastating nature of pancreatic cancer and its early diagnosis, and the need for novel data analytic approaches. The future research practices might want to place greater emphasis on phylogenetics as one of the analytical paradigms, as our findings presented here are on the cusp of this shift, especially in the current era of Big Data and innovation policies advocating for greater data sharing and reanalysis. PMID:27428255

  6. Predictors for local invasive recurrence of ductal carcinoma in situ of the breast: a meta-analysis.

    PubMed

    Zhang, Xining; Dai, Hongji; Liu, Ben; Song, Fengju; Chen, Kexin

    2016-01-01

    The introduction of mammographic screening has considerably increased the detection rate of ductal carcinoma in situ (DCIS), which has a high probability of recurrence. We carried out a meta-analysis to evaluate the predictive factors including biomarkers, tumor characteristics, and modes of detection on the risk of local invasive recurrence (LIR) following DCIS. Searches were performed in PubMed and EMBASE up to 8 July 2014. Risk estimates (hazard ratios, odds ratios, and relative risks) and their 95% confidence intervals (CIs) were extracted to calculate the strength of the associations between predictive factors and the risk of LIR after treatment of DCIS. STATA 12.0 was used to combine results in this meta-analysis. A total of 18 articles were included in the analysis. Pooled risk estimates and 95% CIs were 1.36 (1.04-1.69) for the positive margin, 1.38 (1.12-1.63) for the nonscreening detection method, 1.04 (0.84-1.24) for high nuclear grade 1, 1.32 (0.98-1.66) for intermediate nuclear grade 2, 1.18 (0.98-1.37) for comedonecrosis, 1.00 (0.92-1.08) for large tumor size, 1.34 (0.82-1.87) for multifocality, 0.74 (0.36-1.12) for estrogen receptor-positive tumors, 0.89 (0.47-1.31) for progesterone receptor-positive tumors, and 1.25 (0.7-1.81) for HER2/neu-positive tumors. Positive margin and non-screening-detected cancers were associated with a higher risk of LIR following DCIS. These predictive factors, after further validation, could be considered to tailor treatment for individual patients. PMID:25714649

  7. Characteristics and behaviour of screen-detected ductal carcinoma in situ of the breast: comparison with symptomatic patients.

    PubMed

    Koh, Valerie Cui Yun; Lim, Jeffrey Chun Tatt; Thike, Aye Aye; Cheok, Poh Yian; Thu, Minn Minn Myint; Tan, Veronique Kiak Mien; Tan, Benita Kiat Tee; Ong, Kong Wee; Ho, Gay Hui; Tan, Wai Jin; Tan, Yongcheng; Salahuddin, Ahmed Syed; Busmanis, Inny; Chong, Angela Pek Yoon; Iqbal, Jabed; Thilagaratnam, Shyamala; Wong, Jill Su Lin; Tan, Puay Hoon

    2015-07-01

    Breast cancer is the most common malignancy in Singapore women. Ductal carcinoma in situ (DCIS) is the putative, non-obligate precursor of the majority of invasive breast cancers. The efficacy of the Singapore breast-screening pilot project in detecting early stage breast cancer led to the launch of a national breast-screening programme, BreastScreen Singapore (BSS), in January 2002. In this study, we compared clinicopathological and immunohistochemical characteristics, as well as clinical outcomes, between screen-detected and symptomatic DCIS. The study cohort comprised 1202 cases of DCIS diagnosed at Singapore General Hospital from 1994 to 2010. Comparison of clinicopathological parameters, immunohistochemical results of ER, PR, HER2, CK14, EGFR, and 34βE12, and clinical outcomes was carried out between the 2 groups. Amongst 1202 cases, 610 (50.7%) were screen-detected and 592 (49.3%) were symptomatic DCIS. Screen-detected cases were smaller in size (P < 0.001), of lower nuclear grade (P = 0.004), and more frequently expressed ER (P < 0.001). Luminal A phenotype was more frequently observed in screen-detected DCIS, while triple-negative and HER2 phenotypes were more common in symptomatic DCIS (P < 0.001). The basal-like phenotype was also more frequent in symptomatic DCIS (P = 0.041). Mean and median follow-up was 99.7 and 97.8 months, respectively, with a maximum follow-up of 246.0 months. More symptomatic patients developed invasive recurrences compared to screen-detected patients (P = 0.001). A trend for better disease-free survival was observed in screen-detected patients (P = 0.076). Patients who were screen-detected experienced better overall survival than those with symptomatic DCIS (P = 0.007). Our data indicate a more favourable outcome of screen-detected DCIS patients confirming the role of BSS in early identification of this curable disease.

  8. Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer

    PubMed Central

    Saloman, Jami L.; Albers, Kathryn M.; Li, Dongjun; Hartman, Douglas J.; Crawford, Howard C.; Muha, Emily A.; Rhim, Andrew D.; Davis, Brian M.

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is characterized by an exuberant inflammatory desmoplastic response. The PDAC microenvironment is complex, containing both pro- and antitumorigenic elements, and remains to be fully characterized. Here, we show that sensory neurons, an under-studied cohort of the pancreas tumor stroma, play a significant role in the initiation and progression of the early stages of PDAC. Using a well-established autochthonous model of PDAC (PKC), we show that inflammation and neuronal damage in the peripheral and central nervous system (CNS) occurs as early as the pancreatic intraepithelial neoplasia (PanIN) 2 stage. Also at the PanIN2 stage, pancreas acinar-derived cells frequently invade along sensory neurons into the spinal cord and migrate caudally to the lower thoracic and upper lumbar regions. Sensory neuron ablation by neonatal capsaicin injection prevented perineural invasion (PNI), astrocyte activation, and neuronal damage, suggesting that sensory neurons convey inflammatory signals from Kras-induced pancreatic neoplasia to the CNS. Neuron ablation in PKC mice also significantly delayed PanIN formation and ultimately prolonged survival compared with vehicle-treated controls (median survival, 7.8 vs. 4.5 mo; P = 0.001). These data establish a reciprocal signaling loop between the pancreas and nervous system, including the CNS, that supports inflammation associated with oncogenic Kras-induced neoplasia. Thus, pancreatic sensory neurons comprise an important stromal cell population that supports the initiation and progression of PDAC and may represent a potential target for prevention in high-risk populations. PMID:26929329

  9. Preoperative breast magnetic resonance imaging and contralateral breast cancer occurrence among older women with ductal carcinoma in situ.

    PubMed

    Wang, Shi-Yi; Long, Jessica B; Killelea, Brigid K; Evans, Suzanne B; Roberts, Kenneth B; Silber, Andrea; Gross, Cary P

    2016-07-01

    Although preoperative magnetic resonance imaging (MRI) can detect mammographically occult contralateral breast cancers (CBCs) among women with ductal carcinoma in situ (DCIS), the impact of MRI on the incidence of subsequent CBC events is unclear. We examined whether MRI use decreases CBC occurrences and detection of invasive disease among women who develop a CBC. Utilizing the Surveillance, Epidemiology, and End Results-Medicare dataset, we assessed overall, synchronous (<6 months after primary cancer diagnosis), and subsequent (≥6 months after diagnosis, i.e., metachronous) CBC occurrence in women aged 67-94 years diagnosed with DCIS during 2004-2009, with follow-up through 2011. We applied a matched propensity score approach to compare the stage-specific incidence rate of CBC according to MRI use. Our sample consisted of 9166 beneficiaries, 1258 (13.7 %) of whom received preoperative MRI. After propensity score matching, preoperative MRI use was significantly associated with a higher synchronous CBC detection rate (108.6 vs. 29.7 per 1000 person-years; hazard ratio [HR] = 3.65; p < .001) with no significant differences in subsequent CBC rate (6.7 vs. 6.8 per 1000 person-years; HR = 0.90; p = .71). The 6-year cumulative incidence of any CBC (in situ plus invasive) remained significantly higher among women undergoing MRI, compared with those not undergoing MRI (9 vs. 4 %, p < .001). Women undergoing MRI also had a higher incidence of invasive CBC (4 vs. 3 %, p = .04). MRI use resulted in an increased detection of synchronous CBC but did not prevent subsequent CBC occurrence, suggesting that many of the undetected CBC lesions may not become clinically evident.

  10. hERG1 channels drive tumour malignancy and may serve as prognostic factor in pancreatic ductal adenocarcinoma

    PubMed Central

    Lastraioli, E; Perrone, G; Sette, A; Fiore, A; Crociani, O; Manoli, S; D'Amico, M; Masselli, M; Iorio, J; Callea, M; Borzomati, D; Nappo, G; Bartolozzi, F; Santini, D; Bencini, L; Farsi, M; Boni, L; Di Costanzo, F; Schwab, A; Onetti Muda, A; Coppola, R; Arcangeli, A

    2015-01-01

    Background: hERG1 channels are aberrantly expressed in human cancers. The expression, functional role and clinical significance of hERG1 channels in pancreatic ductal adenocarcinoma (PDAC) is lacking. Methods: hERG1 expression was tested in PDAC primary samples assembled as tissue microarray by immunohistochemistry using an anti-hERG1 monoclonal antibody (α-hERG1-MoAb). The functional role of hERG1 was studied in PDAC cell lines and primary cultures. ERG1 expression during PDAC progression was studied in Pdx-1-Cre,LSL-KrasG12D/+,LSL-Trp53R175H/+ transgenic (KPC) mice. ERG1 expression in vivo was determined by optical imaging using Alexa-680-labelled α-hERG1-MoAb. Results: (i) hERG1 was expressed at high levels in 59% of primary PDAC; (ii) hERG1 blockade decreased PDAC cell growth and migration; (iii) hERG1 was physically and functionally linked to the Epidermal Growth Factor-Receptor pathway; (iv) in transgenic mice, ERG1 was expressed in PanIN lesions, reaching high expression levels in PDAC; (v) PDAC patients whose primary tumour showed high hERG1 expression had a worse prognosis; (vi) the α-hERG1-MoAb could detect PDAC in vivo. Conclusions: hERG1 regulates PDAC malignancy and its expression, once validated in a larger cohort also comprising of late-stage, non-surgically resected cases, may be exploited for diagnostic and prognostic purposes in PDAC either ex vivo or in vivo. PMID:25719829

  11. Selective inhibition of pancreatic ductal adenocarcinoma cell growth by the mitotic MPS1 kinase inhibitor NMS-P715.

    PubMed

    Slee, Roger B; Grimes, Brenda R; Bansal, Ruchi; Gore, Jesse; Blackburn, Corinne; Brown, Lyndsey; Gasaway, Rachel; Jeong, Jaesik; Victorino, Jose; March, Keith L; Colombo, Riccardo; Herbert, Brittney-Shea; Korc, Murray

    2014-02-01

    Most solid tumors, including pancreatic ductal adenocarcinoma (PDAC), exhibit structural and numerical chromosome instability (CIN). Although often implicated as a driver of tumor progression and drug resistance, CIN also reduces cell fitness and poses a vulnerability that can be exploited therapeutically. The spindle assembly checkpoint (SAC) ensures correct chromosome-microtubule attachment, thereby minimizing chromosome segregation errors. Many tumors exhibit upregulation of SAC components such as MPS1, which may help contain CIN within survivable limits. Prior studies showed that MPS1 inhibition with the small molecule NMS-P715 limits tumor growth in xenograft models. In cancer cell lines, NMS-P715 causes cell death associated with impaired SAC function and increased chromosome missegregation. Although normal cells appeared more resistant, effects on stem cells, which are the dose-limiting toxicity of most chemotherapeutics, were not examined. Elevated expression of 70 genes (CIN70), including MPS1, provides a surrogate measure of CIN and predicts poor patient survival in multiple tumor types. Our new findings show that the degree of CIN70 upregulation varies considerably among PDAC tumors, with higher CIN70 gene expression predictive of poor outcome. We identified a 25 gene subset (PDAC CIN25) whose overexpression was most strongly correlated with poor survival and included MPS1. In vitro, growth of human and murine PDAC cells is inhibited by NMS-P715 treatment, whereas adipose-derived human mesenchymal stem cells are relatively resistant and maintain chromosome stability upon exposure to NMS-P715. These studies suggest that NMS-P715 could have a favorable therapeutic index and warrant further investigation of MPS1 inhibition as a new PDAC treatment strategy.

  12. Microvascular density and endothelial area correlate with Ki-67 proliferative index in surgically-treated pancreatic ductal adenocarcinoma patients

    PubMed Central

    AMMENDOLA, MICHELE; SACCO, ROSARIO; MARECH, ILARIA; SAMMARCO, GIUSEPPE; ZUCCALÀ, VALERIA; LUPOSELLA, MARIA; PATRUNO, ROSA; GIORDANO, MARCELLA; RUGGIERI, EUSTACHIO; ZIZZO, NICOLA; GADALETA, COSMO DAMIANO; RANIERI, GIROLAMO

    2015-01-01

    Previous experimental and clinical data have indicated that tumour cell proliferation is associated with angiogenesis; in addition, an increased microvascular density (MVD) of tumours has been associated with poor prognosis in solid and haematological malignancies. However, limited data exists regarding the association between tumour cell proliferation and angiogenesis in primary tumour tissue from pancreatic ductal adenocarcinoma (PDAC) patients; therefore, the present study aimed to investigate this association. A series of 31 PDAC patients with stage Tumour (T)2–3 Node (N)0–1 Metastasis (M)0 were recruited into the present study and subsequently underwent surgery. PDAC tissue and adjacent normal tissue (ANT), resected during surgery, were evaluated using immunohistochemistry and image analysis methods to determine MVD, endothelial area (EA) and Ki-67 expression, which is an indicator of cell proliferation rate. The results demonstrated a correlation between the above parameters with each other as well as the main clinico-pathological features of PDAC. Significant differences were identified in MVD, EA and Ki-67 proliferation index between PDAC and ANT. It was demonstrated that MVD, EA and Ki-67 proliferation index were significantly correlated with each other in tumour tissue (r=0.69–0.81; P=0.001–0.003). However, no other significant correlations were identified. These data therefore suggested that angiogenesis and cell proliferation rate were significantly increased in PDAC compared with ANT, which provides a biological basis for the potential use of novel combinations of angiogenesis inhibitors and anti-proliferative chemotherapeutic drugs in the treatment of PDAC. PMID:26622606

  13. Different Biological Action of Oleic Acid in ALDHhigh and ALDHlow Subpopulations Separated from Ductal Carcinoma In Situ of Breast Cancer

    PubMed Central

    Kim, Hoe Suk; Jung, Minji; Choi, Sul Ki; Moon, Woo Kyung; Kim, Seung Ja

    2016-01-01

    The mechanisms underlying breast cancer progression of ductal carcinoma in situ (DCIS) associated with fatty acids are largely unknown. In the present study, we compared the action of oleic acid (OA) on two human DCIS cell lines, MCF10DCIS.COM (ER/PR/HER2-negative) and SUM225 (HER2 overexpressed). OA led to a significant increase in proliferation, migration, lipid accumulation and the expression of lipogenic proteins, such as SREBP-1, FAS and ACC-1, in MCF10DCIS.COM cells but not SUM225 cells. The ALDHhigh subpopulation analyzed by the ALDEFLUOR assay was approximately 39.2±5.3% of MCF10DCIS.COM cells but was small (3.11±0.9%) in SUM225 cells. We further investigated the different biological action of OA in the distinct ALDHlow and ALDHhigh subpopulations of MCF10DCIS.COM cells. OA led to an increase in the expression of ALDH1A1, ALDH1A2 and ALDH1A3 in MCF10DCIS.COM cells. SREBP-1 and ACC-1 were highly expressed in ALDHhigh cells relative to ALDHlow cells, whereas FAS was higher in ALDHlow cells. In the presence of OA, ALDHhigh cells were more likely to proliferate and migrate and displayed significantly high levels of SREBP-1 and FAS and strong phosphorylation of FAK and AKT relative to ALDHlow cells. This study suggests that OA could be a critical risk factor to promote the proliferation and migration of ALDHhigh cells in DCIS, leading to breast cancer progression. PMID:27589390

  14. Proteomic analysis of O-GlcNAcylated proteins in invasive ductal breast carcinomas with and without lymph node metastasis.

    PubMed

    Jiang, Kuan; Gao, Yang; Hou, Weiwei; Tian, Fang; Ying, Wantao; Li, Ling; Bai, Bingyang; Hou, Gang; Wang, Peng George; Zhang, Lianwen

    2016-02-01

    The potential role of protein O-GlcNAcylation in cancer has been studied extensively, and the spread of cancer cells to regional lymph nodes is the first step in the dissemination of breast cancer. However, the correlation between O-GlcNAcylation and lymphatic metastasis in breast cancer remains elusive. In this study, we demonstrated that the overall O-GlcNAcylation as well as O-GlcNAc transferase (OGT) tends to decrease in response to the augmentation of lymph node metastasis (LNM) in invasive ductal breast carcinomas (IDCs). Although accumulating evidence indicates that individual O-GlcNAcylation may be important in the pathogenesis of breast cancer, O-GlcNAcylated proteins in IDCs are still largely unexplored. Herein, O-GlcNAcylated proteins of IDCs were chemo-enzymatically enriched and identified via liquid chromatography combined with tandem mass spectrometry. In total, 155 O-GlcNAcylated proteins were determined, of which 41 were only observed in LNM tissues, while 40 were unique in non-LNM samples. Gene ontology analysis showed that O-GlcNAc is primarily a nucleocytoplasmic post-translational modification, and most enriched functional terms were related to cancer development in both metastatic and non-metastatic IDCs. Moreover, several O-GlcNAcylated proteins involved in glycolysis and its accessory pathway were identified from LNM and non-LNM groups, respectively. These results indicate that the O-GlcNAcylation statuses of individual proteins were independent of the overall O-GlcNAcylation levels of metastatic and non-metastatic IDCs. Aberrant O-GlcNAc modification of these proteins might be associated with LNM progression.

  15. Different Biological Action of Oleic Acid in ALDHhigh and ALDHlow Subpopulations Separated from Ductal Carcinoma In Situ of Breast Cancer.

    PubMed

    Kim, Hoe Suk; Jung, Minji; Choi, Sul Ki; Moon, Woo Kyung; Kim, Seung Ja

    2016-01-01

    The mechanisms underlying breast cancer progression of ductal carcinoma in situ (DCIS) associated with fatty acids are largely unknown. In the present study, we compared the action of oleic acid (OA) on two human DCIS cell lines, MCF10DCIS.COM (ER/PR/HER2-negative) and SUM225 (HER2 overexpressed). OA led to a significant increase in proliferation, migration, lipid accumulation and the expression of lipogenic proteins, such as SREBP-1, FAS and ACC-1, in MCF10DCIS.COM cells but not SUM225 cells. The ALDHhigh subpopulation analyzed by the ALDEFLUOR assay was approximately 39.2±5.3% of MCF10DCIS.COM cells but was small (3.11±0.9%) in SUM225 cells. We further investigated the different biological action of OA in the distinct ALDHlow and ALDHhigh subpopulations of MCF10DCIS.COM cells. OA led to an increase in the expression of ALDH1A1, ALDH1A2 and ALDH1A3 in MCF10DCIS.COM cells. SREBP-1 and ACC-1 were highly expressed in ALDHhigh cells relative to ALDHlow cells, whereas FAS was higher in ALDHlow cells. In the presence of OA, ALDHhigh cells were more likely to proliferate and migrate and displayed significantly high levels of SREBP-1 and FAS and strong phosphorylation of FAK and AKT relative to ALDHlow cells. This study suggests that OA could be a critical risk factor to promote the proliferation and migration of ALDHhigh cells in DCIS, leading to breast cancer progression. PMID:27589390

  16. Accelerated Partial Breast Irradiation through Brachytherapy for Ductal Carcinoma in situ: Factors Influencing Utilization and Risks of Second Breast Tumors

    PubMed Central

    Liu, Ying; Schloemann, Derek T.; Lian, Min; Colditz, Graham A.

    2015-01-01

    Purpose To examine influencing factors and outcomes of accelerated partial breast irradiation through brachytherapy (APBIb) versus whole breast irradiation (WBI) for ductal carcinoma in situ (DCIS). Patients and Methods From the Surveillance Epidemiology and End Results program, we identified 40749 women who were diagnosed with first primary DCIS between 2002 and 2011 and treated with breast conserving surgery (BCS) and radiotherapy. A multi-level logistic regression analysis was performed to estimate odds ratios of APBIb use. Hazard ratios (HRs) of developing ipsilateral breast tumors (IBTs) and contralateral breast tumors (CBTs) were analyzed in 1962 patients with APBIb and 7203 propensity score-matched patients with WBI, using Cox proportional hazards regression. Results Overall, 2212 (4.5%) of 40749 women (the whole cohort) received APBIb. Factors associated with the increased use of APBIb included older age, non-Hispanic white race/ethnicity, smaller tumor size, hormone receptor positivity, comedo subtypes and urban residence. During the 46-month follow-up, 74 (0.8%) and 131 (1.4%) of 9165 propensity score-matched patients developed IBTs and CBTs, respectively. Compared with WBI, APBIb was associated with a significantly increased risk of IBTs (HR, 1.74; 95% CI, 1.06 to 2.85) but not CBTs (OR, 0.91; 95% CI, 0.59 to 1.41). Conclusion This population-based study suggests that APBIb use for DCIS was influenced by patient and tumor characteristics as well as urbanization of residence. We observed a moderately increased IBT risk associated with APBIb versus WBI, suggesting that APBIb should be used with caution for DCIS before data from randomized controlled trials with long-term followups are available. PMID:25893591

  17. Pancreatic ductal adenocarcinoma cell lines display a plastic ability to bi‑directionally convert into cancer stem cells.

    PubMed

    Dalla Pozza, Elisa; Dando, Ilaria; Biondani, Giulia; Brandi, Jessica; Costanzo, Chiara; Zoratti, Elisa; Fassan, Matteo; Boschi, Federico; Melisi, Davide; Cecconi, Daniela; Scupoli, Maria Teresa; Scarpa, Aldo; Palmieri, Marta

    2015-03-01

    Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed when metastatic events have occurred. Cancer stem cells (CSCs) play an important role in tumor initiation, metastasis, chemoresistance and relapse. A growing number of studies have suggested that CSCs exist in a dynamic equilibrium with more differentiated cancer cells via a bi‑directional regeneration that is dependent on the environmental stimuli. In this investigation, we obtain, by using a selective medium, PDAC CSCs from five out of nine PDAC cell lines, endowed with different tumorsphere‑forming ability. PDAC CSCs were generally more resistant to the action of five anticancer drugs than parental cell lines and were characterized by an increased expression of EpCAM and CD44v6, typical stem cell surface markers, and a decreased expression of E‑cadherin, the main marker of the epithelial state. PDAC CSCs were able to re‑differentiate into parental cells once cultured in parental growth condition, as demonstrated by re‑acquisition of the epithelial morphology, the decreased expression levels of EpCAM and CD44v6 and the increased sensitivity to anticancer drugs. Finally, PDAC CSCs injected into nude mice developed a larger subcutaneous tumor mass and showed a higher metastatic activity compared to parental cells. The present study demonstrates the ability to obtain CSCs from several PDAC cell lines and that these cells are differentially resistant to various anticancer agents. This variability renders them a model of great importance to deeply understand pancreatic adenocarcinoma biology, to discover new biomarkers and to screen new therapeutic compounds.

  18. Preoperative breast magnetic resonance imaging and contralateral breast cancer occurrence among older women with ductal carcinoma in situ.

    PubMed

    Wang, Shi-Yi; Long, Jessica B; Killelea, Brigid K; Evans, Suzanne B; Roberts, Kenneth B; Silber, Andrea; Gross, Cary P

    2016-07-01

    Although preoperative magnetic resonance imaging (MRI) can detect mammographically occult contralateral breast cancers (CBCs) among women with ductal carcinoma in situ (DCIS), the impact of MRI on the incidence of subsequent CBC events is unclear. We examined whether MRI use decreases CBC occurrences and detection of invasive disease among women who develop a CBC. Utilizing the Surveillance, Epidemiology, and End Results-Medicare dataset, we assessed overall, synchronous (<6 months after primary cancer diagnosis), and subsequent (≥6 months after diagnosis, i.e., metachronous) CBC occurrence in women aged 67-94 years diagnosed with DCIS during 2004-2009, with follow-up through 2011. We applied a matched propensity score approach to compare the stage-specific incidence rate of CBC according to MRI use. Our sample consisted of 9166 beneficiaries, 1258 (13.7 %) of whom received preoperative MRI. After propensity score matching, preoperative MRI use was significantly associated with a higher synchronous CBC detection rate (108.6 vs. 29.7 per 1000 person-years; hazard ratio [HR] = 3.65; p < .001) with no significant differences in subsequent CBC rate (6.7 vs. 6.8 per 1000 person-years; HR = 0.90; p = .71). The 6-year cumulative incidence of any CBC (in situ plus invasive) remained significantly higher among women undergoing MRI, compared with those not undergoing MRI (9 vs. 4 %, p < .001). Women undergoing MRI also had a higher incidence of invasive CBC (4 vs. 3 %, p = .04). MRI use resulted in an increased detection of synchronous CBC but did not prevent subsequent CBC occurrence, suggesting that many of the undetected CBC lesions may not become clinically evident. PMID:27287780

  19. 3,3',5-Triiodo-L-thyronine inhibits ductal pancreatic adenocarcinoma proliferation improving the cytotoxic effect of chemotherapy.

    PubMed

    Michienzi, Simona; Bucci, Barbara; Verga Falzacappa, Cecilia; Patriarca, Valentina; Stigliano, Antonio; Panacchia, Laura; Brunetti, Ercole; Toscano, Vincenzo; Misiti, Silvia

    2007-05-01

    The pancreatic adenocarcinoma is an aggressive and devastating disease, which is characterized by invasiveness, rapid progression, and profound resistance to actual treatments, including chemotherapy and radiotherapy. At the moment, surgical resection provides the best possibility for long-term survival, but is feasible only in the minority of patients, when advanced disease chemotherapy is considered, although the effects are modest. Several studies have shown that thyroid hormone, 3,3',5-triiodo-l-thyronine (T(3)) is able to promote or inhibit cell proliferation in a cell type-dependent manner. The aim of the present study is to investigate the ability of T(3) to reduce the cell growth of the human pancreatic duct cell lines chosen, and to increase the effect of chemotherapeutic drugs at conventional concentrations. Three human cell lines hPANC-1, Capan1, and HPAC have been used as experimental models to investigate the T(3) effects on pancreatic adenocarcinoma cell proliferation. The hPANC-1 and Capan1 cell proliferation was significantly reduced, while the hormone treatment was ineffective for HPAC cells. The T(3)-dependent cell growth inhibition was also confirmed by fluorescent activated cell sorting analysis and by cell cycle-related molecule analysis. A synergic effect of T(3) and chemotherapy was demonstrated by cell kinetic experiments performed at different times and by the traditional isobologram method. We have showed that thyroid hormone T(3) and its combination with low doses of gemcitabine (dFdCyd) and cisplatin (DDP) is able to potentiate the cytotoxic action of these chemotherapic drugs. Treatment with 5-fluorouracil was, instead, largely ineffective. In conclusion, our data support the hypothesis that T(3) and its combination with dFdCyd and DDP may act in a synergic way on adenopancreatic ductal cells. PMID:17470512

  20. Vascular Invasion in Infiltrating Ductal Adenocarcinoma of the Pancreas Can Mimic Pancreatic Intraepithelial Neoplasia: A Histopathologic Study of 209 Cases

    PubMed Central

    Hong, Seung-Mo; Goggins, Michael; Wolfgang, Christopher L.; Schulick, Richard D.; Edil, Barish H.; Cameron, John L.; Handra-Luca, Adriana; Herman, Joseph M.; Hruban, Ralph H.

    2011-01-01

    Although vascular invasion is a well-established indicator of poor prognosis for patients with infiltrating ductal adenocarcinoma of the pancreas (PDAC), the histopathologic characteristics of vascular invasion are not well described. Hematoxylin and eosin stained slides from 209 surgically resected infiltrating PDACs were systematically evaluated for the presence or absence of microscopic vascular invasion. For the cases with vascular invasion, we further categorized the histologic pattern of invasion into conventional and pancreatic intraepithelial neoplasia-like (PanIN-like). In addition, several histopathologic factors in the surrounding blood vessels, including lymphocytic infiltration and luminal fibrosis were carefully accessed. Data were compared to clinicopathologic variables, including patient survival. Microscopic vascular invasion was observed in 136 of the 209 PDACs (65.1%). Vascular invasion mimicking pancreatic intraepithelial neoplasia (PanIN-like invasion) was observed in 94 of the 136 cases (69.1%) with vascular invasion. Microscopic vascular invasion was associated with increased tumor size (p=0.04), higher pT classification (p=0.003), lymph node metastasis (p<0.0001), and perineural invasion (p=0.005). Vascular invasion was inversely correlated with neo-adjuvant therapy (p<0.0001). Examination of adjacent blood vessel revealed that peritumoral blood vessels with intimal lymphocytes (p=0.002), intimal (p=0.007) and medial (p=0.001) fibrosis, and cancer cells in vascular wall (p<0.0001), were all highly associated with intraluminal vascular invasion. In univariate analysis, patients whose cancers had microscopic vascular invasion (median survival, 12.9 months) had a significantly worse survival than did patients with carcinomas without vascular invasion (17.6 months; p=0.01, log-rank test). Microscopic vascular invasion is a poor prognostic indicator and can histologically mimic PanIN. PMID:22082604

  1. Assessment and optimization of electroporation-assisted tumoral nanoparticle uptake in a nude mouse model of pancreatic ductal adenocarcinoma.

    PubMed

    West, Derek Lamont; White, Sarah B; Zhang, Zhouli; Larson, Andrew C; Omary, Reed A

    2014-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a particularly lethal form of cancer. In 2012, the incidence of PDAC was 43,920. Five-year survival for patients with PDAC is around 6%, regardless of staging, making PDAC one of the deadliest forms of cancer. One reason for this dismal prognosis is chemoresistance to the current first-line therapy, gemcitabine. There are multiple factors that contribute to the chemoresistance observed in pancreatic cancer. Among them, desmoplasia has been increasingly seen as a significant contributor to chemoresistance. To overcome desmoplastic chemoresistance, several novel methods of treatment have been developed. Electroporation is one such novel treatment. High electrical fields are applied to cells to create pores that increase cell permeability. It has been previously demonstrated that electroporation enhances the therapeutic efficacy of anticancer drugs in pancreatic tumor models. Nanoparticle-based drug delivery systems constitute a second novel method to overcome desmoplastic chemoresistance. Due to their intrinsic design advantages, nanoparticles have been shown to increase the effectiveness of chemotherapeutic agents, while further reducing or even eliminating side effects. To date, there have been no studies evaluating the cumulative effect of combining both nanoparticle and electroporation strategies to overcome chemoresistance in PDAC. Our preliminary studies assessed the in vitro and in vivo uptake of doxorubicin-loaded iron oxide nanoparticles as a function of electroporation voltage and timing of administration in pancreatic adenocarcinoma cells. Our studies demonstrated that addition of electroporation to administration of nanoparticles significantly increased the amount of intracellular iron oxide nanoparticle uptake by a PANC-1 cell line in an athymic nude mouse model of PDAC. Further, electroporation-assisted nanoparticle uptake could be significantly altered by changing the timing of application of electroporation.

