Pharmacological and genetic inhibition of calcineurin protects against carbachol-induced pathological zymogen activation and acinar cell injury

PubMed Central

Muili, Kamaldeen A.; Ahmad, Mahwish; Orabi, Abrahim I.; Mahmood, Syeda M.; Shah, Ahsan U.; Molkentin, Jeffery D.

2012-01-01

Acute pancreatitis is a major health burden for which there are currently no targeted therapies. Premature activation of digestive proenzymes, or zymogens, within the pancreatic acinar cell is an early and critical event in this disease. A high-amplitude, sustained rise in acinar cell Ca2+ is required for zymogen activation. We previously showed in a cholecystokinin-induced pancreatitis model that a potential target of this aberrant Ca2+ signaling is the Ca2+-activated phosphatase calcineurin (Cn). However, in this study, we examined the role of Cn on both zymogen activation and injury, in the clinically relevant condition of neurogenic stimulation (by giving the acetylcholine analog carbachol) using three different Cn inhibitors or Cn-deficient acinar cells. In freshly isolated mouse acinar cells, pretreatment with FK506, calcineurin inhibitory peptide (CiP), or cyclosporine (CsA) blocked intra-acinar zymogen activation (n = 3; P < 0.05). The Cn inhibitors also reduced leakage of lactate dehydrogenase (LDH) by 79%, 62%, and 63%, respectively (n = 3; P < 0.05). Of the various Cn isoforms, the β-isoform of the catalytic A subunit (CnAβ) was strongly expressed in mouse acinar cells. For this reason, we obtained acinar cells from CnAβ-deficient mice (CnAβ−/−) and observed an 84% and 50% reduction in trypsin and chymotrypsin activation, respectively, compared with wild-type controls (n = 3; P < 0.05). LDH release in the CnAβ-deficient cells was reduced by 50% (n = 2; P < 0.05). The CnAβ-deficient cells were also protected against zymogen activation and cell injury induced by the cholecystokinin analog caerulein. Importantly, amylase secretion was generally not affected by either the Cn inhibitors or Cn deficiency. These data provide both pharmacological and genetic evidence that implicates Cn in intra-acinar zymogen activation and cell injury during pancreatitis. PMID:22323127

Acinar Cell Carcinoma of the Pancreas: Overview of Clinicopathologic Features and Insights into the Molecular Pathology.

PubMed

La Rosa, Stefano; Sessa, Fausto; Capella, Carlo

2015-01-01

Acinar cell carcinomas (ACCs) of the pancreas are rare pancreatic neoplasms accounting for about 1-2% of pancreatic tumors in adults and about 15% in pediatric subjects. They show different clinical symptoms at presentation, different morphological features, different outcomes, and different molecular alterations. This heterogeneous clinicopathological spectrum may give rise to difficulties in the clinical and pathological diagnosis with consequential therapeutic and prognostic implications. The molecular mechanisms involved in the onset and progression of ACCs are still not completely understood, although in recent years, several attempts have been made to clarify the molecular mechanisms involved in ACC biology. In this paper, we will review the main clinicopathological and molecular features of pancreatic ACCs of both adult and pediatric subjects to give the reader a comprehensive overview of this rare tumor type.

Induced PTF1a expression in pancreatic ductal adenocarcinoma cells activates acinar gene networks, reduces tumorigenic properties, and sensitizes cells to gemcitabine treatment.

PubMed

Jakubison, Brad L; Schweickert, Patrick G; Moser, Sarah E; Yang, Yi; Gao, Hongyu; Scully, Kathleen; Itkin-Ansari, Pamela; Liu, Yunlong; Konieczny, Stephen F

2018-05-02

Pancreatic acinar cells synthesize, package, and secrete digestive enzymes into the duodenum to aid in nutrient absorption and meet metabolic demands. When exposed to cellular stresses and insults, acinar cells undergo a dedifferentiation process termed acinar-ductal metaplasia (ADM). ADM lesions with oncogenic mutations eventually give rise to pancreatic ductal adenocarcinoma (PDAC). In healthy pancreata, the basic helix-loop-helix (bHLH) factors MIST1 and PTF1a coordinate an acinar-specific transcription network that maintains the highly developed differentiation status of the cells, protecting the pancreas from undergoing a transformative process. However, when MIST1 and PTF1a gene expression is silenced, cells are more prone to progress to PDAC. In this study, we tested whether induced MIST1 or PTF1a expression in PDAC cells could (i) re-establish the transcriptional program of differentiated acinar cells and (ii) simultaneously reduce tumor cell properties. As predicted, PTF1a induced gene expression of digestive enzymes and acinar-specific transcription factors, while MIST1 induced gene expression of vesicle trafficking molecules as well as activation of unfolded protein response components, all of which are essential to handle the high protein production load that is characteristic of acinar cells. Importantly, induction of PTF1a in PDAC also influenced cancer-associated properties, leading to a decrease in cell proliferation, cancer stem cell numbers, and repression of key ATP-binding cassette efflux transporters resulting in heightened sensitivity to gemcitabine. Thus, activation of pancreatic bHLH transcription factors rescues the acinar gene program and decreases tumorigenic properties in pancreatic cancer cells, offering unique opportunities to develop novel therapeutic intervention strategies for this deadly disease. © 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

Salivary gland acinar cells regenerate functional glandular structures in modified hydrogels

NASA Astrophysics Data System (ADS)

Pradhan, Swati

Xerostomia, a condition resulting from irradiation of the head and neck, affects over 40,000 cancer patients each year in the United States. Direct radiation damage of the acinar cells that secrete fluid and protein results in salivary gland hypofunction. Present medical management for xerostomia for patients treated for upper respiratory cancer is largely ineffective. Patients who have survived their terminal diagnosis are often left with a diminished quality of life and are unable to enjoy the simple pleasures of eating and drinking. This project aims to ultimately reduce human suffering by developing a functional implantable artificial salivary gland. The goal was to create an extracellular matrix (ECM) modified hyaluronic acid (HA) based hydrogel culture system that allows for the growth and differentiation of salivary acinar cells into functional acini-like structures capable of secreting large amounts of protein and fluid unidirectionally and to ultimately engineer a functional artificial salivary gland that can be implanted into an animal model. A tissue collection protocol was established and salivary gland tissue was obtained from patients undergoing head and neck surgery. The tissue specimen was assessed by histology and immunohistochemistry to establish the phenotype of normal salivary gland cells including the native basement membranes. Hematoxylin and eosin staining confirmed normal glandular tissue structures including intercalated ducts, striated ducts and acini. alpha-Amylase and periodic acid schiff stain, used for structures with a high proportion of carbohydrate macromolecules, preferentially stained acinar cells in the tissue. Intercalated and striated duct structures were identified using cytokeratins 19 and 7 staining. Myoepithelial cells positive for cytokeratin 14 were found wrapped around the serous and mucous acini. Tight junction components including ZO-1 and E-cadherin were present between both ductal and acinar cells. Ductal and acinar

Polycystin-2 Expression and Function in Adult Mouse Lacrimal Acinar Cells

PubMed Central

Hilgenberg, Jill D.; Rybalchenko, Volodymyr; Medina-Ortiz, Wanda E.; Gregg, Elaine V.; Koulen, Peter

2011-01-01

Purpose. Lacrimal glands regulate the production and secretion of tear fluid. Dysfunction of lacrimal gland acinar cells can ultimately result in ocular surface disorders, such as dry eye disease. Ca2+ homeostasis is tightly regulated in the cellular environment, and secretion from the acinar cells of the lacrimal gland is regulated by both cholinergic and adrenergic stimuli, which both result in changes in the cytosolic Ca2+ concentration. We have previously described the detailed intracellular distribution of inositol-1,4,5-trisphosphate receptors (IP3Rs), and ryanodine receptors (RyRs) in lacrimal acinar cells, however, little is known regarding the expression and distribution of the third major class of intracellular Ca2+ release channels, transient receptor potential polycystin family (TRPP) channels. Methods. Studies were performed in adult lacrimal gland tissue of Swiss-Webster mice. Expression, localization, and intracellular distribution of TRPP Ca2+ channels were investigated using immunocytochemistry, immunohistochemistry, and electron microscopy. The biophysical properties of single polycystin-2 channels were investigated using a planar lipid bilayer electrophysiology system. Results. All channel-forming isoforms of TRPP channels (polycystin-2, polycystin-L, and polycystin-2L2) were expressed in adult mouse lacrimal gland. Subcellular analysis of immunogold labeling revealed strongest polycystin-2 expression on the membranes of the endoplasmic reticulum, Golgi, and nucleus. Biophysical properties of lacrimal gland polycystin-2 channels were similar to those described for other tissues. Conclusions. The expression of TRPP channels in lacrimal acinar cells suggests a functional role of the proteins in the regulation of lacrimal fluid secretion under physiological and disease conditions, and provides the basis for future studies focusing on physiology and pharmacology. PMID:21508103

Expression and subcellular localization of the ryanodine receptor in rat pancreatic acinar cells.

PubMed Central

Leite, M F; Dranoff, J A; Gao, L; Nathanson, M H

1999-01-01

The ryanodine receptor (RyR) is the principal Ca2+-release channel in excitable cells, whereas the inositol 1,4,5-trisphosphate (InsP3) receptor (InsP3R) is primarily responsible for Ca2+ release in non-excitable cells, including epithelia. RyR also is expressed in a number of non-excitable cell types, but is thought to serve as an auxiliary or alternative Ca2+-release pathway in those cells. Here we use reverse transcription PCR to show that a polarized epithelium, the pancreatic acinar cell, expresses the type 2, but not the type 1 or 3, isoform of RyR. We furthermore use immunochemistry to demonstrate that the type 2 RyR is distributed throughout the basolateral and, to a lesser extent, the apical region of the acinar cell, but is excluded from the trigger zone, where cytosolic Ca2+ signals originate in this cell type. Since propagation of Ca2+ waves in acinar cells is sensitive to ryanodine, caffeine and Ca2+, these findings suggest that Ca2+ waves in this cell type result from the co-ordinated release of Ca2+, first from InsP3Rs in the trigger zone, then from RyRs elsewhere in the cell. RyR may play a fundamental role in Ca2+ signalling in polarized epithelia, including for Ca2+ signals initiated by InsP3. PMID:9882629

The Spindle Cell Neoplasms of the Oral Cavity.

PubMed

Shamim, Thorakkal

2015-01-01

Spindle cell neoplasms are defined as neoplasms that consist of spindle-shaped cells in the histopathology. Spindle cell neoplasms can affect the oral cavity. In the oral cavity, the origin of the spindle cell neoplasms may be traced to epithelial, mesenchymal and odontogenic components. This article aims to review the spindle cell neoplasms of the oral cavity with emphasis on histopathology.

The Spindle Cell Neoplasms of the Oral Cavity

PubMed Central

Shamim, Thorakkal

2015-01-01

Spindle cell neoplasms are defined as neoplasms that consist of spindle-shaped cells in the histopathology. Spindle cell neoplasms can affect the oral cavity. In the oral cavity, the origin of the spindle cell neoplasms may be traced to epithelial, mesenchymal and odontogenic components. This article aims to review the spindle cell neoplasms of the oral cavity with emphasis on histopathology. PMID:26351482

Up-regulation of Store-operated Ca2+ Entry and Nuclear Factor of Activated T Cells Promote the Acinar Phenotype of the Primary Human Salivary Gland Cells*

PubMed Central

Jang, Shyh-Ing; Ong, Hwei Ling; Liu, Xibao; Alevizos, Ilias; Ambudkar, Indu S.

2016-01-01

The signaling pathways involved in the generation and maintenance of exocrine gland acinar cells have not yet been established. Primary human salivary gland epithelial cells, derived from salivary gland biopsies, acquired an acinar-like phenotype when the [Ca2+] in the serum-free medium (keratinocyte growth medium, KGM) was increased from 0.05 mm (KGM-L) to 1.2 mm (KGM-H). Here we examined the mechanism underlying this Ca2+-dependent generation of the acinar cell phenotype. Compared with cells in KGM-L, those in KGM-H display enhancement of Orai1, STIM1, STIM2, and nuclear factor of activated T cells 1 (NFAT1) expression together with an increase in store-operated Ca2+ entry (SOCE), SOCE-dependent nuclear translocation of pGFP-NFAT1, and NFAT-dependent but not NFκB-dependent gene expression. Importantly, AQP5, an acinar-specific protein critical for function, is up-regulated in KGM-H via SOCE/NFAT-dependent gene expression. We identified critical NFAT binding motifs in the AQP5 promoter that are involved in Ca2+-dependent up-regulation of AQP5. These important findings reveal that the Ca2+-induced switch of salivary epithelial cells to an acinar-like phenotype involves remodeling of SOCE and NFAT signaling, which together control the expression of proteins critically relevant for acinar cell function. Our data provide a novel strategy for generating and maintaining acinar cells in culture. PMID:26903518

Protein kinase D1 drives pancreatic acinar cell reprogramming and progression to intraepithelial neoplasia

NASA Astrophysics Data System (ADS)

Liou, Geou-Yarh; Döppler, Heike; Braun, Ursula B.; Panayiotou, Richard; Scotti Buzhardt, Michele; Radisky, Derek C.; Crawford, Howard C.; Fields, Alan P.; Murray, Nicole R.; Wang, Q. Jane; Leitges, Michael; Storz, Peter

2015-02-01

The transdifferentiation of pancreatic acinar cells to a ductal phenotype (acinar-to-ductal metaplasia, ADM) occurs after injury or inflammation of the pancreas and is a reversible process. However, in the presence of activating Kras mutations or persistent epidermal growth factor receptor (EGF-R) signalling, cells that underwent ADM can progress to pancreatic intraepithelial neoplasia (PanIN) and eventually pancreatic cancer. In transgenic animal models, ADM and PanINs are initiated by high-affinity ligands for EGF-R or activating Kras mutations, but the underlying signalling mechanisms are not well understood. Here, using a conditional knockout approach, we show that protein kinase D1 (PKD1) is sufficient to drive the reprogramming process to a ductal phenotype and progression to PanINs. Moreover, using 3D explant culture of primary pancreatic acinar cells, we show that PKD1 acts downstream of TGFα and Kras, to mediate formation of ductal structures through activation of the Notch pathway.

Arginase-II Promotes Tumor Necrosis Factor-α Release From Pancreatic Acinar Cells Causing β-Cell Apoptosis in Aging.

PubMed

Xiong, Yuyan; Yepuri, Gautham; Necetin, Sevil; Montani, Jean-Pierre; Ming, Xiu-Fen; Yang, Zhihong

2017-06-01

Aging is associated with glucose intolerance. Arginase-II (Arg-II), the type-II L -arginine-ureahydrolase, is highly expressed in pancreas. However, its role in regulation of pancreatic β-cell function is not known. Here we show that female (not male) mice deficient in Arg-II (Arg-II -/- ) are protected from age-associated glucose intolerance and reveal greater glucose induced-insulin release, larger islet size and β-cell mass, and more proliferative and less apoptotic β-cells compared with the age-matched wild-type (WT) controls. Moreover, Arg-II is mainly expressed in acinar cells and is upregulated with aging, which enhances p38 mitogen-activated protein kinase (p38 MAPK) activation and release of tumor necrosis factor-α (TNF-α). Accordingly, conditioned medium of isolated acinar cells from old WT (not Arg-II -/- ) mice contains higher TNF-α levels than the young mice and stimulates β-cell apoptosis and dysfunction, which are prevented by a neutralizing anti-TNF-α antibody. In acinar cells, our study demonstrates an age-associated Arg-II upregulation, which promotes TNF-α release through p38 MAPK leading to β-cell apoptosis, insufficient insulin secretion, and glucose intolerance in female rather than male mice. © 2017 by the American Diabetes Association.

Functional somatostatin receptors on a rat pancreatic acinar cell line

DOE Office of Scientific and Technical Information (OSTI.GOV)

Viguerie, N.; Tahiri-Jouti, N.; Esteve, J.P.

1988-07-01

Somatostatin receptors from a rat pancreatic acinar cell line, AR4-2J, were characterized biochemically, structurally, and functionally. Binding of {sup 125}I-(Tyr{sup 11})Somatostatin to AR4-2J cells was saturable, exhibiting a single class of high-affinity binding sites with a maximal binding capacity of 258 {plus minus} 20 fmol/10{sup 6} cells. Somatostatin receptor structure was analyzed by covalently cross-linking {sup 125}I-(Tyr{sup 11})somatostatin to its plasma membrane receptors. Gel electrophoresis and autoradiography of cross-linked proteins revealed a peptide containing the somatostatin receptor. Somatostatin inhibited vasoactive intestinal peptide (VIP)-stimulated adenosine 3{prime},5{prime}-cyclic monophosphate (cAMP) formation in a dose-dependent manner. The concentration of somatostatin that caused half-maximal inhibitionmore » of cAMP formation was close to the receptor affinity for somatostatin. Pertussis toxin pretreatment of AR4-2J cells prevented somatostatin inhibition of VIP-stimulated cAMP formation as well as somatostatin binding. The authors conclude that AR4-2J cells exhibit functional somatostatin receptors that retain both specificity and affinity of the pancreatic acinar cell somatostatin receptors and act via the pertussis toxin-sensitive guanine nucleotide-binding protein N{sub i} to inhibit adenylate cyclase.« less

Pancreatic acinar cell carcinoma extending into the common bile and main pancreatic ducts.

PubMed

Yamaguchi, Rin; Okabe, Yoshinobu; Jimi, Atsuo; Shiota, Koji; Kodama, Takahito; Naito, Yoshiki; Yasunaga, Masafumi; Kinoshita, Hisafumi; Kojiro, Masamichi

2006-10-01

Acinar cell carcinoma (ACC) of the pancreas is relatively rare, accounting for only approximately 1% of all exocrine pancreatic tumors. A 69-year-old man was found to have a mass lesion measuring approximately 4 cm in diameter in the pancreatic head on ultrasound, abdominal dynamic CT, and percutaneous transhepatic cholangiography. Magnetic resonance cholangiopancreatography showed defect of the lower common bile duct (CBD) due to obstruction by the tumor cast. Histopathologically, the pancreatic head tumor invaded the main pancreatic duct (MPD) and CBD with extension into the CBD in a form of tumor cast. The tumor cells consisted of a solid proliferation with abundant eosinophilic cytoplasm and round nuclei in an acinar and trabecular fashion. A 55-year-old man with upper abdominal pain and nausea, had a cystic lesion approximately 3 cm in size in the pancreatic tail on CT. Histopathologically, the tumor was encapsulated by fibrous capsule and had extensive central necrosis with solid areas in the tumor periphery, and invaded with extension into the MPD in a form of tumor cast. The tumor cells resembled acinar cells in solid growths. Two resected cases of ACC with unusual tumor extension into the CBD and the MPD, respectively, are reported.

Calcium signalling in the acinar environment of the exocrine pancreas: physiology and pathophysiology.

PubMed

Gryshchenko, Oleksiy; Gerasimenko, Julia V; Peng, Shuang; Gerasimenko, Oleg V; Petersen, Ole H

2018-02-09

Ca 2+ signalling in different cell types in exocrine pancreatic lobules was monitored simultaneously and signalling responses to various stimuli were directly compared. Ca 2+ signals evoked by K + -induced depolarization were recorded from pancreatic nerve cells. Nerve cell stimulation evoked Ca 2+ signals in acinar but not in stellate cells. Stellate cells are not electrically excitable as they, like acinar cells, did not generate Ca 2+ signals in response to membrane depolarization. The responsiveness of the stellate cells to bradykinin was markedly reduced in experimental alcohol-related acute pancreatitis, but they became sensitive to stimulation with trypsin. Our results provide fresh evidence for an important role of stellate cells in acute pancreatitis. They seem to be a critical element in a vicious circle promoting necrotic acinar cell death. Initial trypsin release from a few dying acinar cells generates Ca 2+ signals in the stellate cells, which then in turn damage more acinar cells causing further trypsin liberation. Physiological Ca 2+ signals in pancreatic acinar cells control fluid and enzyme secretion, whereas excessive Ca 2+ signals induced by pathological agents induce destructive processes leading to acute pancreatitis. Ca 2+ signals in the peri-acinar stellate cells may also play a role in the development of acute pancreatitis. In this study, we explored Ca 2+ signalling in the different cell types in the acinar environment of the pancreatic tissue. We have, for the first time, recorded depolarization-evoked Ca 2+ signals in pancreatic nerves and shown that whereas acinar cells receive a functional cholinergic innervation, there is no evidence for functional innervation of the stellate cells. The stellate, like the acinar, cells are not electrically excitable as they do not generate Ca 2+ signals in response to membrane depolarization. The principal agent evoking Ca 2+ signals in the stellate cells is bradykinin, but in experimental alcohol

Stages of Plasma Cell Neoplasms (Including Multiple Myeloma)

MedlinePlus

... Health Professional Plasma Cell Neoplasms Treatment Research Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment (PDQ®)–Patient Version General Information About Plasma Cell Neoplasms Go to Health Professional Version Key Points ...

Activating transcription factor 3 promotes loss of the acinar cell phenotype in response to cerulein-induced pancreatitis in mice.

PubMed

Fazio, Elena N; Young, Claire C; Toma, Jelena; Levy, Michael; Berger, Kurt R; Johnson, Charis L; Mehmood, Rashid; Swan, Patrick; Chu, Alphonse; Cregan, Sean P; Dilworth, F Jeffrey; Howlett, Christopher J; Pin, Christopher L

2017-09-01

Pancreatitis is a debilitating disease of the exocrine pancreas that, under chronic conditions, is a major susceptibility factor for pancreatic ductal adenocarcinoma (PDAC). Although down-regulation of genes that promote the mature acinar cell fate is required to reduce injury associated with pancreatitis, the factors that promote this repression are unknown. Activating transcription factor 3 (ATF3) is a key mediator of the unfolded protein response, a pathway rapidly activated during pancreatic insult. Using chromatin immunoprecipitation followed by next-generation sequencing, we show that ATF3 is bound to the transcriptional regulatory regions of >30% of differentially expressed genes during the initiation of pancreatitis. Of importance, ATF3-dependent regulation of these genes was observed only upon induction of pancreatitis, with pathways involved in inflammation, acinar cell differentiation, and cell junctions being specifically targeted. Characterizing expression of transcription factors that affect acinar cell differentiation suggested that acinar cells lacking ATF3 maintain a mature cell phenotype during pancreatitis, a finding supported by maintenance of junctional proteins and polarity markers. As a result, Atf3 -/- pancreatic tissue displayed increased tissue damage and inflammatory cell infiltration at early time points during injury but, at later time points, showed reduced acinar-to-duct cell metaplasia. Thus our results reveal a critical role for ATF3 as a key regulator of the acinar cell transcriptional response during injury and may provide a link between chronic pancreatitis and PDAC. © 2017 Fazio et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

The nuclear hormone receptor family member NR5A2 controls aspects of multipotent progenitor cell formation and acinar differentiation during pancreatic organogenesis.

PubMed

Hale, Michael A; Swift, Galvin H; Hoang, Chinh Q; Deering, Tye G; Masui, Toshi; Lee, Youn-Kyoung; Xue, Jumin; MacDonald, Raymond J

2014-08-01

The orphan nuclear receptor NR5A2 is necessary for the stem-like properties of the epiblast of the pre-gastrulation embryo and for cellular and physiological homeostasis of endoderm-derived organs postnatally. Using conditional gene inactivation, we show that Nr5a2 also plays crucial regulatory roles during organogenesis. During the formation of the pancreas, Nr5a2 is necessary for the expansion of the nascent pancreatic epithelium, for the subsequent formation of the multipotent progenitor cell (MPC) population that gives rise to pre-acinar cells and bipotent cells with ductal and islet endocrine potential, and for the formation and differentiation of acinar cells. At birth, the NR5A2-deficient pancreas has defects in all three epithelial tissues: a partial loss of endocrine cells, a disrupted ductal tree and a >90% deficit of acini. The acinar defects are due to a combination of fewer MPCs, deficient allocation of those MPCs to pre-acinar fate, disruption of acinar morphogenesis and incomplete acinar cell differentiation. NR5A2 controls these developmental processes directly as well as through regulatory interactions with other pancreatic transcriptional regulators, including PTF1A, MYC, GATA4, FOXA2, RBPJL and MIST1 (BHLHA15). In particular, Nr5a2 and Ptf1a establish mutually reinforcing regulatory interactions and collaborate to control developmentally regulated pancreatic genes by binding to shared transcriptional regulatory regions. At the final stage of acinar cell development, the absence of NR5A2 affects the expression of Ptf1a and its acinar specific partner Rbpjl, so that the few acinar cells that form do not complete differentiation. Nr5a2 controls several temporally distinct stages of pancreatic development that involve regulatory mechanisms relevant to pancreatic oncogenesis and the maintenance of the exocrine phenotype. © 2014. Published by The Company of Biologists Ltd.

Characterization of synthesis and storage of TGF-alpha in rat parotid acinar and intercalated duct cells.

PubMed

Login, G R; Yang, J; Bryan, K P; Digenis, E C; McBride, J; Elovic, A; Quissell, D O; Dvorak, A M; Wong, D T

1997-03-01

Although the expression and biological role of transforming growth factor-alpha (TGF-alpha) have been explored in a variety of normal cells in mammalian species, little is known about the storage of TGF-alpha in secretory cells of exocrine organs. Parotid glands from four rats were homogenized for RNA isolation followed by reverse transcription-polymerase chain reaction to determine the presence of TGF-alpha message. In situ hybridization using a hamster-specific TGF-alpha riboprobe was done on paraffin sections. Parotid gland and isolated acinar cells were processed for transmission electron microscopy (TEM) and postembedding immunogold labeled for TGF-alpha. Gold particles were counted on approximately 200 granules in 10 acinar cells and in 10 intercalated duct cells. Labeling density was calculated as the number of gold particles per square micrometer +/- SD. Statistical significance was calculated using one-way analysis of variance. Using multiple technologies, we have established that rat parotid acinar and intercalated duct cells synthesize TGF-alpha and store the precursor form of this cytokine in their secretory granules.

ptf1a+ , ela3l- cells are developmentally maintained progenitors for exocrine regeneration following extreme loss of acinar cells in zebrafish larvae.

PubMed

Schmitner, Nicole; Kohno, Kenji; Meyer, Dirk

2017-03-01

The exocrine pancreas displays a significant capacity for regeneration and renewal. In humans and mammalian model systems, the partial loss of exocrine tissue, such as after acute pancreatitis or partial pancreatectomy induces rapid recovery via expansion of surviving acinar cells. In mouse it was further found that an almost complete removal of acinar cells initiates regeneration from a currently not well-defined progenitor pool. Here, we used the zebrafish as an alternative model to study cellular mechanisms of exocrine regeneration following an almost complete removal of acinar cells. We introduced and validated two novel transgenic approaches for genetically encoded conditional cell ablation in the zebrafish, either by caspase-8-induced apoptosis or by rendering cells sensitive to diphtheria toxin. By using the ela3l promoter for exocrine-specific expression, we show that both approaches allowed cell-type-specific removal of >95% of acinar tissue in larval and adult zebrafish without causing any signs of unspecific side effects. We find that zebrafish larvae are able to recover from a virtually complete acinar tissue ablation within 2 weeks. Using short-term lineage-tracing experiments and EdU incorporation assays, we exclude duct-associated Notch-responsive cells as the source of regeneration. Rather, a rare population of slowly dividing ela3l- negative cells expressing ptf1a and CPA was identified as the origin of the newly forming exocrine cells. Cells are actively maintained, as revealed by a constant number of these cells at different larval stages and after repeated cell ablation. These cells establish ela3l expression about 4-6 days after ablation without signs of increased proliferation in between. With onset of ela3l expression, cells initiate rapid proliferation, leading to fast expansion of the ela3l -positive population. Finally, we show that this proliferation is blocked by overexpression of the Wnt-signaling antagonist dkk1b In conclusion, we

ptf1a+, ela3l− cells are developmentally maintained progenitors for exocrine regeneration following extreme loss of acinar cells in zebrafish larvae

PubMed Central

Schmitner, Nicole; Kohno, Kenji

2017-01-01

ABSTRACT The exocrine pancreas displays a significant capacity for regeneration and renewal. In humans and mammalian model systems, the partial loss of exocrine tissue, such as after acute pancreatitis or partial pancreatectomy induces rapid recovery via expansion of surviving acinar cells. In mouse it was further found that an almost complete removal of acinar cells initiates regeneration from a currently not well-defined progenitor pool. Here, we used the zebrafish as an alternative model to study cellular mechanisms of exocrine regeneration following an almost complete removal of acinar cells. We introduced and validated two novel transgenic approaches for genetically encoded conditional cell ablation in the zebrafish, either by caspase-8-induced apoptosis or by rendering cells sensitive to diphtheria toxin. By using the ela3l promoter for exocrine-specific expression, we show that both approaches allowed cell-type-specific removal of >95% of acinar tissue in larval and adult zebrafish without causing any signs of unspecific side effects. We find that zebrafish larvae are able to recover from a virtually complete acinar tissue ablation within 2 weeks. Using short-term lineage-tracing experiments and EdU incorporation assays, we exclude duct-associated Notch-responsive cells as the source of regeneration. Rather, a rare population of slowly dividing ela3l-negative cells expressing ptf1a and CPA was identified as the origin of the newly forming exocrine cells. Cells are actively maintained, as revealed by a constant number of these cells at different larval stages and after repeated cell ablation. These cells establish ela3l expression about 4-6 days after ablation without signs of increased proliferation in between. With onset of ela3l expression, cells initiate rapid proliferation, leading to fast expansion of the ela3l-positive population. Finally, we show that this proliferation is blocked by overexpression of the Wnt-signaling antagonist dkk1b. In

Functional differences in the acinar cells of the murine major salivary glands.

PubMed

Kondo, Y; Nakamoto, T; Jaramillo, Y; Choi, S; Catalan, M A; Melvin, J E

2015-05-01

In humans, approximately 90% of saliva is secreted by the 3 major salivary glands: the parotid (PG), the submandibular (SMG), and the sublingual glands (SLG). Even though it is known that all 3 major salivary glands secrete saliva by a Cl(-)-dependent mechanism, salivary secretion rates differ greatly among these glands. The goal of this study was to gain insight into the properties of the ion-transporting pathways in acinar cells that might account for the differences among the major salivary glands. Pilocarpine-induced saliva was simultaneously collected in vivo from the 3 major salivary glands of mice. When normalized by gland weight, the amount of saliva secreted by the PG was more than 2-fold larger than that obtained from the SMG and SLG. At the cellular level, carbachol induced an increase in the intracellular [Ca(2+)] that was more than 2-fold larger in PG and SMG than in SLG acinar cells. Carbachol-stimulated Cl(-) efflux and the protein levels of the Ca(2+)-activated Cl(-) channel TMEM16A, the major apical Cl(-) efflux pathway in salivary acinar cells, were significantly greater in PG compared with SMG and SLG. In addition, we evaluated the transporter activity of the Na(+)-K(+)-2Cl(-) cotransporters (NKCC1) and anion exchangers (AE), the 2 primary basolateral Cl(-) uptake mechanisms in acinar cells. The SMG NKCC1 activity was about twice that of the PG and more than 12-fold greater than that of the SLG. AE activity was similar in PG and SLG, and both PG and SLG AE activity was about 2-fold larger than that of SMG. In summary, the salivation kinetics of the 3 major glands are distinct, and these differences can be explained by the unique functional properties of each gland related to Cl(-) movement, including the transporter activities of the Cl(-) uptake and efflux pathways, and intracellular Ca(2+) mobilization. © International & American Associations for Dental Research 2015.

Establishment of Functional Acinar-like Cultures from Human Salivary Glands

PubMed Central

Jang, S.I.; Ong, H.L.; Gallo, A.; Liu, X.; Illei, G.

2015-01-01

Disorders of human salivary glands resulting from therapeutic radiation treatment for head and neck cancers or from the autoimmune disease Sjögren syndrome (SS) frequently result in the reduction or complete loss of saliva secretion. Such irreversible dysfunction of the salivary glands is due to the impairment of acinar cells, the major glandular cells of protein, salt secretion, and fluid movement. Availability of primary epithelial cells from human salivary gland tissue is critical for studying the underlying mechanisms of these irreversible disorders. We applied 2 culture system techniques on human minor salivary gland epithelial cells (phmSG) and optimized the growth conditions to achieve the maintenance of phmSG in an acinar-like phenotype. These phmSG cells exhibited progenitor cell markers (keratin 5 and nanog) as well as acinar-specific markers—namely, α-amylase, cystatin C, TMEM16A, and NKCC1. Importantly, with an increase of the calcium concentration in the growth medium, these phmSG cells were further promoted to acinar-like cells in vitro, as indicated by an increase in AQP5 expression. In addition, these phmSG cells also demonstrated functional calcium mobilization, formation of epithelial monolayer with high transepithelial electrical resistance (TER), and polarized secretion of α-amylase secretion after β-adrenergic receptor stimulation. Taken together, suitable growth conditions have been established to isolate and support culture of acinar-like cells from the human salivary gland. These primary epithelial cells can be useful for study of molecular mechanisms involved in regulating the function of acinar cells and in the loss of salivary gland function in patients. PMID:25416669

Establishment of functional acinar-like cultures from human salivary glands.

PubMed

Jang, S I; Ong, H L; Gallo, A; Liu, X; Illei, G; Alevizos, I

2015-02-01

Disorders of human salivary glands resulting from therapeutic radiation treatment for head and neck cancers or from the autoimmune disease Sjögren syndrome (SS) frequently result in the reduction or complete loss of saliva secretion. Such irreversible dysfunction of the salivary glands is due to the impairment of acinar cells, the major glandular cells of protein, salt secretion, and fluid movement. Availability of primary epithelial cells from human salivary gland tissue is critical for studying the underlying mechanisms of these irreversible disorders. We applied 2 culture system techniques on human minor salivary gland epithelial cells (phmSG) and optimized the growth conditions to achieve the maintenance of phmSG in an acinar-like phenotype. These phmSG cells exhibited progenitor cell markers (keratin 5 and nanog) as well as acinar-specific markers-namely, α-amylase, cystatin C, TMEM16A, and NKCC1. Importantly, with an increase of the calcium concentration in the growth medium, these phmSG cells were further promoted to acinar-like cells in vitro, as indicated by an increase in AQP5 expression. In addition, these phmSG cells also demonstrated functional calcium mobilization, formation of epithelial monolayer with high transepithelial electrical resistance (TER), and polarized secretion of α-amylase secretion after β-adrenergic receptor stimulation. Taken together, suitable growth conditions have been established to isolate and support culture of acinar-like cells from the human salivary gland. These primary epithelial cells can be useful for study of molecular mechanisms involved in regulating the function of acinar cells and in the loss of salivary gland function in patients. © International & American Associations for Dental Research 2014.