  2. Examining the Pathogenesis of Breast Cancer Using a Novel Agent-Based Model of Mammary Ductal Epithelium Dynamics

    PubMed Central

    Chapa, Joaquin; Bourgo, Ryan J.; Greene, Geoffrey L.; Kulkarni, Swati; An, Gary

    2013-01-01

    The study of the pathogenesis of breast cancer is challenged by the long time-course of the disease process and the multi-factorial nature of generating oncogenic insults. The characterization of the longitudinal pathogenesis of malignant transformation from baseline normal breast duct epithelial dynamics may provide vital insight into the cascading systems failure that leads to breast cancer. To this end, extensive information on the baseline behavior of normal mammary epithelium and breast cancer oncogenesis was integrated into a computational model termed the Ductal Epithelium Agent-Based Model (DEABM). The DEABM is composed of computational agents that behave according to rules established from published cellular and molecular mechanisms concerning breast duct epithelial dynamics and oncogenesis. The DEABM implements DNA damage and repair, cell division, genetic inheritance and simulates the local tissue environment with hormone excretion and receptor signaling. Unrepaired DNA damage impacts the integrity of the genome within individual cells, including a set of eight representative oncogenes and tumor suppressors previously implicated in breast cancer, with subsequent consequences on successive generations of cells. The DEABM reproduced cellular population dynamics seen during the menstrual cycle and pregnancy, and demonstrated the oncogenic effect of known genetic factors associated with breast cancer, namely TP53 and Myc, in simulations spanning ∼40 years of simulated time. Simulations comparing normal to BRCA1-mutant breast tissue demonstrated rates of invasive cancer development similar to published epidemiologic data with respect to both cumulative incidence over time and estrogen-receptor status. Investigation of the modeling of ERα-positive (ER+) tumorigenesis led to a novel hypothesis implicating the transcription factor and tumor suppressor RUNX3. These data suggest that the DEABM can serve as a potentially valuable framework to augment the

  3. Loss of SOD3 (EcSOD) expression promotes an aggressive phenotype in human pancreatic ductal adenocarcinoma

    PubMed Central

    O’Leary, Brianne R.; Fath, Melissa A.; Bellizzi, Andrew M.; Hrabe, Jennifer E.; Button, Anna M.; Allen, Bryan G.; Case, Adam J.; Altekruse, Sean; Wagner, Brett A.; Buettner, Garry R.; Lynch, Charles F.; Hernandez, Brenda Y.; Cozen, Wendy; Beardsley, Robert A.; Keene, Jeffery; Henry, Michael D.; Domann, Frederick E.; Spitz, Douglas R.; Mezhir, James J.

    2015-01-01

    Purpose Pancreatic ductal adenocarcinoma (PDA) cells are known to produce excessive amounts of reactive oxygen species (ROS), particularly superoxide, which may contribute to the aggressive and refractory nature of this disease. Extracellular superoxide dismutase (EcSOD) is an antioxidant enzyme that catalyzes the dismutation of superoxide in the extracellular environment. The current work tests the hypothesis that EcSOD modulates PDA growth and invasion by modifying the redox balance in PDA. Experimental Design We evaluated the prognostic significance of EcSOD in a human tissue microarray of patients with PDA. EcSOD overexpression was performed in PDA cell lines and animal models of disease. The impact of EcSOD on PDA cell lines was evaluated with Matrigel invasion in combination with a superoxide-specific SOD mimic and a nitric oxide synthase inhibitor to determine the mechanism of action of EcSOD in PDA. Results Loss of EcSOD expression is a common event in PDA, which correlated with worse disease biology. Overexpression of EcSOD in PDA cell lines resulted in decreased invasiveness that appeared to be related to reactions of superoxide with nitric oxide. Pancreatic cancer xenografts overexpressing EcSOD also demonstrated slower growth and peritoneal metastasis. Over-expression of EcSOD or treatment with a superoxide-specific SOD mimic caused significant decreases in PDA cell invasive capacity. Conclusions These results support the hypothesis that loss of EcSOD leads to increased reactions of superoxide with nitric oxide which contributes to the invasive phenotype. These results allow for the speculation that superoxide dismutase mimetics might inhibit PDA progression in human clinical disease. PMID:25634994

  4. Prognostic value of combined preoperative lactate dehydrogenase and alkaline phosphatase levels in patients with resectable pancreatic ductal adenocarcinoma.

    PubMed

    Ji, Fei; Fu, Shun-Jun; Guo, Zhi-Yong; Pang, Hui; Ju, Wei-Qiang; Wang, Dong-Ping; Hua, Yun-Peng; He, Xiao-Shun

    2016-07-01

    Serum enzymes, including lactate dehydrogenase (LDH) and alkaline phosphatase (ALP), have recently been reported to play important roles in tumor growth. Increases in LDH and ALP have been confirmed to predict poor prognosis in patients with various cancers. However, their prognostic value in pancreatic cancer has not been well studied. Therefore, we reviewed the preoperative data on LDH and ALP in 185 pancreatic ductal adenocarcinoma (PDAC) patients who underwent surgery between July 2005 and December 2010 to explore the prognostic value of these markers. The cutoff points were determined based on the upper limit of their normal values. The Chi-square test was used to analyze the relationships between LDH/ALP and clinical characteristics. Univariate and multivariate analyses were performed to identify the predictive value of the above factors for disease-free survival (DFS) and overall survival (OS). We found that elevation of LDH was related to carbohydrate antigen 19-9 (CA19-9), lymph node involvement, tumor size, TNM, distant metastasis, and recurrence. Additionally, ALP was correlated to perineural invasion. After multivariate analysis, LDH and ALP were identified as independent prognostic factors for DFS and OS, and elevation of LDH/ALP was correlated with poor DFS and OS. Notably, there was a positive correlation between LDH and ALP. The predictive power of LDH combined with ALP was more sensitive than that of either one alone. Therefore, we conclude that the preoperative LDH and ALP values are prognostic factors for PADC, and the prognostic accuracy of testing can be enhanced by the combination of LDH and ALP. PMID:27399091

  5. Metformin Restrains Pancreatic Duodenal Homeobox-1 (PDX-1) Function by Inhibiting ERK Signaling in Pancreatic Ductal Adenocarcinoma.

    PubMed

    Zhou, G; Yu, J; Wang, A; Liu, S-H; Sinnett-Smith, J; Wu, J; Sanchez, R; Nemunaitis, J; Ricordi, C; Rozengurt, E; Brunicardi, F C

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is one of the most potent and perilous diseases known, with a median survival rate of 3-5 months due to the combination of only advanced stage diagnosis and ineffective therapeutic options. Metformin (1,1-Dimethylbiguanide hydrochloride), the leading drug used for type 2 diabetes mellitus, emerges as a potential therapy for PDAC and other human cancers. Metformin exerts its anticancer action via a variety of adenosine monophosphate (AMP)-activated protein kinase (AMPK)- dependent and/or AMPK-independent mechanisms. We present data here showing that metformin downregulated pancreatic transcription factor pancreatic duodenal homeobox-1 (PDX-1), suggesting a potential novel mechanism by which metformin exerts its anticancer action. Metformin inhibited PDX-1 expression at both protein and mRNA levels and PDX-1 transactivity as well in PDAC cells. Extracellular signal-regulated kinase (ERK) was identified as a PDX-1-interacting protein by antibody array screening in GFP-PDX-1 stable HEK293 cells. Co-transfection of ERK1 with PDX-1 resulted in an enhanced PDX-1 expression in HEK293 cells in a dose-dependent manner. Immunoprecipitation/Western blotting analysis confirmed the ERK-PDX-1 interaction in PANC-1 cells stimulated by epidermal growth factor (EGF). EGF induced an enhanced PDX-1 expression in PANC-1 cells and this stimulation was inhibited by MEK inhibitor PD0325901. Metformin inhibited EGF-stimulated PDX-1 expression with an accompanied inhibition of ERK kinase activation in PANC- 1 cells. Taken together, our studies show that PDX-1 is a potential novel target for metformin in PDAC cells and that metformin may exert its anticancer action in PDAC by down-regulating PDX-1 via a mechanism involving inhibition of ERK signaling.

  6. The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models.

    PubMed

    Garcia, P L; Miller, A L; Kreitzburg, K M; Council, L N; Gamblin, T L; Christein, J D; Heslin, M J; Arnoletti, J P; Richardson, J H; Chen, D; Hanna, C A; Cramer, S L; Yang, E S; Qi, J; Bradner, J E; Yoon, K J

    2016-02-18

    The primary aim of this study was to evaluate the antitumor efficacy of the bromodomain inhibitor JQ1 in pancreatic ductal adenocarcinoma (PDAC) patient-derived xenograft (tumorgraft) models. A secondary aim of the study was to evaluate whether JQ1 decreases expression of the oncogene c-Myc in PDAC tumors, as has been reported for other tumor types. We used five PDAC tumorgraft models that retain specific characteristics of tumors of origin to evaluate the antitumor efficacy of JQ1. Tumor-bearing mice were treated with JQ1 (50 mg/kg daily for 21 or 28 days). Expression analyses were performed with tumors harvested from host mice after treatment with JQ1 or vehicle control. An nCounter PanCancer Pathways Panel (NanoString Technologies) of 230 cancer-related genes was used to identify gene products affected by JQ1. Quantitative RT-PCR, immunohistochemistry and immunoblots were carried out to confirm that changes in RNA expression reflected changes in protein expression. JQ1 inhibited the growth of all five tumorgraft models (P<0.05), each of which harbors a KRAS mutation; but induced no consistent change in expression of c-Myc protein. Expression profiling identified CDC25B, a regulator of cell cycle progression, as one of the three RNA species (TIMP3, LMO2 and CDC25B) downregulated by JQ1 (P<0.05). Inhibition of tumor progression was more closely related to decreased expression of nuclear CDC25B than to changes in c-Myc expression. JQ1 and other agents that inhibit the function of proteins with bromodomains merit further investigation for treating PDAC tumors. Work is ongoing in our laboratory to identify effective drug combinations that include JQ1.

  7. Myc Promoter-Binding Protein-1 (MBP-1) Is a Novel Potential Prognostic Marker in Invasive Ductal Breast Carcinoma

    PubMed Central

    Contino, Flavia; Mazzarella, Claudia; Sbacchi, Silvia; Roz, Elena; Lupo, Carmelo; Perconti, Giovanni; Giallongo, Agata; Migliorini, Paola; Marrazzo, Antonio; Feo, Salvatore

    2010-01-01

    Background Alpha-enolase is a glycolytic enzyme that catalyses the formation of phosphoenolpyruvate in the cell cytoplasm. α-Enolase and the predominantly nuclear Myc promoter-binding protein-1 (MBP-1) originate from a single gene through the alternative use of translational starting sites. MBP-1 binds to the P2 c-myc promoter and competes with TATA-box binding protein (TBP) to suppress gene transcription. Although several studies have shown an antiproliferative effect of MBP-1 overexpression on several human cancer cells, to date detailed observations of α-enolase and MBP-1 relative expression in primary tumors versus normal tissues and their correlation with clinicopathological features have not been undertaken. Methodology and Findings We analyzed α-enolase and MBP-1 expression in normal breast epithelium and primary invasive ductal breast carcinoma (IDC) from 177 patients by Western blot and immunohistochemical analyses, using highly specific anti-α-enolase monoclonal antibodies. A significant increase in the expression of cytoplasmic α-enolase was observed in 98% of the tumors analysed, compared to normal tissues. Nuclear MBP-1 was found in almost all the normal tissues while its expression was retained in only 35% of the tumors. Statistically significant associations were observed among the nuclear expression of MBP-1 and ErbB2 status, Ki-67 expression, node status and tumor grade. Furthermore MBP-1 expression was associated with good survival of patients with IDC. Conclusions MBP-1 functions in repressing c-myc gene expression and the results presented indicate that the loss of nuclear MBP-1 expression in a large number of IDC may be a critical step in the development and progression of breast cancer and a predictor of adverse outcome. Nuclear MBP-1 appears to be a novel and valuable histochemical marker with potential prognostic value in breast cancer. PMID:20886042

  8. Matricellular protein CCN1 (CYR61) expression is associated with high-grade ductal carcinoma in situ.

    PubMed

    Saglam, Ozlen; Dai, Feng; Husain, Seema; Zhan, Yilei; Toruner, Gokce; Haines, G Kenneth

    2014-06-01

    Cysteine-rich protein 61, connective tissue growth factor, and nephroblastoma overexpressed gene (CCN) comprise a family of matricellular proteins that have multiple physiologic functions including development, tissue repair, cell adhesion, migration, and proliferation. The expression of CCN1, cyclin D1, β-catenin, and p53 was explored by immunohistochemistry in different grades of ductal carcinoma in situ (DCIS) cases. These cases did not contain any infiltrating carcinoma components. In addition, all cysteine-rich protein 61 gene exons (encoding the CCN1 protein) were sequenced in 30 samples. Allred and H-scores were calculated for expression in both DCIS and the surrounding benign breast tissue. All cases of DCIS showed degrees of cytoplasmic CCN1 staining with median H-scores of 170, 160, and 60 in grades 3, 2, and 1, respectively (P = .043). Twelve of 28 DCIS 3, 1 of 15 DCIS 2, and 0 of 18 DCIS 1 also showed nuclear staining for CCN1. The cytoplasmic staining difference was preserved when the cases were divided into estrogen receptor (ER)+/DCIS grade 1, ER+/DCIS 2 and 3, and ER-/DCIS 2 and 3 by the H-score (P = .037). Cyclin D1 expression was positively correlated with the CCN1 cytoplasmic H-score in all DCIS samples (P = .038). Membranous β-catenin expression correlated with the grade of intraepithelial carcinoma by both H-score (P = .047) and Allred score (P = .026). Our results suggest that CCN1 has a role in the development of intraepithelial carcinoma. CCN1 expression correlates with grade of DCIS independent of ER status. It can induce cell cycle progression through cyclin D1. It is warranted to study high expression of CCN1 in DCIS as an independent risk factor in a larger cohort.

  9. Pancreatic fistula after a pancreaticoduodenectomy for ductal adenocarcinoma and its association with morbidity: a multicentre study of the French Surgical Association

    PubMed Central

    Addeo, Pietro; Delpero, Jean Robert; Paye, Francois; Oussoultzoglou, Elie; Fuchshuber, Pascal R; Sauvanet, Alain; Sa Cunha, Antonio; Le Treut, Yves Patrice; Adham, Mustapha; Mabrut, Jean-Yves; Chiche, Laurence; Bachellier, Philippe

    2014-01-01

    Backgrounds A pancreatic fistula (PF) is the most relevant complication after a pancreaticoduodenectomy (PD). This retrospective multicentric study attempts to elucidate the risk factors and complications of a PF in a large cohort of patients undergoing a PD for ductal adenocarcinoma. Methods Using a survey tool, clinical data of 1325 patients undergoing a PD for ductal adenocarcinoma at 37 institutions, between January 2004 and December 2009, were collected. Peri-operative risk factors associated with PF and its association with morbidity and mortality were assessed. Morbidity and PF were graded according to the ISGPF (International Study group for pancreatic fistula) definition and the Dindo–Clavien classification. Results Overall PF, mortality, morbidity and relaparotomy rates were 14.3%, 3.8%, 54.4% and 11.7%, respectively. PF occurred more frequently after a pancreaticojejunostomy (PJ) compared with a pancreaticogastrostomy (PG) (16.8% vs. 10.4%; P = 0.0012). Independent risk factors for PF by multivariate analysis were absence of pre-operative diabetes (P = 0.0014), PJ reconstruction (P = 0.0035), soft pancreatic parenchyma (P < 0.0001) and low-volume centre (P = 0.0286). Clinically relevant PF (grade B and C) and severe complications (Dindo–Clavien grade IIIB, IV, V) were significantly more frequent after PJ than PG (71.6% vs. 28.3%; P = 0.030 and 24.8% vs. 19.1%; P = 0.015, respectively). Overall mortality and relaparotomy rates were similar after PG and PJ. Conclusions A soft pancreatic parenchyma, the absence of pre-operative diabetes, PJ and low-volume centre are independent risk factors for PF after PD for ductal adenocarcinoma. A significantly higher incidence and clinical severity of PF are associated with PJ. PMID:23461663

  10. Myoepithelial cells from pleomorphic adenoma are not influenced by tumor conditioned media from breast ductal adenocarcinoma and melanoma cells: An in vitro study.

    PubMed

    Martinez, Elizabeth Ferreira; Demasi, Ana Paula Dias; Napimoga, Marcelo Henrique; Silva, Carolina Amália Barcellos; Navarini, Natalia Festugatto; Araújo, Ney Soares; DE Araújo, Vera Cavalcanti

    2015-01-01

    Myoepithelial cells have been implicated in the regulation of the transition from in situ to invasive neoplasia in salivary gland tumors. Considering the importance of the microenvironment of the tumor, the present in vitro study therefore analyzed the morphological and phenotypic changes undergone by benign myoepithelial cells from pleomorphic adenoma (PA) stimulated by tumor-conditioned medium. The benign myoepithelial cells were obtained from PA and were cultured with fibronectin extracellular matrix protein, supplemented with tumor-conditioned medium, which was harvested from breast ductal adenocarcinoma AU-565 and melanoma Hs 852.T cells. The morphological alterations were assessed by immunofluorescence analysis using vimentin antibody. The α-smooth muscle actin (α-SMA) and fibroblast growth factor (FGF)-2 proteins were analyzed by indirect immunofluorescence and quantitative polymerase chain reaction (qPCR). No morphological changes were observed in the myoepithelial cells cultured in fibronectin protein under stimulation from either tumor-conditioned medium. The immunofluorescence results, which were supported by qPCR analysis, revealed that only α-SMA was upregulated in the fibronectin substratum, with or without tumor-conditioned medium obtained from breast ductal adenocarcinoma and melanoma cells. No significant difference in FGF-2 mRNA expression was detected when the cells were cultured either in the tumor-conditioned medium or in the fibronectin substratum. The tumor-conditioned medium harvested from breast ductal adenocarcinoma and melanoma did not affect myoepithelial cell differentiation and function, which was reflected by the fact that there was no observed increase in α-SMA and FGF-2 expression, respectively.

  11. A representation and classification scheme for tree-like structures in medical images: an application on branching pattern analysis of ductal trees in x-ray galactograms

    NASA Astrophysics Data System (ADS)

    Megalooikonomou, Vasileios; Kontos, Despina; Danglemaier, Joseph; Javadi, Ailar; Bakic, Predrag R.; Maidment, Andrew D. A.

    2006-03-01

    We propose a multi-step approach for representing and classifying tree-like structures in medical images. Examples of such tree-like structures are encountered in the bronchial system, the vessel topology and the breast ductal network. We assume that the tree-like structures are already segmented. To avoid the tree isomorphism problem we obtain the breadth-first canonical form of a tree. Our approach is based on employing tree encoding techniques, such as the depth-first string encoding and the Prüfer encoding, to obtain a symbolic representation. Thus, the problem of classifying trees is reduced to string classification where node labels are the string terms. We employ the tf-idf text mining technique to assign a weight of significance to each string term (i.e., tree node label). We perform similarity searches and k-nearest neighbor classification of the trees using the tf-idf weight vectors and the cosine similarity metric. We applied our approach to the breast ductal network manually extracted from clinical x-ray galactograms. The goal was to characterize the ductal tree-like parenchymal structures in order to distinguish among different groups of women. Our best classification accuracy reached up to 90% for certain experimental settings (k=4), outperforming on the average by 10% that of a previous state-of-the-art method based on ramification matrices. These results illustrate the effectiveness of the proposed approach in analyzing tree-like patterns in breast images. Developing such automated tools for the analysis of tree-like structures in medical images can potentially provide insight to the relationship between the topology of branching and function or pathology.

  12. Characterization of pancreatic ductal adenocarcinoma using whole transcriptome sequencing and copy number analysis by single-nucleotide polymorphism array.

    PubMed

    Di Marco, Mariacristina; Astolfi, Annalisa; Grassi, Elisa; Vecchiarelli, Silvia; Macchini, Marina; Indio, Valentina; Casadei, Riccardo; Ricci, Claudio; D'Ambra, Marielda; Taffurelli, Giovanni; Serra, Carla; Ercolani, Giorgio; Santini, Donatella; D'Errico, Antonia; Pinna, Antonio Daniele; Minni, Francesco; Durante, Sandra; Martella, Laura Raffaella; Biasco, Guido

    2015-11-01

    The aim of the current study was to implement whole transcriptome massively parallel sequencing (RNASeq) and copy number analysis to investigate the molecular biology of pancreatic ductal adenocarcinoma (PDAC). Samples from 16 patients with PDAC were collected by ultrasound‑guided biopsy or from surgical specimens for DNA and RNA extraction. All samples were analyzed by RNASeq performed at 75x2 base pairs on a HiScanSQ Illumina platform. Single‑nucleotide variants (SNVs) were detected with SNVMix and filtered on dbSNP, 1000 Genomes and Cosmic. Non‑synonymous SNVs were analyzed with SNPs&GO and PROVEAN. A total of 13 samples were analyzed by high resolution copy number analysis on an Affymetrix SNP array 6.0. RNAseq resulted in an average of 264 coding non‑synonymous novel SNVs (ranging from 146‑374) and 16 novel insertions or deletions (In/Dels) (ranging from 6‑24) for each sample, of which a mean of 11.2% were disease‑associated and somatic events, while 34.7% were frameshift somatic In/Dels. From this analysis, alterations in the known oncogenes associated with PDAC were observed, including Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations (93.7%) and inactivation of cyclin‑dependent kinase inhibitor 2A (CDKN2A) (50%), mothers against decapentaplegic homolog 4 (SMAD4) (50%), and tumor protein 53 (TP53) (56%). One case that was negative for KRAS exhibited a G13D neuroblastoma RAS viral oncogene homolog mutation. In addition, gene fusions were detected in 10 samples for a total of 23 different intra‑ or inter‑chromosomal rearrangements, however, a recurrent fusion transcript remains to be identified. SNP arrays identified macroscopic and cryptic cytogenetic alterations in 85% of patients. Gains were observed in the chromosome arms 6p, 12p, 18q and 19q which contain KRAS, GATA binding protein 6, protein kinase B and cyclin D3. Deletions were identified on chromosome arms 1p, 9p, 6p, 18q, 10q, 15q, 17p, 21q and 19q which involve TP53

  13. RTOG 9804: A Prospective Randomized Trial for Good-Risk Ductal Carcinoma In Situ Comparing Radiotherapy With Observation

    PubMed Central

    McCormick, Beryl; Winter, Kathryn; Hudis, Clifford; Kuerer, Henry Mark; Rakovitch, Eileen; Smith, Barbara L.; Sneige, Nour; Moughan, Jennifer; Shah, Amit; Germain, Isabelle; Hartford, Alan C.; Rashtian, Afshin; Walker, Eleanor M.; Yuen, Albert; Strom, Eric A.; Wilcox, Jeannette L.; Vallow, Laura A.; Small, William; Pu, Anthony T.; Kerlin, Kevin; White, Julia

    2015-01-01

    Purpose The Radiation Therapy Oncology Group 9804 study identified good-risk patients with ductal carcinoma in situ (DCIS), a breast cancer diagnosis found frequently in mammographically detected cancers, to test the benefit of radiotherapy (RT) after breast-conserving surgery compared with observation. Patients and Methods This prospective randomized trial (1998 to 2006) in women with mammographically detected low- or intermediate-grade DCIS, measuring less than 2.5 cm with margins ≥ 3 mm, compared RT with observation after surgery. The study was designed for 1,790 patients but was closed early because of lower than projected accrual. Six hundred thirty-six patients from the United States and Canada were entered; tamoxifen use (62%) was optional. Ipsilateral local failure (LF) was the primary end point; LF and contralateral failure were estimated using cumulative incidence, and overall and disease-free survival were estimated using the Kaplan-Meier method. Results Median follow-up time was 7.17 years (range, 0.01 to 11.33 years). Two LFs occurred in the RT arm, and 19 occurred in the observation arm. At 7 years, the LF rate was 0.9% (95% CI, 0.0% to 2.2%) in the RT arm versus 6.7% (95% CI, 3.2% to 9.6%) in the observation arm (hazard ratio, 0.11; 95% CI, 0.03 to 0.47; P < .001). Grade 1 to 2 acute toxicities occurred in 30% and 76% of patients in the observation and RT arms, respectively; grade 3 or 4 toxicities occurred in 4.0% and 4.2% of patients, respectively. Late RT toxicity was grade 1 in 30%, grade 2 in 4.6%, and grade 3 in 0.7% of patients. Conclusion In this good-risk subset of patients with DCIS, with a median follow-up of 7 years, the LF rate was low with observation but was decreased significantly with the addition of RT. Longer follow-up is planned because the timeline for LF in this setting seems protracted. PMID:25605856

  14. Glucose Uptake and Intracellular pH in a Mouse Model of Ductal Carcinoma In situ (DCIS) Suggests Metabolic Heterogeneity

    PubMed Central

    Lobo, Rebecca C.; Hubbard, Neil E.; Damonte, Patrizia; Mori, Hidetoshi; Pénzváltó, Zsófia; Pham, Cindy; Koehne, Amanda L.; Go, Aiza C.; Anderson, Steve E.; Cala, Peter M.; Borowsky, Alexander D.

    2016-01-01

    Mechanisms for the progression of ductal carcinoma in situ (DCIS) to invasive breast carcinoma remain unclear. Previously we showed that the transition to invasiveness in the mammary intraepithelial neoplastic outgrowth (MINO) model of DCIS does not correlate with its serial acquisition of genetic mutations. We hypothesized instead that progression to invasiveness depends on a change in the microenvironment and that precancer cells might create a more tumor-permissive microenvironment secondary to changes in glucose uptake and metabolism. Immunostaining for glucose transporter 1 (GLUT1) and the hypoxia marker carbonic anhydrase 9 (CAIX) in tumor, normal mammary gland and MINO (precancer) tissue showed differences in expression. The uptake of the fluorescent glucose analog dye, 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-D-glucose (2-NBDG), reflected differences in the cellular distributions of glucose uptake in normal mammary epithelial cells (nMEC), MINO, and Met1 cancer cells, with a broad distribution in the MINO population. The intracellular pH (pHi) measured using the fluorescent ratio dye 2′,7′-bis(2-carboxyethyl)-5(6)-155 carboxyfluorescein (BCECF) revealed expected differences between normal and cancer cells (low and high, respectively), and a mixed distribution in the MINO cells, with a subset of cells in the MINO having an increased rate of acidification when proton efflux was inhibited. Invasive tumor cells had a more alkaline baseline pHi with high rates of proton production coupled with higher rates of proton export, compared with nMEC. MINO cells displayed considerable variation in baseline pHi that separated into two distinct populations: MINO high and MINO low. MINO high had a noticeably higher mean acidification rate compared with nMEC, but relatively high baseline pHi similar to tumor cells. MINO low cells also had an increased acidification rate compared with nMEC, but with a more acidic pHi similar to nMEC. These findings

  15. Assessment of different 3D culture systems to study tumor phenotype and chemosensitivity in pancreatic ductal adenocarcinoma.

    PubMed

    Zeeberg, Katrine; Cardone, Rosa Angela; Greco, Maria Raffaella; Saccomano, Mara; Nøhr-Nielsen, Asbjørn; Alves, Frauke; Pedersen, Stine Falsig; Reshkin, Stephan Joel

    2016-07-01

    Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease with a very poor prognosis, due to the influence of the tumor stroma, which promotes tumor growth, early invasion and chemoradiation resistance. Efforts to develop models for identifying novel anticancer therapeutic compounds have been hampered by the limited ability of in vitro models to mimic these in vivo tumor-stroma interactions. This has led to the development of various three-dimensional (3D) culture platforms recapitulating the in vivo tumor-stroma crosstalk and designed to better understand basic cancer processes and screen drug action. However, a consensus for different experimental 3D platforms is still missing in PDAC. We compared four PDAC cell lines of different malignancy grown in 2D monolayers to three of the more commonly used 3D techniques (ultralow adhesion concave microwells, Matrigel inclusion and organotypic systems) and to tumors derived from their orthotopic implantation in mice. In these 3D platforms, we observed that cells grow with very different tumor morphologies and the organotypic setting most closely resembles the tumor cytoarchitecture obtained by orthotopically implanting the four cell lines in mice. We then analyzed the molecular and cellular responses of one of these cell lines to epidermal growth factor receptor (EGFR) stimulation with EGF and inhibition with erlotinib and found that only in the 3D platforms, and especially the organotypic, cells: i) responded to EGF by changing the expression of signalling components underlying cell-stroma crosstalk and tissue architecture, growth, invasion and drug resistance (E-cadherin, EGFR, ezrin, β1 integrin, NHERF1 and HIF-1α) similar to those reported in vivo; ii) had stimulated growth and increased erlotinib sensitivity in response to EGF, more faithfully mimicking their known in vivo behaviour. Altogether, these results, indicate the organotypic as the most relevant physiological 3D system to study the

  16. Potential predictive role of chemotherapy-induced changes of soluble CD40 ligand in untreated advanced pancreatic ductal adenocarcinoma.

    PubMed

    Azzariti, Amalia; Brunetti, Oronzo; Porcelli, Letizia; Graziano, Giusi; Iacobazzi, Rosa Maria; Signorile, Michele; Scarpa, Aldo; Lorusso, Vito; Silvestris, Nicola

    2016-01-01

    Pancreas ductal adenocarcinoma lacks predictive biomarkers. CD40 is a member of the tumor necrosis factor superfamily. CD40-sCD40L interaction is considered to contribute to the promotion of tumor cell growth and angiogenesis. The aim of the present study was to investigate the role of serum sCD40L as a predictor in metastatic pancreatic cancer. We evaluated 27 consecutive pancreatic cancer patients treated with FOLFIRINOX (21 patients) or gemcitabine plus nab-paclitaxel combination (six patients). The sCD40L level was measured in serum by enzyme-linked immunosorbent assay at baseline, at first evaluation (all patients), and at time to progression (18 patients). The radiological response was evaluated according to the Response Evaluation Criteria in Solid Tumors, Version 1.1. The Wilcoxon signed-rank test was used to compare pre-post treatment sCD40L levels with respect to clinical response, while Pearson's correlation coefficient was used for the correlation between sCD40L and CA19.9 pre- and post-treatment. The Kruskal-Wallis test was also conducted for further comparisons. We observed a statistically significant reduction in the sCD40L level after 3 months of treatment in patients with partial response (11,718.05±7,097.13 pg/mL vs 4,689.42±5,409.96 pg/mL; P<0.01). Conversely, in patients with progressive disease, the biomarker statistically increased in the same time (9,351.51±7,356.91 pg/mL vs 22,282.92±11,629.35 pg/mL; P<0.01). This trend of sCD40L was confirmed in 18 patients at time to progression after the first evaluation. No differences were recorded within the stable disease group. Moreover, there was a positive correlation between the sCD40L and CA19.9 pre-post treatment variation percentage (Pearson's correlation coefficient =0.52; P<0.05). Our data suggest a possible predictive role of sCD40L in pancreatic cancer patients, similar to CA19.9. PMID:27555786

  17. Characterization of pancreatic ductal adenocarcinoma using whole transcriptome sequencing and copy number analysis by single-nucleotide polymorphism array.

    PubMed

    Di Marco, Mariacristina; Astolfi, Annalisa; Grassi, Elisa; Vecchiarelli, Silvia; Macchini, Marina; Indio, Valentina; Casadei, Riccardo; Ricci, Claudio; D'Ambra, Marielda; Taffurelli, Giovanni; Serra, Carla; Ercolani, Giorgio; Santini, Donatella; D'Errico, Antonia; Pinna, Antonio Daniele; Minni, Francesco; Durante, Sandra; Martella, Laura Raffaella; Biasco, Guido

    2015-11-01

    The aim of the current study was to implement whole transcriptome massively parallel sequencing (RNASeq) and copy number analysis to investigate the molecular biology of pancreatic ductal adenocarcinoma (PDAC). Samples from 16 patients with PDAC were collected by ultrasound‑guided biopsy or from surgical specimens for DNA and RNA extraction. All samples were analyzed by RNASeq performed at 75x2 base pairs on a HiScanSQ Illumina platform. Single‑nucleotide variants (SNVs) were detected with SNVMix and filtered on dbSNP, 1000 Genomes and Cosmic. Non‑synonymous SNVs were analyzed with SNPs&GO and PROVEAN. A total of 13 samples were analyzed by high resolution copy number analysis on an Affymetrix SNP array 6.0. RNAseq resulted in an average of 264 coding non‑synonymous novel SNVs (ranging from 146‑374) and 16 novel insertions or deletions (In/Dels) (ranging from 6‑24) for each sample, of which a mean of 11.2% were disease‑associated and somatic events, while 34.7% were frameshift somatic In/Dels. From this analysis, alterations in the known oncogenes associated with PDAC were observed, including Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations (93.7%) and inactivation of cyclin‑dependent kinase inhibitor 2A (CDKN2A) (50%), mothers against decapentaplegic homolog 4 (SMAD4) (50%), and tumor protein 53 (TP53) (56%). One case that was negative for KRAS exhibited a G13D neuroblastoma RAS viral oncogene homolog mutation. In addition, gene fusions were detected in 10 samples for a total of 23 different intra‑ or inter‑chromosomal rearrangements, however, a recurrent fusion transcript remains to be identified. SNP arrays identified macroscopic and cryptic cytogenetic alterations in 85% of patients. Gains were observed in the chromosome arms 6p, 12p, 18q and 19q which contain KRAS, GATA binding protein 6, protein kinase B and cyclin D3. Deletions were identified on chromosome arms 1p, 9p, 6p, 18q, 10q, 15q, 17p, 21q and 19q which involve TP53

  18. Ductal Carcinoma In Situ With Microinvasion: Prognostic Implications, Long-Term Outcomes, and Role of Axillary Evaluation

    SciTech Connect

    Parikh, Rahul R.; Haffty, Bruce G.; Lannin, Donald; Moran, Meena S.

    2012-01-01

    Purpose: To compare the clinical-pathologic features and long-term outcomes for women with ductal carcinoma in situ (DCIS) vs. DCIS with microinvasion (DCISM) treated with breast conservation therapy (BCT), to assess the impact of microinvasion. Patients and Methods: A total of 393 patients with DCIS/DCISM from our database were analyzed to assess differences in clinical-pathologic features and outcomes for the two cohorts. Results: The median follow-up was 8.94 years, and the mean age was 55.8 years for the entire group. The DCISM cohort was comprised of 72 of 393 patients (18.3%). Surgical evaluation of the axilla was performed in 58.3% (n = 42) of DCISM vs. 18.1% (n = 58) of DCIS, with only 1 of 42 DCISM (2.3%) vs. 0 of 58 DCIS with axillary metastasis. Surgical axillary evaluation was not an independent predictor of local-regional relapse (LRR), distant relapse-free survival (DRFS), or overall survival (OS) in Cox proportional hazards analysis (p > 0.05). For the DCIS vs. DCISM groups, respectively, the 10-year breast relapse-free survival was 89.0% vs. 90.7% (p = 0.36), DRFS was 98.5% vs. 97.9% (p = 0.78), and OS was 93.2% vs. 95.7% (p = 0.95). The presence of microinvasion did not correlate with LRR, age, presentation, race, family history, margin status, and use of adjuvant hormonal therapy (all p > 0.05). In univariate analysis, pathology (DCIS vs. DCISM) was not an independent predictor of LRR (hazard ratio [HR], 1.58; 95% confidence interval [CI], 0.58-4.30; p = 0.36), DRFS (HR, 0.72; 95% CI, 0.07-6.95; p = 0.77), or OS (HR, 1.03; 95% CI, 0.28-3.82; p = 0.95). Conclusions: Our data imply that the natural history of DCISM closely resembles that of DCIS, with a low incidence of local-regional and distant failures. On the basis of our large dataset, the incidence of axillary metastasis in DCISM appears to be small and not appear to correlate to outcomes, and thus, microinvasion alone should not be the sole criterion for more aggressive treatment.

  19. Potential predictive role of chemotherapy-induced changes of soluble CD40 ligand in untreated advanced pancreatic ductal adenocarcinoma

    PubMed Central

    Azzariti, Amalia; Brunetti, Oronzo; Porcelli, Letizia; Graziano, Giusi; Iacobazzi, Rosa Maria; Signorile, Michele; Scarpa, Aldo; Lorusso, Vito; Silvestris, Nicola

    2016-01-01

    Pancreas ductal adenocarcinoma lacks predictive biomarkers. CD40 is a member of the tumor necrosis factor superfamily. CD40–sCD40L interaction is considered to contribute to the promotion of tumor cell growth and angiogenesis. The aim of the present study was to investigate the role of serum sCD40L as a predictor in metastatic pancreatic cancer. We evaluated 27 consecutive pancreatic cancer patients treated with FOLFIRINOX (21 patients) or gemcitabine plus nab-paclitaxel combination (six patients). The sCD40L level was measured in serum by enzyme-linked immunosorbent assay at baseline, at first evaluation (all patients), and at time to progression (18 patients). The radiological response was evaluated according to the Response Evaluation Criteria in Solid Tumors, Version 1.1. The Wilcoxon signed-rank test was used to compare pre–post treatment sCD40L levels with respect to clinical response, while Pearson’s correlation coefficient was used for the correlation between sCD40L and CA19.9 pre- and post-treatment. The Kruskal–Wallis test was also conducted for further comparisons. We observed a statistically significant reduction in the sCD40L level after 3 months of treatment in patients with partial response (11,718.05±7,097.13 pg/mL vs 4,689.42±5,409.96 pg/mL; P<0.01). Conversely, in patients with progressive disease, the biomarker statistically increased in the same time (9,351.51±7,356.91 pg/mL vs 22,282.92±11,629.35 pg/mL; P<0.01). This trend of sCD40L was confirmed in 18 patients at time to progression after the first evaluation. No differences were recorded within the stable disease group. Moreover, there was a positive correlation between the sCD40L and CA19.9 pre–post treatment variation percentage (Pearson’s correlation coefficient =0.52; P<0.05). Our data suggest a possible predictive role of sCD40L in pancreatic cancer patients, similar to CA19.9. PMID:27555786

  20. Association between Genetic Subgroups of Pancreatic Ductal Adenocarcinoma Defined by High Density 500 K SNP-Arrays and Tumor Histopathology

    PubMed Central

    Gutiérrez, María Laura; Muñoz-Bellvis, Luís; Abad, María del Mar; Bengoechea, Oscar; González-González, María

    2011-01-01

    The specific genes and genetic pathways associated with pancreatic ductal adenocarcinoma are still largely unknown partially due to the low resolution of the techniques applied so far to their study. Here we used high-density 500 K single nucleotide polymorphism (SNP)-arrays to define those chromosomal regions which most commonly harbour copy number (CN) alterations and loss of heterozygozity (LOH) in a series of 20 PDAC tumors and we correlated the corresponding genetic profiles with the most relevant clinical and histopathological features of the disease. Overall our results showed that primary PDAC frequently display (>70%) extensive gains of chromosomes 1q, 7q, 8q and 20q, together with losses of chromosomes 1p, 9p, 12q, 17p and 18q, such chromosomal regions harboring multiple cancer- and PDAC-associated genes. Interestingly, these alterations clustered into two distinct genetic profiles characterized by gains of the 2q14.2, 3q22.1, 5q32, 10q26.13, 10q26.3, 11q13.1, 11q13.3, 11q13.4, 16q24.1, 16q24.3, 22q13.1, 22q13.31 and 22q13.32 chromosomal regions (group 1; n = 9) versus gains at 1q21.1 and losses of the 1p36.11, 6q25.2, 9p22.1, 9p24.3, 17p13.3 and Xp22.33 chromosomal regions (group 2; n = 11). From the clinical and histopathological point of view, group 1 cases were associated with smaller and well/moderately-differentiated grade I/II PDAC tumors, whereas and group 2 PDAC displayed a larger size and they mainly consisted of poorly-differentiated grade III carcinomas. These findings confirm the cytogenetic complexity and heterogenity of PDAC and provide evidence for the association between tumor cytogenetics and its histopathological features. In addition, we also show that the altered regions identified harbor multiple cancer associate genes that deserve further investigation to determine their relevance in the pathogenesis of PDAC. PMID:21811587

  1. Glucose Uptake and Intracellular pH in a Mouse Model of Ductal Carcinoma In situ (DCIS) Suggests Metabolic Heterogeneity

    PubMed Central

    Lobo, Rebecca C.; Hubbard, Neil E.; Damonte, Patrizia; Mori, Hidetoshi; Pénzváltó, Zsófia; Pham, Cindy; Koehne, Amanda L.; Go, Aiza C.; Anderson, Steve E.; Cala, Peter M.; Borowsky, Alexander D.

    2016-01-01

    Mechanisms for the progression of ductal carcinoma in situ (DCIS) to invasive breast carcinoma remain unclear. Previously we showed that the transition to invasiveness in the mammary intraepithelial neoplastic outgrowth (MINO) model of DCIS does not correlate with its serial acquisition of genetic mutations. We hypothesized instead that progression to invasiveness depends on a change in the microenvironment and that precancer cells might create a more tumor-permissive microenvironment secondary to changes in glucose uptake and metabolism. Immunostaining for glucose transporter 1 (GLUT1) and the hypoxia marker carbonic anhydrase 9 (CAIX) in tumor, normal mammary gland and MINO (precancer) tissue showed differences in expression. The uptake of the fluorescent glucose analog dye, 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-D-glucose (2-NBDG), reflected differences in the cellular distributions of glucose uptake in normal mammary epithelial cells (nMEC), MINO, and Met1 cancer cells, with a broad distribution in the MINO population. The intracellular pH (pHi) measured using the fluorescent ratio dye 2′,7′-bis(2-carboxyethyl)-5(6)-155 carboxyfluorescein (BCECF) revealed expected differences between normal and cancer cells (low and high, respectively), and a mixed distribution in the MINO cells, with a subset of cells in the MINO having an increased rate of acidification when proton efflux was inhibited. Invasive tumor cells had a more alkaline baseline pHi with high rates of proton production coupled with higher rates of proton export, compared with nMEC. MINO cells displayed considerable variation in baseline pHi that separated into two distinct populations: MINO high and MINO low. MINO high had a noticeably higher mean acidification rate compared with nMEC, but relatively high baseline pHi similar to tumor cells. MINO low cells also had an increased acidification rate compared with nMEC, but with a more acidic pHi similar to nMEC. These findings

  2. Glucose Uptake and Intracellular pH in a Mouse Model of Ductal Carcinoma In situ (DCIS) Suggests Metabolic Heterogeneity.

    PubMed

    Lobo, Rebecca C; Hubbard, Neil E; Damonte, Patrizia; Mori, Hidetoshi; Pénzváltó, Zsófia; Pham, Cindy; Koehne, Amanda L; Go, Aiza C; Anderson, Steve E; Cala, Peter M; Borowsky, Alexander D

    2016-01-01

    Mechanisms for the progression of ductal carcinoma in situ (DCIS) to invasive breast carcinoma remain unclear. Previously we showed that the transition to invasiveness in the mammary intraepithelial neoplastic outgrowth (MINO) model of DCIS does not correlate with its serial acquisition of genetic mutations. We hypothesized instead that progression to invasiveness depends on a change in the microenvironment and that precancer cells might create a more tumor-permissive microenvironment secondary to changes in glucose uptake and metabolism. Immunostaining for glucose transporter 1 (GLUT1) and the hypoxia marker carbonic anhydrase 9 (CAIX) in tumor, normal mammary gland and MINO (precancer) tissue showed differences in expression. The uptake of the fluorescent glucose analog dye, 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-D-glucose (2-NBDG), reflected differences in the cellular distributions of glucose uptake in normal mammary epithelial cells (nMEC), MINO, and Met1 cancer cells, with a broad distribution in the MINO population. The intracellular pH (pHi) measured using the fluorescent ratio dye 2',7'-bis(2-carboxyethyl)-5(6)-155 carboxyfluorescein (BCECF) revealed expected differences between normal and cancer cells (low and high, respectively), and a mixed distribution in the MINO cells, with a subset of cells in the MINO having an increased rate of acidification when proton efflux was inhibited. Invasive tumor cells had a more alkaline baseline pHi with high rates of proton production coupled with higher rates of proton export, compared with nMEC. MINO cells displayed considerable variation in baseline pHi that separated into two distinct populations: MINO high and MINO low. MINO high had a noticeably higher mean acidification rate compared with nMEC, but relatively high baseline pHi similar to tumor cells. MINO low cells also had an increased acidification rate compared with nMEC, but with a more acidic pHi similar to nMEC. These findings demonstrate

  3. Adenomatoid hyperplasia of lower lip.

    PubMed

    Sharma, Gaganjot Kaur; Sharma, Manish; Vanaki, Srinivas S

    2011-10-01

    Adenomatoid hyperplasia (AH) is an uncommon, non-neoplastic swelling on the palate caused due to hyperplasia of the mucinous acini. The lesion clinically presents as a sessile tumor-like nodule resembling pleomorphic adenoma. Histopathologic findings include lobules of enlarged mucinous acini which are filled with secretory granules. The nuclei are squeezed to the basal portions, associated with focal inflammation and ductal dilatation, and a history of trauma is often elicited. Here, we report a rare case of AH of the lower lip in a 20-year-old male patient, which mimics a mucous retention cyst or mucocele. PMID:22135695

  4. High Expression of Urokinase-Type Plasminogen Activator Is Associated with Lymph Node Metastasis of Invasive Ductal Carcinoma of the Breast

    PubMed Central

    Kim, Eun Young; Do, Sung-Im; Hyun, Keehoon; Park, Yong Lai; Kim, Dong-Hoon; Chae, Seoung Wan; Sohn, Jin Hee

    2016-01-01

    Purpose In the present study, we evaluated the levels of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor 1 (PAI-1) by performing immunohistochemical staining to determine whether they were reliable prognostic markers in patients with breast cancer. Methods Demographic and clinicopathological parameters of 214 patients with invasive ductal carcinoma (IDC) and 80 patients with ductal carcinoma in situ (DCIS) who were diagnosed and treated from 2006 to 2010 were analyzed. Tissue microarray was constructed and immunohistochemical staining was performed for each specimen. Results Univariate analyses showed that age at diagnosis, history of hormone replacement therapy, radiation therapy, skin and chest wall invasion, Paget disease, lymphovascular invasion, estrogen receptor positivity, and triple-negative subtype were significantly associated with patient prognosis (p<0.005). Patients with DCIS showed higher PAI-1 expression than patients with IDC (82.5% and 36.2%, respectively; p=0.012). Lymph node metastasis was more frequent in patients with high uPA levels than in patients with low uPA levels (p=0.001). Conclusion Our results suggested that PAI-1 was involved in tumor progression in the early stages of breast cancer, such as DCIS. In addition, our results suggested that high uPA levels were associated with the lymph node metastasis of IDC. PMID:27382391

  5. Eliminating "ductal carcinoma in situ" and "lobular carcinoma in situ" (DCIS and LCIS) terminology in clinical breast practice: The cognitive psychology point of view.

    PubMed

    Pravettoni, Gabriella; Yoder, Whitney R; Riva, Silvia; Mazzocco, Ketti; Arnaboldi, Paola; Galimberti, Viviana

    2016-02-01

    There is evidence from the literature that the terms "ductal carcinoma in situ" and "lobular carcinoma in situ" (DCIS and LCIS) should be eliminated in clinical breast cancer practice and replaced with the new "ductal intraepithelial neoplasia" (DIN) and "lobular intraepithelial neoplasia" (LIN) terminology. The main purpose of the present article is to expand on this argument from a cognitive psychology perspective and offer suggestions for further research, emphasizing how the elimination of the term "carcinoma" in "in situ" breast cancer diagnoses has the potential to reduce both patient and health care professional confusion and misperceptions that are often associated with the DCIS and LCIS diagnoses, as well as limit the adverse psychological effects of women receiving a DCIS or LCIS diagnosis. We comment on the recent peer-reviewed literature on the clinical implications and psychological consequences for breast cancer patients receiving a DCIS or LCIS diagnosis and we use a cognitive perspective to offer new insight into the benefits of embracing the new DIN and LIN terminology. Using cognitive psychology and cognitive science in general, as a foundation, further research is advocated in order to yield data in support of changing the terminology and therefore, offer a chance to significantly improve the lives and psychological sequelae of women facing such a diagnosis. Typology: Controversies/Short Commentary. PMID:26614547

  6. Expression of cell-cycle regulatory proteins BUBR1, MAD2, Aurora A, cyclin A and cyclin E in invasive ductal breast carcinomas.

    PubMed

    Du, Juan; Du, Qiang; Zhang, Yang; Sajdik, Constantin; Ruan, Yuan; Tian, Xin-xia; Fang, Wei-gang

    2011-06-01

    Cyclin A, cyclin E, BUBR1, MAD2 and Aurora A are all cell-cycle regulatory proteins and have been proven to play crucial roles in carcinogenesis. However, their expression patterns in invasive ductal breast carcinoma (IDBC) are controversial and unclear. In this study, we examined the expression status of these candidate proteins in a set of 117 invasive ductal carcinomas, and evaluated their associations with known clinicopathological parameters and the expressions of estrogen receptor, progesterone receptor, Ki-67 and Her-2. Univariate and multivariate data analyses both displayed that positive BUBR1 expression was associated with a high Ki-67 labeling index, and negative MAD2 expression was associated with Her-2 overexpression. Positive BUBR1 expression was also associated with a high histological tumor grade in univariate analysis, but not in multivariate analysis. In addition, high Aurora A expression was weakly associated with lymph node metastasis, and cyclin A was strongly associated with the expression of cyclin E in both univariate and multivariate models. In conclusion, this study suggests that evaluation of BUBR1, MAD2 and Aurora A expression levels is likely to improve accuracy of prognostic predictions in IDBC.

  7. Eliminating "ductal carcinoma in situ" and "lobular carcinoma in situ" (DCIS and LCIS) terminology in clinical breast practice: The cognitive psychology point of view.

    PubMed

    Pravettoni, Gabriella; Yoder, Whitney R; Riva, Silvia; Mazzocco, Ketti; Arnaboldi, Paola; Galimberti, Viviana

    2016-02-01

    There is evidence from the literature that the terms "ductal carcinoma in situ" and "lobular carcinoma in situ" (DCIS and LCIS) should be eliminated in clinical breast cancer practice and replaced with the new "ductal intraepithelial neoplasia" (DIN) and "lobular intraepithelial neoplasia" (LIN) terminology. The main purpose of the present article is to expand on this argument from a cognitive psychology perspective and offer suggestions for further research, emphasizing how the elimination of the term "carcinoma" in "in situ" breast cancer diagnoses has the potential to reduce both patient and health care professional confusion and misperceptions that are often associated with the DCIS and LCIS diagnoses, as well as limit the adverse psychological effects of women receiving a DCIS or LCIS diagnosis. We comment on the recent peer-reviewed literature on the clinical implications and psychological consequences for breast cancer patients receiving a DCIS or LCIS diagnosis and we use a cognitive perspective to offer new insight into the benefits of embracing the new DIN and LIN terminology. Using cognitive psychology and cognitive science in general, as a foundation, further research is advocated in order to yield data in support of changing the terminology and therefore, offer a chance to significantly improve the lives and psychological sequelae of women facing such a diagnosis. Typology: Controversies/Short Commentary.

  8. Gradual telomere shortening and increasing chromosomal instability among PanIN grades and normal ductal epithelia with and without cancer in the pancreas.

    PubMed

    Matsuda, Yoko; Ishiwata, Toshiyuki; Izumiyama-Shimomura, Naotaka; Hamayasu, Hideki; Fujiwara, Mutsunori; Tomita, Ken-Ichiro; Hiraishi, Naoki; Nakamura, Ken-Ichi; Ishikawa, Naoshi; Aida, Junko; Takubo, Kaiyo; Arai, Tomio

    2015-01-01

    A large body of evidence supports a key role for telomere dysfunction in carcinogenesis due to the induction of chromosomal instability. To study telomere shortening in precancerous pancreatic lesions, we measured telomere lengths using quantitative fluorescence in situ hybridization in the normal pancreatic duct epithelium, pancreatic intraepithelial neoplasias (PanINs), and cancers. The materials employed included surgically resected pancreatic specimens without cancer (n = 33) and with invasive ductal carcinoma (n = 36), as well as control autopsy cases (n = 150). In comparison with normal ducts, telomere length was decreased in PanIN-1, -2 and -3 and cancer. Furthermore, telomeres were shorter in cancer than in PanIN-1 and -2. Telomere length in cancer was not associated with histological type, lesion location, or cancer stage. PanINs with or without cancer showed similar telomere lengths. The incidences of atypical mitosis and anaphase bridges, which are morphological characteristics of chromosomal instability, were negatively correlated with telomere length. The telomeres in normal duct epithelium became shorter with aging, and those in PanINs or cancers were shorter than in age-matched controls, suggesting that telomere shortening occurs even when histological changes are absent. Our data strongly suggest that telomere shortening occurs in the early stages of pancreatic carcinogenesis and progresses with precancerous development. Telomere shortening and chromosomal instability in the duct epithelium might be associated with carcinogenesis of the pancreas. Determination of telomere length in pancreatic ductal lesions may be valuable for accurate detection and risk assessment of pancreatic cancer.

  9. The impact of sentinel lymph node biopsy and magnetic resonance imaging on important outcomes among patients with ductal carcinoma in situ.

    PubMed

    Tuttle, Todd M; Shamliyan, Tatyana; Virnig, Beth A; Kane, Robert L

    2010-01-01

    The objective of this systematic review was to determine the impact of sentinel lymph node (SLN) biopsy and breast magnetic resonance imaging (MRI) on important outcomes for patients with ductal carcinoma in situ. We identified no study that directly evaluated important outcomes for SLN biopsy. So, we determined the incidence of SLN metastases among patients with ductal carcinoma in situ. Using American Joint Committee on Cancer criteria, the incidence of pN1 and pN1(mic) SLN metastases were 0.9% and 1.5%, respectively. Because the incidence of SLN metastasis is very low, SLN biopsy is not likely to affect important outcomes. We identified one study that directly evaluated important outcomes after breast MRI. In this study, the use of MRI did not affect local recurrence rates after breast-conserving surgery and radiation. Although MRI may identify occult multicentric or contralateral breast cancer in some patients, it may also lead to unnecessary biopsies and overtreatment. PMID:20956814

  10. Analysis of Gene Expression in PTHrP−/− Mammary Buds Supports a Role for BMP Signaling and MMP2 in the Initiation of Ductal Morphogenesis

    PubMed Central

    Hens, Julie; Dann, Pamela; Hiremath, Minoti; Pan, Tien-Chi; Chodosh, Lewis; Wysolmerski, John

    2010-01-01

    Parathyroid hormone-related protein (PTHrP) acts on the mammary mesenchyme and is required for proper embryonic mammary development. In order to understand PTHrP’s effects on mesenchymal cells, we profiled gene expression in WT and PTHrP−/− mammary buds, and in WT and K14-PTHrP ventral skin at E15.5. By cross-referencing the differences in gene expression between these groups, we identified 35 genes potentially regulated by PTHrP in the mammary mesenchyme, including 6 genes known to be involved in BMP signaling. One of these genes was MMP2. We demonstrated that PTHrP and BMP4 regulate MMP2 gene expression and MMP2 activity in mesenchymal cells. Using mammary bud cultures, we demonstrated that MMP2 acts downstream of PTHrP to stimulate ductal outgrowth. Future studies on the functional role of other genes on this list should expand our knowledge of how PTHrP signaling triggers the onset of ductal outgrowth from the embryonic mammary buds. PMID:19795511

  11. Role of preoperative breast MRI in ductal carcinoma in situ for prediction of the presence and assessment of the extent of occult invasive component.

    PubMed

    Nori, Jacopo; Meattini, Icro; Giannotti, Elisabetta; Abdulcadir, Dalmar; Mariscotti, Giovanna; Calabrese, Massimo; Angelino, Francesca; Chiesa, Fabio; Saieva, Calogero; Vanzi, Ermanno; Boeri, Cecilia; Bianchi, Simonetta; Sanchez, Luis; Orzalesi, Lorenzo; Casella, Donato; Susini, Tommaso; Livi, Lorenzo

    2014-01-01

    Ductal carcinoma in situ (DCIS) is a common neoplasm that may be associated with focal invasive breast cancer lesions. The aim of our study was to evaluate the role of preoperative magnetic resonance imaging (MRI) in determining occult invasive presence and disease extent in patients with preoperative diagnosis of pure DCIS. We analyzed 125 patients with postoperative pure DCIS (n = 91) and DCIS plus invasive component (n = 34). Diagnostic mammography (MRX) showed a size underestimation rate of 30.4% while MRI showed an overestimation rate of 28.6%. Comparing the mean absolute error between preoperative MRI and MRX evaluations and final disease extent, MRI showed an improved accuracy of 51.2%. In our analysis preoperative breast MRI showed a better accuracy in predicting postoperative pathologic extent of disease, adding strength to the growing evidences that preoperative MRI can lead to a more appropriate management of DCIS patients. PMID:24750509

  12. Cyclooxygenase-2 expression is related to nuclear grade in ductal carcinoma in situ and is increased in its normal adjacent epithelium

    NASA Technical Reports Server (NTRS)

    Shim, Veronica; Gauthier, Mona L.; Sudilovsky, Daniel; Mantei, Kristin; Chew, Karen L.; Moore, Dan H.; Cha, Imok; Tlsty, Thea D.; Esserman, Laura J.

    2003-01-01

    Cyclooxygenase-2 (COX-2) is emerging as an important cancer biomarker and is now an experimental target for solid tumor treatment.However, no study has exclusively focused on COX-2 expression in early lesions such as ductal carcinoma in situ (DCIS). We examined COX-2 expression by immunohistochemistry in 46 cases of women undergoing surgical resection for DCIS. We found that COX-2 expression was detected in 85% of all DCIS specimens, with increased COX-2 staining correlating with higher nuclear grade. Strikingly, COX-2 staining intensity in the normal adjacent epithelium was stronger than in the DCIS lesion itself. Our observations demonstrate that COX-2 is up-regulated in the normal adjacent epithelium and supports the hypothesis that the surrounding epithelial tissue is part of the disease process in DCIS.

  13. Bilateral ductal carcinoma in situ of the breast after radiation therapy for Ewing's sarcoma of the vertebra in a young woman: report of a case.

    PubMed

    Keskek, Mehmet; Kilic, Mehmet; Ertan, Tamer; Erdem, Adnan; Yoldas, Omer

    2008-01-01

    Thoracic radiation in the early years of life is a known risk factor for breast cancer later in life. A 21-year-old woman who had received thoracic radiation therapy for Ewing's sarcoma of the vertebra 9 years earlier was referred to our hospital for investigation of a palpable mass in her left breast. Ultrasonography and excisional biopsy showed ductal carcinoma in situ (DCIS) of the left breast, with no detectable pathology in the right breast except that it was more hypoplastic than the left breast. Considering the known risk factors for invasive breast cancer in both breasts, we performed bilateral skin-sparing mastectomy with immediate breast reconstruction using subpectoral implants. The final histopathological diagnosis was bilateral DCIS. PMID:18668319

  14. K-Ras mutation-mediated IGF-1-induced feedback ERK activation contributes to the rapalog resistance in pancreatic ductal adenocarcinomas.

    PubMed

    Wei, Feng; Liu, Yan; Bellail, Anita C; Olson, Jeffrey J; Sun, Shi-Yong; Lu, Guoyue; Ding, Lijuan; Yuan, Changji; Wang, Guangyi; Hao, Chunhai

    2012-09-01

    Mammalian target of rapamycin complex 1 (mTORC1) is frequently activated in human cancers; however, clinical trials of rapalog (the mTORC1 inhibitors) have shown that pancreatic ductal adenocarcinomas (PDACs) resist to the treatment. Rapalog treatment activated the extracellular signal-regulated kinase (ERK) pathway in K-Ras mt PDAC cells. K-Ras knockdown abolished the insulin-like growth factor-1 (IGF-1)-induced ERK pathway in the K-Ras mt PDAC cells and enhanced the therapeutic efficacy of everolimus in treating K-Ras mt PDAC cells-derived mouse xenografts. The results indicate that targeting of K-Ras mutation may lead to the development of therapies that overcome rapalog resistance in PDAC.

  15. Gradual Telomere Shortening and Increasing Chromosomal Instability among PanIN Grades and Normal Ductal Epithelia with and without Cancer in the Pancreas

    PubMed Central

    Matsuda, Yoko; Ishiwata, Toshiyuki; Izumiyama-Shimomura, Naotaka; Hamayasu, Hideki; Fujiwara, Mutsunori; Tomita, Ken-ichiro; Hiraishi, Naoki; Nakamura, Ken-ichi; Ishikawa, Naoshi; Aida, Junko; Takubo, Kaiyo; Arai, Tomio

    2015-01-01

    A large body of evidence supports a key role for telomere dysfunction in carcinogenesis due to the induction of chromosomal instability. To study telomere shortening in precancerous pancreatic lesions, we measured telomere lengths using quantitative fluorescence in situ hybridization in the normal pancreatic duct epithelium, pancreatic intraepithelial neoplasias (PanINs), and cancers. The materials employed included surgically resected pancreatic specimens without cancer (n = 33) and with invasive ductal carcinoma (n = 36), as well as control autopsy cases (n = 150). In comparison with normal ducts, telomere length was decreased in PanIN-1, −2 and −3 and cancer. Furthermore, telomeres were shorter in cancer than in PanIN-1 and −2. Telomere length in cancer was not associated with histological type, lesion location, or cancer stage. PanINs with or without cancer showed similar telomere lengths. The incidences of atypical mitosis and anaphase bridges, which are morphological characteristics of chromosomal instability, were negatively correlated with telomere length. The telomeres in normal duct epithelium became shorter with aging, and those in PanINs or cancers were shorter than in age-matched controls, suggesting that telomere shortening occurs even when histological changes are absent. Our data strongly suggest that telomere shortening occurs in the early stages of pancreatic carcinogenesis and progresses with precancerous development. Telomere shortening and chromosomal instability in the duct epithelium might be associated with carcinogenesis of the pancreas. Determination of telomere length in pancreatic ductal lesions may be valuable for accurate detection and risk assessment of pancreatic cancer. PMID:25658358

  16. Metastatic ductal carcinoma of the breast to the thyroid gland diagnosed with fine needle aspiration: A case report with emphasis on morphologic and immunophenotypic features.