Age-related alterations in IL-1beta, TNF-alpha, and IL-6 concentrations in parotid acinar cells from BALB/c and non-obese diabetic mice.

PubMed

Yamakawa, M; Weinstein, R; Tsuji, T; McBride, J; Wong, D T; Login, G R

2000-08-01

IL-1beta, TNF-alpha, and IL-6 have been implicated in the destruction of parotid gland acinar cells (but not duct cells) in autoimmune sialoadenitis. Here we report the temporal alterations of these cytokines in parotid acinar cells that may lead to this specificity in cell death in the non-obese diabetic (NOD) mouse model for Sjögren's syndrome. Immunohistochemistry on paraffin sections of parotid gland from 5- and 10-week-old BALB/c and NOD mice confirmed the presence of many peri-acinar lymphoid nodules but few T-cells and macrophages between acinar cells. RT-PCR on enzymatically dispersed mouse parotid acinar cells (MPACs) showed no bands for CD3varepsilon, CD20, or F4/80 regardless of mouse strain or age. By ELISA, MPACs from 10-week-old NODs showed a small but highly significant (p<0.003) increase in IL-1beta and a large significant decrease (p<0.008) in IL-6 compared to 5-week-old NODs. Norepinephrine-stimulated amylase release from MPACs was not different regardless of mouse strain or age. These data show that alterations in acinar cell production of IL-1beta and IL-6 in aging NODs precede periductal lymphoid aggregates and acinar cell secretory dysfunction. (J Histochem Cytochem 48:1033-1041,2000)

Isolation of mouse pancreatic alpha, beta, duct and acinar populations with cell surface markers.

PubMed

Dorrell, Craig; Grompe, Maria T; Pan, Fong Cheng; Zhong, Yongping; Canaday, Pamela S; Shultz, Leonard D; Greiner, Dale L; Wright, Chris V; Streeter, Philip R; Grompe, Markus

2011-06-06

Tools permitting the isolation of live pancreatic cell subsets for culture and/or molecular analysis are limited. To address this, we developed a collection of monoclonal antibodies with selective surface labeling of endocrine and exocrine pancreatic cell types. Cell type labeling specificity and cell surface reactivity were validated on mouse pancreatic sections and by gene expression analysis of cells isolated using FACS. Five antibodies which marked populations of particular interest were used to isolate and study viable populations of purified pancreatic ducts, acinar cells, and subsets of acinar cells from whole pancreatic tissue or of alpha or beta cells from isolated mouse islets. Gene expression analysis showed the presence of known endocrine markers in alpha and beta cell populations and revealed that TTR and DPPIV are primarily expressed in alpha cells whereas DGKB and GPM6A have a beta cell specific expression profile. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Congo red modulates ACh-induced Ca2+ oscillations in single pancreatic acinar cells of mice

PubMed Central

Huang, Ze-bing; Wang, Hai-yan; Sun, Na-na; Wang, Jing-ke; Zhao, Meng-qin; Shen, Jian-xin; Gao, Ming; Hammer, Ronald P; Fan, Xue-gong; Wu, Jie

2014-01-01

Aim: Congo red, a secondary diazo dye, is usually used as an indicator for the presence of amyloid fibrils. Recent studies show that congo red exerts neuroprotective effects in a variety of models of neurodegenerative diseases. However, its pharmacological profile remains unknown. In this study, we investigated the effects of congo red on ACh-induced Ca2+ oscillations in mouse pancreatic acinar cells in vitro. Methods: Acutely dissociated pancreatic acinar cells of mice were prepared. A U-tube drug application system was used to deliver drugs into the bath. Intracellular Ca2+ oscillations were monitored by whole-cell recording of Ca2+-activated Cl− currents and by using confocal Ca2+ imaging. For intracellular drug application, the drug was added in pipette solution and diffused into cell after the whole-cell configuration was established. Results: Bath application of ACh (10 nmol/L) induced typical Ca2+ oscillations in dissociated pancreatic acinar cells. Addition of congo red (1, 10, 100 μmol/L) dose-dependently enhanced Ach-induced Ca2+ oscillations, but congo red alone did not induce any detectable response. Furthermore, this enhancement depended on the concentrations of ACh: congo red markedly enhanced the Ca2+ oscillations induced by ACh (10–30 nmol/L), but did not alter the Ca2+ oscillations induced by ACh (100–10000 nmol/L). Congo red also enhanced the Ca2+ oscillations induced by bath application of IP3 (30 μmol/L). Intracellular application of congo red failed to alter ACh-induced Ca2+ oscillations. Conclusion: Congo red significantly modulates intracellular Ca2+ signaling in pancreatic acinar cells, and this pharmacological effect should be fully considered when developing congo red as a novel therapeutic drug. PMID:25345744

Pancreatic panniculitis as a presentation symptom of acinar cell carcinoma.

PubMed

de Frutos Rosa, Diego; Espinosa Taranilla, Laura; González de Canales de Simón, Pilar; Vélez Velázquez, María Dolores; Guirado Koch, Cristina

2018-05-01

Pancreatic panniculitis is a rare skin manifestation associated with pancreatic conditions. This condition has similar characteristics to those of other panniculitis types and its course parallels the triggering condition and may occasionally precede it. We report the case of a female patient with asymptomatic pancreatic panniculitis; the etiologic study identified a pancreatic acinar cell carcinoma with liver metastases.

Lysosome associated membrane proteins maintain pancreatic acinar cell homeostasis: LAMP-2 deficient mice develop pancreatitis.

PubMed

Mareninova, Olga A; Sendler, Matthias; Malla, Sudarshan Ravi; Yakubov, Iskandar; French, Samuel W; Tokhtaeva, Elmira; Vagin, Olga; Oorschot, Viola; Lüllmann-Rauch, Renate; Blanz, Judith; Dawson, David; Klumperman, Judith; Lerch, Markus M; Mayerle, Julia; Gukovsky, Ilya; Gukovskaya, Anna S

2015-11-01

The pathogenic mechanism of pancreatitis is poorly understood. Recent evidence implicates defective autophagy in pancreatitis responses; however, the pathways mediating impaired autophagy in pancreas remain largely unknown. Here, we investigate the role of lysosome associated membrane proteins (LAMPs) in pancreatitis. We analyzed changes in LAMPs in experimental models and human pancreatitis, and the underlying mechanisms: LAMP de-glycosylation and degradation. LAMP cleavage by cathepsin B (CatB) was analyzed by mass spectrometry. We used mice deficient in LAMP-2 to assess its role in pancreatitis. Pancreatic levels of LAMP-1 and LAMP-2 greatly decrease across various pancreatitis models and in human disease. Pancreatitis does not trigger LAMPs' bulk de-glycosylation, but induces their degradation via CatB-mediated cleavage of LAMP molecule close to the boundary between luminal and transmembrane domains. LAMP-2 null mice spontaneously develop pancreatitis that begins with acinar cell vacuolization due to impaired autophagic flux, and progresses to severe pancreas damage characterized by trypsinogen activation, macrophage-driven inflammation, and acinar cell death. LAMP-2 deficiency causes a decrease in pancreatic digestive enzymes content, stimulates the basal and inhibits CCK-induced amylase secretion by acinar cells. The effects of LAMP-2 knockout and acute cerulein pancreatitis overlap, which corroborates the pathogenic role of LAMP decrease in experimental pancreatitis models. The results indicate a critical role for LAMPs, particularly LAMP-2, in maintaining pancreatic acinar cell homeostasis, and provide evidence that defective lysosomal function, resulting in impaired autophagy, leads to pancreatitis. Mice with LAMP-2 deficiency present a novel genetic model of human pancreatitis caused by lysosomal/autophagic dysfunction.

Surgical and molecular pathology of pancreatic neoplasms.

PubMed

Hackeng, Wenzel M; Hruban, Ralph H; Offerhaus, G Johan A; Brosens, Lodewijk A A

2016-06-07

Histologic characteristics have proven to be very useful for classifying different types of tumors of the pancreas. As a result, the major tumor types in the pancreas have long been classified based on their microscopic appearance. Recent advances in whole exome sequencing, gene expression profiling, and knowledge of tumorigenic pathways have deepened our understanding of the underlying biology of pancreatic neoplasia. These advances have not only confirmed the traditional histologic classification system, but also opened new doors to early diagnosis and targeted treatment. This review discusses the histopathology, genetic and epigenetic alterations and potential treatment targets of the five major malignant pancreatic tumors - pancreatic ductal adenocarcinoma, pancreatic neuroendocrine tumor, solid-pseudopapillary neoplasm, acinar cell carcinoma and pancreatoblastoma.

Treatment Options for Plasma Cell Neoplasms (Including Multiple Myeloma)

MedlinePlus

... Health Professional Plasma Cell Neoplasms Treatment Research Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment (PDQ®)–Patient Version General Information About Plasma Cell Neoplasms Go to Health Professional Version Key Points ...

Treatment Option Overview (Plasma Cell Neoplasms Including Multiple Myeloma)

MedlinePlus

... Health Professional Plasma Cell Neoplasms Treatment Research Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment (PDQ®)–Patient Version General Information About Plasma Cell Neoplasms Go to Health Professional Version Key Points ...

Activation of neurokinin-1 receptors up-regulates substance P and neurokinin-1 receptor expression in murine pancreatic acinar cells

PubMed Central

Koh, Yung-Hua; Moochhala, Shabbir; Bhatia, Madhav

2012-01-01

Abstract Acute pancreatitis (AP) has been associated with an up-regulation of substance P (SP) and neurokinin-1 receptor (NK1R) in the pancreas. Increased SP-NK1R interaction was suggested to be pro-inflammatory during AP. Previously, we showed that caerulein treatment increased SP/NK1R expression in mouse pancreatic acinar cells, but the effect of SP treatment was not evaluated. Pancreatic acinar cells were obtained from pancreas of male swiss mice (25–30 g). We measured mRNA expression of preprotachykinin-A (PPTA) and NK1R following treatment of SP (10−6M). SP treatment increased PPTA and NK1R expression in isolated pancreatic acinar cells, which was abolished by pretreatment of a selective NK1R antagonist, CP96,345. SP also time dependently increased protein expression of NK1R. Treatment of cells with a specific NK1R agonist, GR73,632, up-regulated SP protein levels in the cells. Using previously established concentrations, pre-treatment of pancreatic acinar cells with Gö6976 (10 nM), rottlerin (5 μM), PD98059 (30 μM), SP600125 (30 μM) or Bay11-7082 (30 μM) significantly inhibited up-regulation of SP and NK1R. These observations suggested that the PKC-ERK/JNK-NF-κB pathway is necessary for the modulation of expression levels. In comparison, pre-treatment of CP96,345 reversed gene expression in SP-induced cells, but not in caerulein-treated cells. Overall, the findings in this study suggested a possible auto-regulatory mechanism of SP/NK1R expression in mouse pancreatic acinar cells, via activation of NK1R. Elevated SP levels during AP might increase the occurrence of a positive feedback loop that contributes to abnormally high expression of SP and NK1R. PMID:22040127

Inhibitors of ORAI1 Prevent Cytosolic Calcium-Associated Injury of Human Pancreatic Acinar Cells and Acute Pancreatitis in 3 Mouse Models

PubMed Central

Wen, Li; Voronina, Svetlana; Javed, Muhammad A.; Awais, Muhammad; Szatmary, Peter; Latawiec, Diane; Chvanov, Michael; Collier, David; Huang, Wei; Barrett, John; Begg, Malcolm; Stauderman, Ken; Roos, Jack; Grigoryev, Sergey; Ramos, Stephanie; Rogers, Evan; Whitten, Jeff; Velicelebi, Gonul; Dunn, Michael; Tepikin, Alexei V.; Criddle, David N.; Sutton, Robert

2015-01-01

Background & Aims Sustained activation of the cytosolic calcium concentration induces injury to pancreatic acinar cells and necrosis. The calcium release–activated calcium modulator ORAI1 is the most abundant Ca2+ entry channel in pancreatic acinar cells; it sustains calcium overload in mice exposed to toxins that induce pancreatitis. We investigated the roles of ORAI1 in pancreatic acinar cell injury and the development of acute pancreatitis in mice. Methods Mouse and human acinar cells, as well as HEK 293 cells transfected to express human ORAI1 with human stromal interaction molecule 1, were hyperstimulated or incubated with human bile acid, thapsigargin, or cyclopiazonic acid to induce calcium entry. GSK-7975A or CM_128 were added to some cells, which were analyzed by confocal and video microscopy and patch clamp recordings. Acute pancreatitis was induced in C57BL/6J mice by ductal injection of taurolithocholic acid 3-sulfate or intravenous' administration of cerulein or ethanol and palmitoleic acid. Some mice then were given GSK-7975A or CM_128, which inhibit ORAI1, at different time points to assess local and systemic effects. Results GSK-7975A and CM_128 each separately inhibited toxin-induced activation of ORAI1 and/or activation of Ca2+ currents after Ca2+ release, in a concentration-dependent manner, in mouse and human pancreatic acinar cells (inhibition >90% of the levels observed in control cells). The ORAI1 inhibitors also prevented activation of the necrotic cell death pathway in mouse and human pancreatic acinar cells. GSK-7975A and CM_128 each inhibited all local and systemic features of acute pancreatitis in all 3 models, in dose- and time-dependent manners. The agents were significantly more effective, in a range of parameters, when given at 1 vs 6 hours after induction of pancreatitis. Conclusions Cytosolic calcium overload, mediated via ORAI1, contributes to the pathogenesis of acute pancreatitis. ORAI1 inhibitors might be developed

Glycoconjugate pattern of membranes in the acinar cell of the rat pancreas.

PubMed

Willemer, S; Köhler, H; Naumann, R; Kern, H F; Adler, G

1990-01-01

Lectin-binding studies were performed at the ultrastructural level to characterize glycoconjugate patterns on membrane systems in pancreatic acinar cells of the rat. Five lectins reacting with different sugar moieties were applied to ultrathin frozen sections: concanavalin A (ConA): glucose, mannose; wheat-germ agglutinin (WGA): N-acetylglucosamine, sialic acid; Ricinus communis agglutinin I (RCA I): galactose; Ulex europaeus agglutinin I (UEA I): L-fucose; soybean agglutinin (SBA): N-acetylgalactosamine). Binding sites of lectins were visualized either by direct conjugation to colloidal gold or by the use of a three-step procedure involving additional immune reactions. The rough endoplasmic reticulum and the nuclear envelope of acinar cells was selectively labelled for ConA. The membranes of the Golgi apparatus bound all lectins applied with an increasing intensity proceeding from the cis- to the trans-Golgi area for SBA, UEA I and WGA. In contrast RCA I selectively labelled the trans-Golgi cisternae. The membranes of condensing vacuoles and zymogen granules were labelled for all lectins used although the density of the label differed between the lectins. In contrast the content of zymogen granules failed to bind SBA and WGA. Lysosomal bodies (membranes and content) revealed binding sites for all lectins used. The plasma membranes were heavily labelled by all lectins except for SBA which showed only a weak binding to the lateral and the apical plasma membrane. These results are in accordance to current biochemical knowledge of the successive steps in the glycosylation of membrane proteins. It could be demonstrated, that the cryo-section technique is suitable for the fine structural localisation of surface glycoconjugates of plasma membranes and internal membranes in pancreatic acinar cells using plant lectins.

Adenovirus-mediated hAQP1 expression in irradiated mouse salivary glands causes recovery of saliva secretion by enhancing acinar cell volume decrease

PubMed Central

Teos, LY; Zheng, C-Y; Liu, X; Swaim, WD; Goldsmith, CM; Cotrim, AP; Baum, BJ; Ambudkar, IS

2017-01-01

Head and neck irradiation (IR) during cancer treatment causes by-stander effects on the salivary glands leading to irreversible loss of saliva secretion. The mechanism underlying loss of fluid secretion is not understood and no adequate therapy is currently available. Delivery of an adenoviral vector encoding human aquaporin-1 (hAQP1) into the salivary glands of human subjects and animal models with radiation-induced salivary hypofunction leads to significant recovery of saliva secretion and symptomatic relief in subjects. To elucidate the mechanism underlying loss of salivary secretion and the basis for AdhAQP1-dependent recovery of salivary gland function we assessed submandibular gland function in control mice and mice 2 and 8 months after treatment with a single 15-Gy dose of IR (delivered to the salivary gland region). Salivary secretion and neurotransmitter-stimulated changes in acinar cell volume, an in vitro read-out for fluid secretion, were monitored. Consistent with the sustained 60% loss of fluid secretion following IR, a carbachol (CCh)-induced decrease in acinar cell volume from the glands of mice post IR was transient and attenuated as compared with that in cells from non-IR age-matched mice. The hAQP1 expression in non-IR mice induced no significant effect on salivary fluid secretion or CCh-stimulated cell volume changes, except in acinar cells from 8-month group where the initial rate of cell shrinkage was increased. Importantly, the expression of hAQP1 in the glands of mice post IR induced recovery of salivary fluid secretion and a volume decrease in acinar cells to levels similar to those in cells from non-IR mice. The initial rates of CCh-stimulated cell volume reduction in acinar cells from hAQP1-expressing glands post IR were similar to those from control cells. Altogether, the data suggest that expression of hAQP1 increases the water permeability of acinar cells, which underlies the recovery of fluid secretion in the salivary glands

Docosahexaenoic acid inhibits IL-6 expression via PPARγ-mediated expression of catalase in cerulein-stimulated pancreatic acinar cells.

PubMed

Song, Eun Ah; Lim, Joo Weon; Kim, Hyeyoung

2017-07-01

Cerulein pancreatitis mirrors human acute pancreatitis. In pancreatic acinar cells exposed to cerulein, reactive oxygen species (ROS) mediate inflammatory signaling by Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3, and cytokine induction. Docosahexaenoic acid (DHA) acts as an agonist of peroxisome proliferator activated receptor γ (PPARγ), which mediates the expression of some antioxidant enzymes. We hypothesized that DHA may induce PPARγ-target catalase expression and reduce ROS levels, leading to the inhibition of JAK2/STAT3 activation and IL-6 expression in cerulein-stimulated acinar cells. Pancreatic acinar AR42J cells were treated with DHA in the presence or absence of the PPARγ antagonist GW9662, or treated with the PPARγ agonist troglitazone, and then stimulated with cerulein. Expression of IL-6 and catalase, ROS levels, JAK2/STAT3 activation, and nuclear translocation of PPARγ were assessed. DHA suppressed the increase in ROS, JAK2/STAT3 activation, and IL-6 expression induced nuclear translocation of PPARγ and catalase expression in cerulein-stimulated AR42J cells. Troglitazone inhibited the cerulein-induced increase in ROS and IL-6 expression, but induced catalase expression similar to DHA in AR42J cells. GW9662 abolished the inhibitory effect of DHA on cerulein-induced increase in ROS and IL-6 expression in AR42J cells. DHA-induced expression of catalase was suppressed by GW9662 in cerulein-stimulated AR42J cells. Thus, DHA induces PPARγ activation and catalase expression, which inhibits ROS-mediated activation of JAK2/STAT3 and IL-6 expression in cerulein-stimulated pancreatic acinar cells. Copyright © 2017. Published by Elsevier Ltd.

Activation of neurokinin-1 receptors up-regulates substance P and neurokinin-1 receptor expression in murine pancreatic acinar cells.

PubMed

Koh, Yung-Hua; Moochhala, Shabbir; Bhatia, Madhav

2012-07-01

Acute pancreatitis (AP) has been associated with an up-regulation of substance P (SP) and neurokinin-1 receptor (NK1R) in the pancreas. Increased SP-NK1R interaction was suggested to be pro-inflammatory during AP. Previously, we showed that caerulein treatment increased SP/NK1R expression in mouse pancreatic acinar cells, but the effect of SP treatment was not evaluated. Pancreatic acinar cells were obtained from pancreas of male swiss mice (25-30 g). We measured mRNA expression of preprotachykinin-A (PPTA) and NK1R following treatment of SP (10(-6) M). SP treatment increased PPTA and NK1R expression in isolated pancreatic acinar cells, which was abolished by pretreatment of a selective NK1R antagonist, CP96,345. SP also time dependently increased protein expression of NK1R. Treatment of cells with a specific NK1R agonist, GR73,632, up-regulated SP protein levels in the cells. Using previously established concentrations, pre-treatment of pancreatic acinar cells with Gö6976 (10 nM), rottlerin (5 μM), PD98059 (30 μM), SP600125 (30 μM) or Bay11-7082 (30 μM) significantly inhibited up-regulation of SP and NK1R. These observations suggested that the PKC-ERK/JNK-NF-κB pathway is necessary for the modulation of expression levels. In comparison, pre-treatment of CP96,345 reversed gene expression in SP-induced cells, but not in caerulein-treated cells. Overall, the findings in this study suggested a possible auto-regulatory mechanism of SP/NK1R expression in mouse pancreatic acinar cells, via activation of NK1R. Elevated SP levels during AP might increase the occurrence of a positive feedback loop that contributes to abnormally high expression of SP and NK1R. © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Biochemical analysis of secretory proteins synthesized by normal rat pancreas and by pancreatic acinar tumor cells

PubMed Central

1982-01-01

We have examined the secretogogue responsiveness and the pattern of secretory proteins produced by a transplantable rat pancreatic acinar cell tumor. Dispersed tumor cells were found to discharge secretory proteins in vitro when incubated with hormones that act on four different classes of receptors: carbamylcholine, caerulein, secretin- vasoactive intestinal peptide, and bombesin. With all hormones tested, maximal discharge from tumor cells was only about one-half that of control pancreatic lobules, but occurred at the same dose optima except for secretin, whose dose optimum was 10-fold higher. Biochemical analysis of secretory proteins discharged by the tumor cells was carried out by crossed immunoelectrophoresis and by two-dimensional isoelectric focusing-SDS polyacrylamide gel electrophoresis. To establish a baseline for comparison, secretory proteins from normal rat pancreas were identified according to enzymatic activity and correlated with migration position on two-dimensional gels. Our results indicate that a group of basic polypeptides including proelastase, basic trypsinogen, basic chymotrypsinogen, and ribonuclease, two out of three forms of procarboxypeptidase B, and the major lipase species were greatly reduced or absent in tumor cell secretion. In contrast, the amount of acidic chymotrypsinogen was notably increased compared with normal acinar cells. Although the acinar tumor cells are highly differentiated cytologically and express functional receptors for several classes of pancreatic secretagogues, they show quantitative and qualitative differences when compared with normal pancreas with regard to their production of secretory proteins. PMID:6185502

RNA synthesis in the pancreatic acinar cells of aging mice as revealed by electron microscopic radioautography.

PubMed

Nagata, Tetsuji

2012-01-01

For the purpose of studying the aging changes of macromolecular synthesis in the pancreatic acinar cells of experimental animals, we studied 10 groups of aging mice during development and aging from fetal day 19 to postnatal month 24. They were injected with 3H-uridine, a precursor for RNA synthesis, sacrificed and the pancreatic tissues were taken out, fixed and processed for light and electron microscopic radioautography. On many radioautograms the localization of silver grains demonstrating RNA synthesis in pancreatic acinar cells in respective aging groups were analyzed qualitatively. The number of mitochondria per cell, the number of labeled mitochondria with silver grains and the number of silver grains in each cell in respective aging groups were analyzed quantitatively in relation to the aging of animals. The results revealed that the RNA synthetic activity as expressed by the incorporations of RNA precursor, i.e., the number of silver grains in cell nuclei, cell organelles, changed due to the aging of animals. The number of mitochondria, the number of labeled mitochondria and the mitochondrial labeling index labeled with silver grains were counted in each pancreatic acinar cell. It was demonstrated that the number of mitochondria, the number of labeled mitochondria and the labeling indices showing RNA synthesis at various ages increased from embryonic day 19 to postnatal newborn day 1, 3, 9, 14, adult month 1, 2 and 6, reaching the maxima, then decreased to senile stage at postnatal year 1 to 2, indicating the aging changes. Based upon our findings, available literature on macromolecular synthesis in mitochondria of various cells are reviewed.

Assessing the secretory capacity of pancreatic acinar cells.

PubMed

Geron, Erez; Schejter, Eyal D; Shilo, Ben-Zion

2014-08-28

Pancreatic acinar cells produce and secrete digestive enzymes. These cells are organized as a cluster which forms and shares a joint lumen. This work demonstrates how the secretory capacity of these cells can be assessed by culture of isolated acini. The setup is advantageous since isolated acini, which retain many characteristics of the intact exocrine pancreas can be manipulated and monitored more readily than in the whole animal. Proper isolation of pancreatic acini is a key requirement so that the ex vivo culture will represent the in vivo nature of the acini. The protocol demonstrates how to isolate intact acini from the mouse pancreas. Subsequently, two complementary methods for evaluating pancreatic secretion are presented. The amylase secretion assay serves as a global measure, while direct imaging of pancreatic secretion allows the characterization of secretion at a sub-cellular resolution. Collectively, the techniques presented here enable a broad spectrum of experiments to study exocrine secretion.

Critical role for NHE1 in intracellular pH regulation in pancreatic acinar cells.

PubMed

Brown, David A; Melvin, James E; Yule, David I

2003-11-01

The primary function of pancreatic acinar cells is to secrete digestive enzymes together with a NaCl-rich primary fluid which is later greatly supplemented and modified by the pancreatic duct. A Na+/H+ exchanger(s) [NHE(s)] is proposed to be integral in the process of fluid secretion both in terms of the transcellular flux of Na+ and intracellular pH (pHi) regulation. Multiple NHE isoforms have been identified in pancreatic tissue, but little is known about their individual functions in acinar cells. The Na+/H+ exchange inhibitor 5-(N-ethyl-N-isopropyl) amiloride completely blocked pHi recovery after an NH4Cl-induced acid challenge, confirming a general role for NHE in pHi regulation. The targeted disruption of the Nhe1 gene also completely abolished pHi recovery from an acid load in pancreatic acini in both HCO3--containing and HCO3--free solutions. In contrast, the disruption of either Nhe2 or Nhe3 had no effect on pHi recovery. In addition, NHE1 activity was upregulated in response to muscarinic stimulation in wild-type mice but not in NHE1-deficient mice. Fluctuations in pHi could potentially have major effects on Ca2+ signaling following secretagogue stimulation; however, the targeted disruption of Nhe1 was found to have no significant effect on intracellular Ca2+ homeostasis. These data demonstrate that NHE1 is the major regulator of pHi in both resting and muscarinic agonist-stimulated pancreatic acinar cells.

Sulforaphane Protects Pancreatic Acinar Cell Injury by Modulating Nrf2-Mediated Oxidative Stress and NLRP3 Inflammatory Pathway

PubMed Central

Dong, Zhaojun; Shang, Haixiao; Chen, Yong Q.; Pan, Li-Long

2016-01-01

Acute pancreatitis (AP) is characterized by early activation of intra-acinar proteases followed by acinar cell death and inflammation. Cellular oxidative stress is a key mechanism underlying these pathological events. Sulforaphane (SFN) is a natural organosulfur antioxidant with undescribed effects on AP. Here we investigated modulatory effects of SFN on cellular oxidation and inflammation in AP. AP was induced by cerulean hyperstimulation in BALB/c mice. Treatment group received a single dose of 5 mg/kg SFN for 3 consecutive days before AP. We found that SFN administration attenuated pancreatic injury as evidenced by serum amylase, pancreatic edema, and myeloperoxidase, as well as by histological examination. SFN administration reverted AP-associated dysregulation of oxidative stress markers including pancreatic malondialdehyde and redox enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx). In acinar cells, SFN treatment upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) expression and Nrf2-regulated redox genes including quinoneoxidoreductase-1, heme oxidase-1, SOD1, and GPx1. In addition, SFN selectively suppressed cerulein-induced activation of the nucleotide-binding domain leucine-rich repeat containing family, pyrin domain-containing 3 (NLRP3) inflammasome, in parallel with reduced nuclear factor- (NF-) κB activation and modulated NF-κB-responsive cytokine expression. Together, our data suggested that SFN modulates Nrf2-mediated oxidative stress and NLRP3/NF-κB inflammatory pathways in acinar cells, thereby protecting against AP. PMID:27847555

Sulforaphane Protects Pancreatic Acinar Cell Injury by Modulating Nrf2-Mediated Oxidative Stress and NLRP3 Inflammatory Pathway.

PubMed

Dong, Zhaojun; Shang, Haixiao; Chen, Yong Q; Pan, Li-Long; Bhatia, Madhav; Sun, Jia

2016-01-01

Acute pancreatitis (AP) is characterized by early activation of intra-acinar proteases followed by acinar cell death and inflammation. Cellular oxidative stress is a key mechanism underlying these pathological events. Sulforaphane (SFN) is a natural organosulfur antioxidant with undescribed effects on AP. Here we investigated modulatory effects of SFN on cellular oxidation and inflammation in AP. AP was induced by cerulean hyperstimulation in BALB/c mice. Treatment group received a single dose of 5 mg/kg SFN for 3 consecutive days before AP. We found that SFN administration attenuated pancreatic injury as evidenced by serum amylase, pancreatic edema, and myeloperoxidase, as well as by histological examination. SFN administration reverted AP-associated dysregulation of oxidative stress markers including pancreatic malondialdehyde and redox enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx). In acinar cells, SFN treatment upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) expression and Nrf2-regulated redox genes including quinoneoxidoreductase-1, heme oxidase-1, SOD1, and GPx1. In addition, SFN selectively suppressed cerulein-induced activation of the nucleotide-binding domain leucine-rich repeat containing family, pyrin domain-containing 3 (NLRP3) inflammasome, in parallel with reduced nuclear factor- (NF-) κ B activation and modulated NF- κ B-responsive cytokine expression. Together, our data suggested that SFN modulates Nrf2-mediated oxidative stress and NLRP3/NF- κ B inflammatory pathways in acinar cells, thereby protecting against AP.

The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma

PubMed Central

Krah, Nathan M; De La O, Jean-Paul; Swift, Galvin H; Hoang, Chinh Q; Willet, Spencer G; Chen Pan, Fong; Cash, Gabriela M; Bronner, Mary P; Wright, Christopher VE; MacDonald, Raymond J; Murtaugh, L Charles

2015-01-01

Understanding the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) may provide therapeutic strategies for this deadly disease. Recently, we and others made the surprising finding that PDAC and its preinvasive precursors, pancreatic intraepithelial neoplasia (PanIN), arise via reprogramming of mature acinar cells. We therefore hypothesized that the master regulator of acinar differentiation, PTF1A, could play a central role in suppressing PDAC initiation. In this study, we demonstrate that PTF1A expression is lost in both mouse and human PanINs, and that this downregulation is functionally imperative in mice for acinar reprogramming by oncogenic KRAS. Loss of Ptf1a alone is sufficient to induce acinar-to-ductal metaplasia, potentiate inflammation, and induce a KRAS-permissive, PDAC-like gene expression profile. As a result, Ptf1a-deficient acinar cells are dramatically sensitized to KRAS transformation, and reduced Ptf1a greatly accelerates development of invasive PDAC. Together, these data indicate that cell differentiation regulators constitute a new tumor suppressive mechanism in the pancreas. DOI: http://dx.doi.org/10.7554/eLife.07125.001 PMID:26151762

A Single Injection of Interleukin-1 Induces Reversible Aqueous-tear Deficiency, Lacrimal Gland Inflammation, and Acinar and Ductal Cell Proliferation

PubMed Central

Zoukhri, Driss; Macari, Elizabeth; Kublin, Claire L.

2011-01-01

Emerging studies from our laboratory demonstrate that interleukin-1 (IL-1) family members play a major role in impairing lacrimal gland functions. Here we have extended our investigations to observe the effects of IL-1 on aqueous tear production, lacrimal gland secretion, lacrimal gland histology, and acinar and ductal cell proliferation. We demonstrate that a single injection of IL-1 into the lacrimal glands inhibited neurally- as well as agonist-induced protein secretion resulting in decreased tear output. Meanwhile, IL-1 injection induced a severe, but reversible (7–13 days), inflammatory response that led to destruction of lacrimal gland acinar epithelial cells. Finally, we demonstrate that as the inflammatory response subsided and lacrimal gland secretion and tear production returned to normal levels, there was increased proliferation of acinar and ductal epithelial cells. Our work uncovers novel effects of IL-1 on lacrimal gland functions and the potential regenerative capacity of the mouse lacrimal gland. PMID:17362931

Nicotine promotes initiation and progression of KRAS-induced pancreatic cancer via Gata6-dependent dedifferentiation of acinar cells in mice.

PubMed

Hermann, Patrick C; Sancho, Patricia; Cañamero, Marta; Martinelli, Paola; Madriles, Francesc; Michl, Patrick; Gress, Thomas; de Pascual, Ricardo; Gandia, Luis; Guerra, Carmen; Barbacid, Mariano; Wagner, Martin; Vieira, Catarina R; Aicher, Alexandra; Real, Francisco X; Sainz, Bruno; Heeschen, Christopher

2014-11-01

Although smoking is a leading risk factor for pancreatic ductal adenocarcinoma (PDAC), little is known about the mechanisms by which smoking promotes initiation or progression of PDAC. We studied the effects of nicotine administration on pancreatic cancer development in Kras(+/LSLG12Vgeo);Elas-tTA/tetO-Cre (Ela-KRAS) mice, Kras(+/LSLG12D);Trp53+/LSLR172H;Pdx-1-Cre (KPC) mice (which express constitutively active forms of KRAS), and C57/B6 mice. Mice were given nicotine for up to 86 weeks to produce blood levels comparable with those of intermediate smokers. Pancreatic tissues were collected and analyzed by immunohistochemistry and reverse transcriptase polymerase chain reaction; cells were isolated and assayed for colony and sphere formation and gene expression. The effects of nicotine were also evaluated in primary pancreatic acinar cells isolated from wild-type, nAChR7a(-/-), Trp53(-/-), and Gata6(-/-);Trp53(-/-) mice. We also analyzed primary PDAC cells that overexpressed GATA6 from lentiviral expression vectors. Administration of nicotine accelerated transformation of pancreatic cells and tumor formation in Ela-KRAS and KPC mice. Nicotine induced dedifferentiation of acinar cells by activating AKT-ERK-MYC signaling; this led to inhibition of Gata6 promoter activity, loss of GATA6 protein, and subsequent loss of acinar differentiation and hyperactivation of oncogenic KRAS. Nicotine also promoted aggressiveness of established tumors as well as the epithelial-mesenchymal transition, increasing numbers of circulating cancer cells and their dissemination to the liver, compared with mice not exposed to nicotine. Nicotine induced pancreatic cells to acquire gene expression patterns and functional characteristics of cancer stem cells. These effects were markedly attenuated in K-Ras(+/LSL-G12D);Trp53(+/LSLR172H);Pdx-1-Cre mice given metformin. Metformin prevented nicotine-induced pancreatic carcinogenesis and tumor growth by up-regulating GATA6 and promoting

Plasma Cell Neoplasms (Including Multiple Myeloma)—Patient Version

Cancer.gov

Plasma cell neoplasms occur when abnormal plasma cells form cancerous tumors. When there is only one tumor, the disease is called a plasmacytoma. When there are multiple tumors, it is called multiple myeloma. Start here to find information on plasma cell neoplasms treatment, research, and statistics.