    PubMed

    Magers, Martin J; Dueber, Julie C; Lew, Madelyn; Pang, Judy C; Davenport, Robertson D

    2016-06-01

    Metastases to the thyroid are uncommon [<0.2% of thyroid fine needle aspirations (FNA)]. Of metastases to the thyroid, breast carcinoma is relatively common. The diagnosis of metastasis to the thyroid has important therapeutic and prognostic implications. To our knowledge, a morphologic and immunophenotypic comparison of metastatic ductal carcinoma of the breast and primary thyroid carcinomas has not been reported. Here, we report the case of a 37-year-old female with a history of metastatic ductal carcinoma of the breast (modified Bloom-Richardson grade 2; ER+, PgR+, HER2+) diagnosed 6 years prior. She developed hoarseness, prompting a CT scan. Multiple thyroid nodules were found, including a 1.5 cm hypoechoic, solid, irregularly-shaped nodule. On FNA, cells were arranged singly and in crowded groups, varied in size and degree of pleomorphism, and exhibited rare nuclear grooves, inconspicuous nucleoli, and rare intracytoplasmic lumina with no nuclear pseudoinclusions or colloid (Figs. 1A and B). These findings raised the differential of papillary thyroid carcinoma (Fig. 1C), follicular neoplasm (Fig. 1D), medullary carcinoma (Fig. 1E), parathyroid (Fig. 1F), and metastatic breast carcinoma. Immunostaining for GATA-3 (+), ER (+), PAX-8 (-), and TTF-1 (-) was consistent with metastatic breast carcinoma (Fig. 2). We conclude that metastatic breast carcinoma to the thyroid may morphologically mimic primary thyroid carcinoma on FNA; a panel of immunomarkers, such as GATA-3, hormonal marker(s), PAX-8, and TTF-1, may be useful in some cases. GATA-3 immunostaining for metastatic breast carcinoma was helpful in our case and has not been previously reported in a thyroid metastasis sampled by FNA. Diagn. Cytopathol. 2016;44:530-534. © 2016 Wiley Periodicals, Inc.

  17. Expression of CD151/Tspan24 and integrin alpha 3 complex in aid of prognostication of HER2-negative high-grade ductal carcinoma in situ

    PubMed Central

    Romanska, Hanna M; Potemski, Piotr; Kusinska, Renata; Kopczynski, Janusz; Sadej, Rafal; Kordek, Radzislaw

    2015-01-01

    The pro-tumorigenic and pro-metastatic functions of the tetraspanin protein CD151 (Tspan24) are thought to be dependent on its ability to form complexes with laminin-binding integrin receptors (i.e. alpha6beta1, alpha3beta1, alpha6beta4). We have previously reported that in invasive ductal carcinoma (IDC), CD151/alpha3beta1 complex was of prognostic value in patients with HER2-negative tumors. Extrapolating these findings to the pre-invasive setting, we aimed to make an assessment of a potential relationship between expression of the CD151/alpha3beta1 complex in DCIS and Van Nuys prognostic index (VNPI) in high-grade ductal carcinoma in situ (DCIS) in relation to the HER2 status. Protein distributions were analyzed in 49 samples of pure DCIS using immunohistochemistry. For each case immunoreactivity was assessed in at least 5 ducts (325 ducts in total) and an average score was taken for statistical analyses. When analyzed in the whole cohort, there was no statistical association between the VNPI and any of the proteins scored either separately or in combination. When stratified according to the HER2 status, in the HER2-negative subgroup, CD151 assessed in combination with alpha3beta1 was significantly correlated with VNPI (P = 0.044), while neither protein analyzed individually showed any significant link with the prognostic index. Expression of the CD151/alpha3beta1 complex in HER2-negative DCIS might reflect tumor behavior relevant to the patient outcome and thus might aid prognostication of the disease. PMID:26464707

  18. A Phase I Safety, Pharmacokinetic, and Pharmacodynamic Presurgical Trial of Vitamin E δ-tocotrienol in Patients with Pancreatic Ductal Neoplasia

    PubMed Central

    Springett, Gregory M.; Husain, Kazim; Neuger, Anthony; Centeno, Barbara; Chen, Dung-Tsa; Hutchinson, Tai Z.; Lush, Richard M.; Sebti, Saïd; Malafa, Mokenge P.

    2015-01-01

    Background Vitamin E δ-tocotrienol (VEDT), a natural vitamin E from plants, has shown anti-neoplastic and chemoprevention activity in preclinical models of pancreatic cancer. Here, we investigated VEDT in patients with pancreatic ductal neoplasia in a window-of-opportunity preoperative clinical trial to assess its safety, tolerability, pharmacokinetics, and apoptotic activity. Methods Patients received oral VEDT at escalating doses (from 200 to 3200 mg) daily for 13 days before surgery and one dose on the day of surgery. Dose escalation followed a three-plus-three trial design. Our primary endpoints were safety, VEDT pharmacokinetics, and monitoring of VEDT-induced neoplastic cell apoptosis (ClinicalTrials.gov number NCT00985777). Findings In 25 treated patients, no dose-limiting toxicity was encountered; thus no maximum-tolerated dose was reached. One patient had a drug-related adverse event (diarrhea) at a 3200-mg daily dose level. The effective half-life of VEDT was ~ 4 h. VEDT concentrations in plasma and exposure profiles were quite variable but reached levels that are bioactive in preclinical models. Biological activity, defined as significant induction of apoptosis in neoplastic cells as measured by increased cleaved caspase-3 levels, was seen in the majority of patients at the 400-mg to 1600-mg daily dose levels. Interpretation VEDT from 200 to 1600 mg daily taken orally for 2 weeks before pancreatic surgery was well tolerated, reached bioactive levels in blood, and significantly induced apoptosis in the neoplastic cells of patients with pancreatic ductal neoplasia. These promising results warrant further clinical investigation of VEDT for chemoprevention and/or therapy of pancreatic cancer. PMID:26844278

  19. Increased expression of CD146 and microvessel density (MVD) in invasive micropapillary carcinoma of the breast: Comparative study with invasive ductal carcinoma-not otherwise specified.

    PubMed

    Li, Weidong; Yang, Dongling; Wang, Shuling; Guo, Xiaojing; Lang, Ronggang; Fan, Yu; Gu, Feng; Zhang, Xinmin; Niu, Yun; Yan, Xiyun; Fu, Li

    2011-12-15

    Invasive micropapillary carcinoma (IMPC) is a rare variant of ductal carcinoma of the breast, and is characterized by a high metastatic potential and an aggressive clinical course. Studies of CD146 expression and function in breast cancer remain scarce. The aim of this study was to evaluate the role of CD146 and microvessel density (MVD) in breast IMPC. CD146 mRNA expression and immunohistochemistry for CD146 and MVD measured by CD31 were assessed in 82 cases of IMPC and 137 cases of invasive ductal carcinoma, not otherwise specified (IDC-NOS). The mRNA level of CD146 in cancer specimens was higher in IMPC than in IDC-NOS. CD146 expression in tumor cells was up-regulated in IMPC as compared with that in IDC-NOS, and was positively correlated with histological grade, ER, PR status, and P53 expression in IMPC and IDC-NOS. CD146 expression in vascular endothelial cells was significantly higher than that in IDC, and was positively correlated with tumor progression in IMPC and IDC-NOS. MVD in IMPC was significantly higher than that in IDC. CD146 expression in tumor cells was positively correlated with that in vascular endothelial cells of IMPC and IDC-NOS. The association of CD146 expression with MVD and its correlation with progression in breast carcinoma indicated that CD146 is a potentially useful prognostic marker for breast cancer. CD146 could be a new drug target in the treatment of breast cancer.

  20. Invasive ductal carcinomas of the breast showing partial reversed cell polarity are associated with lymphatic tumor spread and may represent part of a spectrum of invasive micropapillary carcinoma.

    PubMed

    Acs, Geza; Esposito, Nicole N; Rakosy, Zsuzsa; Laronga, Christine; Zhang, Paul J

    2010-11-01

    Invasive micropapillary carcinomas (IMPC) of the breast are aggressive tumors frequently associated with lymphatic invasion and nodal metastasis even when micropapillary (MP) differentiation is very focal within the tumors. We have noticed that some breast carcinomas showing lymphatic spread but lacking histologic features of IMPC have occasional tumor cell clusters reminiscent of those of IMPC without the characteristic prominent retraction artifact. To study the clinicopathologic significance of such features, we prospectively selected 1323 invasive ductal carcinomas and determined the presence and extent of MP differentiation and retraction artifact in the tumors. One representative tumor block per case was used for immunostaining for epithelial membrane antigen (EMA). Partial reverse cell polarity (PRCP) was defined as prominent linear EMA reactivity on at least part of the periphery of tumor cell clusters usually associated with decreased cytoplasmic staining. The clinicopathologic features of carcinomas with PRCP were compared with IMPC and invasive ductal (no special type) carcinomas without this feature. Of the 1323 cases, 96 (7.3%) and 92 (7.0%) showed MP features and the presence of PRCP, respectively. We found that the presence of both PRCP and MP features were strongly associated with decreased cytoplasmic EMA immunoreactivity and the presence of lymphatic invasion and nodal metastasis, even if such features were present only very focally. Our results suggest that breast carcinomas with PRCP may have the same implication as MP differentiation and these tumors may represent part of a spectrum of IMPC. Complete or partial reversal of cell polarity may play a significant role in lymphatic tumor spread.

  1. Genomic and mutational profiling of ductal carcinomas in situ and matched adjacent invasive breast cancers reveals intra-tumour genetic heterogeneity and clonal selection

    PubMed Central

    Lambros, Maryou B; Campion-Flora, Adriana; Rodrigues, Daniel Nava; Gauthier, Arnaud; Cabral, Cecilia; Pawar, Vidya; Mackay, Alan; A’Hern, Roger; Marchiò, Caterina; Palacios, Jose; Natrajan, Rachael; Weigelt, Britta; Reis-Filho, Jorge S

    2016-01-01

    The mechanisms underlying the progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) of the breast are yet to be fully elucidated. Several hypotheses have been put forward to explain the progression from DCIS to IDC, including the selection of a subpopulation of cancer cells with specific genetic aberrations, the acquisition of new genetic aberrations or non-genetic mechanisms mediated by the tumour microenvironment. To determine whether synchronously diagnosed ipsilateral DCIS and IDCs have modal populations with distinct repertoires of gene copy number aberrations and mutations in common oncogenes, matched frozen samples of DCIS and IDCs were retrieved from 13 patients and subjected to microarray-based comparative genomic hybridisation (aCGH), and Sequenom MassARRAY (Oncocarta v1.0 panel). Fluorescence in situ hybridisation and Sanger sequencing were employed to validate the aCGH and Sequenom findings, respectively. Although the genomic profiles of matched DCIS and IDCs were similar, in three of 13 matched pairs amplification of distinct loci (i.e. 1q41, 2q24.2, 6q22.31, 7q11.21, 8q21.2 and 9p13.3) was either restricted to, or more prevalent in, the modal population of cancer cells of one of the components. Sequenom MassARRAY identified PIK3CA mutations restricted to the DCIS component in two cases, and in a third case, the frequency of the PIK3CA mutant allele reduced from 49% in the DCIS to 25% in the IDC component. Despite the genomic similarities between synchronous DCIS and IDC, our data provide strong circumstantial evidence to suggest that in some cases the progression from DCIS to IDC is driven by the selection of non-modal clones that harbour a specific repertoire of genetic aberrations. PMID:22252965

  2. GPRC5A is a potential oncogene in pancreatic ductal adenocarcinoma cells that is upregulated by gemcitabine with help from HuR.

    PubMed

    Zhou, H; Telonis, A G; Jing, Y; Xia, N L; Biederman, L; Jimbo, M; Blanco, F; Londin, E; Brody, J R; Rigoutsos, I

    2016-01-01

    GPRC5A is an orphan G-protein coupled receptor with an intriguing dual behavior, acting as an oncogene in some cancers and as a tumor suppressor in other cancers. In the pancreatic cancer context, very little is known about GPRC5A. By analyzing messenger RNA (mRNA) expression data from 675 human cancer cell lines and 10 609 samples from The Cancer Genome Atlas (TCGA) we found that GPRC5A's abundance in pancreatic cancer is highest (cell lines) or second highest (TCGA) among all tissues and cancer types. Further analyses of an independent set of 252 pancreatic normal and cancer samples showed GPRC5A mRNA to be more than twofold upregulated in primary tumor samples compared with normal pancreas (P-value<10(-5)), and even further upregulated in pancreatic cancer metastases to various organs (P-value=0.0021). Immunostaining of 208 cores (103 samples) of a tissue microarray showed generally low expression of GPRC5A protein in normal pancreatic ductal cells; on the other hand, in primary and metastatic samples, GPRC5A protein levels were dramatically increased in pancreatic ductal cells. In vitro studies of multiple pancreatic cancer cell lines showed that an increase in GPRC5A protein levels promoted pancreatic cancer cell growth and migration. Unexpectedly, when we treated pancreatic cancer cell lines with gemcitabine (2',2'-difluorodeoxycytidine), we observed an increase in GPRC5A protein abundance. On the other hand, when we knocked down GPRC5A we sensitized pancreatic cancer cells to gemcitabine. Through further experimentation we showed that the monotonic increase in GPRC5A protein levels that we observe for the first 18 h following gemcitabine treatment results from interactions between GPRC5A's mRNA and the RNA-binding protein HuR, which is an established key mediator of gemcitabine's efficacy in cancer cells. As we discovered, the interaction between GPRC5A and HuR is mediated by at least one HuR-binding site in GPRC5A's mRNA. Our findings indicate that GPRC

  3. GPRC5A is a potential oncogene in pancreatic ductal adenocarcinoma cells that is upregulated by gemcitabine with help from HuR.

    PubMed

    Zhou, H; Telonis, A G; Jing, Y; Xia, N L; Biederman, L; Jimbo, M; Blanco, F; Londin, E; Brody, J R; Rigoutsos, I

    2016-07-14

    GPRC5A is an orphan G-protein coupled receptor with an intriguing dual behavior, acting as an oncogene in some cancers and as a tumor suppressor in other cancers. In the pancreatic cancer context, very little is known about GPRC5A. By analyzing messenger RNA (mRNA) expression data from 675 human cancer cell lines and 10 609 samples from The Cancer Genome Atlas (TCGA) we found that GPRC5A's abundance in pancreatic cancer is highest (cell lines) or second highest (TCGA) among all tissues and cancer types. Further analyses of an independent set of 252 pancreatic normal and cancer samples showed GPRC5A mRNA to be more than twofold upregulated in primary tumor samples compared with normal pancreas (P-value<10(-5)), and even further upregulated in pancreatic cancer metastases to various organs (P-value=0.0021). Immunostaining of 208 cores (103 samples) of a tissue microarray showed generally low expression of GPRC5A protein in normal pancreatic ductal cells; on the other hand, in primary and metastatic samples, GPRC5A protein levels were dramatically increased in pancreatic ductal cells. In vitro studies of multiple pancreatic cancer cell lines showed that an increase in GPRC5A protein levels promoted pancreatic cancer cell growth and migration. Unexpectedly, when we treated pancreatic cancer cell lines with gemcitabine (2',2'-difluorodeoxycytidine), we observed an increase in GPRC5A protein abundance. On the other hand, when we knocked down GPRC5A we sensitized pancreatic cancer cells to gemcitabine. Through further experimentation we showed that the monotonic increase in GPRC5A protein levels that we observe for the first 18 h following gemcitabine treatment results from interactions between GPRC5A's mRNA and the RNA-binding protein HuR, which is an established key mediator of gemcitabine's efficacy in cancer cells. As we discovered, the interaction between GPRC5A and HuR is mediated by at least one HuR-binding site in GPRC5A's mRNA. Our findings indicate that GPRC

  4. GPRC5A is a potential oncogene in pancreatic ductal adenocarcinoma cells that is upregulated by gemcitabine with help from HuR

    PubMed Central

    Zhou, H; Telonis, A G; Jing, Y; Xia, N L; Biederman, L; Jimbo, M; Blanco, F; Londin, E; Brody, J R; Rigoutsos, I

    2016-01-01

    GPRC5A is an orphan G-protein coupled receptor with an intriguing dual behavior, acting as an oncogene in some cancers and as a tumor suppressor in other cancers. In the pancreatic cancer context, very little is known about GPRC5A. By analyzing messenger RNA (mRNA) expression data from 675 human cancer cell lines and 10 609 samples from The Cancer Genome Atlas (TCGA) we found that GPRC5A's abundance in pancreatic cancer is highest (cell lines) or second highest (TCGA) among all tissues and cancer types. Further analyses of an independent set of 252 pancreatic normal and cancer samples showed GPRC5A mRNA to be more than twofold upregulated in primary tumor samples compared with normal pancreas (P-value<10−5), and even further upregulated in pancreatic cancer metastases to various organs (P-value=0.0021). Immunostaining of 208 cores (103 samples) of a tissue microarray showed generally low expression of GPRC5A protein in normal pancreatic ductal cells; on the other hand, in primary and metastatic samples, GPRC5A protein levels were dramatically increased in pancreatic ductal cells. In vitro studies of multiple pancreatic cancer cell lines showed that an increase in GPRC5A protein levels promoted pancreatic cancer cell growth and migration. Unexpectedly, when we treated pancreatic cancer cell lines with gemcitabine (2′,2′-difluorodeoxycytidine), we observed an increase in GPRC5A protein abundance. On the other hand, when we knocked down GPRC5A we sensitized pancreatic cancer cells to gemcitabine. Through further experimentation we showed that the monotonic increase in GPRC5A protein levels that we observe for the first 18 h following gemcitabine treatment results from interactions between GPRC5A's mRNA and the RNA-binding protein HuR, which is an established key mediator of gemcitabine's efficacy in cancer cells. As we discovered, the interaction between GPRC5A and HuR is mediated by at least one HuR-binding site in GPRC5A's mRNA. Our findings indicate that

  5. Chromosome 1 aneusomy with 1p36 under-representation is related to histologic grade, DNA aneuploidy, high c-erb B-2 and loss of bcl-2 expression in ductal breast carcinoma.

    PubMed

    Farabegoli, F; Ceccarelli, C; Santini, D; Trerè, D; Baldini, N; Taffurelli, M; Derenzini, M

    1996-10-21

    Chromosome 1 abnormalities with loss of 1p36 have been investigated in 95 breast-cancer samples by means of a dual-target fluorescence in-situ hybridization (FISH) technique using the pUC 1.77 and p1-79 probes, specific for the 1q12 and 1p36 regions, respectively. Abnormalities for one or both probes were detected in 83/95 samples. Relative 1p36 under-representation was found in 79/95. The clinical relevance of these alterations was studied by comparing the FISH results with several parameters currently used in breast-cancer pathology. Distinct patterns of chromosome 1 abnormalities were found among the histologic types of breast carcinoma. Lobular or mucinous samples showed few or no alterations, whereas most ductal samples had high chromosome 1 polysomy with under-representation of 1p36. In ductal carcinomas, chromosome 1 alterations increased with histologic grade, DNA aneuploidy, loss of bcl-2 and high c-erb B-2 expression. These associations were found to be statistically significant. No correlation between chromosome 1 alterations and nuclear grade, age, size, lymph-node involvement, hormonal receptor presence, proliferation activity or p53 protein expression was detected. These results indicate the utility of this FISH technique for a better definition of the biological characteristics of ductal carcinomas.

  6. Polycomb repressor complex 1 promotes gene silencing through H2AK119 mono-ubiquitination in acinar-to-ductal metaplasia and pancreatic cancer cells

    PubMed Central

    Reinhard, Tobias; Popp, Anna; Schäffer, Isabell; Raulefs, Susanne; Kong, Bo; Esposito, Irene

    2016-01-01

    Acinar-to-ductal metaplasia (ADM) occurring in cerulein-mediated pancreatitis or in oncogenic Kras-driven pancreatic cancer development is accompanied by extensive changes in the transcriptional program. In this process, acinar cells shut down the expression of acinar specific differentiation genes and re-express genes usually found in embryonic pancreatic progenitor cells. Previous studies have demonstrated that a loss of acinar-specific transcription factors sensitizes the cells towards oncogenic transformation, ultimately resulting in cancer development. However, the mechanism behind the transcriptional silencing of acinar cell fate genes in ADM and pancreatic cancer is largely unknown. Here, we analyzed whether elevated levels of the polycomb repressor complex 1 (PRC1) components Bmi1 and Ring1b and their catalyzed histone modification H2AK119ub in ADMs and tumor cells, are responsible for the mediation of acinar gene silencing. Therefore, we performed chromatin-immunoprecipitation in in vitro generated ADMs and isolated murine tumor cells against the repressive histone modifications H3K27me3 and H2AK119ub. We established that the acinar transcription factor complex Ptf1-L is epigenetically silenced in ADMs as well as in pancreatic tumor cells. For the first time, this work presents a possible mechanism of acinar gene silencing, which is an important prerequisite in the initiation and maintenance of a dedifferentiated cell state in ADMs and tumor cells. PMID:26716510

  7. The Polycomb group protein RING1B is overexpressed in ductal breast carcinoma and is required to sustain FAK steady state levels in breast cancer epithelial cells

    PubMed Central

    Bosch, Almudena; Panoutsopoulou, Konstantina; Corominas, Josep Maria; Gimeno, Ramón; Moreno-Bueno, Gema; Martín-Caballero, Juan; Morales, Saleta; Lobato, Tania; Martínez-Romero, Carles; Farias, Eduardo F.; Mayol, Xavier; Cano, Amparo; Hernández-Muáoz, Inmaculada

    2014-01-01

    In early stages of metastasis malignant cells must acquire phenotypic changes to enhance their migratory behavior and their ability to breach the matrix surrounding tumors and blood vessel walls. Epigenetic regulation of gene expression allows the acquisition of these features that, once tumoral cells have escape from the primary tumor, can be reverted. Here we report that the expression of the Polycomb epigenetic repressor Ring1B is enhanced in tumoral cells that invade the stroma in human ductal breast carcinoma and its expression is coincident with that of Fak in these tumors. Ring1B knockdown in breast cancer cell lines revealed that Ring1B is required to sustain Fak expression in basal conditions as well as in Tgfβ-treated cells. Functionally, endogenous Ring1B is required for cell migration and invasion in vitro and for in vivo invasion of the mammary fat pad by tumoral cells. Finally we identify p63 as a target of Ring1B to regulate Fak expression: Ring1B depletion results in enhanced p63 expression, which in turns represses Fak expression. Importantly, Fak downregulation upon Ring1B depletion is dependent on p63 expression. Our findings provide new insights in the biology of the breast carcinoma and open new avenues for breast cancer prognosis and therapy. PMID:24742605

  8. Antibody-based targeting of alternatively spliced tissue factor: a new approach to impede the primary growth and spread of pancreatic ductal adenocarcinoma

    PubMed Central

    Unruh, Dusten; Ünlü, Betül; Lewis, Clayton S.; Qi, Xiaoyang; Chu, Zhengtao; Sturm, Robert; Keil, Ryan; Ahmad, Syed A.; Sovershaev, Timofey; Adam, Mariette; Van Dreden, Patrick; Woodhams, Barry J.; Ramchandani, Divya; Weber, Georg F.; Rak, Janusz W.; Wolberg, Alisa S.; Mackman, Nigel; Versteeg, Henri H.; Bogdanov, Vladimir Y.

    2016-01-01

    Alternatively spliced Tissue Factor (asTF) is a secreted form of Tissue Factor (TF), the trigger of blood coagulation whose expression levels are heightened in several forms of solid cancer, including pancreatic ductal adenocarcinoma (PDAC). asTF binds to β1 integrins on PDAC cells, whereby it promotes tumor growth, metastatic spread, and monocyte recruitment to the stroma. In this study, we determined if targeting asTF in PDAC would significantly impact tumor progression. We here report that a novel inhibitory anti-asTF monoclonal antibody curtails experimental PDAC progression. Moreover, we show that tumor-derived asTF is able to promote PDAC primary growth and spread during early as well as later stages of the disease. This raises the likelihood that asTF may comprise a viable target in early- and late-stage PDAC. In addition, we show that TF expressed by host cells plays a significant role in PDAC spread. Together, our data demonstrate that targeting asTF in PDAC is a novel strategy to stem PDAC progression and spread. PMID:26967388

  9. Cholangio-venous reflux as a cause of recurrent hyperamylasemia in choledochal dilatation with anomalous pancreaticobiliary ductal union: an experimental study.

    PubMed

    Ohkawa, H; Sawaguchi, S; Khalil, B; Ishikawa, A; Yamazaki, Y

    1985-02-01

    Cylindrical choledochal dilatation, associated with anomalous pancreaticobiliary ductal union, causes recurrent episodes of right hypochondrial pain, vomiting, and fever. The symptoms are very often accompanied by hyperamylasemia, which is generally considered to be due to acute pancreatitis. However, our clinical experience and experimental studies have led us to the conclusion that pancreatitis is not the sole cause of hyperamylasemia. In this paper we report our further investigations of the cause of the hyperamylasemia. In 22 mongrel adult dogs, intracholedochal infusion was performed under a continuous hydrostatic pressure of 20 cm H2O for 2 hours. Solutions of amylase from three different sources and a lipase were used in the range of concentrations found clinically in the bile within a cylindrical choledochal dilatation. In the 3 groups, hyperamylasemia was proven by quantitative estimation of serum amylase level and/or by the changes in specific amylase isozymes. Lipase was also shown to transfer into the blood stream. In an additional experiment on 5 dogs, only the extrahepatic biliary tree, including the gallbladder, was infused with a solution of amylase from Bacillus subtilis. This produced no increase in the serum amylase. Our experiments suggest that amylase passes from the hepatocholedochal system into the blood stream. This phenomenon has long been known as cholangiovenous reflux.

  10. Targeted Delivery of C/EBPα -saRNA by Pancreatic Ductal Adenocarcinoma-specific RNA Aptamers Inhibits Tumor Growth In Vivo

    PubMed Central

    Yoon, Sorah; Huang, Kai-Wen; Reebye, Vikash; Mintz, Paul; Tien, Yu-Wen; Lai, Hong-Shiee; Sætrom, Pål; Reccia, Isabella; Swiderski, Piotr; Armstrong, Brian; Jozwiak, Agnieszka; Spalding, Duncan; Jiao, Long; Habib, Nagy; Rossi, John J

    2016-01-01

    The 5-year survival rate for pancreatic ductal adenocarcinoma (PDAC) remains dismal despite current chemotherapeutic agents and inhibitors of molecular targets. As the incidence of PDAC constantly increases, more effective multidrug approaches must be made. Here, we report a novel method of delivering antitumorigenic therapy in PDAC by upregulating the transcriptional factor CCAAT/enhancer-binding protein-α (C/EBPα), recognized for its antiproliferative effects. Small activating RNA (saRNA) duplexes designed to increase C/EBPα expression were linked onto PDAC-specific 2′-Fluropyrimidine RNA aptamers (2′F-RNA) - P19 and P1 for construction of a cell type–specific delivery vehicle. Both P19- and P1-C/EBPα-saRNA conjugates increased expression of C/EBPα and significantly suppressed cell proliferation. Tail vein injection of the saRNA/aptamer conjugates in PANC-1 and in gemcitabine-resistant AsPC-1 mouse-xenografts led to reduced tumor size with no observed toxicity. To exploit the specificity of the P19/P1 aptamers for PDAC cells, we also assessed if conjugation with Cy3 would allow it to be used as a diagnostic tool on archival human pancreatic duodenectomy tissue sections. Scoring pattern from 72 patients suggested a positive correlation between high fluorescent signal in the high mortality patient groups. We propose a novel aptamer-based strategy for delivery of targeted molecular therapy in advanced PDAC where current modalities fail. PMID:26983359

  11. Large, central acellular zones indicating myoepithelial tumor differentiation in high-grade invasive ductal carcinomas as markers of predisposition to lung and brain metastases.

    PubMed

    Tsuda, H; Takarabe, T; Hasegawa, F; Fukutomi, T; Hirohashi, S

    2000-02-01

    High-grade invasive ductal carcinomas (IDCs) of the breast with large, central acellular zones on their cut surfaces are usually associated with the myoepithelial immunophenotype of carcinoma cells, which includes the expression of S-100 protein, alpha-smooth muscle actin, and keratin 14. To clarify the clinical significance of these features of IDCs, the authors compared the incidence of the myoepithelial immunophenotype immunohistochemically, patient prognosis, and metastatic sites of the tumor between 20 high-grade IDCs with large, central acellular zones and 40 control high-grade IDCs without these zones. The myoepithelial immunophenotype was detected in 16 IDCs (80%) with large, central acellular zones but in only seven IDCs (18%) without. The risk ratio of metastasis, especially in the brain and lung, and death from cancer were significantly higher (p = 0.0096 and p = 0.030) for the 20 IDCs with large, central acellular zones than for those without by Cox's univariate analysis. Using Cox's multivariate analysis, large, central acellular zones in IDCs were an indicator of high risk of brain and lung metastases and of death by cancer independent of nodal status and tumor size. Examination of large, central acellular zones and myoepithelial immunophenotype in high-grade IDCs appears helpful in predicting patient prognosis and preferential metastatic sites of the tumors.

  12. OSI-027 inhibits pancreatic ductal adenocarcinoma cell proliferation and enhances the therapeutic effect of gemcitabine both in vitro and in vivo.

    PubMed

    Zhi, Xiao; Chen, Wei; Xue, Fei; Liang, Chao; Chen, Bryan Wei; Zhou, Yue; Wen, Liang; Hu, Liqiang; Shen, Jian; Bai, Xueli; Liang, Tingbo

    2015-09-22

    Despite its relative rarity, pancreatic ductal adenocarcinoma (PDAC) accounts for a large percentage of cancer deaths. In this study, we investigated the in vitro efficacy of OSI-027, a selective inhibitor of mammalian target of rapamycin complex 1 (mTORC1) and mTORC2, to treat PDAC cell lines alone, and in combination with gemcitabine (GEM). Similarly, we tested the efficacy of these two compounds in a xenograft mouse model of PDAC. OSI-027 significantly arrested cell cycle in G0/G1 phase, inhibited the proliferation of Panc-1, BxPC-3, and CFPAC-1 cells, and downregulated mTORC1, mTORC2, phospho-Akt, phospho-p70S6K, phospho-4E-BP1, cyclin D1, and cyclin-dependent kinase 4 (CDK4) in these cells. Moreover, OSI-027 also downregulated multidrug resistance (MDR)-1, which has been implicated in chemotherapy resistance in PDAC cells and enhanced apoptosis induced by GEM in the three PDAC cell lines. When combined, OSI-027 with GEM showed synergistic cytotoxic effects both in vitro and in vivo. This is the first evidence of the efficacy of OSI-027 in PDAC and may provide the groundwork for a new clinical PDAC therapy. PMID:26213847

  13. Ductal branch-oriented pancreatic resection for an intraductal papillary mucinous neoplasm in the uncinate process that caused recurrent acute pancreatitis: a case report of successful treatment.

    PubMed

    Natsume, Toshiyuki; Maruyama, Takashi; Kobayashi, Akitoshi; Shimizu, Shinichiro; Tanaka, Hajime; Matsuzaki, Hiroshi; Miyazaki, Akinari; Ohta, Takumi; Sato, Yayoi; Yamamoto, Yuji; Aikawa, Mizuho; Otsuka, Ryota; Yanagihara, Akitoshi

    2013-12-01

    Acute pancreatitis reportedly occurs in about 15 % of cases of branch duct (BD)-intraductal papillary mucinous neoplasms (IPMNs), with two-thirds of BD-IPMNs being located in the head or uncinate process of the pancreas. However, the surgical indications and optimal treatment methods for BD-IPMNs have not been established. A 59-year-old Japanese male with epigastralgia was admitted to our hospital. A multidetector row computed tomography (MDCT) scan disclosed grade I acute pancreatitis. Magnetic resonance cholangiopancreatography disclosed a 1.5-cm BD-IPMN in the uncinate process. Two months after discharge, the epigastralgia recurred, and MDCT again revealed grade I pancreatitis. Due to the repeated episodes of pancreatitis, we performed ductal branch-oriented pancreatic resection. To detect the inferior branch of the Wirsung duct and avoid the development of a pancreatic fistula, we injected indigo carmine into the tumor which confirmed ligation of the inferior branch. Histopathologically, the tumor proved to be an adenoma. The postoperative course was uneventful in both the short- and long-term follow-up and, to date, there has been no recurrence of pancreatitis, or diabetes mellitus during the 6 years since pancreatectomy. This procedure is one of the methods that can be used for the successful resection of a BD-IPMN in the uncinate process that caused recurrent acute pancreatitis.

  14. Effective treatment of ductal carcinoma in situ with a HER-2- targeted alpha-particle emitting radionuclide in a preclinical model of human breast cancer.

    PubMed

    Yoshida, Takahiro; Jin, Kideok; Song, Hong; Park, Sunju; Huso, David L; Zhang, Zhe; Liangfeng, Han; Zhu, Charles; Bruchertseifer, Frank; Morgenstern, Alfred; Sgouros, George; Sukumar, Saraswati

    2016-05-31

    The standard treatment for ductal carcinoma in situ (DCIS) of the breast is surgical resection, followed by radiation. Here, we tested localized therapy of DCIS in mice using the immunoconjugate 225Ac linked-trastuzumab delivered through the intraductal (i.duc) route. Trastuzumab targets HER-2/neu, while the alpha-emitter 225Ac (half-life, 10 days) delivers highly cytotoxic, focused doses of radiation to tumors. Systemic 225Ac, however, elicits hematologic toxicity and at high doses free 213Bi, generated by its decay, causes renal toxicity. I.duc delivery of the radioimmunoconjugate could bypass its systemic toxicity. Bioluminescent imaging showed that the therapeutic efficacy of intraductal 225Ac-trastuzumab (10-40 nCi per mammary gland; 30-120 nCi per mouse) in a DCIS model of human SUM225 cancer cells in NSG mice was significantly higher (p<0.0003) than intravenous (120 nCi per mouse) administration, with no kidney toxicity or loss of body weight. Our findings suggest that i.duc radioimmunotherapy using 225Ac-trastuzumab deserves greater attention for future clinical development as a treatment modality for early breast cancer.

  15. D-dopachrome tautomerase is over-expressed in pancreatic ductal adenocarcinoma and acts cooperatively with macrophage migration inhibitory factor to promote cancer growth.

    PubMed

    Guo, Dawei; Guo, Jinshuai; Yao, Junchao; Jiang, Kun; Hu, Jianhua; Wang, Bo; Liu, Haiyang; Lin, Lin; Sun, Wenyu; Jiang, Xiaofeng

    2016-11-01

    Previous studies have established the important role of MIF in the development of pancreatic ductal adenocarcinoma (PDAC) for both therapeutic and diagnostic perspectives, but little is known about the expression and function of D-dopachrome tautomerase (DDT), a functional homolog of MIF, in PDAC. In the present study, we demonstrated that DDT was over-expressed in PDAC tissues in a pattern correlated with MIF. In the pancreatic cancer cell lines, PANC-1, BXPC-3 and ASPC-1, both DDT and MIF were expressed and co-localized with each other in the endosomal compartments and plasma membrane. Knockdown of DDT and MIF in PANC-1 cells cooperatively inhibited ERK1/2 and AKT phosphorylation, increased p53 expression, and reduced cell proliferation, invasion and tumor formation. These effects were rescued by the re-expression of MIF or DDT, but not by the forced expression of the tautomerase-deficient mutants of DDT and MIF, P1G-DDT and P1G-MIF. Finally, we observed that 4-iodo-6-phenylpyrimidine (4-IPP), a covalent tautomerase inhibitor of both DDT and MIF, attenuated PANC-1 cell proliferation and colony formation in vitro and tumor growth in vivo. Thus, targeting the tautomerase sites of both MIF and DDT may offer more efficient therapeutic benefits to PDAC patients. PMID:27434219

  16. Genomic characterization of patient-derived xenograft models established from fine needle aspirate biopsies of a primary pancreatic ductal adenocarcinoma and from patient-matched metastatic sites

    PubMed Central

    de Abreu, Francine B.; Gardner, Timothy B.; Gordon, Stuart R.; Barth, Richard J.; Colacchio, Thomas A.; Wood, Matthew; Kacsoh, Balint Z.; Bouley, Stephanie J.; Cui, Jingxuan; Hamilton, Joanna; Choi, Jungbin A.; Lange, Joshua T.; Peterson, Jason D.; Padmanabhan, Vijayalakshmi; Tomlinson, Craig R.; Tsongalis, Gregory J.; Suriawinata, Arief A.; Smith, Kerrington D.

    2016-01-01

    N-of-1 trials target actionable mutations, yet such approaches do not test genomically-informed therapies in patient tumor models prior to patient treatment. To address this, we developed patient-derived xenograft (PDX) models from fine needle aspiration (FNA) biopsies (FNA-PDX) obtained from primary pancreatic ductal adenocarcinoma (PDAC) at the time of diagnosis. Here, we characterize PDX models established from one primary and two metastatic sites of one patient. We identified an activating KRAS G12R mutation among other mutations in these models. In explant cells derived from these PDX tumor models with a KRAS G12R mutation, treatment with inhibitors of CDKs (including CDK9) reduced phosphorylation of a marker of CDK9 activity (phospho-RNAPII CTD Ser2/5) and reduced viability/growth of explant cells derived from PDAC PDX models. Similarly, a CDK inhibitor reduced phospho-RNAPII CTD Ser2/5, increased apoptosis, and inhibited tumor growth in FNA-PDX and patient-matched metastatic-PDX models. In summary, PDX models can be constructed from FNA biopsies of PDAC which in turn can enable genomic characterization and identification of potential therapies. PMID:26934555

  17. A comparison of quality of life, disease impact and risk perception in women with invasive breast cancer and ductal carcinoma in situ.

    PubMed

    van Gestel, Y R B M; Voogd, A C; Vingerhoets, A J J M; Mols, F; Nieuwenhuijzen, G A P; van Driel, O J Repelaer; van Berlo, C L H; van de Poll-Franse, L V

    2007-02-01

    We compared the health-related quality of life, impact of the disease, risk perception of recurrence and dying of breast cancer, and understanding of diagnosis of patients with ductal carcinoma in situ (DCIS) and invasive breast cancer 2-3 years after treatment. We included all women (N=211) diagnosed with DCIS or invasive breast cancer TNM stage I (T1, N0, and M0) in three community hospitals in the southern part of The Netherlands in the period 2002-2003. After verifying the medical files, 180 disease free patients proved eligible for study entry, 47 of whom had DCIS and 133 stage I invasive breast cancer. One-hundred and thirty-five patients returned a completed questionnaire (75% response). No significant differences were found between women with DCIS and invasive breast cancer on the physical and mental component scale of the RAND SF-36, nor on the WHO-5, which assesses well-being. In contrast, women with DCIS reportedly had a better physical health, better sex life and better relationships with friends/acquaintances than women with invasive breast cancer. Despite their better prognosis, the DCIS-group had comparable perceptions of the risk of recurrence and dying of breast cancer as women with invasive breast cancer. However, this did not appear to affect their well-being significantly.

  18. Regulation of the fetal mouse ductus arteriosus is dependent on interaction of nitric oxide and COX enzymes in the ductal wall

    PubMed Central

    Reese, Jeff; O’Mara, Patrick W.; Poole, Stanley D.; Brown, Naoko; Tolentino, Chelsea; Eckman, Delrae M.; Aschner, Judy L.

    2009-01-01

    Nitric oxide (NO) and cyclooxygenase (COX)-derived prostaglandins are critical regulators of the fetal ductus arteriosus. To examine the interaction of these pathways within the ductus wall, the ductus arteriosus of term and preterm fetal mice was evaluated by pressurized myography. The isolated preterm ductus was more sensitive to NOS inhibition than at term. Sequential NOS and COX inhibition caused 36% constriction of the preterm ductus regardless of drug order. In contrast, constriction of the term ductus was dependent on the sequence of inhibition; NOS inhibition prior to COX inhibition produced greater constriction than when inhibitors were given in reverse order (36±6% versus 23±5%). Selective COX-1 or COX-2 inhibition prior to L-NAME induced the expected degree of constriction. However, NOS inhibition followed by selective COX-2 inhibition caused unexpected ductal dilation. These findings are consistent with NO-induced activation of COX in the ductus arteriosus wall and the production of a COX-2-derived constrictor prostanoid that contributes to the balance of vasoactive forces that maintain fetal ductus arteriosus tone. PMID:19049898

  19. Clinical implications for loss or diminution of expression of Raf-1 kinase inhibitory protein and its phosphorylated form in ductal breast cancer

    PubMed Central

    Al-Mulla, Fahd; Bitar, Milad S; Thiery, Jean Paul; Zea, Tan Tuan; Chatterjee, Devasis; Bennett, Lindsay; Park, Sungdae; Edwards, Joanne; Yeung, Kam C

    2013-01-01

    Raf Kinase inhibitory protein (RKIP) is a well-established metastasis suppressor that is frequently downregulated in aggressive cancers. The impact of RKIP and its phosphorylated form on disease-free survival (DFS) and other clinicopathological parameters in breast cancer is yet to be discovered. To this end, we examined RKIP expression in 3 independent breast cancer cohorts. At the Protein level, loss or reduced total RKIP expression was associated with large-sized tumors characterized by high proliferative index, high-grade and diminished estrogen (ER) and progesterone receptor expression. Loss or diminution of RKIP expression was significantly associated with shorter DFS in all cohorts. Moreover, the complete loss of p-RKIP was an independent prognostic factor using multivariate analysis in operable invasive ductal breast cancer. We show for the first time that ER, partly, drives RKIP expression through MTA3-Snail axis. Consistent with this finding, we found that, at the mRNA level, RKIP expression varied significantly across the different molecular subtypes of breast cancer with the Luminal (ER+) subtype expressing high levels of RKIP and the more aggressive Claudin-low (ER-) subtype, which depicted the highest epithelial to mesenchymal transition (EMT) registered the lowest RKIP expression levels. In conclusion, loss of expression/diminution of RKIP or its phosphorylated form is associated with poor diseases-free survival in breast cancer. Determining the expression of RKIP and p-RKIP adds significant prognostic value to the management and subtyping of this disease. PMID:24224123

  20. Three-Dimensional Assessment of Automated Breast Volume Scanner Compared with Handheld Ultrasound in Pre-Operative Breast Invasive Ductal Carcinomas: A Pilot Study of 51 Cases.

    PubMed

    Xu, Chaoli; Wei, Shuping; Xie, Yingdong; Guan, Xiaoxiang; Yang, Bin

    2016-09-01

    The aim of the work described here was to compare the accuracy of conventional handheld ultrasound (HHUS) with that of an automated breast volume scanner (ABVS) in 3-D assessment of pre-operative invasive ductal carcinomas. HHUS and ABVS were used in 51 patients to obtain the largest tumor diameter, tumor volume and tumor surface area. The volumetric measurement was also obtained from ABVS data with medical software. With tumor size and volume on pathology as the gold standard, Bland-Altman analysis was used to compare variability. Correlation coefficients and receiver operating characteristic curves were established for all measurements for T2 classification. The correlation coefficients of all ABVS measurements were stronger than those of HHUS measurements, with the ABVS volumetric measurement significantly different with a higher accuracy of 88.24% (45/51) and predicting T-classification with higher area under the receiver operating characteristic curves (0.936). Therefore, 3-D measurements provide stronger correlations with pathology in tumor size measurement. However, more clinical trials are needed to confirm our findings.

  1. Difference in characteristics and outcomes between medullary breast carcinoma and invasive ductal carcinoma: a population based study from SEER 18 database

    PubMed Central

    Li, Jun-Jing; Song, Chuan-Gui; Shao, Zhi-Ming

    2016-01-01

    Medullary breast carcinoma (MBC) is a unique histological subtype of breast cancer. Our study was designed to identify difference in characteristics and outcomes between MBC and invasive ductal carcinoma (IDC), and further confirm the prognostic factors of MBC. Utilizing Surveillance, Epidemiology, and End Results (SEER), we identified 84,764 eligible patients, including 309 MBC and 84,455 IDC. Compared with the IDC group, the MBC group was associated with younger age at diagnosis, higher grade, more advanced stage, larger tumor size, and higher proportion of triple-negative breast cancer (TNBC). Kaplan-Meier analysis and univariate Cox proportional hazard regression model showed that patients with IDC had significantly better breast cancer-specific survival (BCSS) compared to MBC, but they had similar overall survival (OS). However, MBC histology was no longer a surrogate for worse BCSS or OS after 1:1 matching by age, American Joint Committee on Cancer (AJCC) stage, grade and breast subtype. In addition, it was exposed that not married status, high grade, large tumor size, positive nodal status, the subtype of TNBC and no receipt of radiation therapy were significantly associated with poor BCSS and OS. In conclusion, MBC demonstrated more aggressive behavior but similar outcomes compared to IDC, which may be determined by prognostic factors such as breast subtype. These results not only confer deeper insight into MBC but contribute to individualized and tailored therapy, and thereby may improve clinical management and outcomes. PMID:27009810

  2. Genomic characterization of patient-derived xenograft models established from fine needle aspirate biopsies of a primary pancreatic ductal adenocarcinoma and from patient-matched metastatic sites.

    PubMed

    Allaway, Robert J; Fischer, Dawn A; de Abreu, Francine B; Gardner, Timothy B; Gordon, Stuart R; Barth, Richard J; Colacchio, Thomas A; Wood, Matthew; Kacsoh, Balint Z; Bouley, Stephanie J; Cui, Jingxuan; Hamilton, Joanna; Choi, Jungbin A; Lange, Joshua T; Peterson, Jason D; Padmanabhan, Vijayalakshmi; Tomlinson, Craig R; Tsongalis, Gregory J; Suriawinata, Arief A; Greene, Casey S; Sanchez, Yolanda; Smith, Kerrington D

    2016-03-29

    N-of-1 trials target actionable mutations, yet such approaches do not test genomically-informed therapies in patient tumor models prior to patient treatment. To address this, we developed patient-derived xenograft (PDX) models from fine needle aspiration (FNA) biopsies (FNA-PDX) obtained from primary pancreatic ductal adenocarcinoma (PDAC) at the time of diagnosis. Here, we characterize PDX models established from one primary and two metastatic sites of one patient. We identified an activating KRAS G12R mutation among other mutations in these models. In explant cells derived from these PDX tumor models with a KRAS G12R mutation, treatment with inhibitors of CDKs (including CDK9) reduced phosphorylation of a marker of CDK9 activity (phospho-RNAPII CTD Ser2/5) and reduced viability/growth of explant cells derived from PDAC PDX models. Similarly, a CDK inhibitor reduced phospho-RNAPII CTD Ser2/5, increased apoptosis, and inhibited tumor growth in FNA-PDX and patient-matched metastatic-PDX models. In summary, PDX models can be constructed from FNA biopsies of PDAC which in turn can enable genomic characterization and identification of potential therapies.

  3. Challenges in ductal carcinoma in situ risk communication and decision-making: report from an American Cancer Society and National Cancer Institute workshop.

    PubMed

    Partridge, Ann H; Elmore, Joann G; Saslow, Debbie; McCaskill-Stevens, Worta; Schnitt, Stuart J

    2012-01-01

    In September 2010, the American Cancer Society and National Cancer Institute convened a conference to review current issues in ductal carcinoma in situ (DCIS) risk communication and decision-making and to identify directions for future research. Specific topics included patient and health care provider knowledge and attitudes about DCIS and its treatment, how to explain DCIS to patients given the heterogeneity of the disease, consideration of nomenclature changes, and the usefulness of decision tools/aids. This report describes the proceedings of the workshop in the context of the current literature and discusses future directions. Evidence suggests that there is a lack of clarity about the implications and risks of a diagnosis of DCIS among patients, providers, and researchers. Research is needed to understand better the biology and mechanisms of the progression of DCIS to invasive breast cancer and the factors that predict those subtypes of DCIS that do not progress, as well as efforts to improve the communication and informed decision-making surrounding DCIS.

  4. An Increased Abundance of Tumor-Infiltrating Regulatory T Cells Is Correlated with the Progression and Prognosis of Pancreatic Ductal Adenocarcinoma

    PubMed Central

    Tang, Yichen; Xu, Xuejun; Guo, Shixiang; Zhang, Chaobin; Tang, Yan; Tian, Yi; Ni, Bing; Lu, Binfeng; Wang, Huaizhi

    2014-01-01

    CD4+CD25+Foxp3+ regulatory T cells (Tregs) can inhibit cytotoxic responses. Though several studies have analyzed Treg frequency in the peripheral blood mononuclear cells (PBMCs) of pancreatic ductal adenocarcinoma (PDA) patients using flow cytometry (FCM), few studies have examined how intratumoral Tregs might contribute to immunosuppression in the tumor microenvironment. Thus, the potential role of intratumoral Tregs in PDA patients remains to be elucidated. In this study, we found that the percentages of Tregs, CD4+ T cells and CD8+ T cells were all increased significantly in tumor tissue compared to control pancreatic tissue, as assessed via FCM, whereas the percentages of these cell types in PBMCs did not differ between PDA patients and healthy volunteers. The percentages of CD8+ T cells in tumors were significantly lower than in PDA patient PBMCs. In addition, the relative numbers of CD4+CD25+Foxp3+ Tregs and CD8+ T cells were negatively correlated in the tissue of PDA patients, and the abundance of Tregs was significantly correlated with tumor differentiation. Additionally, Foxp3+ T cells were observed more frequently in juxtatumoral stroma (immediately adjacent to the tumor epithelial cells). Patients showing an increased prevalence of Foxp3+ T cells had a poorer prognosis, which was an independent factor for patient survival. These results suggest that Tregs may promote PDA progression by inhibiting the antitumor immunity of CD8+ T cells at local intratumoral sites. Moreover, a high proportion of Tregs in tumor tissues may reflect suppressed antitumor immunity. PMID:24637664

  5. Extended Survival after Complete Pathological Response in Metastatic Pancreatic Ductal Adenocarcinoma Following Induction Chemotherapy, Chemoradiotherapy, and a Novel Immunotherapy Agent, IMM-101.

    PubMed

    Costa Neves, Mafalda; Giakoustidis, Alex; Stamp, Gordon; Gaya, Andy; Mudan, Satvinder

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis. Median survival for metastatic patients is six to nine months and survivors beyond one year are exceptional. Pancreatic cancer is resistant to conventional chemotherapy and is often diagnosed at advanced stages. However, immunotherapy is a rapidly advancing new treatment modality, which shows promise in many solid tumor types.​ We present a patient with metastatic pancreatic cancer who underwent a synchronous resection of the primary tumour (pancreatoduodenectomy) and metastatic site (left hepatectomy) after multimodality neoadjuvant treatment with gemcitabine, nab-paclitaxel, and immunotherapy backbone with IMM-101 (an intradermally applied immunomodulator), as well as consolidation chemoradiation. Pathology of the specimens showed a complete response in both sites of the disease. The patient remains alive four years from the initial diagnosis and continues on maintenance immunotherapy. This exceptional response to initial chemo-immunotherapy was followed by a novel and off-protocol approach of low-dose capecitabine and IMM-101 as a maintenance strategy. The survival benefit and sustained performance status could set this as a new paradigm for the treatment of oligometastatic pancreatic cancer following response to systemic therapy and immunotherapy.​. PMID:26870619

  6. Disease Free Probability after the First Primary Ductal Carcinoma In Situ of the Breast: A Comparison between African-American and White-American Women

    PubMed Central

    Stark, Azadeh; Stapp, Robert; Raghunathan, Aditya; Yan, Xiaowei; Kirchner, H. Lester; Griggs, Jennifer; Newman, Lisa; Chitale, Dhananjay; Dick, Andrew

    2014-01-01

    BACKGROUND Compelling evidence about the differences in the biology and behavior of invasive breast cancer between African-American (AA) and White-American (WA) women motivate inquiry into comparing the clinicopathology of non-invasive breast cancer (ductal carcinoma in situ, DCIS). METHODS AA and WA women diagnosed with their first primary DCIS between 1990 and1999 were identified from the institutional tumor registry. Data on method of presentation, treatment, pateint characteristics were retreived from electronic medical records. Patients were followed up through the medical records until the diagnosis of a subsequent cancer or the last-day of contact with the institution. RESULTS A total of 100 (29.6%) AAs and 236 (70.4%) WAs with the mean age of 60 (SD±13) and 57 (SD±12), respectively, contributed to this study. DCIS was detected during routine screening mammography for 81% (n=81) of AAs and 88.4% (n=206) of WAs (P=0.073). Differences in the distributions of grade, margin status, necrosis, or treatment modalities were not statistically significant between AAs and WAs. Analysis of competing risks Cox proportional hazard multivariate modeling yielded a significant 8-year cumulative risk of a second cancer for AAs but only in the ipsilateral breast (HR=3.96, 95% CI 1.42–11.04, P=.01). CONCLUSION Despite comparable clinical presentation and treatment, 8 years after the initial treatment, AAs expereinced a higher risk of second breast cancer in ipsilateral but not in the contralateral breast. The observed excess risk of a second cancer in the ipsilateral breast may suggest of intrinsic differences in the biology of cancer. PMID:21874310

  7. Breast Cancer Heterogeneity Examined by High-Sensitivity Quantification of PIK3CA, KRAS, HRAS, and BRAF Mutations in Normal Breast and Ductal Carcinomas.

    PubMed

    Myers, Meagan B; Banda, Malathi; McKim, Karen L; Wang, Yiying; Powell, Michael J; Parsons, Barbara L

    2016-04-01

    Mutant cancer subpopulations have the potential to derail durable patient responses to molecularly targeted cancer therapeutics, yet the prevalence and size of such subpopulations are largely unexplored. We employed the sensitive and quantitative Allele-specific Competitive Blocker PCR approach to characterize mutant cancer subpopulations in ductal carcinomas (DCs), examining five specific hotspot point mutations (PIK3CA H1047R, KRAS G12D, KRAS G12V, HRAS G12D, and BRAF V600E). As an approach to aid interpretation of the DC results, the mutations were also quantified in normal breast tissue. Overall, the mutations were prevalent in normal breast and DCs, with 9/9 DCs having measureable levels of at least three of the five mutations. HRAS G12D was significantly increased in DCs as compared to normal breast. The most frequent point mutation reported in DC by DNA sequencing, PIK3CA H1047R, was detected in all normal breast tissue and DC samples and was present at remarkably high levels (mutant fractions of 1.1 × 10(-3) to 4.6 × 10(-2)) in 4/10 normal breast samples. In normal breast tissue samples, PIK3CA mutation levels were positively correlated with age. However, the PIK3CA H1047R mutant fraction distributions for normal breast tissues and DCs were similar. The results suggest PIK3CA H1047R mutant cells have a selective advantage in breast, contribute to breast cancer susceptibility, and drive tumor progression during breast carcinogenesis, even when present as only a subpopulation of tumor cells. PMID:27108388

  8. Curcuminoids and ω-3 fatty acids with anti-oxidants potentiate cytotoxicity of natural killer cells against pancreatic ductal adenocarcinoma cells and inhibit interferon γ production.

    PubMed

    Halder, Ramesh C; Almasi, Anasheh; Sagong, Bien; Leung, Jessica; Jewett, Anahid; Fiala, Milan

    2015-01-01

    Pancreatic cancer has a poor prognosis attributed in part to immune suppression and deactivation of natural killer (NK) cells. Curcuminoids have a potential for improving the therapy of pancreatic cancer given promising results in cancer models and a clinical trial, but their oral absorption is limited. Our objective in this study is to show curcuminoid anti-oncogenic effects alone and together with human NK cells. We tested curcuminoids in an emulsion of ω-3 fatty acids and anti-oxidants ("Smartfish") regarding their direct cytocidal effect and enhancement of the cytocidal activity of NK cells in pancreatic ductal adenocarcinoma (PDAC) cells (Mia Paca 2 and L3.6). Curcuminoids (at ≥10 μM) with ω-3 fatty acids and anti-oxidants or with the lipidic mediator resolvin D1 (RvD1) (26 nM) induced high caspase-3 activity in PDAC cells. Importantly, curcuminoids with ω-3 fatty acids and anti-oxidants or with RvD1 significantly potentiated NK cell cytocidal function and protected them against degradation. In a co-culture of cancer cells with NK cells, interferon-γ (IFN-γ) production by NK cells was not altered by ω-3 fatty acids with anti-oxidants or by RvD1 but was inhibited by curcuminoids. The inhibition was not eliminated by ω-3 fatty acids or RvD1 but was relieved by removing curcuminoids after adding NK cells. In conclusion, curcuminoids with ω-3 fatty acids and anti-oxidants or with RvD1 have increased cytotoxic activity on PDAC cells alone and with NK cells. The effects of curcuminoids with ω-3 fatty acids and anti-oxidants on pancreatic cancer will be investigated in a mouse model with humanized immune system.

  9. Surgical Excision Without Radiation for Ductal Carcinoma in Situ of the Breast: 12-Year Results From the ECOG-ACRIN E5194 Study

    PubMed Central

    Solin, Lawrence J.; Gray, Robert; Hughes, Lorie L.; Wood, William C.; Lowen, Mary Ann; Badve, Sunil S.; Baehner, Frederick L.; Ingle, James N.; Perez, Edith A.; Recht, Abram; Sparano, Joseph A.; Davidson, Nancy E.

    2015-01-01

    Purpose To determine the 12-year risk of developing an ipsilateral breast event (IBE) for women with ductal carcinoma in situ (DCIS) of the breast treated with surgical excision (lumpectomy) without radiation. Patients and Methods A prospective clinical trial was performed for women with DCIS who were selected for low-risk clinical and pathologic characteristics. Patients were enrolled onto one of two study cohorts (not randomly assigned): cohort 1: low- or intermediate-grade DCIS, tumor size 2.5 cm or smaller (n = 561); or cohort 2: high-grade DCIS, tumor size 1 cm or smaller (n = 104). Protocol specifications included excision of the DCIS tumor with a minimum negative margin width of at least 3 mm. Tamoxifen (not randomly assigned) was given to 30% of the patients. An IBE was defined as local recurrence of DCIS or invasive carcinoma in the treated breast. Median follow-up time was 12.3 years. Results There were 99 IBEs, of which 51 (52%) were invasive. The IBE and invasive IBE rates increased over time in both cohorts. The 12-year rates of developing an IBE were 14.4% for cohort 1 and 24.6% for cohort 2 (P = .003). The 12-year rates of developing an invasive IBE were 7.5% and 13.4%, respectively (P = .08). On multivariable analysis, study cohort and tumor size were both significantly associated with developing an IBE (P = .009 and P = .03, respectively). Conclusion For patients with DCIS selected for favorable clinical and pathologic characteristics and treated with excision without radiation, the risks of developing an IBE and an invasive IBE increased through 12 years of follow-up, without plateau. These data help inform the treatment decision-making process for patients and their physicians. PMID:26371148

  10. Curcuminoids and ω-3 fatty acids with anti-oxidants potentiate cytotoxicity of natural killer cells against pancreatic ductal adenocarcinoma cells and inhibit interferon γ production

    PubMed Central

    Halder, Ramesh C.; Almasi, Anasheh; Sagong, Bien; Leung, Jessica; Jewett, Anahid; Fiala, Milan

    2015-01-01

    Pancreatic cancer has a poor prognosis attributed in part to immune suppression and deactivation of natural killer (NK) cells. Curcuminoids have a potential for improving the therapy of pancreatic cancer given promising results in cancer models and a clinical trial, but their oral absorption is limited. Our objective in this study is to show curcuminoid anti-oncogenic effects alone and together with human NK cells. We tested curcuminoids in an emulsion of ω-3 fatty acids and anti-oxidants (“Smartfish”) regarding their direct cytocidal effect and enhancement of the cytocidal activity of NK cells in pancreatic ductal adenocarcinoma (PDAC) cells (Mia Paca 2 and L3.6). Curcuminoids (at ≥10 μM) with ω-3 fatty acids and anti-oxidants or with the lipidic mediator resolvin D1 (RvD1) (26 nM) induced high caspase-3 activity in PDAC cells. Importantly, curcuminoids with ω-3 fatty acids and anti-oxidants or with RvD1 significantly potentiated NK cell cytocidal function and protected them against degradation. In a co-culture of cancer cells with NK cells, interferon-γ (IFN-γ) production by NK cells was not altered by ω-3 fatty acids with anti-oxidants or by RvD1 but was inhibited by curcuminoids. The inhibition was not eliminated by ω-3 fatty acids or RvD1 but was relieved by removing curcuminoids after adding NK cells. In conclusion, curcuminoids with ω-3 fatty acids and anti-oxidants or with RvD1 have increased cytotoxic activity on PDAC cells alone and with NK cells. The effects of curcuminoids with ω-3 fatty acids and anti-oxidants on pancreatic cancer will be investigated in a mouse model with humanized immune system. PMID:26052286

  11. Clinical-Pathologic Features and Long-Term Outcomes of Tubular Carcinoma of the Breast Compared With Invasive Ductal Carcinoma Treated With Breast Conservation Therapy

    SciTech Connect

    Liu, Gene-Fu F.; Yang Qifeng; Haffty, Bruce G.; Moran, Meena S.