New saliva secretion model based on the expression of Na+-K+ pump and K+ channels in the apical membrane of parotid acinar cells.

PubMed

Almássy, János; Siguenza, Elias; Skaliczki, Marianna; Matesz, Klara; Sneyd, James; Yule, David I; Nánási, Péter P

2018-04-01

The plasma membrane of parotid acinar cells is functionally divided into apical and basolateral regions. According to the current model, fluid secretion is driven by transepithelial ion gradient, which facilitates water movement by osmosis into the acinar lumen from the interstitium. The osmotic gradient is created by the apical Cl - efflux and the subsequent paracellular Na + transport. In this model, the Na + -K + pump is located exclusively in the basolateral membrane and has essential role in salivary secretion, since the driving force for Cl - transport via basolateral Na + -K + -2Cl - cotransport is generated by the Na + -K + pump. In addition, the continuous electrochemical gradient for Cl - flow during acinar cell stimulation is maintained by the basolateral K + efflux. However, using a combination of single-cell electrophysiology and Ca 2+ -imaging, we demonstrate that photolysis of Ca 2+ close to the apical membrane of parotid acinar cells triggered significant K + current, indicating that a substantial amount of K + is secreted into the lumen during stimulation. Nevertheless, the K + content of the primary saliva is relatively low, suggesting that K + might be reabsorbed through the apical membrane. Therefore, we investigated the localization of Na + -K + pumps in acinar cells. We show that the pumps appear evenly distributed throughout the whole plasma membrane, including the apical pole of the cell. Based on these results, a new mathematical model of salivary fluid secretion is presented, where the pump reabsorbs K + from and secretes Na + to the lumen, which can partially supplement the paracellular Na + pathway.

Snail1 is required for the maintenance of the pancreatic acinar phenotype

PubMed Central

Loubat-Casanovas, Jordina; Peña, Raúl; Gonzàlez, Núria; Alba-Castellón, Lorena; Rosell, Santi; Francí, Clara; Navarro, Pilar; de Herreros, Antonio García

2016-01-01

The Snail1 transcriptional factor is required for correct embryonic development, yet its expression in adult animals is very limited and its functional roles are not evident. We have now conditionally inactivated Snail1 in adult mice and analyzed the phenotype of these animals. Snail1 ablation rapidly altered pancreas structure: one month after Snail1 depletion, acinar cells were markedly depleted, and pancreas accumulated adipose tissue. Snail1 expression was not detected in the epithelium but was in pancreatic mesenchymal cells (PMCs). Snail1 ablation in cultured PMCs downregulated the expression of several β-catenin/Tcf-4 target genes, modified the secretome of these cells and decreased their ability to maintain acinar markers in cultured pancreas cells. Finally, Snail1 deficiency modified the phenotype of pancreatic tumors generated in transgenic mice expressing c-myc under the control of the elastase promoter. Specifically, Snail1 depletion did not significantly alter the size of the tumors but accelerated acinar-ductal metaplasia. These results demonstrate that Snail1 is expressed in PMCs and plays a pivotal role in maintaining acinar cells within the pancreas in normal and pathological conditions. PMID:26735179

Sirtuin-1 regulates acinar-to-ductal metaplasia and supports cancer cell viability in pancreatic cancer.

PubMed

Wauters, Elke; Sanchez-Arévalo Lobo, Victor J; Pinho, Andreia V; Mawson, Amanda; Herranz, Daniel; Wu, Jianmin; Cowley, Mark J; Colvin, Emily K; Njicop, Erna Ngwayi; Sutherland, Rob L; Liu, Tao; Serrano, Manuel; Bouwens, Luc; Real, Francisco X; Biankin, Andrew V; Rooman, Ilse

2013-04-01

The exocrine pancreas can undergo acinar-to-ductal metaplasia (ADM), as in the case of pancreatitis where precursor lesions of pancreatic ductal adenocarcinoma (PDAC) can arise. The NAD(+)-dependent protein deacetylase Sirtuin-1 (Sirt1) has been implicated in carcinogenesis with dual roles depending on its subcellular localization. In this study, we examined the expression and the role of Sirt1 in different stages of pancreatic carcinogenesis, i.e. ADM models and established PDAC. In addition, we analyzed the expression of KIAA1967, a key mediator of Sirt1 function, along with potential Sirt1 downstream targets. Sirt1 was co-expressed with KIAA1967 in the nuclei of normal pancreatic acinar cells. In ADM, Sirt1 underwent a transient nuclear-to-cytoplasmic shuttling. Experiments where during ADM, we enforced repression of Sirt1 shuttling, inhibition of Sirt1 activity or modulation of its expression, all underscore that the temporary decrease of nuclear and increase of cytoplasmic Sirt1 stimulate ADM. Our results further underscore that important transcriptional regulators of acinar differentiation, that is, Pancreatic transcription factor-1a and β-catenin can be deacetylated by Sirt1. Inhibition of Sirt1 is effective in suppression of ADM and in reducing cell viability in established PDAC tumors. KIAA1967 expression is differentially downregulated in PDAC and impacts on the sensitivity of PDAC cells to the Sirt1/2 inhibitor Tenovin-6. In PDAC, acetylation of β-catenin is not affected, unlike p53, a well-characterized Sirt1-regulated protein in tumor cells. Our results reveal that Sirt1 is an important regulator and potential therapeutic target in pancreatic carcinogenesis. ©2012 AACR.

Gata6 is required for complete acinar differentiation and maintenance of the exocrine pancreas in adult mice.

PubMed

Martinelli, Paola; Cañamero, Marta; del Pozo, Natalia; Madriles, Francesc; Zapata, Agustín; Real, Francisco X

2013-10-01

Previous studies have suggested an important role of the transcription factor Gata6 in endocrine pancreas, while GATA6 haploinsufficient inactivating mutations cause pancreatic agenesis in humans. We aimed to analyse the effects of Gata6 inactivation on pancreas development and function. We deleted Gata6 in all epithelial cells in the murine pancreas at the onset of its development. Acinar proliferation, apoptosis, differentiation and exocrine functions were assessed using reverse transcriptase quantitative PCR (RT-qPCR), chromatin immunoprecipitation, immunohistochemistry and enzyme assays. Adipocyte transdifferentiation was assessed using electron microscopy and genetic lineage tracing. Gata6 is expressed in all epithelial cells in the adult mouse pancreas but it is only essential for exocrine pancreas homeostasis: while dispensable for pancreatic development after e10.5, it is required for complete acinar differentiation, for establishment of polarity and for the maintenance of acinar cells in the adult. Gata6 regulates directly the promoter of genes coding for digestive enzymes and the transcription factors Rbpjl and Mist1. Upon pancreas-selective Gata6 inactivation, massive loss of acinar cells and fat replacement take place. This is accompanied by increased acinar apoptosis and proliferation, acinar-to-ductal metaplasia and adipocyte transdifferentiation. By contrast, the endocrine pancreas is spared. Our data show that Gata6 is required for the complete differentiation of acinar cells through multiple transcriptional regulatory mechanisms. In addition, it is required for the maintenance of the adult acinar cell compartment. Our studies suggest that GATA6 alterations may contribute to diseases of the human adult exocrine pancreas.

Acid-base interactions during exocrine pancreatic secretion. Primary role for ductal bicarbonate in acinar lumen function.

PubMed

Freedman, S D; Scheele, G A

1994-03-23

The role of acid-base interactions during coordinated acinar and duct cell secretion in the exocrine pancreas is described. The sequence of acid-base events may be summarized as follows: (1) Sorting of secretory proteins and membrane components into the regulated secretory pathway of pancreatic acinar cells is triggered by acid- and calcium-induced aggregation and association mechanisms located in the trans-Golgi network. (2) Cholecystokinin-stimulated exocytosis in acinar cells releases the acidic contents of secretory granules into the acinar lumen. (3) Secretin-stimulated bicarbonate secretion from duct and duct-like cells neutralizes the acidic pH of exocytic contents, which leads to dissociation of protein aggregates and solubilization of (pro)enzymes within the acinar lumen. (4) Stimulated fluid secretion transports solubilized enzymes through the ductal system. (5) Further alkalinization of acinar lumen pH accelerates the enzymatic cleavage of the glycosyl phosphatidyl-inositol anchor associated with GP2 and thus releases the GP2/proteoglycan matrix from lumenal membranes, a process that appears to be required for vesicular retrieval of granule membranes from the apical plasma membrane and their reuse in the secretory process. We conclude that the central function of bicarbonate secretion by centroacinar and duct cells in the pancreas is to neutralize and then alkalinize the pH of the acinar lumen, sequential process that are required for (a) solubilization of secreted proteins and (b) cellular retrieval of granule membranes, respectively.

Insulation of a G protein-coupled receptor on the plasmalemmal surface of the pancreatic acinar cell

PubMed Central

1995-01-01

Receptor desensitization is a key process for the protection of the cell from continuous or repeated exposure to high concentrations of an agonist. Well-established mechanisms for desensitization of guanine nucleotide-binding protein (G protein)-coupled receptors include phosphorylation, sequestration/internalization, and down-regulation. In this work, we have examined some mechanisms for desensitization of the cholecystokinin (CCK) receptor which is native to the pancreatic acinar cell, and have found the predominant mechanism to be distinct from these recognized processes. Upon fluorescent agonist occupancy of the native receptor, it becomes "insulated" from the effects of acid washing and becomes immobilized on the surface of the plasma membrane in a time- and temperature-dependent manner. This localization was assessed by ultrastructural studies using a colloidal gold conjugate of CCK, and lateral mobility of the receptor was assessed using fluorescence recovery after photobleaching. Of note, recent application of the same morphologic techniques to a CCK receptor-bearing Chinese hamster ovary cell line demonstrated prominent internalization via the clathrin-dependent endocytic pathway, as well as entry into caveolae (Roettger, B.F., R.U. Rentsch, D. Pinon, E. Holicky, E. Hadac, J.M. Larkin, and L.J. Miller, 1995, J. Cell Biol. 128: 1029-1041). These organelles are not observed to represent prominent compartments for the same receptor to traverse in the acinar cell, although fluorescent insulin is clearly internalized in these cells via receptor-mediated endocytosis. In this work, the rate of lateral mobility of the CCK receptor is observed to be similar in both cell types (1-3 x 10(-10) cm2/s), while the fate of the agonist-occupied receptor is quite distinct in each cell. This supports the unique nature of desensitization processes which occur in a cell-specific manner. A plasmalemmal site of insulation of this important receptor on the pancreatic acinar cell

Plasma Cell Neoplasms (Including Multiple Myeloma)—Health Professional Version

Cancer.gov

There are several types of plasma cell neoplasms, including monoclonal gammopathy of undetermined significance (MGUS), isolated plasmacytoma of the bone, extramedullary plasmacytoma, and multiple myeloma. Find evidence-based information on plasma cell neoplasms treatment, research, and statistics.

Effects of Ghrelin miRNA on Inflammation and Calcium Pathway in Pancreatic Acinar Cells of Acute Pancreatitis.

PubMed

Tang, Xiping; Tang, Guodu; Liang, Zhihai; Qin, Mengbin; Fang, Chunyun; Zhang, Luyi

The study investigated the effects of endogenous targeted inhibition of ghrelin gene on inflammation and calcium pathway in an in vitro pancreatic acinar cell model of acute pancreatitis. Lentiviral expression vector against ghrelin gene was constructed and transfected into AR42J cells. The mRNA and protein expression of each gene were detected by reverse transcription polymerase chain reaction, Western blotting, or enzyme-linked immunosorbent assay. The concentration of intracellular calcium ([Ca]i) was determined by calcium fluorescence mark probe combined with laser scanning confocal microscopy. Compared with the control group, cerulein could upregulate mRNA and protein expression of inflammatory factors, calcium pathway, ghrelin, and [Ca]i. mRNA and protein expression of inflammatory factors increased significantly in cells transfected with ghrelin miRNA compared with the other groups. Intracellular calcium and expression of some calcium pathway proteins decreased significantly in cells transfected with ghrelin miRNA compared with the other groups. Targeted inhibition of ghrelin gene in pancreatic acinar cells of acute pancreatitis can upregulate the expression of the intracellular inflammatory factors and alleviate the intracellular calcium overload.

Perspectives on testicular germ cell neoplasms.

PubMed

Cheng, Liang; Lyu, Bingjian; Roth, Lawrence M

2017-01-01

Our knowledge of testicular germ cell neoplasms has progressed in the last few decades due to the description of germ cell neoplasia in situ (GCNIS) and a variety of specific forms of intratubular germ cell neoplasia, the discovery of isochromosome 12p and its importance in the development of invasiveness in germ cell tumors (GCTs), the identification of specific transcription factors for GCTs, and the recognition that a teratomatous component in mixed GCT represents terminal differentiation. Isochromosome 12p and 12p overrepresentation, collectively referred to as 12p amplification, are fundamental abnormalities that account for many types of malignant GCTs of the testis. Embryonal carcinoma is common in the testis but rare in the ovary, whereas the converse is true for mature cystic teratoma. Spermatocytic tumor occurs only in the testis; it has not been described in the ovary or extragonadal sites. The origin of ovarian mature cystic teratoma is similar to that of prepubertal-type testicular teratoma and dermoid cyst at any age in that it arises from a nontransformed germ cell, whereas postpubertal-type testicular teratoma arises from a malignant germ cell, most commonly through the intermediary of GCNIS. Somatic neoplasms, often referred to as monodermal teratomas, arise not infrequently from mature cystic teratoma of the ovary, whereas such neoplasms are rare in testicular teratoma with the exception of carcinoid. Integration of classical morphologic observations and emerging novel molecular studies will result in better understanding of the pathogenesis of GCTs and will optimize patient therapy. Copyright © 2016 Elsevier Inc. All rights reserved.

Hydrogen sulfide: a novel gaseous signaling molecule and intracellular Ca2+ regulator in rat parotid acinar cells.

PubMed

Moustafa, Amira; Habara, Yoshiaki

2015-10-01

In addition to nitric oxide (NO), hydrogen sulfide (H2S) is recognized as a crucial gaseous messenger that exerts many biological actions in various tissues. An attempt was made to assess the roles and underlying mechanisms of both gases in isolated rat parotid acinar cells. Ductal cells and some acinar cells were found to express NO and H2S synthases. Cevimeline, a muscarinic receptor agonist upregulated endothelial NO synthase in parotid tissue. NO and H2S donors increased the intracellular Ca(2+) concentration ([Ca(2+)]i). This was not affected by inhibitors of phospholipase C and inositol 1,4,5-trisphosphate receptors, but was decreased by blockers of ryanodine receptors (RyRs), soluble guanylyl cyclase, and protein kinase G. The H2S donor evoked NO production, which was decreased by blockade of NO synthases or phosphoinositide 3-kinase or by hypotaurine, an H2S scavenger. The H2S donor-induced [Ca(2+)]i increase was diminished by a NO scavenger or the NO synthases blocker. These results suggest that NO and H2S play important roles in regulating [Ca(2+)]i via soluble guanylyl cyclase-cGMP-protein kinase G-RyRs, but not via inositol 1,4,5-trisphosphate receptors. The effect of H2S may be partially through NO produced via phosphoinositide 3-kinase-Akt-endothelial NO synthase. It was concluded that both gases regulate [Ca(2+)]i in a synergistic way, mainly via RyRs in rat parotid acinar cells. Copyright © 2015 the American Physiological Society.

Bortezomib as a new therapeutic approach for blastic plasmacytoid dendritic cell neoplasm

PubMed Central

Philippe, Laure; Ceroi, Adam; Bôle-Richard, Elodie; Jenvrin, Alizée; Biichle, Sabeha; Perrin, Sophie; Limat, Samuel; Bonnefoy, Francis; Deconinck, Eric; Saas, Philippe; Garnache-Ottou, Francine; Angelot-Delettre, Fanny

2017-01-01

Blastic plasmacytoid dendritic cell neoplasm is an aggressive hematologic malignancy with a poor prognosis. No consensus regarding optimal treatment modalities is currently available. Targeting the nuclear factor-kappa B pathway is considered a promising approach since blastic plasmacytoid dendritic cell neoplasm has been reported to exhibit constitutive activation of this pathway. Moreover, nuclear factor-kappa B inhibition in blastic plasmacytoid dendritic cell neoplasm cell lines, achieved using either an experimental specific inhibitor JSH23 or the clinical drug bortezomib, interferes in vitro with leukemic cell proliferation and survival. Here we extended these data by showing that primary blastic plasmacytoid dendritic cell neoplasm cells from seven patients were sensitive to bortezomib-induced cell death. We confirmed that bortezomib efficiently inhibits the phosphorylation of the RelA nuclear factor-kappa B subunit in blastic plasmacytoid dendritic cell neoplasm cell lines and primary cells from patients in vitro and in vivo in a mouse model. We then demonstrated that bortezomib can be associated with other drugs used in different chemotherapy regimens to improve its impact on leukemic cell death. Indeed, when primary blastic plasmacytoid dendritic cell neoplasm cells from a patient were grafted into mice, bortezomib treatment significantly increased the animals’ survival, and was associated with a significant decrease of circulating leukemic cells and RelA nuclear factor-kappa B subunit expression. Overall, our results provide a rationale for the use of bortezomib in combination with other chemotherapy for the treatment of patients with blastic plasmacytoid dendritic cell neoplasm. Based on our data, a prospective clinical trial combining proteasome inhibitor with classical drugs could be envisaged. PMID:28798071

Bortezomib as a new therapeutic approach for blastic plasmacytoid dendritic cell neoplasm.

PubMed

Philippe, Laure; Ceroi, Adam; Bôle-Richard, Elodie; Jenvrin, Alizée; Biichle, Sabeha; Perrin, Sophie; Limat, Samuel; Bonnefoy, Francis; Deconinck, Eric; Saas, Philippe; Garnache-Ottou, Francine; Angelot-Delettre, Fanny

2017-11-01

Blastic plasmacytoid dendritic cell neoplasm is an aggressive hematologic malignancy with a poor prognosis. No consensus regarding optimal treatment modalities is currently available. Targeting the nuclear factor-kappa B pathway is considered a promising approach since blastic plasmacytoid dendritic cell neoplasm has been reported to exhibit constitutive activation of this pathway. Moreover, nuclear factor-kappa B inhibition in blastic plasmacytoid dendritic cell neoplasm cell lines, achieved using either an experimental specific inhibitor JSH23 or the clinical drug bortezomib, interferes in vitro with leukemic cell proliferation and survival. Here we extended these data by showing that primary blastic plasmacytoid dendritic cell neoplasm cells from seven patients were sensitive to bortezomib-induced cell death. We confirmed that bortezomib efficiently inhibits the phosphorylation of the RelA nuclear factor-kappa B subunit in blastic plasmacytoid dendritic cell neoplasm cell lines and primary cells from patients in vitro and in vivo in a mouse model. We then demonstrated that bortezomib can be associated with other drugs used in different chemotherapy regimens to improve its impact on leukemic cell death. Indeed, when primary blastic plasmacytoid dendritic cell neoplasm cells from a patient were grafted into mice, bortezomib treatment significantly increased the animals' survival, and was associated with a significant decrease of circulating leukemic cells and RelA nuclear factor-kappa B subunit expression. Overall, our results provide a rationale for the use of bortezomib in combination with other chemotherapy for the treatment of patients with blastic plasmacytoid dendritic cell neoplasm. Based on our data, a prospective clinical trial combining proteasome inhibitor with classical drugs could be envisaged. Copyright© Ferrata Storti Foundation.

Whole exome sequencing reveals recurrent mutations in BRCA2 and FAT genes in acinar cell carcinomas of the pancreas.

PubMed

Furukawa, Toru; Sakamoto, Hitomi; Takeuchi, Shoko; Ameri, Mitra; Kuboki, Yuko; Yamamoto, Toshiyuki; Hatori, Takashi; Yamamoto, Masakazu; Sugiyama, Masanori; Ohike, Nobuyuki; Yamaguchi, Hiroshi; Shimizu, Michio; Shibata, Noriyuki; Shimizu, Kyoko; Shiratori, Keiko

2015-03-06

Acinar cell carcinoma of the pancreas is a rare tumor with a poor prognosis. Compared to pancreatic ductal adenocarcinoma, its molecular features are poorly known. We studied a total of 11 acinar cell carcinomas, including 3 by exome and 4 by target sequencing. Exome sequencing revealed 65 nonsynonymous mutations and 22 indels with a mutation rate of 3.4 mutations/Mb per tumor, on average. By accounting for not only somatic but also germline mutations with loss of the wild-type allele, we identified recurrent mutations of BRCA2 and FAT genes. BRCA2 showed somatic or germline premature termination mutations, with loss of the wild-type allele in 3 of 7 tumors. FAT1, FAT3, and FAT4 showed somatic or germline missense mutations in 4 of 7 tumors. The germline FAT mutations were with loss of the wild-type allele. Loss of BRCA2 expression was observed in 5 of 11 tumors. One patient with a BRCA2-mutated tumor experienced complete remission of liver metastasis following cisplatinum chemotherapy. In conclusion, acinar cell carcinomas show a distinct mutation pattern and often harbor somatic or germline mutations of BRCA2 and FAT genes. This result may warrant assessment of BRCA2 abrogation in patients with the carcinoma to determine their sensitivity to chemotherapy.

CD1a immunopositivity in perivascular epithelioid cell neoplasms: true expression or technical artifact? A streptavidin-biotin and polymer-based detection system immunohistochemical study of perivascular epithelioid cell neoplasms and their morphologic mimics.

PubMed

Ahrens, William A; Folpe, Andrew L

2011-03-01

Perivascular epithelioid cell neoplasms comprise a family of rare neoplasms composed of morphologically distinctive perivascular epithelioid cells exhibiting a "myomelanocytic" immunophenotype. The distinction of perivascular epithelioid cell neoplasms from other tumors with melanocytic and smooth muscle differentiation can be difficult. A recent study has suggested that perivascular epithelioid cell neoplasms routinely express CD1a, a Langerhans cell-associated transmembrane glycoprotein involved in antigen presentation and that expression of this marker may be helpful in the distinction of perivascular epithelioid cell neoplasms from various mimics. We evaluated a series of perivascular epithelioid cell neoplasms and potential mimics for CD1a expression. A total of 54 cases (27 perivascular epithelioid cell neoplasms, 11 leiomyosarcomas, 10 melanomas, 6 clear cell sarcomas) were evaluated in 2 laboratories (Mayo Clinic Rochester: 31 cases, Carolinas Medical Center: 23 cases). Selected positive cases were retested at Carolinas Medical Center (11 cases) and Mayo Clinic Rochester (10 cases). Mayo Clinic Rochester methods were as follows: MTB1 clone (1:20, Novocastra, Newcastle-upon-Tyne, UK), heat-induced epitope retrieval in EDTA (pH 8.0), and Dako Advance detection system (Dako Corp, Carpinteria, CA) with background-reducing diluent. Carolinas Medical Center methods were as follows: MTB1 clone (1:30; CellMarque, Rocklin, CA), heat-induced epitope retrieval in Medium Cell Conditioner #1 (pH 8.0-9.0), and streptavidin-biotin detection system with diaminobenzidine chromogen, with and without biotin blocking. Scores were as follows: 1+, 5% to 25%; 2+, 26% to 50%; and 3+, more than 51%. Langerhans cells served as a positive internal control in all tested cases. All Mayo Clinic Rochester cases were negative. Sixteen Carolinas Medical Center perivascular epithelioid cell neoplasms (14 renal angiomyolipomas, 1 soft tissue perivascular epithelioid cell neoplasm, 1

Competence of failed endocrine progenitors to give rise to acinar but not ductal cells is restricted to early pancreas development.

PubMed

Beucher, Anthony; Martín, Mercè; Spenle, Caroline; Poulet, Martine; Collin, Caitlin; Gradwohl, Gérard

2012-01-15

During mouse pancreas development, the transient expression of Neurogenin3 (Neurog3) in uncommitted pancreas progenitors is required to determine endocrine destiny. However it has been reported that Neurog3-expressing cells can eventually adopt acinar or ductal fates and that Neurog3 levels were important to secure the islet destiny. It is not known whether the competence of Neurog3-induced cells to give rise to non-endocrine lineages is an intrinsic property of these progenitors or depends on pancreas developmental stage. Using temporal genetic labeling approaches we examined the dynamic of endocrine progenitor differentiation and explored the plasticity of Neurog3-induced cells throughout development. We found that Neurog3(+) progenitors develop into hormone-expressing cells in a fast process taking less then 10h. Furthermore, fate-mapping studies in heterozygote (Neurog3(CreERT/+)) and Neurog3-deficient (Neurog3(CreERT/CreERT)) embryos revealed that Neurog3-induced cells have different potential over time. At the early bud stage, failed endocrine progenitors can adopt acinar or ductal fate, whereas later in the branching pancreas they do not contribute to the acinar lineage but Neurog3-deficient cells eventually differentiate into duct cells. Thus these results provide evidence that the plasticity of Neurog3-induced cells becomes restricted during development. Furthermore these data suggest that during the secondary transition, endocrine progenitor cells arise from bipotent precursors already committed to the duct/endocrine lineages and not from domain of cells having distinct potentialities. Copyright © 2011 Elsevier Inc. All rights reserved.

Competence of failed endocrine progenitors to give rise to acinar but not ductal cells is restricted to early pancreas development

PubMed Central

Beucher, Anthony; Martín, Mercè; Spenle, Caroline; Poulet, Martine; Collin, Caitlin; Gradwohl, Gérard

2011-01-01

SUMMARY During mouse pancreas development, the transient expression of Neurogenin3 (Neurog3) in uncommitted pancreas progenitors is required to determine endocrine destiny. However it has been reported that Neurog3-expressing cells can eventually adopt acinar or ductal fates and that Neurog3 levels were important to secure the islet destiny. It is not known whether the competence of Neurog3-induced cells to give rise to non-endocrine lineages is an intrinsic property of these progenitors or depends on pancreas developmental stage. Using temporal genetic labeling approaches we examined the dynamic of endocrine progenitor differentiation and explored the plasticity of Neurog3-induced cells throughout development. We found that Neurog3+ progenitors develop into hormone-expressing cells in a fast process taking less then 10h. Furthermore, fate-mapping studies in heterozygote (Neurog3CreERT/+) and Neurog3-deficient (Neurog3CreERT/CreERT) embryos revealed that Neurog3-induced cells have different potential over time. At the early bud stage, failed endocrine progenitors can adopt acinar or ductal fate, whereas later in the branching pancreas they do not contribute to the acinar lineage but Neurog3-deficient cells eventually differentiate into duct cells. Thus these results provide evidence that the plasticity of Neurog3-induced cells becomes restricted during development. Furthermore these data suggest that during the secondary transition endocrine progenitor cells arise from single bipotent progenitor already committed to the duct/endocrine lineages and not from domain of cells having both potentialities. PMID:22056785

Dendritic cell and histiocytic neoplasms: biology, diagnosis, and treatment.

PubMed

Dalia, Samir; Shao, Haipeng; Sagatys, Elizabeth; Cualing, Hernani; Sokol, Lubomir

2014-10-01

Dendritic and histiocytic cell neoplasms are rare malignancies that make up less than 1% of all neoplasms arising in lymph nodes or soft tissues. These disorders have distinctive disease biology, clinical presentations, pathology, and unique treatment options. Morphology and immunohistochemistry evaluation by a hematopathologist remains key for differentiating between these neoplasms. In this review, we describe tumor biology, clinical features, pathology, and treatment of follicular dendritic cell sarcoma, interdigitating dendritic cell sarcoma, indeterminate dendritic cell sarcoma, histiocytic sarcoma, fibroblastic reticular cell tumors, and disseminated juvenile xanthogranuloma. A literature search for articles published between 1990 and 2013 was undertaken. Articles are reviewed and salient findings are systematically described. Patients with dendritic cell and histiocytic neoplasms have distinct but variable clinical presentations; however, because many tumors have recently been recognized, their true incidence is uncertain. Although the clinical features can present in many organs, most occur in the lymph nodes or skin. Most cases are unifocal and solitary presentations have good prognoses with surgical resection. The role of adjuvant therapy in these disorders remains unclear. In cases with disseminated disease, prognosis is poor and data on treatment options are limited, although chemotherapy and referral to a tertiary care center should be considered. Excisional biopsy is the preferred method of specimen collection for tissue diagnosis, and immunohistochemistry is the most important diagnostic method for differentiating these disorders from other entities. Dendritic cell and histiocytic cell neoplasms are rare hematological disorders with variable clinical presentations and prognoses. Immunohistochemistry remains important for diagnosis. Larger pooled analyses or clinical trials are needed to better understand optimal treatment options in these rare

Blastic plasmacytoid dendritic cell neoplasm in an elderly woman.

PubMed

Foong, H B B; Chong, M; Taylor, E M; Carlson, J A; Petrella, T

2013-04-01

Blastic plasmacytoid dendritic cell neoplasm (a.k.a. NK cell lymphoma, CD4+CD56+ haematodermic neoplasm) is a rare aggressive tumour that arises from plasmacytoid dendritic cell precursors. We report the first case from Malaysia of a 79-year-old Chinese woman who presented with purpuric plaques and nodules produced by pleomorphic CD4+, CD56+, CD68+, CD123+ and CD303+, but CD2APmononuclear cell infiltrates. Leukemic dissemination occurred and she succumbed to disease without treatment 4 weeks after diagnosis and 9 months after onset of cutaneous disease.

Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment (PDQ®)—Patient Version

Cancer.gov

Plasma cell neoplasms occur when abnormal plasma cells or myeloma cells form tumors in the bones or soft tissues of the body. Multiple myeloma, plasmacytoma, lymphoplasmacytic lymphoma, and monoclonal gammopathy of undetermined significance (MGUS) are different types of plasma cell neoplasms. Find out about risk factors, symptoms, diagnostic tests, prognosis, and treatment for these diseases.

Case report: primary acinar cell carcinoma of the liver treated with multimodality therapy

PubMed Central

Basturk, Olca; Shia, Jinru; Klimstra, David S.; Alago, William; D’Angelica, Michael I.; Abou-Alfa, Ghassan K.; O’Reilly, Eileen M.; Lowery, Maeve A.

2017-01-01

We describe a case of primary acinar cell carcinoma (ACC) originating in the liver in a 54-year-old female, diagnosed following persistent abnormal elevated liver function. Imaging revealed two masses, one dominant lesion in the right hepatic lobe and another in segment IVA. A right hepatectomy was performed to remove the larger lesion, while the mass in segment IVA was unresectable due to its proximity to the left hepatic vein. Immunohistochemical staining showed positivity for trypsin and chymotrypsin. Postoperatively the patient underwent hepatic arterial embolization of the other unresectable lesion followed by FOLFOX chemotherapy. At 20 months from diagnosis the patient is currently under observation with a decreasing necrotic mass and no other disease evident. Based on histology, immunohistochemistry and radiological findings a diagnosis of primary ACC of the liver was made. Genomic assessment of somatic mutations within the patient’s tumor was also performed through next generation sequencing and findings were consistent with an acinar malignancy. This case highlights a rare tumor subtype treated with a combination of therapeutic modalities through a multidisciplinary approach. PMID:29184698

Pancreatic Fat Accumulation, Fibrosis, and Acinar Cell Injury in the Zucker Diabetic Fatty Rat Fed a Chronic High-Fat Diet

PubMed Central

Matsuda, Akiko; Makino, Naohiko; Tozawa, Tomohiro; Shirahata, Nakao; Honda, Teiichiro; Ikeda, Yushi; Sato, Hideyuki; Ito, Miho; Kakizaki, Yasuharu; Akamatsu, Manabu; Ueno, Yoshiyuki; Kawata, Sumio

2014-01-01

Objective The histological alteration of the exocrine pancreas in obesity has not been clarified. In the present study, we investigated biochemical and histological changes in the exocrine pancreas of obese model rats. Methods Zucker lean rats were fed a standard diet, and Zucker diabetic fatty (ZDF) rats were divided into 2 groups fed a standard diet and a high-fat diet, respectively. These experimental groups were fed each of the diets from 6 weeks until 12, 18, 24 weeks of age. We performed blood biochemical assays and histological analysis of the pancreas. Results In the ZDF rats fed a high-fat diet, the ratio of accumulated pancreatic fat area relative to exocrine gland area was increased significantly at 18 weeks of age in comparison with the other 2 groups (P < 0.05), and lipid droplets were observed in acinar cells. Subsequently, at 24 weeks of age in this group, pancreatic fibrosis and the serum exocrine pancreatic enzyme levels were increased significantly relative to the other 2 groups (P < 0.01). Conclusions In ZDF rats fed a chronic high-fat diet, fat accumulates in pancreatic acinar cells, and this fatty change seems to be related to subsequent pancreatic fibrosis and acinar cell injury. PMID:24717823

The exocrine pancreas: the acinar-ductal tango in physiology and pathophysiology.

PubMed

Hegyi, Peter; Petersen, Ole H

2013-01-01

There are many reviews of pancreatic acinar cell function and also of pancreatic duct function, but there is an almost total absence of synthetic reviews bringing the integrated functions of these two vitally and mutually interdependent cells together. This is what we have attempted to do in this chapter. In the first part, we review the normal integrated function of the acinar-ductal system, with particular emphasis on how regulation of one type of cell also influences the other cell type. In the second part, we review a range of pathological processes, particularly those involved in acute pancreatitis (AP), an often-fatal human disease in which the pancreas digests itself, in order to explore how malfunction of one of the cell types adversely affects the function of the other.

Homer2 protein regulates plasma membrane Ca²⁺-ATPase-mediated Ca²⁺ signaling in mouse parotid gland acinar cells.

PubMed

Yang, Yu-Mi; Lee, Jiae; Jo, Hae; Park, Soonhong; Chang, Inik; Muallem, Shmuel; Shin, Dong Min

2014-09-05

Homer proteins are scaffold molecules with a domain structure consisting of an N-terminal Ena/VASP homology 1 protein-binding domain and a C-terminal leucine zipper/coiled-coil domain. The Ena/VASP homology 1 domain recognizes proline-rich motifs and binds multiple Ca(2+)-signaling proteins, including G protein-coupled receptors, inositol 1,4,5-triphosphate receptors, ryanodine receptors, and transient receptor potential channels. However, their role in Ca(2+) signaling in nonexcitable cells is not well understood. In this study, we investigated the role of Homer2 on Ca(2+) signaling in parotid gland acinar cells using Homer2-deficient (Homer2(-/-)) mice. Homer2 is localized at the apical pole in acinar cells. Deletion of Homer2 did not affect inositol 1,4,5-triphosphate receptor localization or channel activity and did not affect the expression and activity of sarco/endoplasmic reticulum Ca(2+)-ATPase pumps. In contrast, Homer2 deletion markedly increased expression of plasma membrane Ca(2+)-ATPase (PMCA) pumps, in particular PMCA4, at the apical pole. Accordingly, Homer2 deficiency increased Ca(2+) extrusion by acinar cells. These findings were supported by co-immunoprecipitation of Homer2 and PMCA in wild-type parotid cells and transfected human embryonic kidney 293 (HEK293) cells. We identified a Homer-binding PPXXF-like motif in the N terminus of PMCA that is required for interaction with Homer2. Mutation of the PPXXF-like motif did not affect the interaction of PMCA with Homer1 but inhibited its interaction with Homer2 and increased Ca(2+) clearance by PMCA. These findings reveal an important regulation of PMCA by Homer2 that has a central role on PMCA-mediated Ca(2+) signaling in parotid acinar cells. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Mixed acinar-neuroendocrine-ductal carcinoma of the pancreas: a tale of three lineages.

PubMed

Anderson, Mark J; Kwong, Christina A; Atieh, Mohammed; Pappas, Sam G

2016-06-02

Most pancreatic cancers arise from a single cell type, although mixed pancreatic carcinomas represent a rare exception. The rarity of these aggressive malignancies and the limitations of fine-needle aspiration (FNA) pose significant barriers to diagnosis and appropriate management. We report a case of a 54-year-old man presenting with abdominal pain, jaundice and a hypodense lesion within the uncinate process on CT. FNA suggested poorly differentiated adenocarcinoma, which was subsequently resected via pancreaticoduodenectomy. Pathological analysis yielded diagnosis of invasive mixed acinar-neuroendocrine-ductal pancreatic carcinoma. Given the rare and deadly nature of these tumours, clinicians must be aware of their pathophysiology and do practice with a high degree of clinical suspicion, when appropriate. Surgical resection and thorough pathological analysis with immunohistochemical staining and electron microscopy remain the standards of care for mixed pancreatic tumours without gross evidence of metastasis. Diligent characterisation of the presentation and histological findings associated with these neoplasms should continue in order to promote optimal diagnostic and therapeutic strategies. 2016 BMJ Publishing Group Ltd.

Early onset of a nasal perivascular epithelioid cell neoplasm not related to tuberous sclerosis complex.

PubMed

Gana, S; Morbini, P; Giourgos, G; Matti, E; Chu, F; Danesino, C; Pagella, F

2012-06-01

Perivascular epithelioid cell neoplasms are a group of rare tumours reported in various organs under a variety of designations. Such tumours are of interest primarily because of the distinctive morphology of their cell population and their immunoreactivity with melanocytic and myoid markers. There is a strong association between perivascular epithelioid cell neoplasms and tuberous sclerosis complex. Perivascular epithelioid cell neoplasms very rarely occur in the upper aero-digestive tract. To date only three cases of nasal perivascular epithelioid cell neoplasms have been reported in the literature. The present report refers to a 22-year old woman, without any stigmata of tuberous sclerosis complex, with early onset of a polypoid nasal mass with pathological and immunohistochemical features entirely compatible with those of a perivascular epithelioid cell neoplasm.

Perivascular epithelioid cell neoplasms: pathology and pathogenesis.

PubMed

Folpe, Andrew L; Kwiatkowski, David J

2010-01-01

This review article summarizes our current understanding of the clinical, pathologic, immunohistochemical, and genetic aspects of perivascular epithelioid cell neoplasms, a rare group of related tumors defined by both morphologic and immunophenotypic criteria.

Transdifferentiation of mouse adipose-derived stromal cells into acinar cells of the submandibular gland using a co-culture system

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Jingu; Park, Sangkyu; Roh, Sangho, E-mail: sangho@snu.ac.kr

A loss of salivary gland function often occurs after radiation therapy in head and neck tumors, though secretion of saliva by the salivary glands is essential for the health and maintenance of the oral environment. Transplantation of salivary acinar cells (ACs), in part, may overcome the side effects of therapy. Here we directly differentiated mouse adipose-derived stromal cells (ADSCs) into ACs using a co-culture system. Multipotent ADSCs can be easily collected from stromal vascular fractions of adipose tissues. The isolated ADSCs showed positive expression of markers such as integrin beta-1 (CD29), cell surface glycoprotein (CD44), endoglin (CD105), and Nanog. Themore » cells were able to differentiate into adipocytes, osteoblasts, and neural-like cells after 14 days in culture. ADSCs at passage 2 were co-cultured with mouse ACs in AC culture medium using the double-chamber (co-culture system) to avoid mixing the cell types. The ADSCs in this co-culture system expressed markers of ACs, such as α-amylases and aquaporin5, in both mRNA and protein. ADSCs cultured in AC-conditioned medium also expressed AC markers. Cellular proliferation and senescence analyses demonstrated that cells in the co-culture group showed lower senescence and a higher proliferation rate than the AC-conditioned medium group at Days 14 and 21. The results above imply direct conversion of ADSCs into ACs under the co-culture system; therefore, ADSCs may be a stem cell source for the therapy for salivary gland damage. - Highlights: • ADSCs could transdifferentiate into acinar cells (ACs) using ACs co-culture (CCA). • Transdifferentiated ADSCs expressed ACs markers such as α-amylase and aquaporin5. • High proliferation and low senescence were presented in CCA at Day 14. • Transdifferentiation of ADSCs into ACs using CCA may be an appropriate method for cell-based therapy.« less

Class I histone deacetylase inhibition improves pancreatitis outcome by limiting leukocyte recruitment and acinar-to-ductal metaplasia.

PubMed

Bombardo, Marta; Saponara, Enrica; Malagola, Ermanno; Chen, Rong; Seleznik, Gitta M; Haumaitre, Cecile; Quilichini, Evans; Zabel, Anja; Reding, Theresia; Graf, Rolf; Sonda, Sabrina

2017-11-01

Pancreatitis is a common inflammation of the pancreas with rising incidence in many countries. Despite improvements in diagnostic techniques, the disease is associated with high risk of severe morbidity and mortality and there is an urgent need for new therapeutic interventions. In this study, we evaluated whether histone deacetylases (HDACs), key epigenetic regulators of gene transcription, are involved in the development of the disease. We analysed HDAC regulation during cerulein-induced acute, chronic and autoimmune pancreatitis using different transgenic mouse models. The functional relevance of class I HDACs was tested with the selective inhibitor MS-275 in vivo upon pancreatitis induction and in vitro in activated macrophages and primary acinar cell explants. HDAC expression and activity were up-regulated in a time-dependent manner following induction of pancreatitis, with the highest abundance observed for class I HDACs. Class I HDAC inhibition did not prevent the initial acinar cell damage. However, it effectively reduced the infiltration of inflammatory cells, including macrophages and T cells, in both acute and chronic phases of the disease, and directly disrupted macrophage activation. In addition, MS-275 treatment reduced DNA damage in acinar cells and limited acinar de-differentiation into acinar-to-ductal metaplasia in a cell-autonomous manner by impeding the EGF receptor signalling axis. These results demonstrate that class I HDACs are critically involved in the development of acute and chronic forms of pancreatitis and suggest that blockade of class I HDAC isoforms is a promising target to improve the outcome of the disease. © 2017 The British Pharmacological Society.

Pancreatic neuroendocrine neoplasms: a current summary of diagnostic, prognostic, and differential diagnostic information.

PubMed

Wick, M R; Graeme-Cook, F M

2001-06-01

Pancreatic endocrine tumors (PETs) continue to be challenging diagnostic and prognostic lesions in surgical pathology and clinical medicine. These neoplasms can be graded into 1 of 3 tiers, based on histologic characteristics in likeness to epithelial neuroendocrine tumors in other anatomic sites. However, grade 1 tumors are by far the most common and are the most difficult to prognosticate. The most helpful features by which to gauge the behavior of such lesions include size (3 cm or larger); mitotic activity (2 or more mitoses per 10 high-power [x400] microscopic fields); marked nuclear atypia, especially with atypical mitoticfigures; predominant tumor synthesis of gastrin, vasoactive intestinal polypeptide, somatostatin, glucagon, calcitonin, or adrenocorticotropic hormone; complete nonfunctionality of the tumor at an immunohistochemical level; or invasion of blood vessels, nerves, or adjacent organs by the neoplasm. Differential diagnosis of PETs includes lesions such as solid-pseudopapillary neoplasms, acinar carcinomas, metastatic neuroendocrine tumors, and plasmacytomas.

CT findings associated with blastic plasmacytoid dendritic cell neoplasm: a case report

PubMed Central

Choi, Jung W; Jeong, Katherine; Sokol, Lubomir

2016-01-01

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy that is frequently misdiagnosed. We present a case of a 53-year-old man diagnosed with blastic plasmacytoid dendritic cell neoplasm with extensive computed tomography (CT) findings and provide an imaging focused review of this uncommon malignancy. PMID:27504192

Ethanol exerts dual effects on calcium homeostasis in CCK-8-stimulated mouse pancreatic acinar cells.

PubMed

Fernández-Sánchez, Marcela; del Castillo-Vaquero, Angel; Salido, Ginés M; González, Antonio

2009-10-30

A significant percentage of patients with pancreatitis often presents a history of excessive alcohol consumption. Nevertheless, the patho-physiological effect of ethanol on pancreatitis remains poorly understood. In the present study, we have investigated the early effects of acute ethanol exposure on CCK-8-evoked Ca2+ signals in mouse pancreatic acinar cells. Changes in [Ca2+]i and ROS production were analyzed employing fluorescence techniques after loading cells with fura-2 or CM-H2DCFDA, respectively. Ethanol, in the concentration range from 1 to 50 mM, evoked an oscillatory pattern in [Ca2+]i. In addition, ethanol evoked reactive oxygen species generation (ROS) production. Stimulation of cells with 1 nM or 20 pM CCK-8, respectively led to a transient change and oscillations in [Ca2+]i. In the presence of ethanol a transformation of 20 pM CCK-8-evoked physiological oscillations into a single transient increase in [Ca2+]i in the majority of cells was observed. Whereas, in response to 1 nM CCK-8, the total Ca2+ mobilization was significantly increased by ethanol pre-treatment. Preincubation of cells with 1 mM 4-MP, an inhibitor of alcohol dehydrogenase, or 10 microM of the antioxidant cinnamtannin B-1, reverted the effect of ethanol on total Ca2+ mobilization evoked by 1 nM CCK-8. Cinnamtannin B-1 blocked ethanol-evoked ROS production. ethanol may lead, either directly or through ROS generation, to an over stimulation of pancreatic acinar cells in response to CCK-8, resulting in a higher Ca2+ mobilization compared to normal conditions. The actions of ethanol on CCK-8-stimulation of cells create a situation potentially leading to Ca2+ overload, which is a common pathological precursor that mediates pancreatitis.

Beneficial effect of the bioflavonoid quercetin on cholecystokinin-induced mitochondrial dysfunction in isolated rat pancreatic acinar cells.

PubMed

Weber, Heike; Jonas, Ludwig; Wakileh, Michael; Krüger, Burkhard

2014-03-01

The pathogenesis of acute pancreatitis (AP) is still poorly understood. Thus, a reliable pharmacological therapy is currently lacking. In recent years, an impairment of the energy metabolism of pancreatic acinar cells, caused by Ca(2+)-mediated depolarization of the inner mitochondrial membrane and a decreased ATP supply, has been implicated as an important pathological event. In this study, we investigated whether quercetin exerts protection against mitochondrial dysfunction. Following treatment with or without quercetin, rat pancreatic acinar cells were stimulated with supramaximal cholecystokinin-8 (CCK). CCK caused a decrease in the mitochondrial membrane potential (MMP) and ATP concentration, whereas the mitochondrial dehydrogenase activity was significantly increased. Quercetin treatment before CCK application exerted no protection on MMP but increased ATP to a normal level, leading to a continuous decrease in the dehydrogenase activity. The protective effect of quercetin on mitochondrial function was accompanied by a reduction in CCK-induced changes to the cell membrane. Concerning the molecular mechanism underlying the protective effect of quercetin, an increased AMP/ATP ratio suggests that the AMP-activated protein kinase system may be activated. In addition, quercetin strongly inhibited CCK-induced trypsin activity. The results indicate that the use of quercetin may be a therapeutic strategy for reducing the severity of AP.

Pancreatic acinar cells: ionic dependence of acetylcholine-induced membrane potential and resistance change.

PubMed Central

Nishiyama, A; Petersen, O H

1975-01-01

1. Intracellular recordings of membrane potential, input resistance and time constant have been made in vitro from the exocrine acinar cells of the mouse pancreas using glass micro-electrodes. The acinar cells were stimulated by acetylcholine (ACh). In some cases ACh was simply directly added to the tissue superfusion bath, in other experiments ACh was applied locally to pancreatic acini by micro-iontophoresis. 2. Current-voltage relations were investigated by injecting rectangular de- or hyperpolarizing current pulses through the recording micro-electrode. Within a relatively wide range (-20 to -70 mV) there was a linear relation between injected current and change in membrane potential. The slope of such linear curves corresponded to an input resistance of about 3-8 M omega. The membrane time constant was about 5-10 msec. 3. ACh depolarized the cell membrane and caused a marked reduction of input resistance and time constant. The minimum latency of the ACh-induced depolarization (microiontophoretic application) was 100-300 msec. Maximal depolarization was about 20 mV. The effect of this local ACh application was abolished by atropine (1-4 x 10-6 M). The blocking effect of atropine was fully reversible. 4. Stimulating with ACh during the passage of large depolarizing current pulses made it possible simultaneously to observe the effect of ACh at two different levels of resting potential (RP). At the spontaneous RP of about minus 40 mV ACh evoked a depolarization of usual magnitude (15-20 mV) while at the artificially displaced level of about -10 mV a small hyperpolarization (about 5 mV) was observed. It therefore appears that the reversal potential of the transmitter equilibrium potential is about -20 mV. 5. Replacement of the superfusion fluid C1 by sulphate or methylsulphate caused an initial short-lasting depolarization, thereafter the normal resting potential was reassumed... PMID:1142124

Prostate specific antigen and acinar density: a new dimension, the "Prostatocrit".

PubMed

Robinson, Simon; Laniado, Marc; Montgomery, Bruce

2017-01-01

Prostate-specific antigen densities have limited success in diagnosing prostate cancer. We emphasise the importance of the peripheral zone when considered with its cellular constituents, the "prostatocrit". Using zonal volumes and asymmetry of glandular acini, we generate a peripheral zone acinar volume and density. With the ratio to the whole gland, we can better predict high grade and all grade cancer. We can model the gland into its acinar and stromal elements. This new "prostatocrit" model could offer more accurate nomograms for biopsy. 674 patients underwent TRUS and biopsy. Whole gland and zonal volumes were recorded. We compared ratio and acinar volumes when added to a "clinic" model using traditional PSA density. Univariate logistic regression was used to find significant predictors for all and high grade cancer. Backwards multiple logistic regression was used to generate ROC curves comparing the new model to conventional density and PSA alone. Prediction of all grades of prostate cancer: significant variables revealed four significant "prostatocrit" parameters: log peripheral zone acinar density; peripheral zone acinar volume/whole gland acinar volume; peripheral zone acinar density/whole gland volume; peripheral zone acinar density. Acinar model (AUC 0.774), clinic model (AUC 0.745) (P=0.0105). Prediction of high grade prostate cancer: peripheral zone acinar density ("prostatocrit") was the only significant density predictor. Acinar model (AUC 0.811), clinic model (AUC 0.769) (P=0.0005). There is renewed use for ratio and "prostatocrit" density of the peripheral zone in predicting cancer. This outperforms all traditional density measurements. Copyright® by the International Brazilian Journal of Urology.

Isoproterenol-stimulated labelling of particulate proteins by using [adenylate-32P]NAD+ independent on a cAMP-dependent protein kinase in parotid acinar cells.

PubMed

Sugiya, H; Hara-Yokoyama, M; Furuyama, S

1992-03-30

When saponin-permeabilized rat parotid acinar cells were incubated with [adenylate-32P]NAD+, labelling of proteins (33, 27 and 23 kDa) in particulate fractions of the cells was stimulated by isoproterenol. The effect of isoproterenol was completely blocked by a beta-antagonist. Both forskolin or cAMP mimicked the effect of isoproterenol on the labelling. However, an inhibitor of cAMPdPK failed to induce complete inhibition of the effects of isoproterenol, forskolin and cAMP. When the labelled proteins were treated with snake venom phosphodiesterase, neither [32P]5'-AMP nor [32P]phosphoribosyladenosine was released. These results suggest that covalent modification of proteins with NAD+, which is distinct from ADP-ribosylation and cAMPdPK-dependent phosphorylation, is coupled to beta-receptor-cAMP signalling system in rat parotid acinar cells.

Early to Late Endosome Trafficking Controls Secretion and Zymogen Activation in Rodent and Human Pancreatic Acinar Cells.

PubMed

Messenger, Scott W; Thomas, Diana Dh; Cooley, Michelle M; Jones, Elaina K; Falkowski, Michelle A; August, Benjamin K; Fernandez, Luis A; Gorelick, Fred S; Groblewski, Guy E

2015-11-01

Pancreatic acinar cells have an expanded apical endosomal system, the physiological and pathophysiological significance of which is still emerging. Phosphatidylinositol-3,5-bisphosphate (PI(3,5)P 2 ) is an essential phospholipid generated by PIKfyve, which phosphorylates phosphatidylinositol-3-phosphate (PI(3)P). PI(3,5)P 2 is necessary for maturation of early endosomes (EE) to late endosomes (LE). Inhibition of EE to LE trafficking enhances anterograde endosomal trafficking and secretion at the plasma membrane by default through a recycling endosome (RE) intermediate. We assessed the effects of modulating PIKfyve activity on apical trafficking and pancreatitis responses in pancreatic acinar cells. Inhibition of EE to LE trafficking was achieved using pharmacological inhibitors of PIKfyve, expression of dominant negative PIKfyve K1877E, or constitutively active Rab5-GTP Q79L. Anterograde endosomal trafficking was manipulated by expression of constitutively active and dominant negative Rab11a mutants. The effects of these agents on secretion, endolysosomal exocytosis of lysosome associated membrane protein (LAMP1), and trypsinogen activation in response to high-dose CCK-8, bile acids and cigarette toxin was determined. PIKfyve inhibition increased basal and stimulated secretion. Adenoviral overexpression of PIKfyve decreased secretion leading to cellular death. Expression of Rab5-GTP Q79L or Rab11a-GTP Q70L enhanced secretion. Conversely, dominant-negative Rab11a-GDP S25N reduced secretion. High-dose CCK inhibited endolysosomal exocytosis that was reversed by PIKfyve inhibition. PIKfyve inhibition blocked intracellular trypsin accumulation and cellular damage responses to high CCK-8, tobacco toxin, and bile salts in both rodent and human acini. These data demonstrate that EE-LE trafficking acutely controls acinar secretion and the intracellular activation of zymogens leading to the pathogenicity of acute pancreatitis.

Role of alveolar topology on acinar flows and convective mixing.

PubMed

Hofemeier, Philipp; Sznitman, Josué

2014-06-01

Due to experimental challenges, computational simulations are often sought to quantify inhaled aerosol transport in the pulmonary acinus. Commonly, these are performed using generic alveolar topologies, including spheres, toroids, and polyhedra, to mimic the complex acinar morphology. Yet, local acinar flows and ensuing particle transport are anticipated to be influenced by the specific morphological structures. We have assessed a range of acinar models under self-similar breathing conditions with respect to alveolar flow patterns, convective flow mixing, and deposition of fine particles (1.3 μm diameter). By tracking passive tracers over cumulative breathing cycles, we find that irreversible flow mixing correlates with the location and strength of the recirculating vortex inside the cavity. Such effects are strongest in proximal acinar generations where the ratio of alveolar to ductal flow rates is low and interalveolar disparities are most apparent. Our results for multi-alveolated acinar ducts highlight that fine 1 μm inhaled particles subject to alveolar flows are sensitive to the alveolar topology, underlining interalveolar disparities in particle deposition patterns. Despite the simplicity of the acinar models investigated, our findings suggest that alveolar topologies influence more significantly local flow patterns and deposition sites of fine particles for upper generations emphasizing the importance of the selected acinar model. In distal acinar generations, however, the alveolar geometry primarily needs to mimic the space-filling alveolar arrangement dictated by lung morphology.

Activation of muscarinic receptors in rat parotid acinar cells induces AQP5 trafficking to nuclei and apical plasma membrane.

PubMed

Cho, Gota; Bragiel, Aneta M; Wang, Di; Pieczonka, Tomasz D; Skowronski, Mariusz T; Shono, Masayuki; Nielsen, Søren; Ishikawa, Yasuko

2015-04-01

The subcellular distribution of aquaporin-5 (AQP5) in rat parotid acinar cells in response to muscarinic acetylcholine receptor (mAChR) activation remains unclear. Immunoconfocal and immunoelectron microscopy were used to visualize the distribution of AQP5 in parotid acinar cells. Western blotting was used to analyze AQP5 levels in membranes. To clarify the characteristics of membrane domains associated with AQP5, detergent solubility and sucrose-density flotation experiments were performed. Under control conditions, AQP5 was diffusely distributed on the apical plasma membrane (APM) and apical plasmalemmal region and throughout the cytoplasm. Upon mAChR activation, AQP5 was predominantly located in the nucleus, APM and lateral plasma membrane (LPM). Subsequently, localization of AQP5 in the nucleus, APM and LPM was decreased. Prolonged atropine treatment inhibited mAChR agonist-induced translocation of AQP5 to the nucleus, APM and LPM. AQP5 levels were enhanced in isolated nuclei and nuclear membranes prepared from parotid tissues incubated with mAChR agonist. mAChR agonist induced AQP5 levels in both soluble and insoluble nuclear fractions solubilized with Triton X-100 or Lubrol WX. Small amounts of AQP5 in nuclei were detected using low-density sucrose gradient. When AQP5 was present in the nuclear membrane, nuclear size decreased. The activation of mAChR induced AQP5 translocation to the nucleus, APM and LPM, and AQP5 may trigger water transport across the nuclear membrane and plasma membrane in rat parotid acinar cells. AQP5 translocates to the nuclear membrane and may trigger the movement of water, inducing shrinkage of the nucleus and the start of nuclear functions. Copyright © 2015 Elsevier B.V. All rights reserved.

Differential Expression of Glycolysis-Related Proteins in Follicular Neoplasms versus Hürthle Cell Neoplasms: A Retrospective Analysis

PubMed Central

Kim, Hye Min

2017-01-01

Purpose Although currently classified as variants of follicular neoplasms (FNs), Hürthle cell neoplasms (HCNs) exhibit distinct biological characteristics. Hence, the metabolism of both neoplasms may also be different. The aims of this study were to investigate and compare the expression of glycolysis-related proteins in HCNs and FNs and to determine the clinical implications of such expression. Methods Tissue microarrays were constructed with 265 samples of FNs (112 follicular carcinomas (FCs) and 153 follicular adenomas (FAs)) as well as 108 samples of HCNs (27 Hürthle cell carcinomas (HCCs) and 81 Hürthle cell adenomas (HCAs)). Immunohistochemical staining for the glycolysis-related molecules Glut-1, hexokinase II, CAIX, and MCT4 was performed. Results The expression levels of Glut-1, hexokinase II, CAIX, and MCT4 were significantly higher in HCNs than in FNs (p < 0.001). Glut-1, hexokinase II, CAIX, and MCT4 expression levels were highest in HCC, followed by HCA, FC, and FA (all p < 0.001). In HCC, hexokinase II positivity was associated with large tumor size (>4 cm) (p = 0.046), CAIX positivity with vascular invasion (p = 0.005), and MCT4 positivity with extrathyroidal extension (p = 0.030). Conclusion The expression levels of the glycolysis-related proteins Glut-1, hexokinase II, CAIX, and MCT4 were higher in HCNs than in FNs and in HCCs than in HCAs. PMID:28790533

Megamitochondria in the serous acinar cells of the submandibular gland of the neotropical fruit bat, Artibeus obscurus.

PubMed

Tandler, B; Nagato, T; Phillips, C J

1997-05-01

As part of a continuing investigation of the comparative ultrastructure of chiropteran salivary glands, we examined the submandibular glands of eight species of neotropical fruit bats in the genus Artibeus. We previously described secretory granules of unusual substructure in the seromucous demilunar cells of this organ in some species in this genus. In the present study, we turned our attention to the serous acinar cells in the same glands. Specimens of eight species of Artibeus were collected in neotropical localities. Salivary glands were extirpated in the field and thin slices were fixed by immersion in triple aldehyde-DMSO or in modified half-strength Karnovsky's fixative. Tissues were further processed for electron microscopy by conventional means. In contrast to seromucous cells, which exhibit species-specific diversification in bats of this genus, the secretory apparatus and secretory granules in the serous acinar cells are highly conserved across all seven species. The single exception involves the mitochondria in one species. In this instance, some of the serous cell mitochondria in Artibeus obscurus are modified into megamitochondria. Such organelles usually have short, peripheral cristae; a laminar inclusion is present in the matrix compartment of every outsized organelle. Inclusions of this nature never are present in normal-size mitochondria in the serous cells. None of the megamitochondria were observed in the process of degeneration. The giant mitochondria in A. obscurus have a matrical structure that is radically different from that of the only other megamitochondria reported to occur in bat salivary glands. The factors that lead to variation in megamitochondrial substructure in different species, as well as the functional capacities of such giant organelles, are unknown.

The role of anisotropic expansion for pulmonary acinar aerosol deposition

PubMed Central

Hofemeier, Philipp; Sznitman, Josué

2016-01-01

Lung deformations at the local pulmonary acinar scale are intrinsically anisotropic. Despite progress in imaging modalities, the true heterogeneous nature of acinar expansion during breathing remains controversial, where our understanding of inhaled aerosol deposition still widely emanates from studies under self-similar, isotropic wall motions. Building on recent 3D models of multi-generation acinar networks, we explore in numerical simulations how different hypothesized scenarios of anisotropic expansion influence deposition outcomes of inhaled aerosols in the acinar depths. While the broader range of particles acknowledged to reach the acinar region (dp = 0.005–5.0 μm) are largely unaffected by the details of anisotropic expansion under tidal breathing, our results suggest nevertheless that anisotropy modulates the deposition sites and fractions for a narrow band of sub-micron particles (dp ~ 0.5–0.75 μm), where the fate of aerosols is greatly intertwined with local convective flows. Our findings underscore how intrinsic aerosol motion (i.e. diffusion, sedimentation) undermines the role of anisotropic wall expansion that is often attributed in determining aerosol mixing and acinar deposition. PMID:27614613

Dietary-induced changes in the fatty acid profile of rat pancreatic membranes are associated with modifications in acinar cell function and signalling.

PubMed

Yago, Maria D; Diaz, Ricardo J; Ramirez, Rolando; Martinez, Maria A; Mañas, Mariano; Martinez-Victoria, Emilio

2004-02-01

The effects of dietary lipids on the fatty acid composition of rat pancreatic membranes and acinar cell function were investigated. Weaning rats were fed for 8 weeks on one of two diets which contained 100 g virgin olive oil (OO) or sunflower-seed oil (SO)/kg. Pancreatic plasma membranes were isolated and fatty acids determined. Amylase secretion and cytosolic concentrations of Ca(2+) and Mg(2+) were measured in pancreatic acini. Membrane fatty acids were profoundly affected by the diets; the rats fed OO had higher levels of 18 : 1n-9 (42.86 (sem 1.99) %) and total MUFA compared with the animals fed SO (25.37 (sem 1.11) %). Reciprocally, the SO diet resulted in greater levels of total and n-6 PUFA than the OO diet. The most striking effect was observed for 18 : 2n-6 (SO 17.88 (sem 1.32) %; OO 4.45 (sem 0.60) %), although the levels of 20 : 4n-6 were also different. The proportion of total saturated fatty acids was similar in both groups, and there was only a slight, not significant (P=0.098), effect on the unsaturation index. Compared with the OO group, acinar cells from the rats fed SO secreted more amylase at rest but less in response to cholecystokinin octapeptide, and this was paralleled by reduced Ca(2+) responses to the secretagogue. The results confirm that rat pancreatic cell membranes are strongly influenced by the type of dietary fat consumed and this is accompanied by a modulation of the secretory activity of pancreatic acinar cells that involves, at least in part, Ca(2+) signalling.

Blastic plasmacytoid dendritic cell neoplasm: report of two pediatric cases.

PubMed

Dharmani, Preeti Ashok; Mittal, Neha Manish; Subramanian, P G; Galani, Komal; Badrinath, Yajamanam; Amare, Pratibha; Gujral, Sumeet

2015-01-01

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare subtype of acute leukemia that typically follows a highly aggressive clinical course in adults, whereas experience in children with this disease is very limited. We report cases of two children in whom bone marrow showed infiltration by large atypical monocytoid 'blast-like' cells which on immunophenotyping expressed CD4, CD56, HLA-DR and CD33 while were negative for CD34 other T-cell, B-cell and myeloid markers. The differential diagnoses considered were AML, T/NK-cell leukemia and acute undifferentiated leukemia. Additional markers CD303/BDCA-2 and CD123 which are recently validated plasmacytoid dendritic cell markers were done which helped us clinch the diagnosis of this rare neoplasm. An accurate diagnosis of BPDCN is essential in order to provide prompt treatment. Due to its rarity and only recent recognition as a distinct clinicopathological entity, no standardized therapeutic approach has been established for BPDCN.

Dexamethasone treatment induces the reprogramming of pancreatic acinar cells to hepatocytes and ductal cells.

PubMed

Al-Adsani, Amani; Burke, Zoë D; Eberhard, Daniel; Lawrence, Katherine L; Shen, Chia-Ning; Rustgi, Anil K; Sakaue, Hiroshi; Farrant, J Mark; Tosh, David

2010-10-27

The pancreatic exocrine cell line AR42J-B13 can be reprogrammed to hepatocytes following treatment with dexamethasone. The question arises whether dexamethasone also has the capacity to induce ductal cells as well as hepatocytes. AR42J-B13 cells were treated with and without dexamethasone and analyzed for the expression of pancreatic exocrine, hepatocyte and ductal markers. Addition of dexamethasone inhibited pancreatic amylase expression, induced expression of the hepatocyte marker transferrin as well as markers typical of ductal cells: cytokeratin 7 and 19 and the lectin peanut agglutinin. However, the number of ductal cells was low compared to hepatocytes. The proportion of ductal cells was enhanced by culture with dexamethasone and epidermal growth factor (EGF). We established several features of the mechanism underlying the transdifferentiation of pancreatic exocrine cells to ductal cells. Using a CK19 promoter reporter, we show that a proportion of the ductal cells arise from differentiated pancreatic exocrine-like cells. We also examined whether C/EBPβ (a transcription factor important in the conversion of pancreatic cells to hepatocytes) could alter the conversion from acinar cells to a ductal phenotype. Overexpression of an activated form of C/EBPβ in dexamethasone/EGF-treated cells provoked the expression of hepatocyte markers and inhibited the expression of ductal markers. Conversely, ectopic expression of a dominant-negative form of C/EBPβ, liver inhibitory protein, inhibited hepatocyte formation in dexamethasone-treated cultures and enhanced the ductal phenotype. These results indicate that hepatocytes and ductal cells may be induced from pancreatic exocrine AR42J-B13 cells following treatment with dexamethasone. The conversion from pancreatic to hepatocyte or ductal cells is dependent upon the expression of C/EBPβ.

IL-1 beta and IL-6 in mouse parotid acinar cells: characterization of synthesis, storage, and release.

PubMed

Tanda, N; Ohyama, H; Yamakawa, M; Ericsson, M; Tsuji, T; McBride, J; Elovic, A; Wong, D T; Login, G R

1998-01-01

Synthesis, storage, and secretion of the proinflammatory cytokine interleukin-1 beta (IL-1 beta) and the anti-inflammatory cytokine IL-6 have not been established in normal exocrine gland secretory cells. Parotid glands and isolated acinar cells prepared from BALB/c mice were homogenized for RNA isolation and reverse transcription-polymerase chain reaction (RT-PCR). IL-1 beta and IL-6 enzyme-linked immunosorbent assays (ELISAs) were done on supernatants prepared from mouse parotid acinar cell (MPAC) preparations unstimulated or stimulated between 0 and 10 min with 10(-5) M norepinephrine at 37 degrees C. MPACs were fixed in paraformaldehyde, frozen sectioned for light and electron microscopy, and labeled with antibodies to IL-1 beta and IL-6. Mouse specific riboprobes to IL-1 and IL-6 were used for in situ hybridization. RT-PCR yielded the expected IL-1 (336-bp) and IL-6 (614-bp) mRNA products. By ELISA, stimulated MPACs showed a significant increase in IL-1 beta (P < 0.03) and IL-6 (P < 0.01) release into supernatants by 10 min that paralleled the time course of amylase release. In situ hybridization showed the presence of transcripts for IL-1 and IL-6 in glandular epithelial cells. Gold-labeled IL-1 beta and IL-6 were significantly higher (P < 0.01) in granules than in the nucleus and cytoplasm. This study shows that MPACs synthesize IL-1 beta and IL-6 and release these cytokines from their granules after alpha- and beta-adrenergic stimulation.

The role of anisotropic expansion for pulmonary acinar aerosol deposition.

PubMed

Hofemeier, Philipp; Sznitman, Josué

2016-10-03

Lung deformations at the local pulmonary acinar scale are intrinsically anisotropic. Despite progress in imaging modalities, the true heterogeneous nature of acinar expansion during breathing remains controversial, where our understanding of inhaled aerosol deposition still widely emanates from studies under self-similar, isotropic wall motions. Building on recent 3D models of multi-generation acinar networks, we explore in numerical simulations how different hypothesized scenarios of anisotropic expansion influence deposition outcomes of inhaled aerosols in the acinar depths. While the broader range of particles acknowledged to reach the acinar region (d p =0.005-5.0μm) are largely unaffected by the details of anisotropic expansion under tidal breathing, our results suggest nevertheless that anisotropy modulates the deposition sites and fractions for a narrow band of sub-micron particles (d p ~0.5-0.75μm), where the fate of aerosols is greatly intertwined with local convective flows. Our findings underscore how intrinsic aerosol motion (i.e. diffusion, sedimentation) undermines the role of anisotropic wall expansion that is often attributed in determining aerosol mixing and acinar deposition. Copyright © 2016 Elsevier Ltd. All rights reserved.