    2009-12-01

    Purpose: To evaluate our institutional experience of treating tubular carcinoma of the breast (TC) and invasive ductal carcinoma (IDC) with conservative surgery and radiation therapy, to compare clinical-pathologic features and long-term outcomes. Methods and Materials: A review of our institution's tumor registry from 1975 to 2007, followed by a central pathology review of available slides, yielded 71 cases of Stage I/II TC and 2,238 cases of Stage I/II IDC treated with breast conservation therapy. Clinical-pathologic features and outcomes were analyzed by subtype to detect significant differences. Results: The median follow-up was 7 years. The TC cohort presented more frequently with pT1 disease (97% vs. 80%, p = 0.0007), pN0 disease (95% vs. 74%, p = 0.0004), hormone-receptor positivity (ER+, 89% vs. 62%, p = 0.0001; PR+, 81% vs. 52%, p = 0.0001), and HER-2 negativity (89% vs. 71%, p = 0.04). Clinical outcomes also favored the TC cohort, with lower rates of breast cancer-related death (1% vs. 10%; p = 0.0109) and distant metastasis (1% vs. 13%; p = 0.0028) and higher rates of 10-year overall (90% vs. 80%; p = 0.033), cause-specific (99% vs. 86%; p = 0.011), and disease-free (99% vs. 82%; p = 0.003) survival. There was a nonsignificant trend toward improved breast cancer relapse-free survival for the TC cohort (95% vs. 87%; p = 0.062) but no difference in nodal relapse-free survival or contralateral breast cancer relapse-free survival (all p values >0.05) between the cohorts. Conclusion: Our institutional experience suggests that TC, when compared with IDC, is associated with more favorable clinical-pathologic features and comparable, if not superior, outcomes after breast conservation therapy, suggesting the appropriateness of a conservative approach to this rare subtype.

  12. Multi-Institutional Experience of Ductal Carcinoma In Situ in Black vs White Patients Treated With Breast-Conserving Surgery and Whole Breast Radiation Therapy

    SciTech Connect

    Nelson, Carl; Bai, Harrison; Neboori, Hanmanth; Takita, Cristiane; Motwani, Sabin; Wright, Jean L.; Hobeika, Georges; Haffty, Bruce G.; Jones, Tiffanie; Goyal, Sharad; Moran, Meena S.

    2012-11-01

    Purpose: Given the paucity of data on racial disparities in ductal carcinoma in situ (DCIS), the data from a multi-institutional cohort of DCIS patients treated with breast-conserving surgery and whole breast radiation therapy (RT) were analyzed to determine whether racial disparities or differences exist. Methods and Materials: A total of 533 white and 76 black DCIS patients from 3 university-based cancer centers were uniformly treated with breast-conserving surgery and RT. All patient data were collected and analyzed as a function of race. Results: The median follow-up was 5.2 years. No significant racial differences were seen in tumor size, age at diagnosis, estrogen receptor status, necrosis, or grade (all P>.05). Of the treatment parameters, the RT dose delivered, boost, positive margin rates, frequency of hormone receptor status assessment, and receipt of hormonal therapy for the 2 cohorts did not significantly differ (all P>.05). The local relapse-free survival was similar at 5 years (96.1% and 98.1%, P=.399) and 10 years (92.8% vs 95.8%, P=.360), with no significant overall survival difference at 10 years (94.0% vs 88.9%, P=.290) between the white and black patients, respectively. On multivariate analysis, race was not an independent predictor of local relapse-free survival or overall survival when accounting for age, grade, and margin status. Conclusion: In our large cohort of DCIS patients uniformly treated at 3 institutions with breast conservation without any apparent differences in treatment delivery parameters, we demonstrated that the clinical and pathologic features and local survival outcomes did not differ as a function of race. Our results suggest that when black patients with DCIS are appropriately selected for breast conservation and receive adjuvant RT without racial disparities in the treatment parameters, differences in the outcomes as a function of race do not exist.

  13. Implications of the Notch1-Snail/Slug-epithelial to mesenchymal transition axis for lymph node metastasis in infiltrating ductal carcinoma.

    PubMed

    Cao, Yu-Wen; Wan, Guo-Xing; Sun, Jian-Ping; Cui, Xiao-Bin; Hu, Jian-Ming; Liang, Wei-Hua; Zheng, Yu-Qin; Li, Wen-Qin; Li, Feng

    2015-02-01

    Emerging evidence suggests that activation of the Notch1 signaling pathway inducing epithelial to mesenchymal transition (EMT) mediated by Snail/Slug promotes invasion and metastasis of breast cancer cells in vitro. However, the implication of the Notch1-Snail/Slug-EMT axis in breast cancer patients remains unclear. A total of 200 formalin-fixed paraffin-embedded samples of invasive ductal carcinoma (IDC), and 37 adjacent non-neoplastic tissue (ANNT) samples from patients who had not been treated with neoadjuvant therapy were examined. Expression of Notch1, Slug, Snail, E-cadherin, N-cadherin, and vimentin was determined by immunohistochemistry on tissue microarrays (TMAs). The correlation between protein expression and clinicopathological characteristics of breast cancer patients was also evaluated. Results showed that a significantly high percentage of cases with high expression of Notch1 (74%, 148/200), Slug (36%, 72/200), Snail (62%, 124/200), and N-cadherin (77%, 153/200) and a low percentage of cases with high expression of E-cadherin (27%, 54/200) were observed in IDC compared to those in ANNTs. High Notch1, Slug, Snail, and N-cadherin expression and low E-cadherin expression in patients with IDC were significantly correlated with lymph node metastasis. In addition, correlation analysis results revealed that high Notch1 expression was significantly associated with high Slug, Snail, and N-cadherin expression and low E-cadherin expression in IDC. Furthermore, a high Snail expression was significantly associated with low E-cadherin expression, and a high Slug expression was found to be significantly associated with increased N-cadherin expression in patients with IDC. Hence, our study suggested that the Notch1-Snail/Slug-EMT axis may be implicated in the lymph node metastasis affecting patients with IDC. PMID:25645984

  14. Metabonomic alterations from pancreatic intraepithelial neoplasia to pancreatic ductal adenocarcinoma facilitate the identification of biomarkers in serum for early diagnosis of pancreatic cancer.

    PubMed

    Lin, Xianchao; Zhan, Bohan; Wen, Shi; Li, Zhishui; Huang, Heguang; Feng, Jianghua

    2016-08-16

    Pancreatic cancer is a highly malignant disease with a poor prognosis and it is essential to diagnose and treat the disease at an early stage. The aim of this study was to understand the underlying biochemical mechanisms of pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC) and to identify potential serum biomarkers for early detection of pancreatic cancer. 7,12-Dimethylbenz(a)anthracene (DMBA)-induced PanIN and PDAC rat models were established and the serum samples were collected. The serum samples were measured using (1)H nuclear magnetic resonance (NMR) spectroscopy and analyzed by chemometric methods including principal component analysis (PCA) and (orthogonal) partial least squares discriminant analysis ((O)PLS-DA). The related biochemical pathways were derived from KEGG analysis of the significantly different metabolites. As results, some serum metabolites demonstrated alarming metabolic changes in the precursor lesion of pancreatic cancer (PanIN-2 in this study). These changes involved elevated levels of ketone compounds including 3-hydroxybutyrate, acetoacetate, and acetone, some amino acids including asparagine, glutamate, threonine, and phenylalanine, glycoproteins and lipoproteins including N-acetylglycoprotein, LDL and VLDL, and some metabolites that have been shown to contribute to mutagenicity and cancer promotion such as deoxyguanosine and cytidine. More metabolites were shown to be significantly different between PanIN and PDAC, suggesting that a more complex set of changes occurs from noninvasive precursor lesion to invasive cancer. The serum metabonomic changes of rats with PanIN and PDAC may extend our understanding of pancreatic molecular pathogenesis, and the metabolic variations from PanIN to PDAC will be helpful to understand evolution processes of the pancreatic disease. NMR-based metabonomic analysis of animal models will be beneficial for the human study and will be helpful for the early detection of

  15. Single nucleotide polymorphism in the microRNA-199a binding site of HIF1A gene is associated with pancreatic ductal adenocarcinoma risk and worse clinical outcomes.

    PubMed

    Wang, Xiuchao; Ren, He; Zhao, Tiansuo; Ma, Weidong; Dong, Jie; Zhang, Shengjie; Xin, Wen; Yang, Shengyu; Jia, Li; Hao, Jihui

    2016-03-22

    Hypoxia-inducible factor-1 alpha (HIF-1α) is over-expressed in many cancers including pancreatic ductal adenocarcinoma (PDAC) and correlated with poor prognosis. We aim to determine the effect of germline genetic variants on the regulation of the homeostasis of the miRNA-gene regulatory loop in HIF1A gene and PDAC risk. HIF1A rs2057482 single nucleotide polymorphism (SNP) was genotyped in 410 PDAC cases and 490 healthy controls. The CC genotype SNP HIF1A is significantly correlated with PDAC risk (OR = 1.719, 95% CI: 1.293-2.286) and shorter overall survival (OS, P<0.0001) compared with the CT/TT alleles group. The C/T variants of rs2057482, a SNP located near the miR-199a binding site in HIF1A, could lead to differential regulation of HIF1A by miR-199a. Specifically, the C allele of rs2057482 weakened miR-199a-induced repression of HIF-1α expression on both mRNA and protein levels. In the PDAC tissue, individuals with the rs2057482-CC genotype expressed significantly higher levels of HIF-1α protein than those with the rs2057482-CT/TT genotype (P<0.0001). Both the CC genotype of SNP HIF1A and increased HIF-1α expression are significantly associated with shorter OS of patients with PDAC. After adjusted by TNM staging, differentiation grade, and the levels of CA19-9, both SNP HIF1A and HIF-1α expression retained highly significance on OS (P<0.0001). Taken together, our study demonstrates that host genetic variants could disturb the regulation of the miR-199a/HIF1A regulatory loop and alter PDAC risk and poor prognosis. In conclusion, the rs2057482-CC genotype increases the susceptibility to PDAC and associated with cancer progression.

  16. ITRAQ-based quantitative proteomics reveals apolipoprotein A-I and transferrin as potential serum markers in CA19-9 negative pancreatic ductal adenocarcinoma.

    PubMed

    Lin, Chao; Wu, Wen-Chuan; Zhao, Guo-Chao; Wang, Dan-Song; Lou, Wen-Hui; Jin, Da-Yong

    2016-08-01

    Currently the diagnosis of pancreatic ductal adenocarcinoma (PDAC) relies on CA19-9 and radiological means, whereas some patients do not have elevated levels of CA19-9 secondary to pancreatic cancer. The purpose of this study was to identify potential serum biomarkers for CA19-9 negative PDAC.A total of 114 serum samples were collected from 3 groups: CA19-9 negative PDAC patients (n = 34), CA19-9 positive PDAC patients (n = 44), and healthy volunteers (n = 36), whereas the first 12 samples from each group were used for isobaric tags for relative and absolute quantitation (iTRAQ) analysis. Thereafter, candidate biomarkers were selected for validation by enzyme-linked immunosorbent assay (ELISA) with the rest specimens.Using the iTRAQ approach, a total of 5 proteins were identified as significantly different between CA19-9 negative PDAC patients and healthy subjects according to our defined criteria. Apolipoprotein A-I (APOA-I) and transferrin (TF) were selected to validate the proteomic results by ELISA in a further 78 serum specimens. It revealed that TF significantly correlated with the degree of histological differentiation (P = 0.042), and univariate and multivariate analyses indicated that TF is an independent prognostic factor for survival (hazard ratio, 0.302; 95% confidence interval, 0.118-0.774; P = 0.013) of patients with PDAC after curative surgery.ITRAQ-based quantitative proteomics revealed that APOA-I and TF may be potential CA19-9 negative PDAC serum markers.

  17. The Spatiotemporal Pattern of Glis3 Expression Indicates a Regulatory Function in Bipotent and Endocrine Progenitors during Early Pancreatic Development and in Beta, PP and Ductal Cells

    PubMed Central

    Kang, Hong Soon; Takeda, Yukimasa; Jeon, Kilsoo

    2016-01-01

    The transcription factor Glis-similar 3 (Glis3) has been implicated in the development of neonatal, type 1 and type 2 diabetes. In this study, we examined the spatiotemporal expression of Glis3 protein during embryonic and neonatal pancreas development as well as its function in PP cells. To obtain greater insights into the functions of Glis3 in pancreas development, we examined the spatiotemporal expression of Glis3 protein in a knockin mouse strain expressing a Glis3-EGFP fusion protein. Immunohistochemistry showed that Glis3-EGFP was not detectable during early pancreatic development (E11.5 and E12.5) and at E13.5 and 15.5 was not expressed in Ptf1a+ cells in the tip domains indicating that Glis3 is not expressed in multipotent pancreatic progenitors. Glis3 was first detectable at E13.5 in the nucleus of bipotent progenitors in the trunk domains, where it co-localized with Sox9, Hnf6, and Pdx1. It remained expressed in preductal and Ngn3+ endocrine progenitors and at later stages becomes restricted to the nucleus of pancreatic beta and PP cells as well as ductal cells. Glis3-deficiency greatly reduced, whereas exogenous Glis3, induced Ppy expression, as reported for insulin. Collectively, our study demonstrates that Glis3 protein exhibits a temporal and cell type-specific pattern of expression during embryonic and neonatal pancreas development that is consistent with a regulatory role for Glis3 in promoting endocrine progenitor generation, regulating insulin and Ppy expression in beta and PP cells, respectively, and duct morphogenesis. PMID:27270601

  18. The Spatiotemporal Pattern of Glis3 Expression Indicates a Regulatory Function in Bipotent and Endocrine Progenitors during Early Pancreatic Development and in Beta, PP and Ductal Cells.

    PubMed

    Kang, Hong Soon; Takeda, Yukimasa; Jeon, Kilsoo; Jetten, Anton M

    2016-01-01

    The transcription factor Glis-similar 3 (Glis3) has been implicated in the development of neonatal, type 1 and type 2 diabetes. In this study, we examined the spatiotemporal expression of Glis3 protein during embryonic and neonatal pancreas development as well as its function in PP cells. To obtain greater insights into the functions of Glis3 in pancreas development, we examined the spatiotemporal expression of Glis3 protein in a knockin mouse strain expressing a Glis3-EGFP fusion protein. Immunohistochemistry showed that Glis3-EGFP was not detectable during early pancreatic development (E11.5 and E12.5) and at E13.5 and 15.5 was not expressed in Ptf1a+ cells in the tip domains indicating that Glis3 is not expressed in multipotent pancreatic progenitors. Glis3 was first detectable at E13.5 in the nucleus of bipotent progenitors in the trunk domains, where it co-localized with Sox9, Hnf6, and Pdx1. It remained expressed in preductal and Ngn3+ endocrine progenitors and at later stages becomes restricted to the nucleus of pancreatic beta and PP cells as well as ductal cells. Glis3-deficiency greatly reduced, whereas exogenous Glis3, induced Ppy expression, as reported for insulin. Collectively, our study demonstrates that Glis3 protein exhibits a temporal and cell type-specific pattern of expression during embryonic and neonatal pancreas development that is consistent with a regulatory role for Glis3 in promoting endocrine progenitor generation, regulating insulin and Ppy expression in beta and PP cells, respectively, and duct morphogenesis. PMID:27270601

  19. ITRAQ-based quantitative proteomics reveals apolipoprotein A-I and transferrin as potential serum markers in CA19-9 negative pancreatic ductal adenocarcinoma

    PubMed Central

    Lin, Chao; Wu, Wen-Chuan; Zhao, Guo-Chao; Wang, Dan-Song; Lou, Wen-Hui; Jin, Da-Yong

    2016-01-01

    Abstract Currently the diagnosis of pancreatic ductal adenocarcinoma (PDAC) relies on CA19-9 and radiological means, whereas some patients do not have elevated levels of CA19-9 secondary to pancreatic cancer. The purpose of this study was to identify potential serum biomarkers for CA19-9 negative PDAC. A total of 114 serum samples were collected from 3 groups: CA19-9 negative PDAC patients (n = 34), CA19-9 positive PDAC patients (n = 44), and healthy volunteers (n = 36), whereas the first 12 samples from each group were used for isobaric tags for relative and absolute quantitation (iTRAQ) analysis. Thereafter, candidate biomarkers were selected for validation by enzyme-linked immunosorbent assay (ELISA) with the rest specimens. Using the iTRAQ approach, a total of 5 proteins were identified as significantly different between CA19-9 negative PDAC patients and healthy subjects according to our defined criteria. Apolipoprotein A-I (APOA-I) and transferrin (TF) were selected to validate the proteomic results by ELISA in a further 78 serum specimens. It revealed that TF significantly correlated with the degree of histological differentiation (P = 0.042), and univariate and multivariate analyses indicated that TF is an independent prognostic factor for survival (hazard ratio, 0.302; 95% confidence interval, 0.118–0.774; P = 0.013) of patients with PDAC after curative surgery. ITRAQ-based quantitative proteomics revealed that APOA-I and TF may be potential CA19-9 negative PDAC serum markers. PMID:27495108

  20. miR-186 and 326 predict the prognosis of pancreatic ductal adenocarcinoma and affect the proliferation and migration of cancer cells.

    PubMed

    Zhang, Zheng-liang; Bai, Zheng-hai; Wang, Xiao-bo; Bai, Ling; Miao, Fei; Pei, Hong-hong

    2015-01-01

    MicroRNAs can function as key tumor suppressors or oncogenes and act as biomarkers for cancer diagnosis or prognosis. Although high-throughput assays have revealed many miRNA biomarkers for pancreatic ductal adenocarcinoma (PDAC), only a few have been validated in independent populations or investigated for functional significance in PDAC pathogenesis. In this study, we correlated the expression of 36 potentially prognostic miRNAs within PDAC tissue with clinico-pathological features and survival in 151 Chinese patients. We then analyzed the functional roles and target genes of two miRNAs in PDAC development. We found that high expression of miR-186 and miR-326 predict poor and improved survival, respectively. miR-186 was over-expressed in PDAC patients compared with controls, especially in patients with large tumors (>2 cm), lymph node metastasis, or short-term survival (< 24 months). In contrast, miR-326 was down-regulated in patients compared with controls and displayed relatively increased expression in the patients with long-term survival or without venous invasion. Functional experiments revealed that PDAC cell proliferation and migration was decreased following inhibition and enhanced following over-expression of miR-186. In contrast, it was enhanced following inhibition and decreased after over-expression of miR-326. A luciferase assay indicated that miR-186 can bind directly to the 3'-UTR of NR5A2 to repress gene expression. These findings suggest that miR-186 over-expression contributes to the invasive potential of PDAC, likely via suppression of NR5A2, thereby leading to a poor prognosis; high miR-326 expression prolongs survival likely via the decreasing invasive potential of PDAC cells. These two miRNAs can be used as markers for clinical diagnosis and prognosis, and they represent therapeutic targets for PDAC.

  1. Screen-detected ductal carcinoma in situ found on stereotactic vacuum-assisted biopsy of suspicious microcalcifications without mass: radiological-histological correlation

    PubMed Central

    Kasprzak, Piotr; Biecek, Przemyslaw; Halon, Agnieszka; Matkowski, Rafal

    2016-01-01

    Abstract Background Commonly identified on screening mammography breast microcalcifications are the predominant manifestation of ductal carcinoma in situ (DCIS). The aim of this study was to investigate the association between clinico-radiological features and histological findings in patients with screen-detected DCIS. Patients and methods Consecutive 127 patients with pure DCIS found on stereotactic vacuum-assisted biopsy of screen-detected suspicious microcalcifications without mass entered the study. Patient age, type and distribution of microcalcifications, DCIS nuclear grade (NG) and the presence of comedonecrosis were investigated. Association between parameters was statistically analysed with P < 0.05 as a significance level. Results. Powdery microcalcifications were most often clustered while regional were most common of casting-type (P < 0.001). High, intermediate and low NG of DCIS was significantly related to casting-type, crushed stone-like and powdery microcalcifications, respectively (P < 0.01). Low and intermediate NG DCIS were the most common in clustered and grouped microcalcifications while high NG DCIS was the most often when regional distribution was observed (P < 0.05). Comedonecrosis was significantly more common in high NG DCIS (P < 0.01). The association between comedonecrosis and type of microcalcifications was not significant, but with their distribution was close to the significance level (P = 0.07). Patient age was not significantly related to imaging or histological findings. Conclusions The association between pattern of mammographic microcalcifications and histological findings related to more aggressive disease can be helpful in optimal surgery planning in patients with screen-detected DCIS, regarding the extent of breast intervention and consideration of synchronous sentinel node biopsy. PMID:27247546

  2. Lectin histochemistry reveals SNA as a prognostic carbohydrate-dependent probe for invasive ductal carcinoma of the breast: a clinicopathological and immunohistochemical auxiliary tool

    PubMed Central

    dos-Santos, Petra B; Zanetti, Juliana S; Vieira-de-Mello, Gabriela S; Rêgo, Moacyr BM; A, Alfredo Ribeiro-Silva; Beltrão, Eduardo Isidoro Carneiro

    2014-01-01

    Increased sialylation and β1,6-branched oligosaccharides has been associated with a variety of structural changes in cell surface carbohydrates, most notably in tumorigenesis. Lectins are defined as proteins that preferentially recognize and bind carbohydrate complexes protruding from glycolipids and glycoproteins. This interaction with carbohydrates can be as specific as the interaction between antigen and antibody. Due to this type of interaction lectins have been used as experimental auxiliary tools in histopathological diagnosis of cancer. This study was designed to evaluate the differential expression of sialic acids and β1,6-N-acetylglucosaminyltransferase V (MGAT5) in invasive (IDC) and in situ (DCIS) ductal carcinoma of the breast and its possible application as prognostic biomarkers. A possible transition between pre-malign and malign lesions was evaluated using DCIS samples. Biopsies were analyzed regarding the expression of MUC1, p53, Ki-67, estrogen receptor, progesterone receptor, HER-2 and MGAT5. α2,6-linked sialic acids residues recognized by SNA lectin was overexpressed in 33.3% of IDC samples and it was related with Ki-67 (p=0.042), PR (p=0.029), lymphnodes status (p=0.017) and death (p=0.011). Regarding survival analysis SNA was the only lectin able to correlate with specific-disease survival and disease-free survival (p=0.024 and p=0.041, respectively), besides, it presents itself as an independent variable by Cox Regression analysis (p= 0.004). Comparing IDC and DCIS cases, only SNA showed different staining pattern (p=0.034). The presence of sialic acids on tumor cell surface can be an indicative of poor prognosis and our study provides further evidence that SNA lectin can be used as a prognostic probe in IDC and DCIS patients. PMID:24966944

  3. Correlation of intensity of MT-I/II expression with Ki-67 and MCM-2 proteins in invasive ductal breast carcinoma.

    PubMed

    Wojnar, Andrzej; Pula, Bartosz; Piotrowska, Aleksandra; Jethon, Aleksandra; Kujawa, Krzysztof; Kobierzycki, Christopher; Rys, Janusz; Podhorska-Okolow, Marzena; Dziegiel, Piotr

    2011-09-01

    The purpose of the study was to evaluate the clinical significance of the intensity of metallothionein (MT-I/II) expression and its relationship to two different proliferation markers, Ki-67 antigen and minichromosome maintaince 2 protein (MCM-2) in 117 patients with invasive ductal breast carcinoma (IDC). A significantly higher MT-I/II expression was noted in the grade 3 (G3) carcinomas as compared to those of G1 and G2. A positive correlation was observed between the MT-I/II expression and both proliferation markers, Ki-67 (r=0.20, p=0.0343) and MCM-2 (r=0.25, p=0.0065). Also a strong positive correlation was noted between Ki-67 and MCM-2 expression (r=0.52, p<0.0001). No significant correlations were found between the analyzed markers and tumour size, lymph node metastasis, oestrogen expression (ER), progesterone receptor (PR) or human epidermal growth-factor receptor (HER-2) expression. Out of the three studied markers only the high expression of Ki-67 exhibited a negative impact on patient overall and event free survival and was an independent prognostic factor. MT-I/II and MCM-2 protein expression was not correlated with poor patient outcome, although MCM-2 expression correlated (Fisher's exact test) positively with grade of malignancy (p=0.0018) and negatively with ER (p=0.0002) and PR (p=0.0056) expression. To conclude, MT-I/II may play a key role in IDC proliferation, but is not a useful prognostic factor of this disease.

  4. Calretinin expression in high-grade invasive ductal carcinoma of the breast is associated with basal-like subtype and unfavorable prognosis.

    PubMed

    Taliano, Ross J; Lu, Shaolei; Singh, Kamaljeet; Mangray, Shamlal; Tavares, Rose; Noble, Lelia; Resnick, Murray B; Yakirevich, Evgeny

    2013-12-01

    Calretinin, a calcium-binding protein, is a widely used marker for mesothelial differentiation. There is accumulating evidence of calretinin expression in epithelial and mesenchymal malignancies, as well. The objectives of this study were to (1) further delineate the expression of calretinin in grade 3 breast carcinomas in the context of molecular subtypes and (2) identify the impact of calretinin expression on overall and disease-free survival. On the basis of immunohistochemical expression of estrogen receptor, progesterone receptor, human epidermal growth factor receptor-2 (HER2), cytokeratin 5/6, and epidermal growth factor receptor, 214 grade 3 invasive ductal carcinomas were stratified into 36 luminal A, 63 luminal B, 24 HER2 positive, 81 basal-like (including 13 metaplastic carcinomas), and 10 unclassified. Tissue microarrays were analyzed for immunohistochemical expression of calretinin. High-level calretinin expression was identified in a significant proportion of basal-like (54.3%), HER2 (33.3%), and unclassified (30%) tumors. In contrast, luminal A and B subtypes demonstrated high-level calretinin expression in only 11.1% and 12.7%, respectively (P < .0001). Within the basal-like group, 38.5% of the metaplastic carcinomas demonstrated high-level expression, associated predominantly with the epithelial component and squamous metaplasia. High-level calretinin expression was strongly associated with decreased overall survival in the entire cohort of grade 3 cancer (P = .0096) and in the basal-like group (P = .039). Multivariate analysis revealed that both tumor stage and high-level calretinin expression were independent predictors of overall survival (P = .0002 and P = .0023, respectively). In conclusion, high-level calretinin expression is most common in grade 3 tumors with a basal-like phenotype and is associated with poor overall survival.

  5. Differential copy number aberrations in novel candidate genes associated with progression from in situ to invasive ductal carcinoma of the breast.

    PubMed

    Liao, Shaoxi; Desouki, Mohamed M; Gaile, Daniel P; Shepherd, Lori; Nowak, Norma J; Conroy, Jeffrey; Barry, William T; Geradts, Joseph

    2012-12-01

    Only a minority of intraductal carcinomas of the breast give rise to stromally invasive disease. We microdissected 206 paraffin blocks representing 116 different cases of low-grade ductal carcinoma in situ (DCIS). Fifty-five were pure DCIS (PD) cases without progression to invasive carcinoma. Sixty-one cases had a small invasive component. DNA was extracted from microdissected sections and hybridized to high-density bacterial artificial chromosome arrays. Array comparative genomic hybridization analysis of 118 hybridized DNA samples yielded data on 69 samples that were suitable for further statistical analysis. This cohort included 20 pure DCIS cases, 25 mixed DCIS (MD), and 24 mixed invasive carcinoma samples. PD cases had a higher frequency of DNA copy number changes than MD cases, and the latter had similar DNA profiles compared to paired invasive carcinomas. Copy number changes on 13 chromosomal arms occurred at different rates in PD versus MD lesions. Eight of 19 candidate genes residing at those loci were confirmed to have differential copy number changes by quantitative PCR. NCOR2/SMRT and NR4A1 (both on 12q), DYNLRB2 (16q), CELSR1, UPK3A, and ST13 (all on 22q) were more frequently amplified in PD. Moreover, NCOR2, NR4A1, and DYNLRB2 showed more frequent copy number losses in MD. GRAP2 (22q) was more often amplified in MD, whereas TAF1C (16q) was more commonly deleted in PD. A multigene model comprising these candidate genes discriminated between PD and MD lesions with high accuracy. These findings suggest that the propensity to invade the stroma may be encoded in the genome of intraductal carcinomas.

  6. Co-Expression of p16, Ki67 and COX-2 Is Associated with Basal Phenotype in High-Grade Ductal Carcinoma In Situ of the Breast.

    PubMed

    Perez, Amanda Arantes; Balabram, Débora; Rocha, Rafael Malagoli; da Silva Souza, Átila; Gobbi, Helenice

    2015-06-01

    We assessed the co-expression of cell cycle-related biomarkers in a series of 121 consecutive cases of high-grade ductal carcinoma in situ (DCIS), pure or associated with invasive carcinoma, and their associations with the different immunoprofiles of DCIS. Cases were identified from the histopathology files of the Breast Pathology Laboratory, Federal University of Minas Gerais, Brazil, from 2003 to 2008. The expression of estrogen receptor, progesterone receptor, HER2 overexpression, cytokeratin 5, epidermal growth factor receptor 1, cyclooxygenase-2, p16 and Ki67 were assessed. Tumors were placed into five subgroups according to their immunohistochemical profile: luminal A, luminal B, HER2, basal-like and "not classified". We found that the basal phenotype was associated with a higher frequency of p16-positive cases (83%) and the luminal A phenotype showed a higher frequency of p16-negative cases (93%; p=0.000). The association of biomarkers p16(+)/Ki67(+)/COX2(+) was expressed in 02/06 cases (33.3%) of the basal phenotype but in only 01/70 cases (1.4%) of the luminal A phenotype (p=0.01). The co-expression of p16(+)/Ki67(+)/COX2(-) was associated with a basal phenotype (p=0.004). P16 expression, p16(+)/Ki67(+)/COX2(+) and p16(+)/Ki67(+)/COX2(-) co-expression showed significant associations with the basal phenotype and these profiles could be used to guide more aggressive treatment strategies in patients with high-grade DCIS.

  7. Endogenous n-3 polyunsaturated fatty acids delay progression of pancreatic ductal adenocarcinoma in Fat-1-p48(Cre/+)-LSL-Kras(G12D/+) mice.

    PubMed

    Mohammed, Altaf; Janakiram, Naveena B; Brewer, Misty; Duff, Ashley; Lightfoot, Stan; Brush, Richard S; Anderson, Robert E; Rao, Chinthalapally V

    2012-12-01

    Preclinical studies suggest that diets rich in omega-3 polyunsaturated fatty acids (n-3 PUFAs) may be beneficial for prevention of pancreatic cancer. Nutritional intervention studies are often complex, and there is no clear evidence, without potential confounding factors, on whether conversion of n-6 PUFAs to n-3 PUFAs in pancreatic tissues would provide protection. Experiments were designed using n-3 fatty acid desaturase (Fat-1) transgenic mice, which can convert n-6 PUFA to n-3 FAs endogenously, to determine the impact of n-3 PUFAs on pancreatic intraepithelial neoplasms (PanINs) and their progression to pancreatic ductal adenocarcinoma (PDAC). Six-week-old female p48(Cre/+)-LSL-Kras(G12D/+) and compound Fat-1-p48(Cre/+)-LSL-Kras(G12D/+) mice were fed (AIN-76A) diets containing 10% safflower oil for 35 weeks. Pancreata were evaluated histopathologically for PanINs and PDAC. Results showed a dramatic reduction in incidence of PDAC (84%; P < .02) in Fat-1-p48(Cre/+)-LSL-Kras(G12D/+) mice compared to p48(Cre/+)-LSL-Kras(G12D/+) mice. Importantly, significant reductions of pancreatic ducts with carcinoma (90%; P < .0001) and PanIN 3 (~50%; P < .001) lesions were observed in the compound transgenic mice. The levels of n-3 PUFA were much higher (>85%; P < .05-0.01) in pancreas of compound transgenic mice than in those of p48(Cre/+)-LSL-Kras(G12D/+) mice. Molecular analysis of the pancreas showed a significant down-regulation of proliferating cell nuclear antigen, cyclooxygenase-2, 5-lipoxygenase (5-LOX), 5-LOX-activating protein, Bcl-2, and cyclin D1 expression levels in Fat-1-p48(Cre/+)-LSL-Kras(G12D/+) mice compared to p48(Cre/+)-LSL-Kras(G12D/+) mice. These data highlight the promise of dietary n-3 FAs for chemoprevention of pancreatic cancer in high-risk individuals.

  8. Co-Expression of p16, Ki67 and COX-2 Is Associated with Basal Phenotype in High-Grade Ductal Carcinoma In Situ of the Breast

    PubMed Central

    Perez, Amanda Arantes; Balabram, Débora; Rocha, Rafael Malagoli; da Silva Souza, Átila; Gobbi, Helenice

    2015-01-01

    We assessed the co-expression of cell cycle-related biomarkers in a series of 121 consecutive cases of high-grade ductal carcinoma in situ (DCIS), pure or associated with invasive carcinoma, and their associations with the different immunoprofiles of DCIS. Cases were identified from the histopathology files of the Breast Pathology Laboratory, Federal University of Minas Gerais, Brazil, from 2003 to 2008. The expression of estrogen receptor, progesterone receptor, HER2 overexpression, cytokeratin 5, epidermal growth factor receptor 1, cyclooxygenase-2, p16 and Ki67 were assessed. Tumors were placed into five subgroups according to their immunohistochemical profile: luminal A, luminal B, HER2, basal-like and “not classified”. We found that the basal phenotype was associated with a higher frequency of p16-positive cases (83%) and the luminal A phenotype showed a higher frequency of p16-negative cases (93%; p=0.000). The association of biomarkers p16+/Ki67+/COX2+ was expressed in 02/06 cases (33.3%) of the basal phenotype but in only 01/70 cases (1.4%) of the luminal A phenotype (p=0.01). The co-expression of p16+/Ki67+/COX2- was associated with a basal phenotype (p=0.004). P16 expression, p16+/Ki67+/COX2+ and p16+/Ki67+/COX2- co-expression showed significant associations with the basal phenotype and these profiles could be used to guide more aggressive treatment strategies in patients with high-grade DCIS. PMID:25711229

  9. Initiation of Metastatic Breast Carcinoma by Targeting of the Ductal Epithelium with Adenovirus-Cre: A Novel Transgenic Mouse Model of Breast Cancer

    PubMed Central

    Svoronos, Nikolaos; Tesone, Amelia J.; Stephen, Tom L.; Perales-Puchalt, Alfredo; Nguyen, Jenny; Zhang, Paul J.; Fiering, Steven N.; Tchou, Julia; Conejo-Garcia, Jose R.

    2014-01-01

    Breast cancer is a heterogeneous disease involving complex cellular interactions between the developing tumor and immune system, eventually resulting in exponential tumor growth and metastasis to distal tissues and the collapse of anti-tumor immunity. Many useful animal models exist to study breast cancer, but none completely recapitulate the disease progression that occurs in humans. In order to gain a better understanding of the cellular interactions that result in the formation of latent metastasis and decreased survival, we have generated an inducible transgenic mouse model of YFP-expressing ductal carcinoma that develops after sexual maturity in immune-competent mice and is driven by consistent, endocrine-independent oncogene expression. Activation of YFP, ablation of p53, and expression of an oncogenic form of K-ras was achieved by the delivery of an adenovirus expressing Cre-recombinase into the mammary duct of sexually mature, virgin female mice. Tumors begin to appear 6 weeks after the initiation of oncogenic events. After tumors become apparent, they progress slowly for approximately two weeks before they begin to grow exponentially. After 7-8 weeks post-adenovirus injection, vasculature is observed connecting the tumor mass to distal lymph nodes, with eventual lymphovascular invasion of YFP+ tumor cells to the distal axillary lymph nodes. Infiltrating leukocyte populations are similar to those found in human breast carcinomas, including the presence of αβ and γδ T cells, macrophages and MDSCs. This unique model will facilitate the study of cellular and immunological mechanisms involved in latent metastasis and dormancy in addition to being useful for designing novel immunotherapeutic interventions to treat invasive breast cancer. PMID:24748051

  10. Age distribution patterns of patients with conventional ductal adenocarcinoma of the pancreas. A single-institution study of 580 cases re-evaluated using current histopathological diagnostic criteria.

    PubMed

    Liszka, Łukasz; Pająk, Jacek; Mrowiec, Sławomir; Zielińska-Pająk, Ewa; Lampe, Paweł; Gołka, Dariusz

    2010-01-01

    There are a few studies concerning epidemiology of pancreatic ductal adenocarcinoma (PDAC) in the Polish population. Analysis of age distribution patterns of patients with different types of cancer may be useful for studying their specific biology. In the present study we aimed to describe age distribution patterns of 580 patients with PDAC diagnosed in one centre during a 25-year period. All the histopathological diagnoses were re-reviewed using current histopathological diagnostic criteria. Age distributions of selected subpopulations of patients (defined based on gender, potential tumour resectability and type of the surgery) were compared using mean values, medians, age frequency density plots and logarithmic plots of age-specific frequencies. The mean and median values of patients' age were 60.8 y and 61.0 y, respectively. Females were approximately 2 y older than males at the time of PDAC diagnosis. Females with non-resectable PDAC were approximately 2 y older than females with resectable tumours. Mean age values of males with non-resectable and resectable PDAC were similar. Patients treated with pancreaticoduodenectomy were approximately 2 y older than patients undergoing other types of resections. Age distribution density plots showed that some subgroups of patients studied were somewhat heterogeneous and might include several yet poorly recognized clinico-pathological entities. Logarithmic plots of age-specific frequencies showed that PDAC epidemiology is in concordance with a multistage theory of carcinogenesis. PDAC is an age-dependent cancer. Single-institutional pathology-oriented cancer epidemiological databases may add some information to population-based cancer registries.

  11. Islet Neogenesis Associated Protein (INGAP) induces the differentiation of an adult human pancreatic ductal cell line into insulin-expressing cells through stepwise activation of key transcription factors for embryonic beta cell development.

    PubMed

    Assouline-Thomas, Béatrice; Ellis, Daniel; Petropavlovskaia, Maria; Makhlin, Julia; Ding, Jieping; Rosenberg, Lawrence

    2015-01-01

    Regeneration of β-cells in diabetic patients is an important goal of diabetes research. Islet Neogenesis Associated Protein (INGAP) was discovered in the partially duct-obstructed hamster pancreas. Its bioactive fragment, pentadecapeptide 104-118 (INGAP-P), has been shown to reverse diabetes in animal models and to improve glucose homeostasis in patients with diabetes in clinical trials. Further development of INGAP as a therapy for diabetes requires identification of target cells in the pancreas and characterization of the mechanisms of action. We hypothesized that adult human pancreatic ductal cells retain morphogenetic plasticity and can be induced by INGAP to undergo endocrine differentiation. To test this hypothesis, we treated the normal human pancreatic ductal cell line (HPDE) with either INGAP-P or full-length recombinant protein (rINGAP) for short-term periods. Our data show that this single drug treatment induces both proliferation and transdifferentiation of HPDE cells, the latter being characterized by the rapid sequential activation of endocrine developmental transcription factors Pdx-1, Ngn3, NeuroD, IA-1, and MafA and subsequently the expression of insulin at both the mRNA and the protein levels. After 7 days, C-peptide was detected in the supernatant of INGAP-treated cells, reflecting their ability to secrete insulin. The magnitude of differentiation was enhanced by embedding the cells in Matrigel, which led to islet-like cluster formation. The islet-like clusters cells stained positive for nuclear Pdx-1 and Glut 2 proteins, and were expressing Insulin mRNA. These new data suggest that human adult pancreatic ductal cells retain morphogenetic plasticity and demonstrate that a short exposure to INGAP triggers their differentiation into insulin-expressing cells in vitro. In the context of the urgent search for a regenerative and/or cellular therapy for diabetes, these results make INGAP a promising therapeutic candidate.

  12. Islet Neogenesis Associated Protein (INGAP) induces the differentiation of an adult human pancreatic ductal cell line into insulin-expressing cells through stepwise activation of key transcription factors for embryonic beta cell development.

    PubMed

    Assouline-Thomas, Béatrice; Ellis, Daniel; Petropavlovskaia, Maria; Makhlin, Julia; Ding, Jieping; Rosenberg, Lawrence

    2015-01-01

    Regeneration of β-cells in diabetic patients is an important goal of diabetes research. Islet Neogenesis Associated Protein (INGAP) was discovered in the partially duct-obstructed hamster pancreas. Its bioactive fragment, pentadecapeptide 104-118 (INGAP-P), has been shown to reverse diabetes in animal models and to improve glucose homeostasis in patients with diabetes in clinical trials. Further development of INGAP as a therapy for diabetes requires identification of target cells in the pancreas and characterization of the mechanisms of action. We hypothesized that adult human pancreatic ductal cells retain morphogenetic plasticity and can be induced by INGAP to undergo endocrine differentiation. To test this hypothesis, we treated the normal human pancreatic ductal cell line (HPDE) with either INGAP-P or full-length recombinant protein (rINGAP) for short-term periods. Our data show that this single drug treatment induces both proliferation and transdifferentiation of HPDE cells, the latter being characterized by the rapid sequential activation of endocrine developmental transcription factors Pdx-1, Ngn3, NeuroD, IA-1, and MafA and subsequently the expression of insulin at both the mRNA and the protein levels. After 7 days, C-peptide was detected in the supernatant of INGAP-treated cells, reflecting their ability to secrete insulin. The magnitude of differentiation was enhanced by embedding the cells in Matrigel, which led to islet-like cluster formation. The islet-like clusters cells stained positive for nuclear Pdx-1 and Glut 2 proteins, and were expressing Insulin mRNA. These new data suggest that human adult pancreatic ductal cells retain morphogenetic plasticity and demonstrate that a short exposure to INGAP triggers their differentiation into insulin-expressing cells in vitro. In the context of the urgent search for a regenerative and/or cellular therapy for diabetes, these results make INGAP a promising therapeutic candidate. PMID:26558987

  13. Tumor characteristics of ductal carcinoma in situ of breast visualized on [F-18] fluorodeoxyglucose-positron emission tomography/computed tomography: Results from a retrospective study

    PubMed Central

    Fujioka, Tomoyuki; Kubota, Kazunori; Toriihara, Akira; Machida, Youichi; Okazawa, Kaori; Nakagawa, Tsuyoshi; Saida, Yukihisa; Tateishi, Ukihide

    2016-01-01

    AIM To clarify clinicopathological features of ductal carcinoma in situ (DCIS) visualized on [F-18] fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT). METHODS This study retrospectively reviewed 52 consecutive tumors in 50 patients with pathologically proven pure DCIS who underwent [F-18] FDG-PET/CT before surgery. [F-18] FDG-PET/CT was performed after biopsy in all patients. The mean interval from biopsy to [F-18] FDG-PET/CT was 29.2 d. [F-18] FDG uptake by visual analysis and maximum standardized uptake value (SUVmax) was compared with clinicopathological characteristics. RESULTS [F-18] FDG uptake was visualized in 28 lesions (53.8%) and the mean and standard deviation of SUVmax was 1.63 and 0.90. On univariate analysis, visual analysis and the SUVmax were associated with symptomatic presentation (P = 0.012 and 0.002, respectively), palpability (P = 0.030 and 0.024, respectively), use of core-needle biopsy (CNB) (P = 0.023 and 0.012, respectively), ultrasound-guided biopsy (P = 0.040 and 0.006, respectively), enhancing lesion ≥ 20 mm on magnetic resonance imaging (MRI) (P = 0.001 and 0.010, respectively), tumor size ≥ 20 mm on histopathology (P = 0.002 and 0.008, respectively). However, [F-18] FDG uptake parameters were not significantly associated with age, presence of calcification on mammography, mass formation on MRI, presence of comedo necrosis, hormone status (estrogen receptor, progesterone receptor and human epidermal growth factor receptor-2), and nuclear grade. The factors significantly associated with visual analysis and SUVmax were symptomatic presentation (P = 0.019 and 0.001, respectively), use of CNB (P = 0.001 and 0.031, respectively), and enhancing lesion ≥ 20 mm on MRI (P = 0.001 and 0.049, respectively) on multivariate analysis. CONCLUSION Although DCIS of breast is generally non-avid tumor, symptomatic and large tumors (≥ 20 mm) tend to be visualized on [F-18] FDG-PET/CT. PMID:27648168

  14. A Phase 1/2 and Biomarker Study of Preoperative Short Course Chemoradiation With Proton Beam Therapy and Capecitabine Followed By Early Surgery for Resectable Pancreatic Ductal Adenocarcinoma

    SciTech Connect

    Hong, Theodore S.; Ryan, David P.; Borger, Darrell R.; Blaszkowsky, Lawrence S.; Yeap, Beow Y.; Ancukiewicz, Marek; Deshpande, Vikram; Shinagare, Shweta; Wo, Jennifer Y.; Boucher, Yves; Wadlow, Raymond C.; Kwak, Eunice L.; Allen, Jill N.; Clark, Jeffrey W.; Zhu, Andrew X.; Ferrone, Cristina R.; Mamon, Harvey J.; and others

    2014-07-15

    Purpose: To evaluate the safety, efficacy and biomarkers of short-course proton beam radiation and capecitabine, followed by pancreaticoduodenectomy in a phase 1/2 study in pancreatic ductal adenocarcinoma (PDAC) patients. Methods and Materials: Patients with radiographically resectable, biopsy-proven PDAC were treated with neoadjuvant short-course (2-week) proton-based radiation with capecitabine, followed by surgery and adjuvant gemcitabine. The primary objective was to demonstrate a rate of toxicity grade ≥3 of <20%. Exploratory biomarker studies were performed using surgical specimen tissues and peripheral blood. Results: The phase 2 dose was established at 5 daily doses of 5 GyE. Fifty patients were enrolled, of whom 35 patients were treated in the phase 2 portion. There were no grade 4 or 5 toxicities, and only 2 of 35 patients (4.1%) experienced a grade 3 toxicity event (chest wall pain grade 1, colitis grade 1). Of 48 patients eligible for analysis, 37 underwent pancreaticoduodenectomy. Thirty of 37 (81%) had positive nodes. Locoregional failure occurred in 6 of 37 resected patients (16.2%), and distant recurrence occurred in 35 of 48 patients (72.9%). With median follow-up of 38 months, the median progression-free survival for the entire group was 10 months, and overall survival was 17 months. Biomarker studies showed significant associations between worse survival outcomes and the KRAS point mutation change from glycine to aspartic acid at position 12, stromal CXCR7 expression, and circulating biomarkers CEA, CA19-9, and HGF (all, P<.05). Conclusions: This study met the primary endpoint by showing a rate of 4.1% grade 3 toxicity for neoadjuvant short-course proton-based chemoradiation. Treatment was associated with favorable local control. In exploratory analyses, KRAS{sup G12D} status and high CXCR7 expression and circulating CEA, CA19-9, and HGF levels were associated with poor survival.

  15. Long-term Outcomes of Hypofractionation Versus Conventional Radiation Therapy After Breast-Conserving Surgery for Ductal Carcinoma In Situ of the Breast

    SciTech Connect

    Lalani, Nafisha; Paszat, Lawrence; Sutradhar, Rinku; Thiruchelvam, Deva; Nofech-Mozes, Sharon; Hanna, Wedad; Slodkowska, Elzbieta; Done, Susan J.; Miller, Naomi; Youngson, Bruce; Tuck, Alan; Sengupta, Sandip; Elavathil, Leela; Chang, Martin C.; Jani, Prashant A.; Bonin, Michel; and others

    2014-12-01

    Purpose: Whole-breast radiation therapy (XRT) after breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS) may decrease the risk of local recurrence, but the optimal dose regimen remains unclear. Past studies administered 50 Gy in 25 fractions (conventional); however, treatment pattern studies report that hypofractionated (HF) regimens (42.4 Gy in 16 fractions) are frequently used. We report the impact of HF (vs conventional) on the risk of local recurrence after BCS for DCIS. Methods and Materials: All women with DCIS treated with BCS and XRT in Ontario, Canada from 1994 to 2003 were identified. Treatment and outcomes were assessed through administrative databases and validated by chart review. Survival analyses were performed. To account for systematic differences between women treated with alternate regimens, we used a propensity score adjustment approach. Results: We identified 1609 women, of whom 971 (60%) received conventional regimens and 638 (40%) received HF. A total of 489 patients (30%) received a boost dose, of whom 143 (15%) received conventional radiation therapy and 346 (54%) received HF. The median follow-up time was 9.2 years. The median age at diagnosis was 56 years (interquartile range [IQR], 49-65 years). On univariate analyses, the 10-year actuarial local recurrence–free survival was 86% for conventional radiation therapy and 89% for HF (P=.03). On multivariable analyses, age <45 years (hazard ratio [HR] = 2.4; 95% CI: 1.6-3.4; P<.0001), high (HR=2.9; 95% CI: 1.2-7.3; P=.02) or intermediate nuclear grade (HR=2.7; 95% CI: 1.1-6.6; P=.04), and positive resection margins (HR=1.4; 95% CI: 1.0-2.1; P=.05) were associated with an increased risk of local recurrence. HF was not significantly associated with an increased risk of local recurrence compared with conventional radiation therapy on multivariate analysis (HR=0.8; 95% CI: 0.5-1.2; P=.34). Conclusions: The risk of local recurrence among individuals treated with HF regimens

  16. The significance of relative dose intensity in adjuvant chemotherapy of pancreatic ductal adenocarcinoma-including the analysis of clinicopathological factors influencing relative dose intensity.

    PubMed

    Yabusaki, Norimitsu; Fujii, Tsutomu; Yamada, Suguru; Murotani, Kenta; Sugimoto, Hiroyuki; Kanda, Mitsuro; Nakayama, Goro; Koike, Masahiko; Fujiwara, Michitaka; Kodera, Yasuhiro

    2016-07-01

    Recently, it has been reported that the relative dose intensity (RDI) of adjuvant chemotherapy (AC) influences survival in various cancers, but there are very few reports about RDI in pancreatic ductal adenocarcinoma (PDAC). The optimal timing for initiation of AC for PDAC also remains unknown. The aim of this study was to identify the significance of RDI and the time interval between surgery and initiation of AC on survival of patients with PDAC. Clinicopathological factors that affect RDI were also investigated.A total of 311 consecutive PDAC patients who underwent curative resection between May 2005 and January 2015 were enrolled. Patients who underwent neoadjuvant chemoradiation, had UICC stage IV disease, or had early recurrences within 6 months were excluded, and the remaining 168 cases were analyzed.Patients with RDIs ≥80% (n = 79) showed significantly better overall survival (OS) compared to patients with RDIs <80% (n = 55) (median survival time (MST): 45.6 months, 26.0 months, P < 0.001). Patients with no AC (n = 34) showed the worst OS (MST: 20.8 months). Whether the AC was initiated earlier or later than 8 weeks after surgery did not influence survival, either in patients with RDIs ≥80% (P = 0.79) or in those with <80% (P = 0.73). Patients in the S-1 monotherapy group (n = 49) showed significantly better OS than patients in the gemcitabine monotherapy group (n = 51) (MST: 95.0 months, 26.0 months, respectively; P = 0.001). Univariate analysis conducted after adjusting for the chemotherapeutic drug used identified several prognostic factors; male gender (P = 0.01), intraoperative blood transfusion (P = 0.005), lymph node metastasis (P = 0.03), and postoperative WBC count (P = 0.03). Multivariate analysis identified intra-plus postoperative blood transfusion (P = 0.002) and high postoperative platelet-to-lymphocyte ratios (PLR) (P = 0.04) as independent predictors of poor RDI.Efforts to

  17. Synthesis and evaluation of a radioiodinated peptide probe targeting αvβ6 integrin for the detection of pancreatic ductal adenocarcinoma

    SciTech Connect

    Ueda, Masashi; Fukushima, Takahiro; Ogawa, Kei; Kimura, Hiroyuki; Ono, Masahiro; Yamaguchi, Takashi; Ikehara, Yuzuru; Saji, Hideo

    2014-03-14

    Highlights: • We developed a radioiodinated peptide probe targeting αvβ6 integrin ({sup 123}I-IFMDV2). • {sup 123}I-IFMDV2 had a high affinity and selectivity for αvβ6 integrin. • {sup 123}I-IFMDV2 showed a specific binding to αvβ6 integrin in vivo. • {sup 123}I-IFMDV2 enabled clear visualization of the αvβ6-integrin-positive tumor. - Abstract: Introduction: Pancreatic ductal adenocarcinoma (PDAC) remains a major cause of cancer-related death. Since significant upregulation of αvβ6 integrin has been reported in PDAC, this integrin is a promising target for PDAC detection. In this study, we aimed to develop a radioiodinated probe for the imaging of αvβ6 integrin-positive PDAC with single-photon emission computed tomography (SPECT). Methods: Four peptide probes were synthesized and screened by competitive and saturation binding assays using 2 PDAC cell lines (AsPC-1, αvβ6 integrin-positive; MIA PaCa-2, αvβ6 integrin-negative). The probe showing the best affinity was used to study the biodistribution assay, an in vivo blocking study, and SPECT imaging using tumor bearing mice. Autoradiography and immunohistochemical analysis were also performed. Results: Among the 4 probes examined in this study, {sup 125}I-IFMDV2 showed the highest affinity for αvβ6 integrin expressed in AsPC-1 cells and no affinity for MIA PaCa-2 cells. The accumulation of {sup 125}I-IFMDV2 in the AsPC-1 xenograft was 3–5 times greater than that in the MIA PaCa-2 xenograft, consistent with the expression of αvβ6 integrin in each xenograft, and confirmed by immunohistochemistry. Pretreatment with excess amounts of A20FMDV2 significantly blocked the accumulation of {sup 125}I-IFMDV2 in the AsPC-1 xenograft, but not in the MIA PaCa-2 xenograft. Furthermore, {sup 123}I-IFMDV2 enabled clear visualization of the AsPC-1 xenograft. Conclusion: {sup 123}I-IFMDV2 is a potential SPECT probe for the imaging of αvβ6 integrin in PDAC.

  18. Prostatic adenoma of ductal origin.

    PubMed

    Min, K W; Gyorkey, F

    1980-07-01

    A case of prostatic adenoma believed to originate from the prostatic duct is described. There were morphologic similarities to basal cell adenomas of salivary glands, and it was concluded that the tumor is a benign counterpart of "salivary gland" carcinomas, rarely observed in the prostate.

  19. Factors associated with local recurrence and cause-specific survival in patients with ductal carcinoma in situ of the breast treated with breast-conserving therapy or mastectomy

    SciTech Connect

    Vargas, Carlos; Kestin, Larry; Go, Nel; Krauss, Daniel; Chen, Peter; Goldstein, Neal; Martinez, Alvaro; Vicini, Frank A. . E-mail: fvicini@beaumont.edu

    2005-12-01

    Purpose: We reviewed our institution's experience treating patients with ductal carcinoma in situ (DCIS) of the breast to determine risk factors for ipsilateral breast tumor recurrence (IBTR) and cause-specific survival (CSS) after breast-conserving therapy (BCT) or mastectomy. Materials and Methods: Between 1981 and 1999, 410 cases of DCIS (405 patients) were treated at our institution; 367 were managed with breast-conserving surgery (54 with lumpectomy alone and 313 with adjuvant radiation therapy (RT) [median dose, 45 Gy]). Of these 313 patients, 298 received also a supplemental boost of RT to the lumpectomy cavity (median dose, 16 Gy). Forty-three patients underwent mastectomy; 2 (5%) received adjuvant RT to the chest wall. A true recurrence/marginal miss (TR/MM) IBTR was defined as failure within or adjacent to the tumor bed in patients undergoing BCT. Median follow-up for all patients was 7 years (mean: 6.1 years). Results: Thirty patients (8.2%) experienced an IBTR after BCT (25 [8%] after RT, 5 [9.3%] after no RT), and 2 patients (4.7%) developed a chest wall recurrence after mastectomy. Of the 32 local failures, 20 (63%) were invasive (18/30 [60%] after BCT and 2/2 [100%] after mastectomy), and 37% were DCIS alone. Twenty-four (80%) of the IBTRs were classified as TR/MM. The 10-year freedom from local failure, CSS, and overall survival after BCT or mastectomy were 89% vs. 90% (p = 0.4), 98% vs. 100% (p = 0.7), and 89% vs. 100% (p = 0.3), respectively. Factors associated with IBTR on Cox multivariate analysis were younger age (p = 0.02, hazard ratio [HR] 1.06 per year), electron boost energy {<=}9 MeV (p = 0.03, HR 1.41), final margins {<=}2 mm (p = 0.007; HR, 3.65), and no breast radiation (p = 0.002, HR 5.56). On Cox univariate analysis for BCT patients, IBTR, TR/MM failures, and predominant nuclear Grade 3 were associated with an increased risk of distant metastases and a reduced CSS. Conclusions: After treatment for DCIS, 10-year rates of local control

  20. Coexpression of CD44-positive/CD133-positive cancer stem cells and CD204-positive tumor-associated macrophages is a predictor of survival in pancreatic ductal adenocarcinoma

    PubMed Central

    Hou, Ya-Chin; Chao, Ying-Jui; Tung, Hui-Ling; Wang, Hao-Chen; Shan, Yan-Shen

    2014-01-01

    BACKGROUND The interactions between cancer stem cells (CSCs) and tumor-associated macrophages (TAMs) can promote tumor progression, maintain the CSCs population, and reduce therapeutic effects. The objective of this study was to investigate the coexpression of CSCs and TAMs and its clinical significance in pancreatic ductal adenocarcinoma (PDAC). METHODS Ninety-six patients with PDAC were included in this study. Tissue microarrays were constructed for immunostaining of the CSCs markers CD44 and CD133 and the TAMs marker CD204. Correlations between the expression of CSCs and TAMs markers and clinicopathologic characteristics or disease progression were analyzed. RESULTS Expression levels of CD44/CD133 and CD204 were significantly higher in tumor tissues than in normal tissues (P < .0001). The variables associated with survival were high coexpression of CD44/CD133 (P = .000), high expression of CD204 (P = .011), and tumor grade (P = .014). There was a positive correlation between CD44/CD133 and CD204 expression (r = 0.294; P = .004). Survival analysis indicated that high coexpression of CD44/CD133 and CD204 was associated significantly with shorter overall survival (P = .000) and disease-free survival (P = .003). Multivariate analysis revealed that high CD44/CD133 expression was an independent prognostic factor for disease-free survival, whereas high CD204 expression was an independent predictor for both overall and disease-free survival. CONCLUSIONS Coexpression of CD44/CD133 and CD204 is a useful survival prediction marker for patients with PDAC. Cancer 2014;120:2766–2777. © The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. The clinical significance of pancreatic cancer stem cells and tumor-associated macrophages is explored in patients with pancreatic ductal adenocarcinoma. The results clearly demonstrate that coexpression of 2 cancer stem cell markers (CD44 and CD133) and a tumor

  1. Review of Prostate Anatomy and Embryology and the Etiology of Benign Prostatic Hyperplasia.

    PubMed

    Aaron, LaTayia; Franco, Omar E; Hayward, Simon W

    2016-08-01

    Prostate development follows a common pattern between species and depends on the actions of androgens to induce and support ductal branching morphogenesis of buds emerging from the urogenital sinus. The human prostate has a compact zonal anatomy immediately surrounding the urethra and below the urinary bladder. Rodents have a lobular prostate with lobes radiating away from the urethra. The human prostate is the site of benign hyperplasia, prostate cancer, and prostatitis. The rodent prostate has little naturally occurring disease. Rodents can be used to model aspects of human benign hyperplasia, but care should be taken in data interpretation and extrapolation to the human condition. PMID:27476121

  2. The lipid-reactive oxygen species phenotype of breast cancer. Raman spectroscopy and mapping, PCA and PLSDA for invasive ductal carcinoma and invasive lobular carcinoma. Molecular tumorigenic mechanisms beyond Warburg effect.

    PubMed

    Surmacki, Jakub; Brozek-Pluska, Beata; Kordek, Radzislaw; Abramczyk, Halina

    2015-04-01

    Vibrational signatures of human breast tissue (invasive ductal carcinoma and invasive lobular carcinoma) were used to identify, characterize and discriminate structures in normal (noncancerous) and cancerous tissues by confocal Raman imaging, Raman spectroscopy and IR spectroscopy. The most important differences between normal and cancerous tissues were found in regions characteristic for vibrations of carotenoids, fatty acids, proteins, and interfacial water. Particular attention was paid to the role played by unsaturated fatty acids and their derivatives. K-means clustering and basis analysis followed by PCA and PLSDA is employed to analyze Raman spectroscopic maps of human breast tissue and for a statistical analysis of the samples (82 patients, 164 samples). Raman maps successfully identify regions of carotenoids, fatty acids, and proteins. The intensities, frequencies and profiles of the average Raman spectra differentiate the biochemical composition of normal and cancerous tissues. The paper demonstrates that Raman imaging has reached a clinically relevant level in regard to breast cancer diagnosis applications. The sensitivity and specificity obtained directly from PLSLD and cross validation are equal to 90.5% and 84.8% for calibration and 84.7% and 71.9% for cross-validation respectively.

  3. An analysis of predictive biomarkers in routine histopathological reporting of infiltrating ductal breast carcinoma in a tertiary hospital in Malaysia with a focus on limitations and directions for future development.