General Information about Plasma Cell Neoplasms (Including Multiple Myeloma)

MedlinePlus

... Including Multiple Myeloma) Treatment (PDQ®)–Patient Version General Information About Plasma Cell Neoplasms Go to Health Professional ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

High Volume Washing of the Abdomen in Increasing Survival After Surgery in Patients With Pancreatic Cancer That Can Be Removed by Surgery

ClinicalTrials.gov

2017-10-25

Acinar Cell Carcinoma; Ampulla of Vater Adenocarcinoma; Cholangiocarcinoma; Duodenal Adenocarcinoma; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraductal Papillary Mucinous Neoplasm, Pancreatobiliary-Type; Periampullary Adenocarcinoma

Cathepsin B Activity Initiates Apoptosis via Digestive Protease Activation in Pancreatic Acinar Cells and Experimental Pancreatitis*

PubMed Central

Sendler, Matthias; Maertin, Sandrina; John, Daniel; Persike, Maria; Weiss, F. Ulrich; Krüger, Burkhard; Wartmann, Thomas; Wagh, Preshit; Halangk, Walter; Schaschke, Norbert; Mayerle, Julia; Lerch, Markus M.

2016-01-01

Pancreatitis is associated with premature activation of digestive proteases in the pancreas. The lysosomal hydrolase cathepsin B (CTSB) is a known activator of trypsinogen, and its deletion reduces disease severity in experimental pancreatitis. Here we studied the activation mechanism and subcellular compartment in which CTSB regulates protease activation and cellular injury. Cholecystokinin (CCK) increased the activity of CTSB, cathepsin L, trypsin, chymotrypsin, and caspase 3 in vivo and in vitro and induced redistribution of CTSB to a secretory vesicle-enriched fraction. Neither CTSB protein nor activity redistributed to the cytosol, where the CTSB inhibitors cystatin-B/C were abundantly present. Deletion of CTSB reduced and deletion of cathepsin L increased intracellular trypsin activation. CTSB deletion also abolished CCK-induced caspase 3 activation, apoptosis-inducing factor, as well as X-linked inhibitor of apoptosis protein degradation, but these depended on trypsinogen activation via CTSB. Raising the vesicular pH, but not trypsin inhibition, reduced CTSB activity. Trypsin inhibition did not affect apoptosis in hepatocytes. Deletion of CTSB affected apoptotic but not necrotic acinar cell death. In summary, CTSB in pancreatitis undergoes activation in a secretory, vesicular, and acidic compartment where it activates trypsinogen. Its deletion or inhibition regulates acinar cell apoptosis but not necrosis in two models of pancreatitis. Caspase 3-mediated apoptosis depends on intravesicular trypsinogen activation induced by CTSB, not CTSB activity directly, and this mechanism is pancreas-specific. PMID:27226576

Cathepsin B Activity Initiates Apoptosis via Digestive Protease Activation in Pancreatic Acinar Cells and Experimental Pancreatitis.

PubMed

Sendler, Matthias; Maertin, Sandrina; John, Daniel; Persike, Maria; Weiss, F Ulrich; Krüger, Burkhard; Wartmann, Thomas; Wagh, Preshit; Halangk, Walter; Schaschke, Norbert; Mayerle, Julia; Lerch, Markus M

2016-07-08

Pancreatitis is associated with premature activation of digestive proteases in the pancreas. The lysosomal hydrolase cathepsin B (CTSB) is a known activator of trypsinogen, and its deletion reduces disease severity in experimental pancreatitis. Here we studied the activation mechanism and subcellular compartment in which CTSB regulates protease activation and cellular injury. Cholecystokinin (CCK) increased the activity of CTSB, cathepsin L, trypsin, chymotrypsin, and caspase 3 in vivo and in vitro and induced redistribution of CTSB to a secretory vesicle-enriched fraction. Neither CTSB protein nor activity redistributed to the cytosol, where the CTSB inhibitors cystatin-B/C were abundantly present. Deletion of CTSB reduced and deletion of cathepsin L increased intracellular trypsin activation. CTSB deletion also abolished CCK-induced caspase 3 activation, apoptosis-inducing factor, as well as X-linked inhibitor of apoptosis protein degradation, but these depended on trypsinogen activation via CTSB. Raising the vesicular pH, but not trypsin inhibition, reduced CTSB activity. Trypsin inhibition did not affect apoptosis in hepatocytes. Deletion of CTSB affected apoptotic but not necrotic acinar cell death. In summary, CTSB in pancreatitis undergoes activation in a secretory, vesicular, and acidic compartment where it activates trypsinogen. Its deletion or inhibition regulates acinar cell apoptosis but not necrosis in two models of pancreatitis. Caspase 3-mediated apoptosis depends on intravesicular trypsinogen activation induced by CTSB, not CTSB activity directly, and this mechanism is pancreas-specific. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Immunoglobulin therapy in hematologic neoplasms and after hematopoietic cell transplantation.

PubMed

Ueda, Masumi; Berger, Melvin; Gale, Robert Peter; Lazarus, Hillard M

2018-03-01

Immunoglobulins are used to prevent or reduce infection risk in primary immune deficiencies and in settings which exploit its anti-inflammatory and immune-modulatory effects. Rigorous proof of immunoglobulin efficacy in persons with lympho-proliferative neoplasms, plasma cell myeloma, and persons receiving hematopoietic cell transplants is lacking despite many clinical trials. Further, there are few consensus guidelines or algorithms for use in these conditions. Rapid development of new therapies targeting B-cell signaling and survival pathways and increased use of chimeric antigen receptor T-cell (CAR-T) therapy will likely result in more acquired deficiencies of humoral immunity and infections in persons with cancer. We review immunoglobulin formulations and discuss efficacy and potential adverse effects in the context of preventing infections and in graft-versus-host disease. We suggest an algorithm for evaluating acquired deficiencies of humoral immunity in persons with hematologic neoplasms and recommend appropriate use of immunoglobulin therapy. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

In vivo and in vitro sensitivity of blastic plasmacytoid dendritic cell neoplasm to SL-401, an interleukin-3 receptor targeted biologic agent.

PubMed

Angelot-Delettre, Fanny; Roggy, Anne; Frankel, Arthur E; Lamarthee, Baptiste; Seilles, Estelle; Biichle, Sabeha; Royer, Bernard; Deconinck, Eric; Rowinsky, Eric K; Brooks, Christopher; Bardet, Valerie; Benet, Blandine; Bennani, Hind; Benseddik, Zehaira; Debliquis, Agathe; Lusina, Daniel; Roussel, Mikael; Solly, Françoise; Ticchioni, Michel; Saas, Philippe; Garnache-Ottou, Francine

2015-02-01

Blastic plasmacytoid dendritic cell neoplasm is an aggressive malignancy derived from plasmacytoid dendritic cells. There is currently no accepted standard of care for treating this neoplasm, and therapeutic strategies have never been prospectively evaluated. Since blastic plasmacytoid dendritic cell neoplasm cells express high levels of interleukin-3 receptor α chain (IL3-Rα or CD123), antitumor effects of the interleukin-3 receptor-targeted drug SL-401 against blastic plasmacytoid dendritic cell neoplasm were evaluated in vitro and in vivo. The cytotoxicity of SL-401 was assessed in patient-derived blastic plasmacytoid dendritic cell neoplasm cell lines (CAL-1 and GEN2.2) and in primary blastic plasmacytoid dendritic cell neoplasm cells isolated from 12 patients using flow cytometry and an in vitro cytotoxicity assay. The cytotoxic effects of SL-401 were compared to those of several relevant cytotoxic agents. SL-401 exhibited a robust cytotoxicity against blastic plasmacytoid dendritic cell neoplasm cells in a dose-dependent manner. Additionally, the cytotoxic effects of SL-401 were observed at substantially lower concentrations than those achieved in clinical trials to date. Survival of mice inoculated with a blastic plasmacytoid dendritic cell neoplasm cell line and treated with a single cycle of SL-401 was significantly longer than that of untreated controls (median survival, 58 versus 17 days, P<0.001). These findings indicate that blastic plasmacytoid dendritic cell neoplasm cells are highly sensitive to SL-401, and support further evaluation of SL-401 in patients suffering from blastic plasmacytoid dendritic cell neoplasm. Copyright© Ferrata Storti Foundation.

In vivo and in vitro sensitivity of blastic plasmacytoid dendritic cell neoplasm to SL-401, an interleukin-3 receptor targeted biologic agent

PubMed Central

Angelot-Delettre, Fanny; Roggy, Anne; Frankel, Arthur E.; Lamarthee, Baptiste; Seilles, Estelle; Biichle, Sabeha; Royer, Bernard; Deconinck, Eric; Rowinsky, Eric K.; Brooks, Christopher; Bardet, Valerie; Benet, Blandine; Bennani, Hind; Benseddik, Zehaira; Debliquis, Agathe; Lusina, Daniel; Roussel, Mikael; Solly, Françoise; Ticchioni, Michel; Saas, Philippe; Garnache-Ottou, Francine

2015-01-01

Blastic plasmacytoid dendritic cell neoplasm is an aggressive malignancy derived from plasmacytoid dendritic cells. There is currently no accepted standard of care for treating this neoplasm, and therapeutic strategies have never been prospectively evaluated. Since blastic plasmacytoid dendritic cell neoplasm cells express high levels of interleukin-3 receptor α chain (IL3-Rα or CD123), antitumor effects of the interleukin-3 receptor-targeted drug SL-401 against blastic plasmacytoid dendritic cell neoplasm were evaluated in vitro and in vivo. The cytotoxicity of SL-401 was assessed in patient-derived blastic plasmacytoid dendritic cell neoplasm cell lines (CAL-1 and GEN2.2) and in primary blastic plasmacytoid dendritic cell neoplasm cells isolated from 12 patients using flow cytometry and an in vitro cytotoxicity assay. The cytotoxic effects of SL-401 were compared to those of several relevant cytotoxic agents. SL-401 exhibited a robust cytotoxicity against blastic plasmacytoid dendritic cell neoplasm cells in a dose-dependent manner. Additionally, the cytotoxic effects of SL-401 were observed at substantially lower concentrations than those achieved in clinical trials to date. Survival of mice inoculated with a blastic plasmacytoid dendritic cell neoplasm cell line and treated with a single cycle of SL-401 was significantly longer than that of untreated controls (median survival, 58 versus 17 days, P<0.001). These findings indicate that blastic plasmacytoid dendritic cell neoplasm cells are highly sensitive to SL-401, and support further evaluation of SL-401 in patients suffering from blastic plasmacytoid dendritic cell neoplasm. PMID:25381130

Metabolic Profile of Pancreatic Acinar and Islet Tissue in Culture

PubMed Central

Suszynski, Thomas M.; Mueller, Kathryn; Gruessner, Angelika C.; Papas, Klearchos K.

2016-01-01

The amount and condition of exocrine impurities may affect the quality of islet preparations especially during culture. In this study, the objective was to determine the oxygen demandand viability of islet and acinar tissue post-isolation and whether they change disproportionately while in culture. We compare the OCR normalized to DNA (OCR/DNA, a measure of fractional viability in units nmol/min/mg DNA), and percent change in OCR and DNA recoveries between adult porcine islet and acinar tissue from the same preparation (paired) over a 6-9 days of standard culture. Paired comparisons were done to quantify differences in OCR/DNA between islet and acinar tissue from the same preparation, at specified time points during culture; the mean (± standard error) OCR/DNA was 74.0 (±11.7) units higher for acinar (vs. islet) tissue on the day of isolation (n=16, p<0.0001), but 25.7 (±9.4) units lower after 1 day (n=8, p=0.03), 56.6 (±11.5) units lower after 2 days (n=12, p=0.0004), and 65.9 (±28.7) units lower after 8 days (n=4, p=0.2) in culture. DNA and OCR recoveries decreased at different rates for acinar versus islet tissue over 6-9 days in culture (n=6). DNA recovery decreased to 24±7% for acinar and 75±8% for islets (p=0.002). Similarly, OCR recovery decreased to 16±3% for acinar and remained virtually constant for islets (p=0.005). Differences in the metabolic profile of acinarand islet tissue should be considered when culturing impure islet preparations. OCR-based measurements may help optimize pre-IT culture protocols. PMID:25131082

Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment (PDQ®)—Health Professional Version

Cancer.gov

Plasma cell neoplasms (including multiple myeloma) treatment include observation, chemotherapy, radiation, stem cell rescue, targeted, and supportive therapies. Corticosteroids and immunomodulatory drugs may be used. Get detailed treatment information in this summary for clinicians.

Renal tubular-cell neoplasms in black-footed ferrets (Mustela nigripes)--38 cases.

PubMed

Lair, S; Barker, I K; Mehren, K G; Williams, E S

2006-05-01

Thirty-eight cases of renal tubular cell neoplasms were diagnosed in 184 captive, adult (>1-year-old), black-footed ferrets (Mustela nigripes) examined from 1985 to 1996. This prevalence (20.7%) is one of the highest reported for this neoplasm in a population of animals. These tumors rarely metastasized (1/38), and usually were incidental postmortem findings, associated clinical disease being present in only 3 (8%) of the 38 cases. The prevalence of renal tubular cell neoplasms found at postmortem examination increased linearly with age, up to 67% in ferrets >8 years old. Both males (prevalence = 19%) and females (prevalence = 24%) were affected. Multiple renal tumors were common, and seven ferrets (18.4% of affected animals) had bilateral tumors. The cause of this neoplastic syndrome could not be determined. Since most of the animals affected by this condition were in their postreproductive years of life, the impact of this neoplastic syndrome on the captive propagation of this species is negligible.

The 2017 WHO update on mature T- and natural killer (NK) cell neoplasms.

PubMed

Matutes, E

2018-05-01

Over the last decade, there has been a significant body of information regarding the biology of the lymphoid neoplasms. This clearly supports the need for updating the 2008 WHO (World Health Organization) classification of haematopoietic and lymphoid tumours. The 2017 WHO classification is not a new edition but an update and revision of the 4th edition. New provisional entities but not new definitive entities are included, and novel molecular data in most of the entities and changes in the nomenclature in few of them have been incorporated. In the context of the mature T- and NK-cell neoplasms, the most relevant updates concern to: 1-dysregulation of the JAK/STAT pathway due to gene mutations which are common to various aggressive and indolent neoplasms; 2-incorporation of new molecular players that are relevant to the pathogenesis of these neoplasms and/or have prognostic implications; 3-inclusion of new provisional entities within the subgroups of anaplastic, primarily intestinal and cutaneous lymphomas such as breast implant-associated anaplastic large cell lymphoma, indolent T-cell lymphoproliferative disorder of the gastrointestinal tract and primary cutaneous acral CD8 + T-cell lymphoma; 4-identification of poor prognostic subtypes of peripheral T-cell lymphomas not otherwise specified (PTCL, NOS) characterized by overexpression of certain genes and of a subgroup PTCL, NOS with a T follicular phenotype that now is included together with angioimmunoblastic T-cell lymphoma under the umbrella of lymphomas with a T follicular helper phenotype; and 5-refinement on the designation and definition of already established entities. A review of the major changes will be outlined. © 2018 John Wiley & Sons Ltd.

[Immunohistochemical study of perivascular epithelioid cell neoplasms].

PubMed

Xia, Qiu-Yuan; Rao, Qiu; Shen, Qin; Liu, Biao; Li, Li; Shi, Qun-Li; Shi, Shan-Shan; Yu, Bo; Zhang, Ru-Song; Ma, Heng-Hui; Lu, Zhen-Feng; Wang, Xuan; Tu, Pin; Zhou, Xiao-Jun

2013-06-01

To study the clinicopathologic features, immunophenotype and genetic changes of perivascular epithelioid cell neoplasms (PEComa). A total of 25 cases of PEComa located in various anatomic sites were selected for immunohistochemical staining (SP or EnVision method). TFE3 fluorescence in-situ hybridization was also performed to determine the TFE3 gene status. The age of patient ranged from 21 to 61 years (mean = 43 years). The male-to-female ratio was 1: 1.3. Histologically, 22 cases represented conventional angiomyolipomas, composed of a mixture of adipose tissue, spindle element, epithelioid smooth muscle cells and abnormal thick-walled blood vessels in various proportions. Three cases involving lung, soft tissue and broad ligament had subtle but distinctive morphologic features. Nested or sheet-like architecture with epithelioid or spindle cells was observed. Immunohistochemical study showed that HMB 45, melan A, smooth muscle actin and cathepsin K were expressed in 80% (20/25), 88% (22/25), 88% (22/25) and 100% (25/25) of PEComa, respectively. Within positive cases, the average proportion of positive tumor cells was 36%, 41%, 35% and 90% respectively for HMB 45, melan A, smooth muscle actin and cathepsin K. TFE3 was negative in all of the 22 renal and hepatic PEComa studied, while it was positive in the 3 cases of extra-hepatorenal PEComa. None of the 25 cases exhibited evidence of TFE3 gene fusion or amplification. Extra-hepatorenal PEComa have distinctive morphologic features and are associated with TFE3 overexpression. Cathepsin K immunostaining demonstrates high sensitivity and specificity in PEComa, better than other commonly employed immunomarkers. This marker is thus useful in diagnosis of PEComa and distinction with other neoplasms.

The Acinar Cage: Basement Membranes Determine Molecule Exchange and Mechanical Stability of Human Breast Cell Acini.

PubMed

Gaiko-Shcherbak, Aljona; Fabris, Gloria; Dreissen, Georg; Merkel, Rudolf; Hoffmann, Bernd; Noetzel, Erik

2015-01-01

The biophysical properties of the basement membrane that surrounds human breast glands are poorly understood, but are thought to be decisive for normal organ function and malignancy. Here, we characterize the breast gland basement membrane with a focus on molecule permeation and mechanical stability, both crucial for organ function. We used well-established and nature-mimicking MCF10A acini as 3D cell model for human breast glands, with ether low- or highly-developed basement membrane scaffolds. Semi-quantitative dextran tracer (3 to 40 kDa) experiments allowed us to investigate the basement membrane scaffold as a molecule diffusion barrier in human breast acini in vitro. We demonstrated that molecule permeation correlated positively with macromolecule size and intriguingly also with basement membrane development state, revealing a pore size of at least 9 nm. Notably, an intact collagen IV mesh proved to be essential for this permeation function. Furthermore, we performed ultra-sensitive atomic force microscopy to quantify the response of native breast acini and of decellularized basement membrane shells against mechanical indentation. We found a clear correlation between increasing acinar force resistance and basement membrane formation stage. Most important native acini with highly-developed basement membranes as well as cell-free basement membrane shells could both withstand physiologically relevant loads (≤ 20 nN) without loss of structural integrity. In contrast, low-developed basement membranes were significantly softer and more fragile. In conclusion, our study emphasizes the key role of the basement membrane as conductor of acinar molecule influx and mechanical stability of human breast glands, which are fundamental for normal organ function.

Immunohistological studies on neoplasms of female and male Onchocerca volvulus: filarial origin and absence of Wolbachia from tumor cells

PubMed Central

BRATTIG, N. W.; HOERAUF, A.; FISCHER, P. U.; LIEBAU, E.; BANDI, C.; DEBRAH, A.; BÜTTNER, M.; BÜTTNER, D. W.

2010-01-01

SUMMARY Up to 5% of untreated female Onchocerca volvulus filariae develop potentially fatal pleomorphic neoplasms, whose incidence is increased following ivermectin treatment. We studied the occurrence of 8 filarial proteins and of Wolbachia endobacteria in the tumor cells. Onchocercomas from patients, untreated and treated with antibiotics and anthelminthics, were examined by immunohistology. Neoplasms were diagnosed in 112 of 3587 female and in 2 of 1570 male O. volvulus. The following proteins and other compounds of O. volvulus were expressed in the cells of the neoplasms: glutathione S-transferase 1, lysosomal aspartic protease, cAMP-dependent protein kinase, alpha-enolase, aspartate aminotransferase, ankyrin E1, tropomyosin, heat shock protein 60, transforming growth factor-beta, and prostaglandin E2. These findings prove the filarial origin of the neoplasms and confirm the pleomorphism of the tumor cells. Signs indicating malignancy of the neoplasms are described. Wolbachia were observed in the hypodermis, oocytes, and embryos of tumor-harbouring filariae using antibodies against Wolbachia surface protein, Wolbachia HtrA-type serine protease, and Wolbachia aspartate aminotransferase. In contrast, Wolbachia were not found in the cells of the neoplasms. Further, neoplasm-containing worms were not observed after more than 10 months after the start of sufficient treatment with doxycycline or doxycycline plus ivermectin. PMID:20199697

Expression of activating natural killer-cell receptors is a hallmark of the innate-like T-cell neoplasm in peripheral T-cell lymphomas.

PubMed

Uemura, Yu; Isobe, Yasushi; Uchida, Akiko; Asano, Junko; Nishio, Yuji; Sakai, Hirotaka; Hoshikawa, Masahiro; Takagi, Masayuki; Nakamura, Naoya; Miura, Ikuo

2018-04-01

Peripheral T- or natural killer (NK)-cell lymphomas are rare and difficult-to-recognize diseases. It remains arduous to distinguish between NK cell- and cytotoxic T-lymphocyte-derived lymphomas through routine histological evaluation. To clarify the cells of origin, we focused on NK-cell receptors and examined the expression using immunohistochemistry in 22 cases with T- and NK-cell neoplasms comprising angioimmunoblastic T-cell lymphoma, anaplastic lymphoma kinase (ALK)-positive and -negative anaplastic large-cell lymphomas, extranodal NK/T-cell lymphoma, nasal type, monomorphic epitheliotropic intestinal T-cell lymphoma, aggressive NK-cell leukemia, and other peripheral T-cell lymphomas. Inhibitory receptor leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1) was detected in 14 (64%) cases, whereas activating receptors DNAM1, NKp46, and NKG2D were expressed in 7 (32%), 9 (41%), and 5 (23%) cases, respectively. Although LILRB1 was detected regardless of the disease entity, the activating NK-cell receptors were expressed predominantly in TIA-1-positive neoplasms (DNAM1, 49%; NKp46, 69%; and NKG2D, 38%). In addition, NKp46 and NKG2D were detected only in NK-cell neoplasms and cytotoxic T-lymphocyte-derived lymphomas including monomorphic epitheliotropic intestinal T-cell lymphoma. One Epstein-Barr virus-harboring cytotoxic T-lymphocyte-derived lymphoma mimicking extranodal NK/T-cell lymphoma, nasal type lacked these NK-cell receptors, indicating different cell origin from NK and innate-like T cells. Furthermore, NKG2D expression showed a negative impact on survival among the 22 examined cases, which mainly received the standard chemotherapy regimen (log-rank test, P = .024). We propose that the presence of activating NK-cell receptors may provide new insights into understanding peripheral T-cell lymphomas and characterizing them as innate-like T-cell neoplasm. © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on

Mixed acinar-endocrine carcinoma of the pancreas: new clinical and pathological features in a contemporary series.

PubMed

Yu, Run; Jih, Lily; Zhai, Jing; Nissen, Nicholas N; Colquhoun, Steven; Wolin, Edward; Dhall, Deepti

2013-04-01

The objective of this study was to characterize the novel clinical and pathological features of mixed acinar-endocrine carcinoma of the pancreas. This was a retrospective review of medical records and surgical pathology specimens of patients with a diagnosis of mixed acinar-endocrine carcinoma of the pancreas at Cedars-Sinai Medical Center between 2005 and 2011. Additional immunohistochemistry was performed on the specimens of some patients. Five patients were identified. The median age at presentation was 74 years (range, 59-89 years), and all patients were male. The presenting symptoms were all related to tumor mass effects. The median size of the tumor was 10 cm (range, 3.9-16 cm). Preoperative clinical diagnosis aided by fine-needle aspiration biopsy was incorrect in all 5 cases. Most tumors (3/5) exhibited predominantly endocrine differentiation without hormonal production. Only 10% to 30% of cells were truly amphicrine, whereas most were differentiated into either endocrine or acinar phenotype. The clinical behavior ranged from moderate to aggressive with postoperative survival from 2.5 months to more than 3 years. Four patients received neoadjuvant or adjuvant chemotherapy with variable responses. Mixed acinar-endocrine carcinoma of the pancreas appears to be not uncommon in men, may harbor predominantly endocrine component, is often misdiagnosed by cytology, and exhibits variable clinical behavior. Mixed acinar-endocrine carcinoma of the pancreas should be considered in older patients with sizable pancreatic mass and may warrant aggressive surgical resection and chemotherapy.

Ultrastructural characterization of pulmonary neoplasms. II. The role of electron microscopy in characterization of uncommon epithelial pulmonary neoplasms, metastatic neoplasms to and from lung, and other tumors, including mesenchymal neoplasms.

PubMed

Herrera, G A; Alexander, C B; Jones, J M

1985-01-01

Ultrastructural analysis through better resolution adds significant information to the evaluation and classification of primary pulmonary neoplasms. Light microscopy is limited in the evaluation of lung neoplasms. In some cases the light microscopic appearance may be entirely misleading, whereas in others it is inconclusive. Immunocytochemistry provides information on cytoplasmic differentiation of various tumors and hence more data on their corresponding phenotypes. The data from immunocytochemistry without corresponding objective electron microscopic evaluation may be very difficult to interpret. Correlation of historical, gross, light, electron microscopic, and immunocytochemical data is essential for a final accurate diagnosis (fig. 20). Fine needle aspiration of pulmonary neoplasms is becoming very fashionable and a diagnosis, including type of neoplasm, is expected on the basis of examination of a limited number of cells which further emphasizes the importance of ultrastructural characterization in helping to establish an accurate diagnosis [63-69]. The current classification of pulmonary neoplasms may need to be modified in the near future to incorporate the newly created data [70-72]. At the present time, there appears to be, at least, a need for a 'double standard', as Sobin [73] has suggested, which would permit the evaluation of the biologic significance of the ultrastructural and immunocytochemical findings (as applied to classification of neoplasms) in an effort to derive meaningful clinicopathologic correlations. Figure 20 emphasizes the additive role which should be played by the various diagnostic modalities to enable a morphologic assessment which would be an accurate predictor of biologic behavior. With an accurate assessment of biologic behavior, a more appropriate and rational approach for therapy is possible. There is also an important role for ultrastructural analysis in metastatic pleural and pulmonary neoplasms, primarily adenocarcinomas, as

Non-squamous cell neoplasms of the larynx: radiologic-pathologic correlation.

PubMed

Becker, M; Moulin, G; Kurt, A M; Dulgerov, P; Vukanovic, S; Zbären, P; Marchal, F; Rüfenacht, D A; Terrier, F

1998-01-01

A variety of benign and malignant non-squamous cell neoplasms may affect the larynx. Most of these uncommon laryngeal neoplasms are located beneath an intact mucosa, making diagnosis difficult with endoscopy alone, and sampling errors may occur if only traditional superficial biopsies are performed. In some laryngeal neoplasms, radiologic evaluation allows the correct diagnosis. Hemangiomas have very high signal intensity at T2-weighted magnetic resonance (MR) imaging and strong enhancement at both computed tomography (CT) and MR imaging after administration of contrast material. Phleboliths, which are pathognomonic for hemangiomas, are easily identified at CT. Chondrogenic tumors typically manifest with coarse or stippled calcifications at CT. Because of their high water content, chondrogenic tumors have very high signal intensity on T2-weighted MR images, whereas only moderate enhancement is observed after administration of contrast material. Lipomas typically manifest at both CT and MR imaging as homogeneous nonenhancing lesions. They are isoattenuating to subcutaneous fat at CT and isointense relative to subcutaneous fat with all MR pulse sequences. Metastases from renal adenocarcinoma typically demonstrate strong contrast enhancement and flow voids at MR imaging, and metastases from melanotic melanoma usually have high signal intensity on T1-weighted MR images and low signal intensity on T2-weighted images owing to the paramagnetic properties of melanin. Although radiologic findings are nonspecific in most other non-squamous cell neoplasms of the larynx (eg, Kaposi sarcoma, hematopoietic tumors, tumors of the minor salivary glands, metastases from amelanotic melanoma), cross-sectional imaging can play an important role in the diagnostic work-up of these unusual tumors by delineating the extent of submucosal tumor spread and directing the endoscopist to the appropriate site for the deep, transmucosal biopsies needed to establish the diagnosis. In addition, CT

Murine pulmonary acinar mechanics during quasi-static inflation using synchrotron refraction-enhanced computed tomography.

PubMed

Sera, Toshihiro; Yokota, Hideo; Tanaka, Gaku; Uesugi, Kentaro; Yagi, Naoto; Schroter, Robert C

2013-07-15

We visualized pulmonary acini in the core regions of the mouse lung in situ using synchrotron refraction-enhanced computed tomography (CT) and evaluated their kinematics during quasi-static inflation. This CT system (with a cube voxel of 2.8 μm) allows excellent visualization of not just the conducting airways, but also the alveolar ducts and sacs, and tracking of the acinar shape and its deformation during inflation. The kinematics of individual alveoli and alveolar clusters with a group of terminal alveoli is influenced not only by the connecting alveolar duct and alveoli, but also by the neighboring structures. Acinar volume was not a linear function of lung volume. The alveolar duct diameter changed dramatically during inflation at low pressures and remained relatively constant above an airway pressure of ∼8 cmH2O during inflation. The ratio of acinar surface area to acinar volume indicates that acinar distension during low-pressure inflation differed from that during inflation over a higher pressure range; in particular, acinar deformation was accordion-like during low-pressure inflation. These results indicated that the alveoli and duct expand differently as total acinar volume increases and that the alveolar duct may expand predominantly during low-pressure inflation. Our findings suggest that acinar deformation in the core regions of the lung is complex and heterogeneous.

Solo, a RhoA-targeting guanine nucleotide exchange factor, is critical for hemidesmosome formation and acinar development in epithelial cells.

PubMed

Fujiwara, Sachiko; Matsui, Tsubasa S; Ohashi, Kazumasa; Deguchi, Shinji; Mizuno, Kensaku

2018-01-01

Cell-substrate adhesions are essential for various physiological processes, including embryonic development and maintenance of organ functions. Hemidesmosomes (HDs) are multiprotein complexes that attach epithelial cells to the basement membrane. Formation and remodeling of HDs are dependent on the surrounding mechanical environment; however, the upstream signaling mechanisms are not well understood. We recently reported that Solo (also known as ARHGEF40), a guanine nucleotide exchange factor targeting RhoA, binds to keratin8/18 (K8/K18) intermediate filaments, and that their interaction is important for force-induced actin and keratin cytoskeletal reorganization. In this study, we show that Solo co-precipitates with an HD protein, β4-integrin. Co-precipitation assays revealed that the central region (amino acids 330-1057) of Solo binds to the C-terminal region (1451-1752) of β4-integrin. Knockdown of Solo significantly suppressed HD formation in MCF10A mammary epithelial cells. Similarly, knockdown of K18 or treatment with Y-27632, a specific inhibitor of Rho-associated kinase (ROCK), suppressed HD formation. As Solo knockdown or Y-27632 treatment is known to disorganize K8/K18 filaments, these results suggest that Solo is involved in HD formation by regulating K8/K18 filament organization via the RhoA-ROCK signaling pathway. We also showed that knockdown of Solo impairs acinar formation in MCF10A cells cultured in 3D Matrigel. In addition, Solo accumulated at the site of traction force generation in 2D-cultured MCF10A cells. Taken together, these results suggest that Solo plays a crucial role in HD formation and acinar development in epithelial cells by regulating mechanical force-induced RhoA activation and keratin filament organization.

Solo, a RhoA-targeting guanine nucleotide exchange factor, is critical for hemidesmosome formation and acinar development in epithelial cells

PubMed Central

Matsui, Tsubasa S.; Ohashi, Kazumasa; Deguchi, Shinji; Mizuno, Kensaku

2018-01-01

Cell-substrate adhesions are essential for various physiological processes, including embryonic development and maintenance of organ functions. Hemidesmosomes (HDs) are multiprotein complexes that attach epithelial cells to the basement membrane. Formation and remodeling of HDs are dependent on the surrounding mechanical environment; however, the upstream signaling mechanisms are not well understood. We recently reported that Solo (also known as ARHGEF40), a guanine nucleotide exchange factor targeting RhoA, binds to keratin8/18 (K8/K18) intermediate filaments, and that their interaction is important for force-induced actin and keratin cytoskeletal reorganization. In this study, we show that Solo co-precipitates with an HD protein, β4-integrin. Co-precipitation assays revealed that the central region (amino acids 330–1057) of Solo binds to the C-terminal region (1451–1752) of β4-integrin. Knockdown of Solo significantly suppressed HD formation in MCF10A mammary epithelial cells. Similarly, knockdown of K18 or treatment with Y-27632, a specific inhibitor of Rho-associated kinase (ROCK), suppressed HD formation. As Solo knockdown or Y-27632 treatment is known to disorganize K8/K18 filaments, these results suggest that Solo is involved in HD formation by regulating K8/K18 filament organization via the RhoA-ROCK signaling pathway. We also showed that knockdown of Solo impairs acinar formation in MCF10A cells cultured in 3D Matrigel. In addition, Solo accumulated at the site of traction force generation in 2D-cultured MCF10A cells. Taken together, these results suggest that Solo plays a crucial role in HD formation and acinar development in epithelial cells by regulating mechanical force-induced RhoA activation and keratin filament organization. PMID:29672603

"Cercariform" cells: a clue to the cytodiagnosis of transitional cell origin of metastatic neoplasms?

PubMed

Powers, C N; Elbadawi, A

1995-07-01

The "cercariform" cell is described as a distinct cytomorphologic clue that may be helpful in the diagnosis of metastatic transitional cell neoplasms, particularly low grade. This cell has a nucleated globular body and a cytoplasmic process with a nontapering, flattened, bulbous or fishtail-like end. The cercariform cell corresponds to intermediate cells in histologic and ultrastructural preparations of normal urothelium. The cercariform appearance is the result of pseudostratification of both normal and low-grade neoplastic urothelium. The unique features of cercariform cells make them readily distinguishable from neoplastic squamous cells as well as spindle cells of mesenchymal origin.

Growth and apoptosis of human natural killer cell neoplasms: role of interleukin-2/15 signaling.

PubMed

Yamasaki, Satoshi; Maeda, Motoi; Ohshima, Koichi; Kikuchi, Masahiro; Otsuka, Teruhisa; Harada, Mine

2004-10-01

Interleukin (IL)-15 plays an important role in the survival of human natural killer (NK) cells. We investigated IL-2/15 signaling in NK cell neoplasms from five patients and in five cell lines (NK-92, KHYG-1, SNK-6, HANK1 and MOTN-1) compared to mature peripheral NK cells from 10 healthy subjects. Apoptosis of NK cell lines was prevented by addition of IL-15 in vitro. Blocking IL-2/15Rbeta on IL-2-stimulated NK-92 cells resulted in reduced expression of Bcl-X(L) and phosphorylated Stat5, which paralleled early apoptosis without altering Bcl-2 expression. These data add IL-2/15Rbeta to the list of factors important for the survival of NK cell neoplasms.

Malignant melanocytic neoplasm of pancreas with liver metastasis: Is it malignant melanoma or clear cell sarcoma?

PubMed

Kodiatte, Thomas Alex; George, Sam Varghese; Chacko, Raju Titus; Ramakrishna, Banumathi

2017-01-01

Malignant melanocytic neoplasm, usually seen in soft tissues, is rare in a visceral location and presents as a diagnostic dilemma. We present a case of pancreatic malignant melanocytic neoplasm with liver metastasis. A 58-year-old man presented with left upper abdominal swelling and loss of appetite. Imaging revealed a large mass arising from the pancreatic tail, and this was diagnosed as malignant neoplasm with melanocytic differentiation on biopsy with the possible differentials of malignant melanoma, clear cell sarcoma (CCS), and perivascular epithelioid cell neoplasm. The patient underwent distal pancreatectomy and splenectomy for the same. Follow-up imaging 6 months later showed a metastatic liver lesion, for which he also underwent a liver resection. BRAF mutational analysis was found to be negative. Both CCS and malignant melanoma have similar morphological features and melanocytic differentiation, but each harbors a distinct genetic background. Differentiation of both has diagnostic and therapeutic implications.

Raman spectroscopy of skin neoplasms

NASA Astrophysics Data System (ADS)

Moryatov, A. A.; Kozlov, S. V.; Kaganov, O. I.; Orlov, A. E.; Zaharov, V. P.; Batrachenko, I. A.; Artemiev, D. N.; Blinov, N. V.

2017-09-01

Skin melanoma is spread inhomogeneously worldwide, particularly in Samara region there are high figures of skin neoplasms sick rate as well—18.6%. Research goal: to develop a new method of early non-invasive differential diagnostics of skin neoplasms. Registration of Raman spectrum was implemented in the distance of 3-4 mm, the spectrum registration from pathologically changed zone was subsequently conducted, then from healthy skin zone. The test time for 1 patient was no longer than 3-5 min. In a range of experiments ex vivo there were the following results: melanoma—24, basal cell cancer—25, squamosus cell sarcinoma—7, nevus pigmentosis—9, other malignant neoplasms—6; in vivo: melanoma—9, basal cell cancer—8, nevus pigmentosis—2, other benign neoplasms—2. The first results of the research dedicated to studying permissive opportunities of Raman spectroscopy, with successive two-phase analysis of received parameters display high efficiency of method of differential diagnostic for skin melanoma and other malignant neoplasms, pigment and benign skin neoplasms. Safety and rapidity of the research reveal a high potential of the technique.

Effect of mitogen-activated protein kinases on chemokine synthesis induced by substance P in mouse pancreatic acinar cells

PubMed Central

Ramnath, Raina Devi; Sun, Jia; Adhikari, Sharmila; Bhatia, Madhav

2007-01-01

Abstract Substance P, acting via its neurokinin 1 receptor (NK1 R), plays an important role in mediating a variety of inflammatory processes. Its interaction with chemokines is known to play a crucial role in the pathogenesis of acute pancreatitis. In pancreatic acinar cells, substance P stimulates the release of NFκB-driven chemokines. However, the signal transduction pathways by which substance P-NK1 R interaction induces chemokine production are still unclear. To that end, we went on to examine the participation of mitogen-activated protein kinases (MAPKs) in substance P-induced synthesis of pro-inflammatory chemokines, monocyte chemoanractant protein-1 (MCP-I), macrophage inflammatory protein-lα (MIP-lα) and macrophage inflammatory protein-2 (MIP-2), in pancreatic acini. In this study, we observed a time-dependent activation of ERK1/2, c-Jun N-terminal kinase (JNK), NFκB and activator protein-1 (AP-1) when pancreatic acini were stimulated with substance P. Moreover, substance P-induced ERK 1/2, JNK, NFκB and AP-1 activation as well as chemokine synthesis were blocked by pre-treatment with either extracellular signal-regulated protein kinase kinase 1 (MEK1) inhibitor or JNK inhibitor. In addition, substance P-induced activation of ERK 112, JNK, NFκB and AP-1-driven chemokine production were attenuated by CP96345, a selective NK1 R antagonist, in pancreatic acinar cells. Taken together, these results suggest that substance P-NK1 R induced chemokine production depends on the activation of MAPKs-mediated NFκB and AP-1 signalling pathways in mouse pancreatic acini. PMID:18205703

Quantitative characterization of the protein contents of the exocrine pancreatic acinar cell by soft x-ray microscopy and advanced digital imaging methods

DOE Office of Scientific and Technical Information (OSTI.GOV)

Loo, Jr., Billy W.

2000-06-01

The study of the exocrine pancreatic acinar cell has been central to the development of models of many cellular processes, especially of protein transport and secretion. Traditional methods used to examine this system have provided a wealth of qualitative information from which mechanistic models have been inferred. However they have lacked the ability to make quantitative measurements, particularly of the distribution of protein in the cell, information critical for grounding of models in terms of magnitude and relative significance. This dissertation describes the development and application of new tools that were used to measure the protein content of the majormore » intracellular compartments in the acinar cell, particularly the zymogen granule. Soft x-ray microscopy permits image formation with high resolution and contrast determined by the underlying protein content of tissue rather than staining avidity. A sample preparation method compatible with x-ray microscopy was developed and its properties evaluated. Automatic computerized methods were developed to acquire, calibrate, and analyze large volumes of x-ray microscopic images of exocrine pancreatic tissue sections. Statistics were compiled on the protein density of several organelles, and on the protein density, size, and spatial distribution of tens of thousands of zymogen granules. The results of these measurements, and how they compare to predictions of different models of protein transport, are discussed.« less

Blastic plasmacytoid dendritic cell neoplasm: update on molecular biology, diagnosis, and therapy.

PubMed

Riaz, Wasif; Zhang, Ling; Horna, Pedro; Sokol, Lubomir

2014-10-01

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with an aggressive clinical course. Most patients with BPDCN have skin lesions and simultaneous involvement of the peripheral blood, bone marrow, and lymph nodes. A search of PubMed and Medline was conducted for English-written articles relating to BPDCN, CD4(+)CD56(+) hematodermic neoplasm, and blastic natural killer cell lymphoma. Data regarding diagnosis, prognosis, and treatment were analyzed. BPDCN is derived from precursor plasmacytoid dendritic cells. The diagnosis of BPDCN is based on the characteristic cytology and immunophenotype of malignant cells coexpressing CD4, CD56, CD123, blood dendritic cell antigens 2 and 4, and CD2AP markers. Multiple chromosomal abnormalities and gene mutations previously reported in patients with myeloid and selected lymphoid neoplasms were identified in approximately 60% of patients with BPDCN. Prospectively controlled studies to guide treatment decisions are lacking. The overall response rate with aggressive acute lymphoblastic leukemia-type induction regimens was as high as 90%, but the durability of response was short. Median survival rates ranged between 12 and 16 months. Patients with relapsed disease may respond to L-asparaginase-containing regimens. Allogeneic hematopoietic stem cell transplantation, particularly when performed during the first remission, may produce durable remissions in selected adults. BPDCN is a rare aggressive disease that typically affects elderly patients. The most commonly affected nonhematopoietic organ is the skin. Although BPDCN is initially sensitive to conventional chemotherapy regimens, this response is relatively short and long-term prognosis is poor. In the near future, novel targeted therapies may improve outcomes for patients with BPDCN.

Duct- and Acinar-Derived Pancreatic Ductal Adenocarcinomas Show Distinct Tumor Progression and Marker Expression.

PubMed

Ferreira, Rute M M; Sancho, Rocio; Messal, Hendrik A; Nye, Emma; Spencer-Dene, Bradley; Stone, Richard K; Stamp, Gordon; Rosewell, Ian; Quaglia, Alberto; Behrens, Axel

2017-10-24

The cell of origin of pancreatic ductal adenocarcinoma (PDAC) has been controversial. Here, we show that identical oncogenic drivers trigger PDAC originating from both ductal and acinar cells with similar histology but with distinct pathophysiology and marker expression dependent on cell of origin. Whereas acinar-derived tumors exhibited low AGR2 expression and were preceded by pancreatic intraepithelial neoplasias (PanINs), duct-derived tumors displayed high AGR2 and developed independently of a PanIN stage via non-mucinous lesions. Using orthotopic transplantation and chimera experiments, we demonstrate that PanIN-like lesions can be induced by PDAC as bystanders in adjacent healthy tissues, explaining the co-existence of mucinous and non-mucinous lesions and highlighting the need to distinguish between true precursor PanINs and PanIN-like bystander lesions. Our results suggest AGR2 as a tool to stratify PDAC according to cell of origin, highlight that not all PanIN-like lesions are precursors of PDAC, and add an alternative progression route to the current model of PDAC development. Copyright © 2017 Francis Crick Institute. Published by Elsevier Inc. All rights reserved.

Canine ovarian neoplasms: a clinicopathologic study of 71 cases, including histology of 12 granulosa cell tumors.

PubMed

Patnaik, A K; Greenlee, P G

1987-11-01

In a retrospective study of 71 primary ovarian tumors in the dog, epithelial tumors (46%) were more common than sex cord stromal (34%) and germ cell tumors (20%). There were more adenocarcinomas (64%) than adenomas. Sex cord stromal tumors were equally divided into Sertoli-Leydig (12/24) and granulosa cell tumors (12/24). There were equal numbers (7/14) of dysgerminomas and teratomas among the germ cell tumors. Most teratomas (6/7) were malignant. Most granulosa cell tumors were solid; two were mostly cystic. Patterns included sheets of round and ovoid to spindle-shaped cells separated by thin, fibrovascular stroma; neoplastic cells formed rosettes or Call-Exner bodies. In some areas, neoplastic cells were in cords or columns and formed cyst-like structures. Four granulosa cell tumors were macrofollicular, having cysts lined with granulosa cells. Median ages of dogs with different ovarian neoplasms were similar; all were more than 10 years old, except the dogs with teratoma (mean age, 4 years). Most neoplasms were unilateral (84%), except the Sertoli-Leydig cell tumors, many of which were bilateral (36%). Size of ovarian neoplasms varied (2 cm3 to 15,000 cm3). Twenty-nine percent of neoplasms metastasized; adenocarcinomas (48%) and malignant teratomas (50%) had the highest rates, and distant metastasis was more common in malignant teratoma. Endometrial hyperplasia was in 67% of the dogs; it was most common in dogs with sex cord stromal tumors (95%). Uterine malignancy was not seen in dogs with granulosa cell tumors, although hyperplasia endometrium was in all dogs with this tumor. Cysts in the contralateral ovaries were most common in dogs with sex cord stromal tumors.

Experimental evidence of age-related adaptive changes in human acinar airways

PubMed Central

Quirk, James D.; Sukstanskii, Alexander L.; Woods, Jason C.; Lutey, Barbara A.; Conradi, Mark S.; Gierada, David S.; Yusen, Roger D.; Castro, Mario

2015-01-01

The progressive decline of lung function with aging is associated with changes in lung structure at all levels, from conducting airways to acinar airways (alveolar ducts and sacs). While information on conducting airways is becoming available from computed tomography, in vivo information on the acinar airways is not conventionally available, even though acini occupy 95% of lung volume and serve as major gas exchange units of the lung. The objectives of this study are to measure morphometric parameters of lung acinar airways in living adult humans over a broad range of ages by using an innovative MRI-based technique, in vivo lung morphometry with hyperpolarized 3He gas, and to determine the influence of age-related differences in acinar airway morphometry on lung function. Pulmonary function tests and MRI with hyperpolarized 3He gas were performed on 24 healthy nonsmokers aged 19-71 years. The most significant age-related difference across this population was a 27% loss of alveolar depth, h, leading to a 46% increased acinar airway lumen radius, hence, decreased resistance to acinar air transport. Importantly, the data show a negative correlation between h and the pulmonary function measures forced expiratory volume in 1 s and forced vital capacity. In vivo lung morphometry provides unique information on age-related changes in lung microstructure and their influence on lung function. We hypothesize that the observed reduction of alveolar depth in subjects with advanced aging represents a remodeling process that might be a compensatory mechanism, without which the pulmonary functional decline due to other biological factors with advancing age would be significantly larger. PMID:26542518

Early Allogeneic Hematopoietic Cell Transplantation in Treating Patients With Relapsed or Refractory High-Grade Myeloid Neoplasms

ClinicalTrials.gov

2018-02-06

Blasts 10 Percent or More of Bone Marrow Nucleated Cells; Chronic Myelomonocytic Leukemia-2; High Grade Malignant Neoplasm; Myelodysplastic Syndrome; Myelodysplastic Syndrome With Excess Blasts-2; Myeloid Neoplasm; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia

Activated macrophages create lineage-specific microenvironments for pancreatic acinar- and β-cell regeneration in mice.

PubMed

Criscimanna, Angela; Coudriet, Gina M; Gittes, George K; Piganelli, Jon D; Esni, Farzad

2014-11-01

Although the cells that contribute to pancreatic regeneration have been widely studied, little is known about the mediators of this process. During tissue regeneration, infiltrating macrophages debride the site of injury and coordinate the repair response. We investigated the role of macrophages in pancreatic regeneration in mice. We used a saporin-conjugated antibody against CD11b to reduce the number of macrophages in mice following diphtheria toxin receptor-mediated cell ablation of pancreatic cells, and evaluated the effects on pancreatic regeneration. We analyzed expression patterns of infiltrating macrophages after cell-specific injury or from the pancreas of nonobese diabetic mice. We developed an in vitro culture system to study the ability of macrophages to induce cell-specific regeneration. Depletion of macrophages impaired pancreatic regeneration. Macrophage polarization, as assessed by expression of tumor necrosis factor-α, interleukin 6, interleukin 10, and CD206, depended on the type of injury. The signals provided by polarized macrophages promoted lineage-specific generation of acinar or endocrine cells. Macrophage from nonobese diabetic mice failed to provide signals necessary for β-cell generation. Macrophages produce cell type-specific signals required for pancreatic regeneration in mice. Additional study of these processes and signals might lead to new approaches for treating type 1 diabetes or pancreatitis. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

Transitional cell neoplasm of the nasolacrimal duct associated with human papillomavirus type 11.

PubMed

Vickers, Jennifer L; Matherne, Ryan J; Allison, Ashley W; Wilkerson, Michael G; Tyring, Stephen K; Bartlett, Brenda L; Rady, Peter L; Kelly, Brent C

2010-07-01

Tumors of the lacrimal sac are rare but noteworthy because of their significant potential to become malignant or life-threatening if treatment is delayed. Dermatologists may be the first to encounter such neoplasms. We report a case of a 53-year-old Caucasian woman who presented with a seven-year history of an asymptomatic, subcutaneous nodule near her right medial canthus. Histology of the lesion revealed transitional epithelium in a papillary growth pattern with numerous goblet cells, scattered mitoses and focal full-thickness atypia. The patient was diagnosed with transitional cell neoplasm (inverted papilloma-type) of the nasolacrimal duct. PCR evaluation identified HPV type 11 in the lesion. Our report is one of a growing number of case reports and series detecting HPV DNA in these tumors which further supports HPV as an etiologic agent in epithelial lacrimal sac tumors. We believe that dermatopathologists need to be aware of this entity, as dermatologists may be the first to encounter these neoplasms. The association of HPV with this tumor does not prove causality.

HCO3(-) secretion by murine nasal submucosal gland serous acinar cells during Ca2+-stimulated fluid secretion.

PubMed

Lee, Robert J; Harlow, Janice M; Limberis, Maria P; Wilson, James M; Foskett, J Kevin

2008-07-01

Airway submucosal glands contribute to airway surface liquid (ASL) composition and volume, both important for lung mucociliary clearance. Serous acini generate most of the fluid secreted by glands, but the molecular mechanisms remain poorly characterized. We previously described cholinergic-regulated fluid secretion driven by Ca(2+)-activated Cl(-) secretion in primary murine serous acinar cells revealed by simultaneous differential interference contrast (DIC) and fluorescence microscopy. Here, we evaluated whether Ca(2+)-activated Cl(-) secretion was accompanied by secretion of HCO(3)(-), possibly a critical ASL component, by simultaneous measurements of intracellular pH (pH(i)) and cell volume. Resting pH(i) was 7.17 +/- 0.01 in physiological medium (5% CO(2)-25 mM HCO(3)(-)). During carbachol (CCh) stimulation, pH(i) fell transiently by 0.08 +/- 0.01 U concomitantly with a fall in Cl(-) content revealed by cell shrinkage, reflecting Cl(-) secretion. A subsequent alkalinization elevated pH(i) to above resting levels until agonist removal, whereupon it returned to prestimulation values. In nominally CO(2)-HCO(3)(-)-free media, the CCh-induced acidification was reduced, whereas the alkalinization remained intact. Elimination of driving forces for conductive HCO(3)(-) efflux by ion substitution or exposure to the Cl(-) channel inhibitor niflumic acid (100 microM) strongly inhibited agonist-induced acidification by >80% and >70%, respectively. The Na(+)/H(+) exchanger (NHE) inhibitor dimethylamiloride (DMA) increased the magnitude (greater than twofold) and duration of the CCh-induced acidification. Gene expression profiling suggested that serous cells express NHE isoforms 1-4 and 6-9, but pharmacological sensitivities demonstrated that alkalinization observed during both CCh stimulation and pH(i) recovery from agonist-induced acidification was primarily due to NHE1, localized to the basolateral membrane. These results suggest that serous acinar cells secrete HCO(3

EPI64B Acts as a GTPase-activating Protein for Rab27B in Pancreatic Acinar Cells*

PubMed Central

Hou, Yanan; Chen, Xuequn; Tolmachova, Tatyana; Ernst, Stephen A.; Williams, John A.

2013-01-01

The small GTPase Rab27B localizes to the zymogen granule membranes and plays an important role in regulating protein secretion by pancreatic acinar cells, as does Rab3D. A common guanine nucleotide exchange factor (GEF) for Rab3 and Rab27 has been reported; however, the GTPase-activating protein (GAP) specific for Rab27B has not been identified. In this study, the expression in mouse pancreatic acini of two candidate Tre-2/Bub2/Cdc16 (TBC) domain-containing proteins, EPI64 (TBC1D10A) and EPI64B (TBC1D10B), was first demonstrated. Their GAP activity on digestive enzyme secretion was examined by adenovirus-mediated overexpression of EPI64 and EPI64B in isolated pancreatic acini. EPI64B almost completely abolished the GTP-bound form of Rab27B, without affecting GTP-Rab3D. Overexpression of EPI64B also enhanced amylase release. This enhanced release was independent of Rab27A, but dependent on Rab27B, as shown using acini from genetically modified mice. EPI64 had a mild effect on both GTP-Rab27B and amylase release. Co-overexpression of EPI64B with Rab27B can reverse the inhibitory effect of Rab27B on amylase release. Mutations that block the GAP activity decreased the inhibitory effect of EPI64B on the GTP-bound state of Rab27B and abolished the enhancing effect of EPI64B on the amylase release. These data suggest that EPI64B can serve as a potential physiological GAP for Rab27B and thereby participate in the regulation of exocytosis in pancreatic acinar cells. PMID:23671284

Diagnostic Approach to Eosinophilic Renal Neoplasms

PubMed Central

Kryvenko, Oleksandr N.; Jorda, Merce; Argani, Pedram; Epstein, Jonathan I.

2015-01-01

Context Eosinophilic renal neoplasms include a spectrum of solid and papillary tumors ranging from indolent benign oncocytoma to highly aggressive malignancies. Recognition of the correct nature of the tumor, especially in biopsy specimens, is paramount for patient management. Objective To review the diagnostic approach to eosinophilic renal neoplasms with light microscopy and ancillary techniques. Data Sources Review of the published literature and personal experience. Conclusions The following tumors are in the differential diagnosis of oncocytic renal cell neoplasm: oncocytoma, chromophobe renal cell carcinoma (RCC), hybrid tumor, tubulocystic carcinoma, papillary RCC, clear cell RCC with predominant eosinophilic cell morphology, follicular thyroid-like RCC, hereditary leiomyomatosis–associated RCC, acquired cystic disease–associated RCC, rhabdoid RCC, microphthalmia transcription factor translocation RCC, epithelioid angiomyolipoma, and unclassified RCC. In low-grade nonpapillary eosinophilic neoplasms, distinction between oncocytoma and low-grade RCC mostly rests on histomorphology; however, cytokeratin 7 immunostain may be helpful. In high-grade nonpapillary lesions, there is more of a role for ancillary techniques, including immunohistochemistry for cytokeratin 7, CA9, CD10, racemase, HMB45, and Melan-A. In papillary eosinophilic neoplasms, it is important to distinguish sporadic type 2 papillary RCC from microphthalmia transcription factor translocation and hereditary leiomyomatosis–associated RCC. Histologic and cytologic features along with immunohistochemistry and fluorescence in situ hybridization tests for TFE3 (Xp11.2) and TFEB [t(6;11)] are reliable confirmatory tests. Eosinophilic epithelial neoplasms with architecture, cytology, and/or immunoprofile not qualifying for either of the established types of RCC should be classified as unclassified eosinophilic RCC and arbitrarily assigned a grade (low or high). PMID:25357116

Effects of the type of dietary fat on acetylcholine-evoked amylase secretion and calcium mobilization in isolated rat pancreatic acinar cells.

PubMed

Yago, María D; Díaz, Ricardo J; Martínez, María A; Audi, Nama'a; Naranjo, José A; Martínez-Victoria, Emilio; Mañas, Mariano

2006-04-01

Olive oil is a major component of the Mediterranean diet, and its role in human health is being actively debated. This study aimed to clarify the mechanism of pancreatic adaptation to dietary fat. For this purpose, we examined whether dietary-induced modification of pancreatic membranes affects acinar cell function in response to the secretagogue acetylcholine (ACh). Weaning male Wistar rats were assigned to one of two experimental groups and fed for 8 weeks with a commercial chow (C) or a semisynthetic diet containing virgin olive oil as dietary fat (OO). The fatty acid composition of pancreatic plasma membranes was determined by gas-liquid chromatography. For assessment of secretory function, viable acini were incubated with ACh and amylase of supernatant was further assayed with a substrate reagent. Changes in cytosolic Ca(2+) concentration in response to ACh were measured by fura-2 AM fluorimetry. Compared to C rats, pancreatic cell membranes of OO rats had a higher level of monounsaturated fatty acids and a lower level of both saturated and polyunsaturated fatty acids, thus, reflecting the type of dietary fat given. Net amylase secretion in response to ACh was greatly enhanced after OO feeding, although this was not paralleled by enhancement of ACh-evoked Ca(2+) peak increases. In conclusion, chronic intake of diets that differ in the fat type influences not only the fatty acid composition of rat pancreatic membranes but also the responsiveness of acinar cells to ACh. This mechanism may be, at least in part, responsible for the adaptation of the exocrine pancreas to the type of fat available.

HCO3− Secretion by Murine Nasal Submucosal Gland Serous Acinar Cells during Ca2+-stimulated Fluid Secretion

PubMed Central

Lee, Robert J.; Harlow, Janice M.; Limberis, Maria P.; Wilson, James M.; Foskett, J. Kevin

2008-01-01

Airway submucosal glands contribute to airway surface liquid (ASL) composition and volume, both important for lung mucociliary clearance. Serous acini generate most of the fluid secreted by glands, but the molecular mechanisms remain poorly characterized. We previously described cholinergic-regulated fluid secretion driven by Ca2+-activated Cl− secretion in primary murine serous acinar cells revealed by simultaneous differential interference contrast (DIC) and fluorescence microscopy. Here, we evaluated whether Ca2+-activated Cl− secretion was accompanied by secretion of HCO3−, possibly a critical ASL component, by simultaneous measurements of intracellular pH (pHi) and cell volume. Resting pHi was 7.17 ± 0.01 in physiological medium (5% CO2–25 mM HCO3−). During carbachol (CCh) stimulation, pHi fell transiently by 0.08 ± 0.01 U concomitantly with a fall in Cl− content revealed by cell shrinkage, reflecting Cl− secretion. A subsequent alkalinization elevated pHi to above resting levels until agonist removal, whereupon it returned to prestimulation values. In nominally CO2–HCO3−-free media, the CCh-induced acidification was reduced, whereas the alkalinization remained intact. Elimination of driving forces for conductive HCO3− efflux by ion substitution or exposure to the Cl− channel inhibitor niflumic acid (100 μM) strongly inhibited agonist-induced acidification by >80% and >70%, respectively. The Na+/H+ exchanger (NHE) inhibitor dimethylamiloride (DMA) increased the magnitude (greater than twofold) and duration of the CCh-induced acidification. Gene expression profiling suggested that serous cells express NHE isoforms 1–4 and 6–9, but pharmacological sensitivities demonstrated that alkalinization observed during both CCh stimulation and pHi recovery from agonist-induced acidification was primarily due to NHE1, localized to the basolateral membrane. These results suggest that serous acinar cells secrete HCO3− during Ca2+-evoked fluid

A fluid secretion pathway unmasked by acinar-specific Tmem16A gene ablation in the adult mouse salivary gland

PubMed Central

Catalán, Marcelo A.; Kondo, Yusuke; Peña-Munzenmayer, Gaspar; Jaramillo, Yasna; Liu, Frances; Choi, Sooji; Crandall, Edward; Borok, Zea; Flodby, Per; Shull, Gary E.; Melvin, James E.

2015-01-01

Activation of an apical Ca2+-activated Cl− channel (CaCC) triggers the secretion of saliva. It was previously demonstrated that CaCC-mediated Cl− current and Cl− efflux are absent in the acinar cells of systemic Tmem16A (Tmem16A Cl− channel) null mice, but salivation was not assessed in fully developed glands because Tmem16A null mice die within a few days after birth. To test the role of Tmem16A in adult salivary glands, we generated conditional knockout mice lacking Tmem16A in acinar cells (Tmem16A−/−). Ca2+-dependent salivation was abolished in Tmem16A−/− mice, demonstrating that Tmem16A is obligatory for Ca2+-mediated fluid secretion. However, the amount of saliva secreted by Tmem16A−/− mice in response to the β-adrenergic receptor agonist isoproterenol (IPR) was comparable to that seen in controls, indicating that Tmem16A does not significantly contribute to cAMP-induced secretion. Furthermore, IPR-stimulated secretion was unaffected in mice lacking Cftr (Cftr∆F508/∆F508) or ClC-2 (Clcn2−/−) Cl− channels. The time course for activation of IPR-stimulated fluid secretion closely correlated with that of the IPR-induced cell volume increase, suggesting that acinar swelling may activate a volume-sensitive Cl− channel. Indeed, Cl− channel blockers abolished fluid secretion, indicating that Cl− channel activity is critical for IPR-stimulated secretion. These data suggest that β-adrenergic–induced, cAMP-dependent fluid secretion involves a volume-regulated anion channel. In summary, our results using acinar-specific Tmem16A−/− mice identify Tmem16A as the Cl− channel essential for muscarinic, Ca2+-dependent fluid secretion in adult mouse salivary glands. PMID:25646474

Altered coupling of muscarinic acetylcholine receptors in pancreatic acinar carcinoma of rat

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chien, J.L.; Warren, J.R.

The structure and function of muscarinic acetylcholine receptors (mAChR) in acinar carcinoma cells have been compared to mAChR in normal pancreatic acinar cells. Similar 80 kD proteins identified by SDS-PAGE of tumor and normal mAChR affinity-labeled with the muscarinic antagonist /sup 3/H-propylbenzilyl-choline mustards, and identical binding of the antagonist N-methylscopolamine to tumor and normal cells (K/sub D/approx.4x10/sup -10/ M), indicate conservation of mAChR proteins in carcinoma cells. Carcinoma mAChR display homogeneous binding of the agonists carbamylcholine (CCh), K/sub D/approx.3x10/sup -5/ M, and oxotremorine (Oxo), K/sub D/approx.x10/sup -6/ M, whereas normal cells display heterogeneous binding, with a minor component of highmore » affinity interactions for CCh, K/sub D/approx.3x10/sup -6/ M, and Oxo, K/sub D/approx.2x/sup -17/ M, and a major component of low affinity interactions for CCh, K/sub D/approx.1x10/sup -4/ M, and Oxo, K/sub D/approx.2x10/sup -5/ M. Both carcinoma and normal cells exhibit concentration-dependent CCh-stimulated increase in cytosolic free Ca/sup 2 +/, as measured by intracellular Quin 2 fluorescence and /sup 45/Ca/sup 2 +/ efflux. However, carcinoma cells demonstrate 50% maximal stimulation of intracellular Ca/sup 2 +/ release at a CCh concentration (EC/sub 50/approx.6x10/sup -7/ M) one log below that observed for normal cells. The authors propose an altered coupling of mAChR to intracellular Ca/sup 2 +/ homeostasis in carcinoma cells, which is manifest as a single activated receptor state for agonist binding, and increased sensitivity to muscarinic receptor stimulation of Ca/sup 2 +/ release.« less

c-MYC amplification and c-myc protein expression in pancreatic acinar cell carcinomas. New insights into the molecular signature of these rare cancers.

PubMed

La Rosa, Stefano; Bernasconi, Barbara; Vanoli, Alessandro; Sciarra, Amedeo; Notohara, Kenji; Albarello, Luca; Casnedi, Selenia; Billo, Paola; Zhang, Lizhi; Tibiletti, Maria Grazia; Sessa, Fausto

2018-05-02

The molecular alterations of pancreatic acinar cell carcinomas (ACCs) and mixed acinar-neuroendocrine carcinomas (MANECs) are not completely understood, and the possible role of c-MYC amplification in tumor development, progression, and prognosis is not known. We have investigated c-MYC gene amplification in a series of 35 ACCs and 4 MANECs to evaluate its frequency and a possible prognostic role. Gene amplification was investigated using interphasic fluorescence in situ hybridization analysis simultaneously hybridizing c-MYC and the centromere of chromosome 8 probes. Protein expression was immunohistochemically investigated using a specific monoclonal anti-c-myc antibody. Twenty cases had clones with different polysomies of chromosome 8 in absence of c-MYC amplification, and 5 cases had one amplified clone and other clones with chromosome 8 polysomy, while the remaining 14 cases were diploid for chromosome 8 and lacked c-MYC amplification. All MANECs showed c-MYC amplification and/or polysomy which were observed in 54% pure ACCs. Six cases (15.3%) showed nuclear immunoreactivity for c-myc, but only 4/39 cases showed simultaneous c-MYC amplification/polysomy and nuclear protein expression. c-myc immunoreactivity as well as c-MYC amplification and/or chromosome 8 polysomy was not statistically associated with prognosis. Our study demonstrates that a subset of ACCs shows c-MYC alterations including gene amplification and chromosome 8 polysomy. Although they are not associated with a different prognostic signature, the fact that these alterations are present in all MANECs suggests a role in the acinar-neuroendocrine differentiation possibly involved in the pathogenesis of MANECs.

Immunotherapy for B-Cell Neoplasms using T Cells expressing Chimeric Antigen Receptors

PubMed Central

Boulassel, Mohamed-Rachid; Galal, Ahmed

2012-01-01

Immunotherapy with T cells expressing chimeric antigen receptors (CAR) is being evaluated as a potential treatment for B-cell neoplasms. In recent clinical trials it has shown promising results. As the number of potential candidate antigens expands, the choice of suitable target antigens becomes more challenging to design studies and to assess optimal efficacy of CAR. Careful evaluation of candidate target antigens is required to ensure that T cells expressing CAR will preferentially kill malignant cells with a minimal toxicity against normal tissues. B cells express specific surface antigens that can theoretically act as targets for CAR design. Although many of these antigens can stimulate effective cellular immune responses in vivo, their implementation in clinical settings remains a challenge. Only targeted B-cell antigens CD19 and CD20 have been tested in clinical trials. This article reviews exploitable B cell surface antigens for CAR design and examines obstacles that could interfere with the identification of potentially useful cellular targets. PMID:23269948

Malignant Perivascular Epithelioid Cell Neoplasm of the Mediastinum and the Lung

PubMed Central

Liang, Wenjie; Xu, Shunliang; Chen, Feng

2015-01-01

Abstract A perivascular epithelioid cell neoplasm (PEComa) in the chest is rare, let alone in the mediastinum and lung. A 63-year-old man was admitted to our hospital with chest pain for more than 2 months and was found to have an opacity in his mediastinum and lung for 3 weeks. Enhanced chest computed tomography (CT) revealed a mass in both the left upper lobe and central anterior mediastinum. To identify the disease, a CT-guided percutaneous transthoracic needle biopsy of the upper left lung lesions was performed. The pathology result was consistent with epithelioid angiomyolipoma/PEComa. After a standard preparation for surgery, the neoplasms in the mediastinum and left lung were resected. The operative findings revealed extensive mediastinal tumor invasion in parts adjacent to the pericardium, including the mediastinal pleura, left pulmonary artery and vein, and phrenic nerve. The left lung tumor had invaded the lung membranes. The final pathologic diagnosis was malignant epithelioid angioleiomyoma in the left upper lung and mediastinum. Later, the mediastinal tumor recurred. The radiography of this case resembles left upper lobe lung cancer with mediastinal lymph node metastasis. Because this tumor lacks fat, the enhanced CT indicated that it was malignant but failed to identify it as a perivascular epithelioid cell neoplasm. This case reminds clinicians that, although most PEComa are benign, some can be malignant. As the radiology indicated, chest PEComas lack fat, which makes their preoperative diagnosis difficult. Therefore, needle biopsy is valuable for a definitive diagnosis. PMID:26039123

Solving the Puzzle of Metastasis: The Evolution of Cell Migration in Neoplasms

PubMed Central

Chen, Jun; Sprouffske, Kathleen; Huang, Qihong; Maley, Carlo C.

2011-01-01

Background Metastasis represents one of the most clinically important transitions in neoplastic progression. The evolution of metastasis is a puzzle because a metastatic clone is at a disadvantage in competition for space and resources with non-metastatic clones in the primary tumor. Metastatic clones waste some of their reproductive potential on emigrating cells with little chance of establishing metastases. We suggest that resource heterogeneity within primary tumors selects for cell migration, and that cell emigration is a by-product of that selection. Methods and Findings We developed an agent-based model to simulate the evolution of neoplastic cell migration. We simulated the essential dynamics of neoangiogenesis and blood vessel occlusion that lead to resource heterogeneity in neoplasms. We observed the probability and speed of cell migration that evolves with changes in parameters that control the degree of spatial and temporal resource heterogeneity. Across a broad range of realistic parameter values, increasing degrees of spatial and temporal heterogeneity select for the evolution of increased cell migration and emigration. Conclusions We showed that variability in resources within a neoplasm (e.g. oxygen and nutrients provided by angiogenesis) is sufficient to select for cells with high motility. These cells are also more likely to emigrate from the tumor, which is the first step in metastasis and the key to the puzzle of metastasis. Thus, we have identified a novel potential solution to the puzzle of metastasis. PMID:21556134

Skin neoplasms of dogs in Sydney.