    PubMed

    Teoh, Kean-Hooi; Looi, Lai-Meng; Sabaratnam, Subathra; Cheah, Phaik-Leng; Nazarina, Abdul Rahman; Mun, Kein-Seong

    2011-06-01

    Predictive biomarkers such as oestrogen (ER) and progesterone (PR) receptors and c-erbB-2 oncoprotein have become a staple in breast cancer reports in the country as they increasingly play an important role in the treatment and prognosis of women with breast cancers. This study reviews the practice of histopathology reporting of these biomarkers in a Malaysian tertiary hospital setting. Retrospective data on demographic, pathological and biomarker profiles of patients with invasive ductal carcinoma who had undergone mastectomy or lumpectomy with axillary node clearance from 2005 to 2006 were retrieved from the Department of Pathology, Penang Hospital and analysed. The prevalence of ER positivity (55.8%), PR positivity (52.5%), c-erbB-2 oncoprotein overexpression (24%) and triple negativity (ER negative, PR negative, c-erbB-2 negative) (15%) by immunohistochemistry were comparable with other studies. Notably, c-erbB-2 overexpression was equivocal (2+) in 15% of cases. Since about a quarter of equivocal (2+) cases usually show amplification by FISH, a small but certain percentage of patients would miss the benefit of anti-c-erbB-2 antibody therapy if FISH is not performed. New ASCO/CAP guidelines on the quantitation of ER and PR will probably increase the prevalence of ER/PR positivity, invariably leading to significant ramifications on the management of patients as more patients would be deemed eligible for endocrine therapy, as well as categorisation of triple negative breast cancers.

  4. 3-D reconstruction and virtual ductoscopy of high-grade ductal carcinoma in situ of the breast with casting type calcifications using refraction-based X-ray CT.

    PubMed

    Ichihara, Shu; Ando, Masami; Maksimenko, Anton; Yuasa, Tetsuya; Sugiyama, Hiroshi; Hashimoto, Eiko; Yamasaki, Katsuhito; Mori, Kensaku; Arai, Yoshinori; Endo, Tokiko

    2008-01-01

    Stereomicroscopic observations of thick sections, or three-dimensional (3-D) reconstructions from serial sections, have provided insights into histopathology. However, they generally require time-consuming and laborious procedures. Recently, we have developed a new algorithm for refraction-based X-ray computed tomography (CT). The aim of this study is to apply this emerging technology to visualize the 3-D structure of a high-grade ductal carcinomas in situ (DCIS) of the breast. The high-resolution two-dimensional images of the refraction-based CT were validated by comparing them with the sequential histological sections. Without adding any contrast medium, the new CT showed strong contrast and was able to depict the non-calcified fine structures such as duct walls and intraductal carcinoma itself, both of which were barely visible in a conventional absorption-based CT. 3-D reconstruction and virtual endoscopy revealed that the high-grade DCIS was located within the dichotomatous branches of the ducts. Multiple calcifications occurred in the necrotic core of the continuous DCIS, resulting in linear and branching (casting type) calcifications, a hallmark of high-grade DCIS on mammograms. In conclusion, refraction-based X-ray CT approaches the low-power light microscopic view of the histological sections. It provides high quality slice data for 3-D reconstruction and virtual ductosocpy.

  5. Predictive factors for invasive cancer in surgical specimens following an initial diagnosis of ductal carcinoma in situ after stereotactic vacuum-assisted breast biopsy in microcalcification-only lesions

    PubMed Central

    Gümüş, Hatice; Mills, Philippa; Fish, David; Gümüş, Metehan; Cox, Karina; Devalia, Haresh; Jones, Sue; Jones, Peter; Sever, Ali R.

    2016-01-01

    PURPOSE The aim of this study was to determine the incidence of invasive breast carcinoma in patients with preoperative diagnosis of ductal carcinoma in situ (DCIS) by stereotactic vacuum-assisted biopsy (SVAB) performed for microcalcification-only lesions, and to identify the predictive factors of invasion. METHODS From 2000 to 2010, the records of 353 DCIS patients presenting with microcalcification-only lesions who underwent SVAB were retrospectively reviewed. The mammographic size of microcalcification cluster, presence of microinvasion within the cores, the total number of calcium specks, and the number of calcium specks within the retrieved core biopsy specimen were recorded. Patients were grouped as those with or without invasion in the final pathologic report, and variables were compared between the two groups. RESULTS The median age was 58 years (range, 34–88 years). At histopathologic examination of the surgical specimen, 63 of 353 patients (17.8%) were found to have an invasive component, although SVAB cores had only shown DCIS preoperatively. The rate of underestimation was significantly higher in patients with microcalcification covering an area of 40 mm or more, in the presence of microinvasion at biopsy, and in cases where less than 40% of the calcium specks were removed from the lesion. CONCLUSION Invasion might be underestimated in DCIS cases diagnosed with SVAB performed for microcalcification-only lesions, especially when the mammographic size of calcification is equal to or more than 40 mm or if microinvasion is found within the biopsy specimen and less than 40% of the calcifications are removed. At least 40% of microcalcification specks should be removed from the lesion to decrease the rate of underestimation with SVAB. PMID:26509833

  6. Final results from a multicenter prospective study ( JROSG 05–5) on postoperative radiotherapy for patients with ductal carcinoma in situ with an involved surgical margin or close margin widths of 1 mm or less

    PubMed Central

    Shikama, Naoto; Sekiguchi, Kenji; Nakamura, Naoki; Sekine, Hiroshi; Nakayama, Yuko; Imanaka, Kazufumi; Akiba, Takeshi; Aoki, Masahiko; Hatayama, Yoshiomi; Ogo, Etsuyo; Kagami, Yoshikazu; Kawashima, Miho; Karasawa, Kumiko

    2015-01-01

    This multicenter prospective study ( Japanese Radiation Oncology Study Group: JROSG 05-5) aimed to evaluate the effectiveness of postoperative radiotherapy (PORT) in patients with ductal carcinoma in situ (DCIS) with an involved surgical margin or close margin widths of ≤1 mm or less. PORT consisted of whole-breast irradiation (50 Gy in 25 fractions) followed by boost irradiation (10 Gy in 5 fractions). Eligibility criteria were as follows: (i) DCIS without an invasive carcinoma component, (ii) age between 20 and 80 years old, (iii) involved margin or close margin widths of ≤1 mm, (iv) refusal of re-resection, (v) performance status of 0–2, and (vi) written informed consent. The primary endpoint was ipsilateral breast tumor recurrence (IBTR), and secondary endpoints were overall survival (OS), relapse-free survival (RFS), recurrence patterns, and adverse events. A total of 37 patients from 12 institutions were enrolled from January 2007 to May 2009. The median follow-up time was 62 months (range, 28–85 months). The median pathological tumor size was 2.5 cm (range, 0.3–8.5 cm). Of the 37 patients, 21 had involved margins, and 16 had close margins. The 5-year IBTR, OS and RFS rates were 6% (95% confidence interval [CI]: 2–21), 97% (95% CI: 83–99) and 91% (95% CI: 77–97), respectively. Two patients developed local recurrence at the original site after 39 and 58 months. No severe adverse events were found. Our study suggests that this PORT regimen could be a treatment option for patients with DCIS with involved margin or close margin who don't desire re-resection. PMID:26093369

  7. The Role of High-Resolution Magic Angle Spinning 1H Nuclear Magnetic Resonance Spectroscopy for Predicting the Invasive Component in Patients with Ductal Carcinoma In Situ Diagnosed on Preoperative Biopsy.

    PubMed

    Chae, Eun Young; Shin, Hee Jung; Kim, Suhkmann; Baek, Hyeon-Man; Yoon, Dahye; Kim, Siwon; Shim, Ye Eun; Kim, Hak Hee; Cha, Joo Hee; Choi, Woo Jung; Lee, Jeong Hyun; Shin, Ji Hoon; Lee, Hee Jin; Gong, Gyungyub

    2016-01-01

    The purpose of this study was to evaluate the role of high-resolution magic angle spinning (HR-MAS) 1H nuclear magnetic resonance (NMR) spectroscopy in patients with ductal carcinoma in situ (DCIS) diagnosed on preoperative biopsy. We investigated whether the metabolic profiling of tissue samples using HR-MAS 1H NMR spectroscopy could be used to distinguish between DCIS lesions with or without an invasive component. Our institutional review board approved this combined retrospective and prospective study. Tissue samples were collected from 30 patients with pure DCIS and from 30 with DCIS accompanying invasive carcinoma. All patients were diagnosed with DCIS by preoperative core-needle biopsy and underwent surgical resection. The metabolic profiling of tissue samples was performed by HR-MAS 1H NMR spectroscopy. All observable metabolite signals were identified and quantified in all tissue samples. Metabolite intensity normalized by total spectral intensities was compared according to the tumor type using the Mann-Whitney test. Multivariate analysis was performed with orthogonal projections to latent structure-discriminant analysis (OPLS-DA). By univariate analysis, the metabolite concentrations of choline-containing compounds obtained with HR-MAS 1H NMR spectroscopy did not differ significantly between the pure DCIS and DCIS accompanying invasive carcinoma groups. However, the GPC/PC ratio was higher in the pure DCIS group than in the DCIS accompanying invasive carcinoma group (p = 0.004, Bonferroni-corrected p = 0.064), as well as the concentration of myo-inositol and succinate. By multivariate analysis, the OPLS-DA models built with HR-MAS MR metabolic profiles could clearly discriminate between pure DCIS and DCIS accompanying invasive carcinoma. Our preliminary results suggest that HR-MAS MR metabolomics on breast tissue may be able to distinguish between DCIS lesions with or without an invasive component. PMID:27560937

  8. The Role of High-Resolution Magic Angle Spinning 1H Nuclear Magnetic Resonance Spectroscopy for Predicting the Invasive Component in Patients with Ductal Carcinoma In Situ Diagnosed on Preoperative Biopsy

    PubMed Central

    Chae, Eun Young; Kim, Suhkmann; Baek, Hyeon-Man; Yoon, Dahye; Kim, Siwon; Shim, Ye Eun; Kim, Hak Hee; Cha, Joo Hee; Choi, Woo Jung; Lee, Jeong Hyun; Shin, Ji Hoon; Lee, Hee Jin; Gong, Gyungyub

    2016-01-01

    The purpose of this study was to evaluate the role of high-resolution magic angle spinning (HR-MAS) 1H nuclear magnetic resonance (NMR) spectroscopy in patients with ductal carcinoma in situ (DCIS) diagnosed on preoperative biopsy. We investigated whether the metabolic profiling of tissue samples using HR-MAS 1H NMR spectroscopy could be used to distinguish between DCIS lesions with or without an invasive component. Our institutional review board approved this combined retrospective and prospective study. Tissue samples were collected from 30 patients with pure DCIS and from 30 with DCIS accompanying invasive carcinoma. All patients were diagnosed with DCIS by preoperative core-needle biopsy and underwent surgical resection. The metabolic profiling of tissue samples was performed by HR-MAS 1H NMR spectroscopy. All observable metabolite signals were identified and quantified in all tissue samples. Metabolite intensity normalized by total spectral intensities was compared according to the tumor type using the Mann-Whitney test. Multivariate analysis was performed with orthogonal projections to latent structure-discriminant analysis (OPLS-DA). By univariate analysis, the metabolite concentrations of choline-containing compounds obtained with HR-MAS 1H NMR spectroscopy did not differ significantly between the pure DCIS and DCIS accompanying invasive carcinoma groups. However, the GPC/PC ratio was higher in the pure DCIS group than in the DCIS accompanying invasive carcinoma group (p = 0.004, Bonferroni-corrected p = 0.064), as well as the concentration of myo-inositol and succinate. By multivariate analysis, the OPLS-DA models built with HR-MAS MR metabolic profiles could clearly discriminate between pure DCIS and DCIS accompanying invasive carcinoma. Our preliminary results suggest that HR-MAS MR metabolomics on breast tissue may be able to distinguish between DCIS lesions with or without an invasive component. PMID:27560937

  9. Strong adverse effect of epidermal growth factor receptor 2 overexpression on prognosis of patients with invasive lobular breast cancer: a comparative study with invasive ductal breast cancer in Chinese population.

    PubMed

    Wang, Tong; Ma, Yuanyuan; Wang, Liang; Liu, Hong; Chen, Meixuan; Niu, Ruifang

    2015-08-01

    The data on the outcome of breast invasive lobular carcinoma (ILC) are conflicting. In addition, the prognostic effect of molecular subtypes on ILC remains unclear. In this study, the clinicopathological and prognostic data between 269 ILC and 816 invasive ductal carcinoma (IDC) cases in a Chinese population were extensively compared, with a median follow-up time of 7.8 years. Compared with the IDC group, ILC tumors had more lymph node invasion, hormonal receptor positivity, and human epidermal growth factor receptor 2 (HER2) negativity. ILC patients showed overall survival (OS) and recurrence/metastasis-free survival (RFS) rates similar to those of IDC patients but exhibited worse disease-free survival (DFS) rate because of the higher rate of contralateral breast cancer (BC). Further analysis showed that OS, RFS, and DFS were similar between ILC and IDC patients in the subgroups of luminal A and triple-negative BC with HER2 negativity but were worse in ILC patients than those in IDC patients in the subgroups of luminal B and HER2 overexpression with positive HER2 expression. Multivariate analysis indicated HER2 positivity as an independent risk factor for OS, RFS, and DFS of ILC patients, which increased the risk in the ILC group than that in IDC group. The interaction of HER2 and ILC was also defined as an independent risk factor for OS, RFS, and DFS of the entire population. In conclusion, overexpression of HER2 exhibited stronger negative effect on the prognosis of ILC patients than that in IDC patients, suggesting that treatment targeting HER2 is crucial for this BC subgroup. PMID:25804795

  10. Pseudoangiomatous hyperplasia of mammary stroma associated with gynaecomastia.

    PubMed Central

    Milanezi, M F; Saggioro, F P; Zanati, S G; Bazan, R; Schmitt, F C

    1998-01-01

    AIMS: To evaluate the prevalence of pseudoangiomatous hyperplasia of mammary stroma in gynaecomastia and its immunohistochemical profile in this setting. METHODS: Eighty eight cases of gynaecomastia recovered from the files of the department of pathology, Botucatu School of Medicine from 1976 to 1996 were studied. In the cases associated with pseudoangiomatous hyperplasia of mammary stroma, immunoreactivity for cytokeratins (CAM 5.2), vimentin, CD34, factor VIII related antigen, and the oestrogen and progesterone receptors were studied. RESULTS: Pseudoangiomatous hyperplasia of mammary stroma was found in 21 of 88 cases of gynaecomastia (23.8%). In all cases, the cells lining the spaces were positive for vimentin, whereas CAM 5.2 and factor VIII related antigen were consistently negative. Nineteen of the 21 cases showed immunoreactivity for CD34. Ductal epithelial cells were positive for both the oestrogen receptor and the progesterone receptor, whereas stromal cells were negative. CONCLUSIONS: Pseudoangiomatous hyperplasia of mammary stroma was present in approximately one quarter of the cases of gynaecomastia. This immunohistochemical study confirms the mesenchymal origin of the stromal cells that line the pseudovascular spaces, as has been found in female cases of pseudoangiomatous hyperplasia of mammary stroma. Images PMID:9659260

  11. Parathyroid hyperplasia

    MedlinePlus

    Enlarged parathyroid glands; Osteoporosis - parathyroid hyperplasia; Bone thinning - parathyroid hyperplasia; Osteopenia - parathyroid hyperplasia; High calcium level - parathyroid hyperplasia; Chronic kidney disease - parathyroid hyperplasia; ...

  12. The inhibition of cell proliferation and induction of apoptosis in pancreatic ductal adenocarcinoma cells by verrucarin A, a macrocyclic trichothecene, is associated with the inhibition of Akt/NF-кB/mTOR prosurvival signaling.

    PubMed

    Deeb, Dorrah; Gao, Xiaohua; Liu, Yongbo; Zhang, Yiguan; Shaw, Jiajiu; Valeriote, Frederick A; Gautam, Subhash C

    2016-09-01

    Pancreatic ductal adenocarcinoma (PDA) remains one of the most difficult to treat of all malignancies. Multimodality regimens provide only short-term symptomatic improvement with minor impact on survival, underscoring the urgent need for novel therapeutics and treatment strategies for PDA. Trichothecenes are powerful mycotoxins that inhibit protein synthesis and induce ribotoxic stress response in mammalian cells. Verrucarin A (VC-A) is a Type D macrocyclic mycotoxin which inhibited cell proliferation and induced apoptosis in breast cancer cells. However, the antitumor activity of VC-A for PDA cells has not been investigated. Here we show potent antitumor activity and the mechanism of action of VC-A in PDA cell lines. VC-A strongly inhibited the proliferation and arrested cells in the S phase of the cell cycle. The blocking of cell cycle progression by VC-A was associated with the inhibition of cell cycle regulatory proteins cyclin D1, cyclin E, cyclin-dependent kinases (cdks) cdk2, cdk4 and cdk inhibitor WAF1/21. VC-A induced apoptosis in PDA cells as indicated by the increased Annexin V FITC-binding, cleavage of poly(ADP-ribose) polymerase‑1 (PARP-1) and procaspases-3, -8 and -9. VC-A also induced mitochondrial depolarization and release of cytochrome c and it inhibited Bcl-2 family proteins that regulate apoptosis (Bcl-2, Bcl-xL, Bax and Bad). In addition, VC-A reduced the levels of inhibitors of apoptosis survivin and c-IAP-2. Finally, VC-A downregulated the expression of prosurvival phospho-Akt (p-Akt), nuclear factor κB (NF-κB) (p65) and mammalian target of rapamycin (p-mTOR) signaling proteins and their downstream mediators. Together, these results demonstrated strong antiproliferative and apoptosis-inducing activity of verrucarin A for PDA cells through cell cycle arrest and inhibition of the prosurvival (antiapoptotic) AKT/NF-κB/mTOR signaling. PMID:27573873

  13. Magnetic Resonance Imaging after Completion of Neoadjuvant Chemotherapy Can Accurately Discriminate between No Residual Carcinoma and Residual Ductal Carcinoma In Situ in Patients with Triple-Negative Breast Cancer

    PubMed Central

    Park, Seho; Yoon, Jung Hyun; Sohn, Joohyuk; Park, Hyung Seok; Moon, Hee Jung; Kim, Min Jung; Kim, Eun-Kyung; Kim, Seung Il; Park, Byeong-Woo

    2016-01-01

    Background The accurate evaluation of favorable response to neoadjuvant chemotherapy (NCT) is critical to determine the extent of surgery. We investigated independent clinicopathological and radiological predictors to discriminate no residual carcinoma (ypT0) from residual ductal carcinoma in situ (ypTis) in breast cancer patients who received NCT. Patients and Methods Parameters of 117 patients attaining pathological complete response (CR) in the breast after NCT between January 2010 and December 2013 were retrospectively evaluated by univariate and multivariate analyses. All patients underwent mammography, ultrasound, and magnetic resonance imaging (MRI) before and after NCT. Results There were 67 (57.3%) patients with ypT0. These patients were associated with hormone receptor-negative status, human epidermal growth factor receptor-2 (HER2)-negative tumors, and a higher likelihood of breast-conservation surgery. Baseline mammographic and MRI presentation of the main lesion, absence of associated microcalcifications, shape, posterior features, and absence of calcifications on ultrasound were significantly associated with ypT0. CR in mammography, ultrasound, or MRI after NCT was also related to ypT0. By multivariate analysis, independent predictors of ypT0 were the triple-negative subtype [Odds ratio (OR), 4.23; 95% confidence interval (CI), 1.11–16.09] and CR in MRI after NCT (OR, 5.23; 95% CI, 1.53–17.85). Stratified analysis by breast cancer subtype demonstrated that MRI well predicted ypT0 in all subtypes except the HER2-positive subtype. In particular, of 40 triple-negative subtypes, 22 showed CR in MRI and 21 (95.5%) were ypT0 after NCT. Conclusion Among imaging modalities, breast MRI can potentially distinguish between ypT0 and ypTis after NCT, especially in patients with triple-negative breast cancer. This information can help clinicians evaluate tumor response to NCT and plan surgery for breast cancer patients of all subtypes except for those with HER2

  14. Management of pancreatic ductal leaks and fistulae.

    PubMed

    Larsen, Michael; Kozarek, Richard

    2014-01-01

    Pancreatic duct leaks can occur as a result of both acute and chronic pancreatitis or in the setting of pancreatic trauma. Manifestations of leaks include pseudocysts, pancreatic ascites, high amylase pleural effusions, disconnected duct syndrome, and internal and external pancreatic fistulas. Patient presentations are highly variable and range from asymptomatic pancreatic cysts to patients with severe abdominal pain and sepsis from infected fluid collections. The diagnosis can often be made by high-quality cross-sectional imaging or during endoscopic retrograde cholangiopancreatography (ERCP). Because of their complexity, pancreatic leak patients are best managed by a multidisciplinary team comprised of therapeutic endoscopists, interventional radiologists, and surgeons in the field of pancreatic interventions. Minor leaks will often resolve with conservative management while severe leaks will frequently require interventions. Endoscopic treatments for pancreatic duct leaks have replaced surgical interventions in many situations. Interventional radiologists also have the ability to offer therapeutic interventions for many leak patients. The mainstay of endotherapy for pancreatic leaks is transpapillary pancreatic duct stenting with a stent that bridges the leak if possible, but varies based on the manifestation and clinical presentation. Fluid collections that result from leaks, such as pseudocysts, can often be treated by endoscopic transluminal drainage with or without endoscopic ultrasound or by percutaneous drainage. Endoscopic interventions have been shown to be effective and have an acceptable complication rate.

  15. Reflex Estrogen Receptor (ER) and Progesterone Receptor (PR) Analysis of Ductal Carcinoma In Situ (DCIS) in Breast Needle Core Biopsy Specimens: An Unnecessary Exercise That Costs the United States $35 Million/y.

    PubMed

    VandenBussche, Christopher J; Cimino-Mathews, Ashley; Park, Ben Ho; Emens, Leisha A; Tsangaris, Theodore N; Argani, Pedram

    2016-08-01

    Most institutions reflexively test all breast core needle biopsy specimens showing ductal carcinoma in situ (DCIS) for estrogen receptor (ER) and progesterone receptor (PR). However, 5 factors suggest that this reflex testing unnecessarily increases costs. First, ER/PR results do not currently impact the next step in standard therapy; namely, surgical excision. Second, a subset of surgical excisions performed for DCIS diagnosed on core needle biopsy will harbor infiltrating mammary carcinoma, which will then need to be retested for ER/PR. Third, because ER and PR labeling is often heterogeneous in DCIS, negative results for ER/PR on small core needle biopsy specimens should logically be repeated on surgical excision specimens with larger amounts of DCIS to be sure that the result is truly negative. Fourth, many patients with pure ER/PR-positive DCIS after surgical excision will decline hormone therapy, so any ER/PR testing of their DCIS is unnecessary. Fifth, PR status in DCIS has no proven independent value. We now examine the unnecessary added costs associated with reflex ER/PR testing of DCIS on core needle biopsy specimens due to these factors. We reviewed 58 core needle biopsies showing pure DCIS that also had a resulting surgical excision specimen at our institution over a period of 2 years. No patient received neoadjuvant hormone therapy. On surgical excision, 5 (8.6%) had only benign findings, 44 (75.9%) had pure DCIS, and 9 (15.5%) had DCIS with invasive mammary carcinoma. The 9 cases with invasive mammary carcinoma in the surgical excision specimen (16%) and the 4 pure DCIS in surgical excision specimens that were ER/PR negative on core needle biopsy would need repeat ER/PR testing. The total unnecessary increased cost of core needle biopsy specimen testing of these 13 cases was $8148.92 ($140/patient for the 58 patients in the study). We found that ER/PR testing results impacted patient management in only 16/49 pure DCIS cases after surgical excision (33

  16. Anastrozole versus tamoxifen for the prevention of locoregional and contralateral breast cancer in postmenopausal women with locally excised ductal carcinoma in situ (IBIS-II DCIS): a double-blind, randomised controlled trial

    PubMed Central

    Forbes, John F; Sestak, Ivana; Howell, Anthony; Bonanni, Bernardo; Bundred, Nigel; Levy, Christelle; von Minckwitz, Gunter; Eiermann, Wolfgang; Neven, Patrick; Stierer, Michael; Holcombe, Chris; Coleman, Robert E; Jones, Louise; Ellis, Ian; Cuzick, Jack

    2016-01-01

    Summary Background Third-generation aromatase inhibitors are more effective than tamoxifen for preventing recurrence in postmenopausal women with hormone-receptor-positive invasive breast cancer. However, it is not known whether anastrozole is more effective than tamoxifen for women with hormone-receptor-positive ductal carcinoma in situ (DCIS). Here, we compare the efficacy of anastrozole with that of tamoxifen in postmenopausal women with hormone-receptor-positive DCIS. Methods In a double-blind, multicentre, randomised placebo-controlled trial, we recruited women who had been diagnosed with locally excised, hormone-receptor-positive DCIS. Eligible women were randomly assigned in a 1:1 ratio by central computer allocation to receive 1 mg oral anastrozole or 20 mg oral tamoxifen every day for 5 years. Randomisation was stratified by major centre or hub and was done in blocks (six, eight, or ten). All trial personnel, participants, and clinicians were masked to treatment allocation and only the trial statistician had access to treatment allocation. The primary endpoint was all recurrence, including recurrent DCIS and new contralateral tumours. All analyses were done on a modified intention-to-treat basis (in all women who were randomised and did not revoke consent for their data to be included) and proportional hazard models were used to compute hazard ratios and corresponding confidence intervals. This trial is registered at the ISRCTN registry, number ISRCTN37546358. Results Between March 3, 2003, and Feb 8, 2012, we enrolled 2980 postmenopausal women from 236 centres in 14 countries and randomly assigned them to receive anastrozole (1449 analysed) or tamoxifen (1489 analysed). Median follow-up was 7·2 years (IQR 5·6–8·9), and 144 breast cancer recurrences were recorded. We noted no statistically significant difference in overall recurrence (67 recurrences for anastrozole vs 77 for tamoxifen; HR 0·89 [95% CI 0·64–1·23]). The non-inferiority of

  17. Prolonged exposure of cholestatic rats to complete dark inhibits biliary hyperplasia and liver fibrosis

    PubMed Central

    Han, Yuyan; Onori, Paolo; Meng, Fanyin; DeMorrow, Sharon; Venter, Julie; Francis, Heather; Franchitto, Antonio; Ray, Debolina; Kennedy, Lindsey; Greene, John; Renzi, Anastasia; Mancinelli, Romina; Gaudio, Eugenio; Glaser, Shannon

    2014-01-01

    Biliary hyperplasia and liver fibrosis are common features in cholestatic liver disease. Melatonin is synthesized by the pineal gland as well as the liver. Melatonin inhibits biliary hyperplasia of bile duct-ligated (BDL) rats. Since melatonin synthesis (by the enzyme serotonin N-acetyltransferase, AANAT) from the pineal gland increases after dark exposure, we hypothesized that biliary hyperplasia and liver fibrosis are diminished by continuous darkness via increased melatonin synthesis from the pineal gland. Normal or BDL rats (immediately after surgery) were housed with light-dark cycles or complete dark for 1 wk before evaluation of 1) the expression of AANAT in the pineal gland and melatonin levels in pineal gland tissue supernatants and serum; 2) biliary proliferation and intrahepatic bile duct mass, liver histology, and serum chemistry; 3) secretin-stimulated ductal secretion (functional index of biliary growth); 4) collagen deposition, liver fibrosis markers in liver sections, total liver, and cholangiocytes; and 5) expression of clock genes in cholangiocytes. In BDL rats exposed to dark there was 1) enhanced AANAT expression/melatonin secretion in pineal gland and melatonin serum levels; 2) improved liver morphology, serum chemistry and decreased biliary proliferation and secretin-stimulated choleresis; and 4) decreased fibrosis and expression of fibrosis markers in liver sections, total liver and cholangiocytes and reduced biliary expression of the clock genes PER1, BMAL1, CLOCK, and Cry1. Thus prolonged dark exposure may be a beneficial noninvasive therapeutic approach for the management of biliary disorders. PMID:25214401

  18. Pancreatic ductal adenocarcinoma: Risk factors, screening, and early detection

    PubMed Central

    Becker, Andrew E; Hernandez, Yasmin G; Frucht, Harold; Lucas, Aimee L

    2014-01-01

    Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States, with over 38000 deaths in 2013. The opportunity to detect pancreatic cancer while it is still curable is dependent on our ability to identify and screen high-risk populations before their symptoms arise. Risk factors for developing pancreatic cancer include multiple genetic syndromes as well as modifiable risk factors. Genetic conditions include hereditary breast and ovarian cancer syndrome, Lynch Syndrome, familial adenomatous polyposis, Peutz-Jeghers Syndrome, familial atypical multiple mole melanoma syndrome, hereditary pancreatitis, cystic fibrosis, and ataxia-telangiectasia; having a genetic predisposition can raise the risk of developing pancreatic cancer up to 132-fold over the general population. Modifiable risk factors, which include tobacco exposure, alcohol use, chronic pancreatitis, diet, obesity, diabetes mellitus, as well as certain abdominal surgeries and infections, have also been shown to increase the risk of pancreatic cancer development. Several large-volume centers have initiated such screening protocols, and consensus-based guidelines for screening high-risk groups have recently been published. The focus of this review will be both the genetic and modifiable risk factors implicated in pancreatic cancer, as well as a review of screening strategies and their diagnostic yields. PMID:25170203

  19. Endoscopic and operative palliation strategies for pancreatic ductal adenocarcinoma.

    PubMed

    Stark, Alexander; Hines, O Joe

    2015-02-01

    Malignant biliary obstruction, duodenal, and gastric outlet obstruction, and tumor-related pain are the complications of unresectable pancreatic adenocarcinoma that most frequently require palliative intervention. Surgery involving biliary bypass with or without gastrojejunostomy was once the mainstay of treatment in these patients. However, advances in non-operative techniques-most notably the widespread availability of endoscopic biliary and duodenal stents-have shifted the paradigm of treatment away from traditional surgical management. Questions regarding the efficacy and durability of endoscopic stents for biliary and gastric outlet obstruction are reviewed and demonstrate high rates of therapeutic success, low rates of morbidity, and decreased cost. Surgery remains an effective treatment modality, and still produces the most durable relief in appropriately selected patients.

  20. Targeting stromal microenvironment in pancreatic ductal adenocarcinoma: controversies and promises

    PubMed Central

    Mei, Lin; Du, Wei

    2016-01-01

    Pancreatic cancer is a highly lethal disease. Conventional therapeutics targeting pancreas cancer cell compartment using cytotoxics improved patient survival but at the expense of significant toxicity. Microscopically, the tumor is characterized by thick desmoplastic stroma that surrounds islands of pancreatic cancer cells. The tumor microenvironment has been found to play important roles in carcinogenesis, the development of drug resistance, and mediating immunosuppression. The understanding the tumor-stromal interaction has led to the development of novel therapeutic approaches. Here, we review the strategies that are currently in (or, near to) clinical evaluation and the underlying preclinical rationales. PMID:27284483