PubMed

Rothwell, T L; Howlett, C R; Middleton, D J; Griffiths, D A; Duff, B C

1987-06-01

In a survey of dogs in Sydney, mastocytomas (16.1%) and histiocytomas (14.0%) were the most common in a total of 1,000 skin neoplasms. The basal cell and appendage group provided 25.5% of the neoplasms. The prevalence of the various neoplasms, the age of affected dogs, the proportion in the sexes, the common sites of occurrence and prevalence in the different breeds were broadly similar to findings in surveys in other countries, except that in the Syndeny dogs there was a greater prevalence of histiocytomas and haemangiopericytomas, a more common occurrence of histiocytomas in mature dogs, an occurrence of histiocytomas in similar numbers on the head, trunk and limbs, and a remarkably common development of squamous cell carcinomas in Dalmatians.

Canine mammary minute oncocytomas with neuroendocrine differentiation associated with multifocal acinar cell oncocytic metaplasia.

PubMed

Nagahara, Rei; Kimura, Masayuki; Itahashi, Megu; Sugahara, Go; Kawashima, Masashi; Murayama, Hirotada; Yoshida, Toshinori; Shibutani, Makoto

2016-11-01

Two solitary and minute tumors of 1 and 1.5 mm diameter were identified by microscopy in the left fourth mammary gland of a 13-year-old female Labrador Retriever dog, in addition to multiple mammary gland tumors. The former tumors were well circumscribed and were composed of small-to-large polyhedral neoplastic oncocytes with finely granular eosinophilic cytoplasm, and were arranged in solid nests separated by fine fibrovascular septa. Scattered lumina of variable sizes containing eosinophilic secretory material were evident. Cellular atypia was minimal, and no mitotic figures were visible. One tumor had several oncocytic cellular foci revealing cellular transition, with perivascular pseudorosettes consisting of columnar epithelial cells surrounding the fine vasculature. Scattered foci of mammary acinar cell hyperplasia showing oncocytic metaplasia were also observed. Immunohistochemically, the cytoplasm of neoplastic cells of the 2 microtumors showed diffuse immunoreactivity to anti-cytokeratin antibody AE1/AE3, and finely granular immunoreactivity for 60-kDa heat shock protein, mitochondrial membrane ATP synthase complex V beta subunit, and chromogranin A. One tumor also had oncocytic cellular foci forming perivascular pseudorosettes showing cellular membrane immunoreactivity for neural cell adhesion molecule. The tumors were negative for smooth muscle actin, neuron-specific enolase, vimentin, desmin, S100, and synaptophysin. Ultrastructural observation confirmed the abundant mitochondria in the cytoplasm of both neoplastic and hyperplastic cells, the former cells also having neuroendocrine granule-like electron-dense bodies. From these results, our case was diagnosed with mammary oncocytomas accompanied by neuroendocrine differentiation. Scattered foci of mammary oncocytosis might be related to the multicentric occurrence of these oncocytomas. © 2016 The Author(s).

Mature B-cell neoplasms in Chernobyl clean-up workers of 1986-1987: summary of cytomorphological and immunocytochemical study in 25 years after Chernobyl accident.

PubMed

Gluzman, D F; Sklyarenko, L M; Nadgornaya, V A; Zavelevich, M P

2011-03-01

The data on the verified cases of mature B-cell neoplasms (chronic lymphocytic leukemia - CLL, B-prolymphocytic leukemia, non-Hodgkin's lymphoma in leukemization phase and multiple myeloma - MM; 146 cases in total) in the consecutive group of Ukrainian clean-up workers within 10-25 years after Chernobyl accident are summarized. B-cell neoplasms represent the most prevalent group among all diagnosed neoplasms of hematopoietic and lymphoid tissues in clean-up worker patients under study (49.4%). MM percentage in the patients of Chernobyl clean-up worker group turned out to be significantly higher than in the patients of the general populations studied at the same period. While the percentage of B-CLL is similar in clean-up worker patients and patients of general population, the trend towards younger age of patients with mature B-cell neoplasms in clean-up worker group is evident. The current concepts on the possible association between mature B-cell neoplasms (mainly B-CLL) and radiation exposure are briefly outlined. Only the precise diagnosis of hematopoietic malignancies combining with large-scale analytical epidemiological studies with careful dose assessment and long-term follow-up may represent the basis for resolving the question whether mature B-cell neoplasms may be radiogenic.

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

PubMed Central

Orlova, Anna; Wingelhofer, Bettina; Neubauer, Heidi A.; Maurer, Barbara; Berger-Becvar, Angelika; Keserű, György Miklós; Gunning, Patrick T.; Valent, Peter; Moriggl, Richard

2018-01-01

ABSTRACT Introduction: Hematopoietic neoplasms are often driven by gain-of-function mutations of the JAK-STAT pathway together with mutations in chromatin remodeling and DNA damage control pathways. The interconnection between the JAK-STAT pathway, epigenetic regulation or DNA damage control is still poorly understood in cancer cell biology. Areas covered: Here, we focus on a broader description of mutational insights into myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas, since sequencing efforts have identified similar combinations of driver mutations in these diseases covering different lineages. We summarize how these pathways might be interconnected in normal or cancer cells, which have lost differentiation capacity and drive oncogene transcription. Expert opinion: Due to similarities in driver mutations including epigenetic enzymes, JAK-STAT pathway activation and mutated checkpoint control through TP53, we hypothesize that similar therapeutic approaches could be of benefit in these diseases. We give an overview of how driver mutations in these malignancies contribute to hematopoietic cancer initiation or progression, and how these pathways can be targeted with currently available tools. PMID:29148847

Water permeability of acinar cell membranes in the isolated perfused rabbit mandibular salivary gland.

PubMed Central

Steward, M C; Seo, Y; Rawlings, J M; Case, R M

1990-01-01

1. The diffusive water permeability of epithelial cell membranes in the perfused rabbit mandibular salivary gland was measured at 37 degrees C by a 1H nuclear magnetic resonance relaxation method using an extracellular relaxation reagent, gadolinium diethylenetriaminepentaacetic acid (Gd(DTPA)). 2. In glands perfused with a HEPES-buffered solution containing 10 mmol l-1 Gd(DTPA), the spin-lattice (T1) relaxation of the water protons showed two exponential components. The water compartment responsible for the slower component corresponded in magnitude to 71 +/- 5% of the wet weight of the gland, and was attributed to the exchangeable intracellular water of the acinar cells. 3. The rate constant for water efflux from the cells was estimated to be 4.1 +/- 0.1 s-1 which would be consistent with a diffusive membrane permeability (Pd) of approximately 3 x 10(-3) cm s-1. Stimulation with acetylcholine (10(-6) mol l-1) did not cause any detectable change in membrane water permeability. 4. Since the basolateral membrane probably provides the main pathway for water efflux, the osmotic water permeability of this barrier (expressed per gland) was estimated to be less than 6.2 cm3 s-1. This would be insufficient to account for the generation of a near-isosmotic fluid at the flow rates observed during secretion, and suggests that a substantial fraction of the flow of water occurs via a paracellular route. PMID:1966053

MULTIHORMONAL ISLET CELL CARCINOMAS IN THREE KOMODO DRAGONS (VARANUS KOMODOENSIS).

PubMed

Eustace, Ronan; Garner, Michael M; Cook, Kimberly; Miller, Christine; Kiupel, Matti

2017-03-01

  Multihormonal pancreatic islet cell carcinomas were found in one female and two male captive geriatric Komodo dragons (Varanus komodoensis). Gross changes in the pancreas were visible in two of the cases. Clinical signs noted in the Komodo dragons were lethargy, weakness, and anorexia. Histologically, the tumors were comprised of nests and cords of well-differentiated neoplastic islet cells with scant amounts of eosinophilic cytoplasm and round, euchromatic nuclei, with rare mitoses. Infiltration by the islet cell tumor into the surrounding acinar tissue was observed in all cases, but no metastatic foci were seen. Multihormone expression was observed in all tumors, which labeled strongly positive for glucagon and somatostatin and focally positive for polypeptide. Pancreatic islet cell neoplasms should be considered in the differential diagnosis for geriatric Komodo dragons presenting with weakness, lethargy, and poor appetite.

Expression of alveolar type II cell markers in acinar adenocarcinomas and adenoid cystic carcinomas arising from segmental bronchi. A study in a heterotopic bronchogenic carcinoma model in dogs.

PubMed Central

TenHave-Opbroek, A. A.; Hammond, W. G.; Benfield, J. R.; Teplitz, R. L.; Dijkman, J. H.

1993-01-01

The type II alveolar epithelial cell is one of two pluripotential stem cell phenotypes in normal mammalian lung morphogenesis; cells manifesting this phenotype have been found to constitute bronchioloalveolar regions of canine adenocarcinomas. We now studied type II cell expression in canine acinar adenocarcinomas and adenoid cystic (bronchial gland) carcinomas, using the same bronchogenic carcinoma model (subcutaneous bronchial autografts treated with 3-methylcholanthrene). Distinctive features of type II cells are the approximately cuboid cell shape, large and roundish nucleus, immunofluorescent staining of the cytoplasm for the surfactant protein SP-A, and presence of multilamellar bodies or their precursory forms. Cells with these type II cell characteristics were found in the basal epithelial layer of all tumor lesions and in upper layers as far as the lumen, singly or in clusters; they were also found in early invasive carcinomatous lesions but not in bronchial glands or bronchial epithelium before carcinogen exposure. Immunoblots of tumor homogenates showed reactive proteins within size classes of SP-A (28 to 36 kd) or its dimeric form (56 to 72 kd). These findings and those previously reported are consistent with the concept that chemical carcinogenesis in the adult bronchial epithelium may lead to type II cell carcinomas of varying glandular (acinar, adenoidcystic or bronchioloalveolar) growth patterns. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 Figure 15 Figure 16 Figure 17 Figure 18 Figure 19 Figure 20 Figure 21 Figure 22 PMID:8386445

Therapy targets in glioblastoma and cancer stem cells: lessons from haematopoietic neoplasms

PubMed Central

Cruceru, Maria Linda; Neagu, Monica; Demoulin, Jean-Baptiste; Constantinescu, Stefan N

2013-01-01

Despite intense efforts to identify cancer-initiating cells in malignant brain tumours, markers linked to the function of these cells have only very recently begun to be uncovered. The notion of cancer stem cell gained prominence, several molecules and signalling pathways becoming relevant for diagnosis and treatment. Whether a substantial fraction or only a tiny minority of cells in a tumor can initiate and perpetuate cancer, is still debated. The paradigm of cancer-initiating stem cells has initially been developed with respect to blood cancers where chronic conditions such as myeloproliferative neoplasms are due to mutations acquired in a haematopoietic stem cell (HSC), which maintains the normal hierarchy to neoplastic haematopoiesis. In contrast, acute leukaemia transformation of such blood neoplasms appears to derive not only from HSCs but also from committed progenitors that cannot differentiate. This review will focus on putative novel therapy targets represented by markers described to define cancer stem/initiating cells in malignant gliomas, which have been called ‘leukaemia of the brain’, given their rapid migration and evolution. Parallels are drawn with other cancers, especially haematopoietic, given the similar rampant proliferation and treatment resistance of glioblastoma multiforme and secondary acute leukaemias. Genes associated with the malignant conditions and especially expressed in glioma cancer stem cells are intensively searched. Although many such molecules might only coincidentally be expressed in cancer-initiating cells, some may function in the oncogenic process, and those would be the prime candidates for diagnostic and targeted therapy. For the latter, combination therapies are likely to be envisaged, given the robust and plastic signalling networks supporting malignant proliferation. PMID:23998913

LMW-E/CDK2 Deregulates Acinar Morphogenesis, Induces Tumorigenesis, and Associates with the Activated b-Raf-ERK1/2-mTOR Pathway in Breast Cancer Patients

PubMed Central

Duong, MyLinh T.; Akli, Said; Wei, Caimiao; Wingate, Hannah F.; Liu, Wenbin; Lu, Yiling; Yi, Min; Mills, Gordon B.; Hunt, Kelly K.; Keyomarsi, Khandan

2012-01-01

Elastase-mediated cleavage of cyclin E generates low molecular weight cyclin E (LMW-E) isoforms exhibiting enhanced CDK2–associated kinase activity and resistance to inhibition by CDK inhibitors p21 and p27. Approximately 27% of breast cancers express high LMW-E protein levels, which significantly correlates with poor survival. The objective of this study was to identify the signaling pathway(s) deregulated by LMW-E expression in breast cancer patients and to identify pharmaceutical agents to effectively target this pathway. Ectopic LMW-E expression in nontumorigenic human mammary epithelial cells (hMECs) was sufficient to generate xenografts with greater tumorigenic potential than full-length cyclin E, and the tumorigenicity was augmented by in vivo passaging. However, cyclin E mutants unable to interact with CDK2 protected hMECs from tumor development. When hMECs were cultured on Matrigel, LMW-E mediated aberrant acinar morphogenesis, including enlargement of acinar structures and formation of multi-acinar complexes, as denoted by reduced BIM and elevated Ki67 expression. Similarly, inducible expression of LMW-E in transgenic mice generated hyper-proliferative terminal end buds resulting in enhanced mammary tumor development. Reverse-phase protein array assay of 276 breast tumor patient samples and cells cultured on monolayer and in three-dimensional Matrigel demonstrated that, in terms of protein expression profile, hMECs cultured in Matrigel more closely resembled patient tissues than did cells cultured on monolayer. Additionally, the b-Raf-ERK1/2-mTOR pathway was activated in LMW-E–expressing patient samples, and activation of this pathway was associated with poor disease-specific survival. Combination treatment using roscovitine (CDK inhibitor) plus either rapamycin (mTOR inhibitor) or sorafenib (a pan kinase inhibitor targeting b-Raf) effectively prevented aberrant acinar formation in LMW-E–expressing cells by inducing G1/S cell cycle arrest. LMW

Glycogen synthase kinase-3β ablation limits pancreatitis-induced acinar-to-ductal metaplasia.

PubMed

Ding, Li; Liou, Geou-Yarh; Schmitt, Daniel M; Storz, Peter; Zhang, Jin-San; Billadeau, Daniel D

2017-09-01

Acinar-to-ductal metaplasia (ADM) is a reversible epithelial transdifferentiation process that occurs in the pancreas in response to acute inflammation. ADM can rapidly progress towards pre-malignant pancreatic intraepithelial neoplasia (PanIN) lesions in the presence of mutant KRas and ultimately pancreatic adenocarcinoma (PDAC). In the present work, we elucidate the role and related mechanism of glycogen synthase kinase-3beta (GSK-3β) in ADM development using in vitro 3D cultures and genetically engineered mouse models. We show that GSK-3β promotes TGF-α-induced ADM in 3D cultured primary acinar cells, whereas deletion of GSK-3β attenuates caerulein-induced ADM formation and PanIN progression in Kras G12D transgenic mice. Furthermore, we demonstrate that GSK-3β ablation influences ADM formation and PanIN progression by suppressing oncogenic KRas-driven cell proliferation. Mechanistically, we show that GSK-3β regulates proliferation by increasing the activation of S6 kinase. Taken together, these results indicate that GSK-3β participates in early pancreatitis-induced ADM and thus could be a target for the treatment of chronic pancreatitis and the prevention of PDAC progression. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Laser Capture Microdissection of Pancreatic Acinar Cells to Identify Proteomic Alterations in a Murine Model of Caerulein-Induced Pancreatitis

PubMed Central

Shapiro, John P; Komar, Hannah M; Hancioglu, Baris; Yu, Lianbo; Jin, Ming; Ogata, Yuko; Hart, Phil A; Cruz-Monserrate, Zobeida; Lesinski, Gregory B; Conwell, Darwin L

2017-01-01

Objectives: Chronic pancreatitis (CP) is characterized by inflammation and fibrosis of the pancreas, leading to pain, parenchymal damage, and loss of exocrine and endocrine function. There are currently no curative therapies; diagnosis remains difficult and aspects of pathogenesis remain unclear. Thus, there is a need to identify novel biomarkers to improve diagnosis and understand pathophysiology. We hypothesize that pancreatic acinar regions contain proteomic signatures relevant to disease processes, including secreted proteins that could be detected in biofluids. Methods: Acini from pancreata of mice injected with or without caerulein were collected using laser capture microdissection followed by mass spectrometry analysis. This protocol enabled high-throughput analysis that captured altered protein expression throughout the stages of CP. Results: Over 2,900 proteins were identified, whereas 331 were significantly changed ≥2-fold by mass spectrometry spectral count analysis. Consistent with pathogenesis, we observed increases in proteins related to fibrosis (e.g., collagen, P<0.001), several proteases (e.g., trypsin 1, P<0.001), and altered expression of proteins associated with diminished pancreas function (e.g., lipase, amylase, P<0.05). In comparison with proteomic data from a public data set of CP patients, a significant correlation was observed between proteomic changes in tissue from both the caerulein model and CP patients (r=0.725, P<0.001). CONCLUSIONS: This study illustrates the ability to characterize proteome changes of acinar cells isolated from pancreata of caerulein-treated mice and demonstrates a relationship between signatures from murine and human CP. PMID:28406494

Therapy targets in glioblastoma and cancer stem cells: lessons from haematopoietic neoplasms.

PubMed

Cruceru, Maria Linda; Neagu, Monica; Demoulin, Jean-Baptiste; Constantinescu, Stefan N

2013-10-01

Despite intense efforts to identify cancer-initiating cells in malignant brain tumours, markers linked to the function of these cells have only very recently begun to be uncovered. The notion of cancer stem cell gained prominence, several molecules and signalling pathways becoming relevant for diagnosis and treatment. Whether a substantial fraction or only a tiny minority of cells in a tumor can initiate and perpetuate cancer, is still debated. The paradigm of cancer-initiating stem cells has initially been developed with respect to blood cancers where chronic conditions such as myeloproliferative neoplasms are due to mutations acquired in a haematopoietic stem cell (HSC), which maintains the normal hierarchy to neoplastic haematopoiesis. In contrast, acute leukaemia transformation of such blood neoplasms appears to derive not only from HSCs but also from committed progenitors that cannot differentiate. This review will focus on putative novel therapy targets represented by markers described to define cancer stem/initiating cells in malignant gliomas, which have been called 'leukaemia of the brain', given their rapid migration and evolution. Parallels are drawn with other cancers, especially haematopoietic, given the similar rampant proliferation and treatment resistance of glioblastoma multiforme and secondary acute leukaemias. Genes associated with the malignant conditions and especially expressed in glioma cancer stem cells are intensively searched. Although many such molecules might only coincidentally be expressed in cancer-initiating cells, some may function in the oncogenic process, and those would be the prime candidates for diagnostic and targeted therapy. For the latter, combination therapies are likely to be envisaged, given the robust and plastic signalling networks supporting malignant proliferation. © 2013 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

KRASG12D expression in lung-resident myeloid cells promotes pulmonary LCH-like neoplasm sensitive to statin treatment

PubMed Central

Giblett, Susan; Pritchard, Catrin

2017-01-01

Langerhans cell histiocytosis (LCH) is a rare histiocytic neoplasm associated with somatic mutations in the genes involved in the RAF/MEK/extracellular signal-regulated kinase (ERK) signaling pathway. Recently, oncogenic mutations in NRAS/KRAS, upstream regulators of the RAF/MEK/ERK pathway, have been reported in pulmonary, but not in nonpulmonary, LCH cases, suggesting organ-specific contribution of oncogenic RAS to LCH pathogenesis. Using a mouse model expressing KRASG12D in the lung by nasal delivery of adenoviral Cre recombinase (Cre), here we show that KRASG12D expression in lung-resident myeloid cells induces pulmonary LCH-like neoplasms composed of pathogenic CD11chighF4/80+CD207+ cells. The pathogenic cells were mitotically inactive, but proliferating precursors were detected in primary cultures of lung tissue. These precursors were derived, at least in part, from CD11cdimCD11bintGr1− lung-resident monocytic cells transformed by KRASG12D. In contrast, BRAFV600E expression induced by the same method failed to develop LCH-like neoplasms, suggesting that each oncogene may initiate pulmonary LCH by transforming different types of lung-resident myeloid cells. In vivo treatment of the KRASG12D-induced LCH-like mouse with the cholesterol-lowering drug atorvastatin ameliorated the pathology, implicating statins as potential therapeutics against a subset of pulmonary LCH. PMID:28550040

A bicarbonate- and weak acid-permeable chloride conductance controlled by cytosolic Ca2+ and ATP in rat submandibular acinar cells.

PubMed

Ishikawa, T

1996-09-01

A Ca(2+)-activated Cl- conductance in rat submandibular acinar cells was identified and characterized using whole-cell patch-clamp technique. When the cells were dialyzed with Cs-glutamate-rich pipette solutions containing 2 mM ATP and 1 microM free Ca2+ and bathed in N-methyl-D-glucamine chloride (NMDG-Cl) or Choline-Cl-rich solutions, they mainly exhibited slowly activating currents. Dialysis of the cells with pipette solutions containing 300 nM or less than 1 nM free Ca2+ strongly reduced the Cl- currents, indicating the currents were Ca(2+)-dependent. Relaxation analysis of the "on" currents of slowly activating currents suggested that the channels were voltage-dependent. The anion permeability sequence of the Cl- channels was: NO3- (2.00) > I- (1.85) > or = Br- (1.69) > Cl- (1.00) > bicarbonate (0.77) > or = acetate (0.70) > propionate (0.41) > > glutamate (0.09). When the ATP concentration in the pipette solutions was increased from 0 to 10 mM, the Ca(2+)-dependency of the Cl- current amplitude shifted to lower free Ca2+ concentrations by about two orders of magnitude. Cells dialyzed with a pipette solution (pCa = 6) containing ATP-gamma S (2 mM) exhibited currents of similar magnitude to those observed with the solution containing ATP (2 mM). The addition of the calmodulin inhibitors trifluoperazine (100 microM) or calmidazolium (25 microM) to the bath solution and the inclusion of KN-62 (1 microM), a specific inhibitor of calmodulin kinase, or staurosporin (10 nM), an inhibitor of protein kinase C to the pipette solution had little, if any, effect on the Ca(2+)-activated Cl- currents. This suggests that Ca2+/Calmodulin or calmodulin kinase II and protein kinase C are not involved in Ca(2+)-activated Cl- currents. The outward Cl- currents at +69 mV were inhibited by NPPB (100 microM), IAA-94 (100 microM), DIDS (0.03-1 mM), 9-AC (300 microM and 1 mM) and DPC (1 mM), whereas the inward currents at -101 mV were not. These results demonstrate the presence of a

Heterologous desensitization of muscarinic receptors by P2Z purinoceptors in rat parotid acinar cells.

PubMed

Fukushi, Y

1999-01-01

We studied the heterologous desensitization of muscarinic receptors by ATP in fura-2-loaded rat parotid acinar cells. Exposure to ATP or 3'-o-(4-benzoyl) benzoyl-ATP shortened the duration and decreased the magnitude of acetylcholine-induced Ca2+ release from intracellular Ca2+ stores in a dose-dependent manner. The shortening was observed only in an early stage of desensitization (within 20 s), whereas the decrease in the magnitude of the response was dependent upon the time the cells were exposed to the nucleotides. Atropine induced a profound shortening during the progressive decrease in the magnitude of acetylcholine-induced Ca2+ release. 3'-o-(4-Benzoyl) benzoyl-ATP did not induce an increase in the cytosolic Ca2+ concentration when the cells were incubated in the Ca2+- and Na+-free medium, but it did induce a strong desensitization of muscarinic receptors. The specific protein kinase C inhibitor bisindoylmaleimide resensitized the 3'-o-(4-benzoyl) benzoyl-ATP-treated muscarinic receptors. Phorbol 12-myristate 13-acetate potentiated the desensitization of muscarinic receptors. Ceramides that prevent the activation of phospholipase D resensitized the 3'-o-(4-benzoyl) benzoyl-ATP-treated muscarinic receptors. These results suggest that ATP, acting through P2Z purinoceptor-mediated phospholipase D, may produce a Ca2+-independent protein kinase C. Heterologous desensitization of muscarinic receptors by protein kinase C may shorten the duration and decrease the magnitude of acetylcholine-induced Ca2+ release.

Malignant Perivascular Epithelioid Cell Neoplasm (PEComa) of the Pelvis: A Case Report.

PubMed

D'Andrea, David; Hanspeter, Esther; D'Elia, Carolina; Martini, Thomas; Pycha, Armin

2016-05-01

Perivascular epithelioid cell neoplasms (PEComa) are rare mesenchymal tumors that can occur in any part of the body and have unpredictable pathological behavior. They are usually benign, but may be malignant. We present a case of malignant PEComa of the pelvic retroperitoneum treated with radical surgery.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN): the cutaneous sanctuary.

PubMed

Pileri, A; Delfino, C; Grandi, V; Agostinelli, C; Pileri, S A; Pimpinelli, N

2012-12-01

Blastic plasmacytoid dendritic cell neoplasm (BPDNC) is a rare tumour, which stems from plasmacytoid dendritic cells. Although the aetiology is still unclear, in the last few years various reports suggested a potential role of chromosomal aberrations in the oncogenesis. The disease is currently enclosed among "acute myeloid leukemia (AML) and related precursor neoplasms" in the last WHO classification. BPDCN has an aggressive course, however, it has been suggested that an exclusive cutaneous involvement at presentation is related to a better clinical outcome. We review the literature about BPDCN, and we present a series of 11 cases, all characterised by disease limited to the skin at presentation. Furthermore, we examined all cases of the last 10 years stored in the database of the multidisciplinary study group on cutaneous lymphomas of the University of Florence. Basing on the clinical features, patient were classified into two groups: with a single-lesion or multiple eruptive-lesions presentation. The former were treated with radiotherapy (limited field, electron beam therapy). The latter were treated with different therapeutic options, depending on age and co-morbidities. All patients with a single lesion achieved complete response. Five of 6 patients with eruptive lesions achieved a clinical response (2 complete and 3 partial response). Notably, the progression free survival was higher in the single-lesion than in the eruptive-lesion group (23 vs. 9 months). However all patients relapsed and 8 of 11 died. Although the small number of selected patients, we could speculate that the concept of "cutaneous sanctuary" is particularly true in patients with a single lesion-presentation. In these patients, especially if >70 year-old aged, radiotherapy should be encouraged as the treatment of choice.

Particle dynamics and deposition in true-scale pulmonary acinar models.

PubMed

Fishler, Rami; Hofemeier, Philipp; Etzion, Yael; Dubowski, Yael; Sznitman, Josué

2015-09-11

Particle transport phenomena in the deep alveolated airways of the lungs (i.e. pulmonary acinus) govern deposition outcomes following inhalation of hazardous or pharmaceutical aerosols. Yet, there is still a dearth of experimental tools for resolving acinar particle dynamics and validating numerical simulations. Here, we present a true-scale experimental model of acinar structures consisting of bifurcating alveolated ducts that capture breathing-like wall motion and ensuing respiratory acinar flows. We study experimentally captured trajectories of inhaled polydispersed smoke particles (0.2 to 1 μm in diameter), demonstrating how intrinsic particle motion, i.e. gravity and diffusion, is crucial in determining dispersion and deposition of aerosols through a streamline crossing mechanism, a phenomenon paramount during flow reversal and locally within alveolar cavities. A simple conceptual framework is constructed for predicting the fate of inhaled particles near an alveolus by identifying capture and escape zones and considering how streamline crossing may shift particles between them. In addition, we examine the effect of particle size on detailed deposition patterns of monodispersed microspheres between 0.1-2 μm. Our experiments underline local modifications in the deposition patterns due to gravity for particles ≥0.5 μm compared to smaller particles, and show good agreement with corresponding numerical simulations.

Particle dynamics and deposition in true-scale pulmonary acinar models

PubMed Central

Fishler, Rami; Hofemeier, Philipp; Etzion, Yael; Dubowski, Yael; Sznitman, Josué

2015-01-01

Particle transport phenomena in the deep alveolated airways of the lungs (i.e. pulmonary acinus) govern deposition outcomes following inhalation of hazardous or pharmaceutical aerosols. Yet, there is still a dearth of experimental tools for resolving acinar particle dynamics and validating numerical simulations. Here, we present a true-scale experimental model of acinar structures consisting of bifurcating alveolated ducts that capture breathing-like wall motion and ensuing respiratory acinar flows. We study experimentally captured trajectories of inhaled polydispersed smoke particles (0.2 to 1 μm in diameter), demonstrating how intrinsic particle motion, i.e. gravity and diffusion, is crucial in determining dispersion and deposition of aerosols through a streamline crossing mechanism, a phenomenon paramount during flow reversal and locally within alveolar cavities. A simple conceptual framework is constructed for predicting the fate of inhaled particles near an alveolus by identifying capture and escape zones and considering how streamline crossing may shift particles between them. In addition, we examine the effect of particle size on detailed deposition patterns of monodispersed microspheres between 0.1–2 μm. Our experiments underline local modifications in the deposition patterns due to gravity for particles ≥0.5 μm compared to smaller particles, and show good agreement with corresponding numerical simulations. PMID:26358580

Nivolumab and Ipilimumab in Treating Patients With Rare Tumors

ClinicalTrials.gov

2018-06-27

Acinar Cell Carcinoma; Adenoid Cystic Carcinoma; Adrenal Cortex Carcinoma; Adrenal Gland Pheochromocytoma; Anal Canal Neuroendocrine Carcinoma; Anal Canal Undifferentiated Carcinoma; Appendix Mucinous Adenocarcinoma; Bartholin Gland Transitional Cell Carcinoma; Bladder Adenocarcinoma; Cervical Adenocarcinoma; Cholangiocarcinoma; Chordoma; Colorectal Squamous Cell Carcinoma; Desmoid-Type Fibromatosis; Endometrial Transitional Cell Carcinoma; Endometrioid Adenocarcinoma; Esophageal Neuroendocrine Carcinoma; Esophageal Undifferentiated Carcinoma; Extrahepatic Bile Duct Carcinoma; Fallopian Tube Adenocarcinoma; Fallopian Tube Transitional Cell Carcinoma; Fibromyxoid Tumor; Gastric Neuroendocrine Carcinoma; Gastric Squamous Cell Carcinoma; Gastrointestinal Stromal Tumor; Giant Cell Carcinoma; Intestinal Neuroendocrine Carcinoma; Intrahepatic Cholangiocarcinoma; Lung Carcinoid Tumor; Lung Sarcomatoid Carcinoma; Major Salivary Gland Carcinoma; Malignant Odontogenic Neoplasm; Malignant Peripheral Nerve Sheath Tumor; Malignant Testicular Sex Cord-Stromal Tumor; Metaplastic Breast Carcinoma; Metastatic Malignant Neoplasm of Unknown Primary Origin; Minimally Invasive Lung Adenocarcinoma; Mixed Mesodermal (Mullerian) Tumor; Mucinous Adenocarcinoma; Mucinous Cystadenocarcinoma; Nasal Cavity Adenocarcinoma; Nasal Cavity Carcinoma; Nasopharyngeal Carcinoma; Nasopharyngeal Papillary Adenocarcinoma; Nasopharyngeal Undifferentiated Carcinoma; Oral Cavity Carcinoma; Oropharyngeal Undifferentiated Carcinoma; Ovarian Adenocarcinoma; Ovarian Germ Cell Tumor; Ovarian Mucinous Adenocarcinoma; Ovarian Squamous Cell Carcinoma; Ovarian Transitional Cell Carcinoma; Pancreatic Acinar Cell Carcinoma; Pancreatic Neuroendocrine Carcinoma; Paraganglioma; Paranasal Sinus Adenocarcinoma; Paranasal Sinus Carcinoma; Parathyroid Gland Carcinoma; Pituitary Gland Carcinoma; Placental Choriocarcinoma; Placental-Site Gestational Trophoblastic Tumor; Primary Peritoneal High Grade Serous Adenocarcinoma

Malignant Perivascular Epithelioid Cell Neoplasm (PEComa) of the Pelvis: A Case Report

PubMed Central

D'Andrea, David; Hanspeter, Esther; D'Elia, Carolina; Martini, Thomas; Pycha, Armin

2016-01-01

Perivascular epithelioid cell neoplasms (PEComa) are rare mesenchymal tumors that can occur in any part of the body and have unpredictable pathological behavior. They are usually benign, but may be malignant. We present a case of malignant PEComa of the pelvic retroperitoneum treated with radical surgery. PMID:27169023

Pembrolizumab in Treating Patients With HIV and Relapsed, Refractory, or Disseminated Malignant Neoplasms

ClinicalTrials.gov

2018-03-22

AIDS-Related Non-Hodgkin Lymphoma; Classical Hodgkin Lymphoma; HIV Infection; Locally Advanced Malignant Neoplasm; Metastatic Malignant Neoplasm; Recurrent Hepatocellular Carcinoma; Recurrent Hodgkin Lymphoma; Recurrent Kaposi Sarcoma; Recurrent Malignant Neoplasm; Recurrent Melanoma of the Skin; Recurrent Non-Hodgkin Lymphoma; Recurrent Non-Small Cell Lung Carcinoma; Refractory Hodgkin Lymphoma; Refractory Malignant Neoplasm; Solid Neoplasm; Stage IIIA Cutaneous Melanoma AJCC v7; Stage IIIA Hepatocellular Carcinoma AJCC v7; Stage IIIA Non-Small Cell Lung Cancer AJCC v7; Stage IIIB Cutaneous Melanoma AJCC v7; Stage IIIB Hepatocellular Carcinoma AJCC v7; Stage IIIB Non-Small Cell Lung Cancer AJCC v7; Stage IIIC Cutaneous Melanoma AJCC v7; Stage IIIC Hepatocellular Carcinoma AJCC v7; Stage IV Cutaneous Melanoma AJCC v6 and v7; Stage IV Non-Small Cell Lung Cancer AJCC v7; Stage IVA Hepatocellular Carcinoma AJCC v7; Stage IVB Hepatocellular Carcinoma AJCC v7

STAT5-glucocorticoid receptor interaction and MTF-1 regulate the expression of ZnT2 (Slc30a2) in pancreatic acinar cells

PubMed Central

Guo, Liang; Lichten, Louis A.; Ryu, Moon-Suhn; Liuzzi, Juan P.; Wang, Fudi; Cousins, Robert J.

2010-01-01

The exocrine pancreas plays an important role in endogenous zinc loss by regulating excretion into the intestinal tract and hence influences the dietary zinc requirement. The present experiments show that the zinc transporter ZnT2 (Slc30a2) is localized to the zymogen granules and that dietary zinc restriction in mice decreased the zinc concentration of zymogen granules and ZnT2 expression. Excess zinc given orally increased ZnT2 expression and was associated with increased pancreatic zinc accumulation. Rat AR42J acinar cells when induced into a secretory phenotype, using the glucocorticoid analog dexamethasone (DEX), exhibited increased ZnT2 expression and labile zinc as measured with a fluorophore. DEX administrated to mice also induced ZnT2 expression that accompanied a reduction of the pancreatic zinc content. ZnT2 promoter analyses identified elements required for responsiveness to zinc and DEX. Zinc regulation was traced to a MRE located downstream from the ZnT2 transcription start site. Responsiveness to DEX is produced by two upstream STAT5 binding sites that require the glucocorticoid receptor for activation. ZnT2 knockdown in the AR42J cells using siRNA resulted in increased cytoplasmic zinc and decreased zymogen granule zinc that further demonstrated that ZnT2 may mediate the sequestration of zinc into zymogen granules. We conclude, based upon experiments with intact mice and pancreatic acinar cells in culture, that ZnT2 participates in zinc transport into pancreatic zymogen granules through a glucocorticoid pathway requiring glucocorticoid receptor and STAT5, and zinc-regulated signaling pathways requiring MTF-1. The ZnT2 transporter appears to function in a physiologically responsive manner involving entero-pancreatic zinc trafficking. PMID:20133611

Malignant perivascular epithelioid cell neoplasm of the mediastinum and the lung: one case report.

PubMed

Liang, Wenjie; Xu, Shunliang; Chen, Feng

2015-06-01

A perivascular epithelioid cell neoplasm (PEComa) in the chest is rare, let alone in the mediastinum and lung. A 63-year-old man was admitted to our hospital with chest pain for more than 2 months and was found to have an opacity in his mediastinum and lung for 3 weeks. Enhanced chest computed tomography (CT) revealed a mass in both the left upper lobe and central anterior mediastinum. To identify the disease, a CT-guided percutaneous transthoracic needle biopsy of the upper left lung lesions was performed. The pathology result was consistent with epithelioid angiomyolipoma/PEComa. After a standard preparation for surgery, the neoplasms in the mediastinum and left lung were resected. The operative findings revealed extensive mediastinal tumor invasion in parts adjacent to the pericardium, including the mediastinal pleura, left pulmonary artery and vein, and phrenic nerve. The left lung tumor had invaded the lung membranes. The final pathologic diagnosis was malignant epithelioid angioleiomyoma in the left upper lung and mediastinum. Later, the mediastinal tumor recurred. The radiography of this case resembles left upper lobe lung cancer with mediastinal lymph node metastasis. Because this tumor lacks fat, the enhanced CT indicated that it was malignant but failed to identify it as a perivascular epithelioid cell neoplasm.This case reminds clinicians that, although most PEComa are benign, some can be malignant. As the radiology indicated, chest PEComas lack fat, which makes their preoperative diagnosis difficult. Therefore, needle biopsy is valuable for a definitive diagnosis.

Cholecystokinin-8-induced hypoplasia of the rat pancreas: influence of nitric oxide on cell proliferation and programmed cell death.

PubMed

Trulsson, Lena M; Gasslander, Thomas; Svanvik, Joar

2004-10-01

The background of cholecystokinin-8 (CCK-8)-induced hypoplasia in the pancreas is not known. In order to increase our understanding we studied the roles of nitric oxide and NF-kappaB in rats. CCK-8 was injected for 4 days, in a mode known to cause hypoplasia, and the nitric oxide formation was either decreased by means of N(omega)-nitro-L-arginine (L-NNA) or increased by S-nitroso-N-acetylpencillamine (SNAP). The activation of NF-kappaB was quantified by ELISA detection, apoptosis with caspase-3 and histone-associated DNA-fragmentation and mitotic activity in the acinar, centroacinar and ductal cells were visualized by the incorporation of [(3)H]-thymidine. Pancreatic histology and weight as well as protein- and DNA contents were also studied. Intermittent CCK injections reduced pancreatic weight, protein and DNA contents and increased apoptosis, acinar cell proliferation and nuclear factor kappaB (NF-kappaB) activation. It also caused vacuolisation of acinar cells. The inhibition of endogenous nitric oxide formation by L-NNA further increased apoptosis and NF-kappaB activation but blocked the increased proliferation and vacuolisation of acinar cells. The DNA content was not further reduced. SNAP given together with CCK-8 increased apoptosis and other pathways of cell death, raised proliferation of acinar cells and strongly reduced the DNA content in the pancreas. Histological examination showed no inflammation in any group. We conclude that during CCK-8-induced pancreatic hypoplasia, endogenously formed nitric oxide suppresses apoptosis but increases cell death along non-apoptotic pathways and stimulates regeneration of acinar cells. Exogenous nitric oxide enhances the acinar cell turnover by increasing both apoptotic and non-apoptotic cell death and cell renewal. In this situation NF-kappaB activation seems not to inhibit apoptosis nor promote cell proliferation.

[Diagnostic molecular pathology of lymphatic and myeloid neoplasms].

PubMed

Klapper, W; Kreipe, H

2015-03-01

Molecular pathology has been an integral part of the diagnostics of tumors of the hematopoietic system substantially longer than for solid neoplasms. In contrast to solid tumors, the primary objective of molecular pathology in hematopoietic neoplasms is not the prediction of drug efficacy but the diagnosis itself by excluding reactive proliferation and by using molecular features for tumor classification. In the case of malignant lymphomas, the most commonly applied molecular tests are those for gene rearrangements for immunoglobulin heavy chains and T-cell receptors. However, this article puts the focus on new and diagnostically relevant assays in hematopathology. Among these are mutations of MYD88 codon 265 in lymphoplasmacytic lymphomas, B-raf V600E in hairy cell leukemia and Stat3 exon 21 in indolent T-cell lymphomas. In myeloproliferative neoplasms, MPL W515, calreticulin exon 9 and the BCR-ABL and JAK2 V617F junctions are the most frequently analyzed differentiation series. In myelodysplastic and myeloproliferative neoplasms, SRSF2, SETBP1 and CSF3R mutations provide important differential diagnostic information. Genes mutated in myelodysplastic syndromes (MDS) are particularly diverse but their analysis significantly improves the differential diagnostics between reactive conditions and MDS. The most frequent changes in MDS include mutations of TET2 and various genes encoding splicing factors.

[Blastic plasmacytoid dendritic cell neoplasm revealed by ecchymotic lesions on the face].

PubMed

Ahogo, K-C; Wantz, M; Cliquennois, M; Gosset, P; Lebas, D; Modiano, P

2014-01-01

Cutaneous CD4+CD56+ malignant tumor proliferation was previously called "CD4/CD56 hematodermic neoplasm". However, the most recent studies have shown that the disease develops from plasmacytoid dendritic cells and the tumor has been renamed "Blastic Plasmacytoid Dendritic Cell Neoplasm" (BPDCN). It is an aggressive disease with a poor prognosis and behaves like acute leukemia in the short to moderate term. A 65-year-old man with no particular history consulted for a left laterocervical lesion of ecchymotic aspect that had appeared one year earlier. Topical corticosteroid therapy had been unsuccessful. Examination of biopsies with lymphocyte typing enabled a diagnosis of BPDCN to be made. At the histopathological level, biopsy showed an infiltrate comprising medium to large cells. Immunohistochemical examination was remarkable for the absence of expression of markers of T- and B-cell lines. However, these tumor cells expressed CD4, CD56 and TCL1. Staging of the disease was normal. Treatment with chemotherapy was initiated in collaboration with a team of hematologists. Autologous bone marrow transplant was then performed. BPDCN is a rare malignant blood dyscrasia. It is distinguished by inaugural skin involvement, with systemic manifestations occurring much later. Histopathological examination of a skin biopsy with immunostaining establishes the diagnosis. In terms of phenotype, the tumor population is highly characteristic. The cells are negative for antigens of T- and B- cell lines. However, these cells express CD4, CD56 and TCL1, which are markers of plasmacytoid dendritic cells. The disease carries a poor prognosis and evolves in the short to middle term in the same way as acute leukemia. First-line treatment consists of the chemotherapy regimens used in aggressive lymphoma or acute leukemia. A bone marrow graft is sometimes performed at the time of initial relapse. Average survival is 12 months for chemotherapy alone and 30 months for transplant after first

Pancreatic mixed serous neuroendocrine neoplasm with clear cells leading to diagnosis of von Hippel Lindau disease.

PubMed

Kakkar, Aanchal; Sharma, Mehar C; Yadav, Rajni; Panwar, Rajesh; Mathur, Sandeep R; Iyer, Venkateswaran K; Sahni, Peush

2016-08-01

Mixed serous neuroendocrine neoplasms are extremely rare tumors that are usually seen in female patients and are often associated with von Hippel Lindau (VHL) disease. We describe the case of a 38-year-old male who presented with complaints of anorexia, weight loss, and abdominal pain. CT abdomen showed a mass in the head of the pancreas, multiple small nodules in the body of pancreas, and bilateral adrenal masses. Fine needle aspiration cytology (FNAC) from the mass showed features of a neuroendocrine tumor, with many of the cells demonstrating abundant clear cytoplasm. Histopathological examination of the pancreaticoduodenectomy specimen showed a mixed serous neuroendocrine neoplasm with two components viz. serous cystadenoma and neuroendocrine tumor (NET) World Health Organization (WHO) grade 2. In addition, he was diagnosed to have bilateral pheochromocytomas and a paraganglioma. The synchronicity of these tumors suggested the possibility of VHL disease. Thus, identification of a NET with clear cells or of a mixed serous neuroendocrine neoplasm should raise suspicion of VHL disease. In a mixed tumor, FNAC may identify only one of the two components. Thorough processing of all pancreatic serous tumors for pathological examination is recommended, as NET may occur as a small nodule within the serous cystadenoma. Copyright © 2016 Elsevier GmbH. All rights reserved.

Occupation of low-affinity cholecystokinin (CCK) receptors by CCK activates signal transduction and stimulates amylase secretion in pancreatic acinar cells.

PubMed

Vinayek, R; Patto, R J; Menozzi, D; Gregory, J; Mrozinski, J E; Jensen, R T; Gardner, J D

1993-03-10

Based on the effects of monensin on binding of 125I-CCK-8 and its lack of effect on CCK-8-stimulated amylase secretion we previously proposed that pancreatic acinar cells possess three classes of CCK receptors: high-affinity receptors, low-affinity receptors and very low-affinity receptors [1]. In the present study we treated pancreatic acini with carbachol to induce a complete loss of high-affinity CCK receptors and then examined the action of CCK-8 on inositol trisphosphate IP3(1,4,5), cytosolic calcium and amylase secretion in an effort to confirm and extend our previous hypothesis. We found that first incubating pancreatic acini with 10 mM carbachol decreased binding of 125I-CCK-8 measured during a second incubation by causing a complete loss of high-affinity CCK receptors with no change in the low-affinity CCK receptors. Carbachol treatment of acini, however, did not alter the action of CCK-8 on IP3(1,4,5), cytosolic calcium or amylase secretion or the action of CCK-JMV-180 on amylase secretion or on the supramaximal inhibition of amylase secretion caused by CCK-8. The present findings support our previous hypothesis that pancreatic acinar cells possess three classes of CCK receptors and suggest that high-affinity CCK receptors do not mediate the action of CCK-8 on enzyme secretion, that low-affinity CCK receptors may mediate the action of CCK on cytosolic calcium that does not involve IP3(1,4,5) and produce the upstroke of the dose-response curve for CCK-8-stimulated amylase secretion and that very low-affinity CCK receptors mediate the actions of CCK on IP3(1,4,5) and cytosolic calcium and produce the downstroke of the dose-response curve for CCK-8-stimulated amylase secretion. Moreover, CCK-JMV-180 is a full agonist for stimulating amylase secretion by acting at low-affinity CCK receptors and is an antagonist at very low-affinity CCK receptors.

Agminated Clear Cell Tumor: An Impostor of PEComa and Distinctive Dermal Clear Cell Mesenchymal Neoplasm.

PubMed

Teixeira, Ana Isabel; Soares-Almeida, Luís; Kutzner, Heinz

2017-03-01

Cutaneous clear cell tumors are a heterogeneous group of cutaneous neoplasms, which may show a wide range of histogenesis. We report the clinicopathological features of an agminated clear cell tumor, arising in a 67-year-old man, otherwise asymptomatic, with distinct histopathological and immunohistochemical features, which did not fit into any existing diagnostic categories. The patient presented with several skin-colored papules at the lateral and posterior aspects of the neck, which on histopathological examination showed circumscribed lobular aggregates of clear cells within the dermis. The immunohistochemical marker panel performed showed diffuse expression of vimentin, NKI-C3, and CD64 while revealing marked negativity for factor XIIIa, CD10, CD13, CD14, CD34, CD68, CD163, lysozyme, HMB45, Renal Cell Carcinoma antigen, calponin, h-caldesmon, Anti-alpha smooth muscle actin antibody [1 A4], S100, and pancytokeratin, leading the authors to postulate a monocytic origin.

Phase II study of alemtuzumab in combination with pentostatin in patients with T-cell neoplasms.

PubMed

Ravandi, Farhad; Aribi, Ahmed; O'Brien, Susan; Faderl, Stefan; Jones, Dan; Ferrajoli, Alessandra; Huang, Xuelin; York, Sergernne; Pierce, Sherry; Wierda, William; Kontoyiannis, Dimitrios; Verstovsek, Srdan; Pro, Barbara; Fayad, Luis; Keating, Michael; Kantarjian, Hagop

2009-11-10

To examine the efficacy and safety of the combination of alemtuzumab and pentostatin in patients with T-cell neoplasms. We treated 24 patients with a variety of T-cell leukemias and lymphomas with a combination of alemtuzumab 30 mg intravenously (IV) three times weekly for up to 3 months and pentostatin 4 mg/m(2) IV weekly for 4 weeks followed by alternate weekly administration for up to 6 months. Prophylactic antibiotics including antiviral, antifungal, and antibacterial agents were administered during the treatment and for 2 months after its completion. The median age of patients was 57 years (range, 21 to 79 years). Eight patients were previously untreated, and 16 had a median of two prior therapies (range, one to six regimens). Thirteen patients responded to treatment (11 complete responses [CRs] and two partial responses), for an overall response rate of 54%. The median response duration was 19.5 months. Monoclonal T-cell receptor chain gene rearrangements were detected by polymerase chain reaction in bone marrow of 20 of 22 evaluable patients and became negative in five of seven evaluable patients in CR. Opportunistic infections caused by pathogens associated with severe T-cell dysfunction were common. The combination of alemtuzumab and pentostatin is feasible and effective in T-cell neoplasms. Although infections, including cytomegalovirus reactivation, are a concern, they may be minimized with adequate prophylactic antibiotic therapy.

Autoimmunity and the risk of myeloproliferative neoplasms

PubMed Central

Kristinsson, Sigurdur Y.; Landgren, Ola; Samuelsson, Jan; Björkholm, Magnus; Goldin, Lynn R.

2010-01-01

The causes of myeloproliferative neoplasm (MPN) are unknown. We conducted a large population-based study including 11,039 myeloproliferative neoplasm patients and 43,550 matched controls with the aim of assessing the associations between a personal history of a broad span of autoimmune diseases and subsequent risk of myeloproliferative neoplasm. We found a prior history of any autoimmune disease to be associated with a significantly increased risk of myeloproliferative neoplasms (odds ratio (OR)=1.2; 95% confidence interval (CI) 1.0–1.3; P=0.021). Specifically, we found an increased risk of MPNs associated with a prior immune thrombocytopenic purpura (2.9; 1.7–7.2), Crohn’s disease (1.8; 1.1–3.0), polymyalgia rheumatica (1.7; 1.2–2.5), giant cell arteritis (5.9; 2.4–14.4), Reiter’s syndrome (15.9; 1.8–142) and aplastic anemia (7.8; 3.7–16.7). The risk of myeloproliferative neoplasms associated with prior autoimmune diseases is modest but statistically significant. Future studies are needed to unravel the effects of these autoimmune diseases themselves, their treatment, or common genetic susceptibility. PMID:20053870

Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable

MedlinePlus

... Myeloproliferative Neoplasms Treatment Myelodysplastic/ Myeloproliferative Neoplasms Treatment Myelodysplastic/ Myeloproliferative Neoplasms Treatment (PDQ®)–Patient Version General Information About Myelodysplastic/ ...

Myelodysplastic/ Myeloproliferative Neoplasms Treatment

MedlinePlus

... Myeloproliferative Neoplasms Treatment Myelodysplastic/ Myeloproliferative Neoplasms Treatment Myelodysplastic/ Myeloproliferative Neoplasms Treatment (PDQ®)–Patient Version General Information About Myelodysplastic/ ...

Secretagogues differentially activate endoplasmic reticulum stress responses in pancreatic acinar cells.

PubMed

Kubisch, Constanze H; Logsdon, Craig D

2007-06-01

Endoplasmic reticulum (ER) stress leads to the accumulation of misfolded proteins in the ER lumen and initiates the unfolded protein response (UPR). Components of the UPR are important in pancreatic development, and recent studies have indicated that the UPR is activated in the arginine model of acute pancreatitis. However, the effects of secretagogues on UPR components in the pancreas are unknown. The present study aimed to examine the effects of different types and concentrations of secretagogues on acinar cell function and specific components of the UPR. Rat pancreatic acini were stimulated with the CCK analogs CCK8 (10 pM-10 nM) or JMV-180 (10 nM-10 microM) or with bombesin (1-100 nM). Components of the UPR, including chaperone BiP expression, PKR-like ER kinase (PERK) phosphorylation, X box-binding protein 1 (XBP1) splicing, and CCAAT/enhancer binding protein homologous protein (CHOP) expression, were measured, as were effects on amylase secretion and intracellular trypsin activation. CCK8 generated a biphasic secretion dose-response curve, and high concentrations increased intracellular active trypsin levels. In contrast, JMV-180 and bombesin secretion dose-response curves were monophasic, and high concentrations did not increase intracellular trypsin activity. All three secretagogues increased BiP levels and XBP1 splicing. However, only supraphysiological levels of CCK8 associated with inhibited amylase secretion and trypsin activation stimulated PERK phosphorylation and expression of CHOP. The effects of CCK8 on UPR components were rapid, occurring within 5-20 min. In conclusion, ER stress response mechanisms appear to be involved in both pancreatic physiology and pathophysiology, and future efforts should be directed at understanding the roles of these mechanisms in the pancreas.

Dysmegakaryocytopoiesis and maintaining platelet count in patients with plasma cell neoplasm.

PubMed

Mair, Yasmin; Zheng, Yan; Cai, Donghong

2013-05-01

Dysmegakaryocytopoiesis in patients with the plasma cell neoplasm (PCN) is rarely discussed in the literature. The puzzling phenomenon, which PCN patients maintaining normal platelet count even when the marrow is mostly replaced by plasma cells, is hardly explored. This study was aimed to determine the frequency of dysmegakaryocytopoiesis in PCN and the relationships between bone marrow (BM) plasma cell percentage, plasma cell immunomarkers, the severity of dysmegakaryocytopoiesis, and peripheral blood platelet count in PCN. We randomly selected 16 cases of PCN, among which 4 were with monoclonal gammopathy of undetermined significance and 12 were with plasma cell myeloma. OUR STUDY SHOWED THAT: (1) Dysmegakaryocytopoiesis was present in all the selected cases of PCN and its severity was not correlated with the percentage of the plasma cells in BM; (2) almost all patients maintained normal platelet count even when BM was mostly replaced by plasma cells; (3) immunomarkers of the neoplastic plasma cells were not associated with dysmegakaryocytopoiesis or maintaining of platelet count. The possible mechanisms behind dysmegakaryocytopoiesis and maintaining of platelet count were also discussed. Despite the universal presence of dysmegakaryocytopoiesis in PCN, the platelet count is maintained at normal range.

Three dimensional cultures: a tool to study normal acinar architecture vs. malignant transformation of breast cells.

PubMed

Pal, Anupama; Kleer, Celina G

2014-04-25

Invasive breast carcinomas are a group of malignant epithelial tumors characterized by the invasion of adjacent tissues and propensity to metastasize. The interplay of signals between cancer cells and their microenvironment exerts a powerful influence on breast cancer growth and biological behavior(1). However, most of these signals from the extracellular matrix are lost or their relevance is understudied when cells are grown in two dimensional culture (2D) as a monolayer. In recent years, three dimensional (3D) culture on a reconstituted basement membrane has emerged as a method of choice to recapitulate the tissue architecture of benign and malignant breast cells. Cells grown in 3D retain the important cues from the extracellular matrix and provide a physiologically relevant ex vivo system(2,3). Of note, there is growing evidence suggesting that cells behave differently when grown in 3D as compared to 2D(4). 3D culture can be effectively used as a means to differentiate the malignant phenotype from the benign breast phenotype and for underpinning the cellular and molecular signaling involved(3). One of the distinguishing characteristics of benign epithelial cells is that they are polarized so that the apical cytoplasm is towards the lumen and the basal cytoplasm rests on the basement membrane. This apico-basal polarity is lost in invasive breast carcinomas, which are characterized by cellular disorganization and formation of anastomosing and branching tubules that haphazardly infiltrates the surrounding stroma. These histopathological differences between benign gland and invasive carcinoma can be reproduced in 3D(6,7). Using the appropriate read-outs like the quantitation of single round acinar structures, or differential expression of validated molecular markers for cell proliferation, polarity and apoptosis in combination with other molecular and cell biology techniques, 3D culture can provide an important tool to better understand the cellular changes during

Acinar cell carcinoma of the pancreas presenting as diffuse pancreatic enlargement: Two case reports and literature review.

PubMed

Luo, Yaping; Hu, Guilan; Ma, Yanru; Guo, Ning; Li, Fang

2017-09-01

Pancreatic acinar cell carcinoma (ACC) is a rare malignant tumor of exocrine pancreas. It is typically a well-marginated large solid mass arising in a certain aspect of the pancreas. Diffuse involvement of ACC in the pancreas is very rare, and may simulate pancreatitis in radiological findings. We report 2 cases of ACC presenting as diffuse enlargement of the pancreas due to tumor involvement without formation of a distinct mass. The patients consisted of a 41-year-old man with weight loss and a 77-year-old man who was asymptomatic. Computed tomography (CT) and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT showed diffuse enlargement of the pancreas forming a sausage-like shape with homogenously increased FDG activity. Endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) biopsy of the pancreatic lesion was performed. Histopathology results from the pancreas confirmed the diagnosis of pancreatic ACC. Because diffuse enlargement of the pancreas is a common imaging feature of pancreatitis, recognition of this rare morphologic pattern of ACC is important for radiological diagnosis of this tumor.

Blastic plasmacytoid dendritic cell neoplasms: clinico-immunohistochemical correlations in a series of 91 patients.

PubMed

Julia, Fanny; Dalle, Stephane; Duru, Gerard; Balme, Brigitte; Vergier, Béatrice; Ortonne, Nicolas; Vignon-Pennamen, Marie D; Costes-Martineau, Valérie; Lamant, Laurence; Dalac, Sophie; Delattre, Claire; Déchelotte, Pierre; Courville, Philippe; Carlotti, Agnès; De Muret, Anne; Fraitag, Sylvie; Levy, Annie; Mitchell, Andrew; Petrella, Tony

2014-05-01

Blastic plasmacytoid dendritic cell neoplasm is a rare clinicopathologic entity, characterized by strong skin tropism and a poor prognosis. The diagnosis is generally made by skin biopsy with appropriate immunohistochemical studies. To identify potential biological prognostic factors for blastic plasmacytoid dendritic cell neoplasm, we performed an extended clinico-immunohistochemical study on a series of 91 well-documented cases collected since 1995 by the French Study Group on Cutaneous Lymphomas. Skin biopsies were analyzed using a panel of 12 immunohistochemical markers (CD4, CD56, CD123, CD303, TCL1, CD68, CD2, CD7, TdT, Ki-67, S100, and MX-1). The results were correlated with survival. The 5 most characteristic markers of this entity (CD4, CD56, CD123, CD303, and TCL1) were expressed simultaneously in only 46% of patients. However, when 4 markers were expressed the diagnosis could still be reliably made without resorting to any additional stains. Expression of TdT and/or S100 correlated with varying degrees of maturation. Statistical survival analyses showed that CD303 expression and high proliferative index (Ki-67) were significantly associated with longer survival.

Action of cholecystokinin and cholinergic agents on calcium transport in isolated pancreatic acinar cells.

PubMed Central

Gardner, J D; Conlon, T P; Kleveman, H L; Adams, T D; Ondetti, M A

1975-01-01

COOH-terminal octapeptide of cholecystokinin (CCK-octapeptide) and the cholinergic agent carbamylcholine each produced a fourfold stimulation of calcium outflux in guinea pig isolated pancreatic acinar cells. Neither agent altered calcium influx. Stimulation of calcium outflux was rapid and specific, was abolished by reducing the incubation temperature to 4 degrees C, and was a saturable function of the secretagogue concentration. The concentrations of CCK-octapeptide and carbamylcholine that produced half-maximal stimulation of calcium outflux were 3.1 x 10(-10) M and 4.9 x 10(-5) M, respectively. The cholinergic antagonist antropine competitively inhibited carbamylcholine stimulation of calcium outflux but did not alter stimulation produced by CCK-octapeptide. Stimulation of calcium outflux by maximal concentrations of carbamycholine plus CCK-octapeptide was the same as that produced by a maximal concentration of either agent alone.Calcium outflux became refractory to stimulation by secretagogues, and incubation with either CCK-ostapeptide or carbamylcholine produced a refractoriness to both agents. The relative potencies with CCK and its related fragments stimulated calcium outflux were CCK-octapeptide greater than heptapeptide greater than CCK greater than hexapeptide = gastrin. Secretin, glucagon, and vasoactive intestinal peptide, at concentrations as high as 10(-5) M, failed to alter calcium outflux and did not affect stimulation by CCK-octapeptide or by carbamycholine. Images PMID:1150877

Steady streaming: A key mixing mechanism in low-Reynolds-number acinar flows

PubMed Central

Kumar, Haribalan; Tawhai, Merryn H.; Hoffman, Eric A.; Lin, Ching-Long

2011-01-01

Study of mixing is important in understanding transport of submicron sized particles in the acinar region of the lung. In this article, we investigate transport in view of advective mixing utilizing Lagrangian particle tracking techniques: tracer advection, stretch rate and dispersion analysis. The phenomenon of steady streaming in an oscillatory flow is found to hold the key to the origin of kinematic mixing in the alveolus, the alveolar mouth and the alveolated duct. This mechanism provides the common route to folding of material lines and surfaces in any region of the acinar flow, and has no bearing on whether the geometry is expanding or if flow separates within the cavity or not. All analyses consistently indicate a significant decrease in mixing with decreasing Reynolds number (Re). For a given Re, dispersion is found to increase with degree of alveolation, indicating that geometry effects are important. These effects of Re and geometry can also be explained by the streaming mechanism. Based on flow conditions and resultant convective mixing measures, we conclude that significant convective mixing in the duct and within an alveolus could originate only in the first few generations of the acinar tree as a result of nonzero inertia, flow asymmetry, and large Keulegan–Carpenter (KC) number. PMID:21580803

Tryptophan autofluorescence imaging of neoplasms of the human colon

NASA Astrophysics Data System (ADS)

Banerjee, Bhaskar; Renkoski, Timothy; Graves, Logan R.; Rial, Nathaniel S.; Tsikitis, Vassiliki Liana; Nfonsom, Valentine; Pugh, Judith; Tiwari, Piyush; Gavini, Hemanth; Utzinger, Urs

2012-01-01

Detection of flat neoplasia is a major challenge in colorectal cancer screening, as missed lesions can lead to the development of an unexpected `incident' cancer prior to the subsequent endoscopy. The use of a tryptophan-related autofluorescence has been reported to be increased in murine intestinal dysplasia. The emission spectra of cells isolated from human adenocarcinoma and normal mucosa of the colon were studied and showed markedly greater emission intensity from cancerous cells compared to cells obtained from the surrounding normal mucosa. A proto-type multispectral imaging system optimized for ultraviolet macroscopic imaging of tissue was used to obtain autofluorescence images of surgical specimens of colonic neoplasms and normal mucosa after resection. Fluorescence images did not display the expected greater emission from the tumor as compared to the normal mucosa, most probably due to increased optical absorption and scattering in the tumors. Increased fluorescence intensity in neoplasms was observed however, once fluorescence images were corrected using reflectance images. Tryptophan fluorescence alone may be useful in differentiating normal and cancerous cells, while in tissues its autofluorescence image divided by green reflectance may be useful in displaying neoplasms.

β-Cell regeneration through the transdifferentiation of pancreatic cells: Pancreatic progenitor cells in the pancreas.

PubMed

Kim, Hyo-Sup; Lee, Moon-Kyu

2016-05-01

Pancreatic progenitor cell research has been in the spotlight, as these cells have the potential to replace pancreatic β-cells for the treatment of type 1 and 2 diabetic patients with the absence or reduction of pancreatic β-cells. During the past few decades, the successful treatment of diabetes through transplantation of the whole pancreas or isolated islets has nearly been achieved. However, novel sources of pancreatic islets or insulin-producing cells are required to provide sufficient amounts of donor tissues. To overcome this limitation, the use of pancreatic progenitor cells is gaining more attention. In particular, pancreatic exocrine cells, such as duct epithelial cells and acinar cells, are attractive candidates for β-cell regeneration because of their differentiation potential and pancreatic lineage characteristics. It has been assumed that β-cell neogenesis from pancreatic progenitor cells could occur in pancreatic ducts in the postnatal stage. Several studies have shown that insulin-producing cells can arise in the duct tissue of the adult pancreas. Acinar cells also might have the potential to differentiate into insulin-producing cells. The present review summarizes recent progress in research on the transdifferentiation of pancreatic exocrine cells into insulin-producing cells, especially duct and acinar cells.

Amino acid sequence and the cellular location of the Na(+)-dependent D-glucose symporters (SGLT1) in the ovine enterocyte and the parotid acinar cell.

PubMed Central

Tarpey, P S; Wood, I S; Shirazi-Beechey, S P; Beechey, R B

1995-01-01

The Na(+)-dependent D-glucose symporter has been shown to be located on the basolateral domain of the plasma membrane of ovine parotid acinar cells. This is in contrast to the apical location of this transporter in the ovine enterocyte. The amino acid sequences of these two proteins have been determined. They are identical. The results indicated that the signals responsible for the differential targeting of these two proteins to the apical and the basal domains of the plasma membrane are not contained within the primary amino acid sequence. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:7492327

Effect of Mutation Order on Myeloproliferative Neoplasms

PubMed Central

Nangalia, Jyoti; Silber, Yvonne; Wedge, David C.; Grinfeld, Jacob; Baxter, E. Joanna; Massie, Charles E.; Papaemmanuil, Elli; Menon, Suraj; Godfrey, Anna L.; Dimitropoulou, Danai; Guglielmelli, Paola; Bellosillo, Beatriz; Besses, Carles; Döhner, Konstanze; Harrison, Claire N.; Vassiliou, George S.; Vannucchi, Alessandro; Campbell, Peter J.; Green, Anthony R.

2015-01-01

BACKGROUND Cancers result from the accumulation of somatic mutations, and their properties are thought to reflect the sum of these mutations. However, little is known about the effect of the order in which mutations are acquired. METHODS We determined mutation order in patients with myeloproliferative neoplasms by genotyping hematopoietic colonies or by means of next-generation sequencing. Stem cells and progenitor cells were isolated to study the effect of mutation order on mature and immature hematopoietic cells. RESULTS The age at which a patient presented with a myeloproliferative neoplasm, acquisition of JAK2 V617F homozygosity, and the balance of immature progenitors were all influenced by mutation order. As compared with patients in whom the TET2 mutation was acquired first (hereafter referred to as “TET2-first patients”), patients in whom the Janus kinase 2 (JAK2) mutation was acquired first (“JAK2-first patients”) had a greater likelihood of presenting with polycythemia vera than with essential thrombocythemia, an increased risk of thrombosis, and an increased sensitivity of JAK2-mutant progenitors to ruxolitinib in vitro. Mutation order influenced the proliferative response to JAK2 V617F and the capacity of double-mutant hematopoietic cells and progenitor cells to generate colony-forming cells. Moreover, the hematopoietic stem-and-progenitor-cell compartment was dominated by TET2 single-mutant cells in TET2-first patients but by JAK2–TET2 double-mutant cells in JAK2-first patients. Prior mutation of TET2 altered the transcriptional consequences of JAK2 V617F in a cell-intrinsic manner and prevented JAK2 V617F from up-regulating genes associated with proliferation. CONCLUSIONS The order in which JAK2 and TET2 mutations were acquired influenced clinical features, the response to targeted therapy, the biology of stem and progenitor cells, and clonal evolution in patients with myeloproliferative neoplasms. (Funded by Leukemia and Lymphoma Research

Malignant TFE3-rearranged perivascular epithelioid cell neoplasm (PEComa) presenting as a subcutaneous mass.

PubMed

Shon, W; Kim, J; Sukov, W; Reith, J

2016-03-01

Perivascular epithelioid cell neoplasms (PEComas) are a group of mesenchymal tumours with concurrent melanocytic and myogenic differentiation. Although many cases are sporadic, PEComas can be associated with tuberous sclerosis. A distinct subset of deep-seated PEComas has been shown to carry TFE3 fusions. To our knowledge, this is the first reported case of primary subcutaneous malignant PEComa with molecular confirmation of TFE3 gene rearrangement. © 2015 British Association of Dermatologists.

Somatic CALR Mutations in Myeloproliferative Neoplasms with Nonmutated JAK2

PubMed Central

Baxter, E.J.; Nice, F.L.; Gundem, G.; Wedge, D.C.; Avezov, E.; Li, J.; Kollmann, K.; Kent, D.G.; Aziz, A.; Godfrey, A.L.; Hinton, J.; Martincorena, I.; Van Loo, P.; Jones, A.V.; Guglielmelli, P.; Tarpey, P.; Harding, H.P.; Fitzpatrick, J.D.; Goudie, C.T.; Ortmann, C.A.; Loughran, S.J.; Raine, K.; Jones, D.R.; Butler, A.P.; Teague, J.W.; O’Meara, S.; McLaren, S.; Bianchi, M.; Silber, Y.; Dimitropoulou, D.; Bloxham, D.; Mudie, L.; Maddison, M.; Robinson, B.; Keohane, C.; Maclean, C.; Hill, K.; Orchard, K.; Tauro, S.; Du, M.-Q.; Greaves, M.; Bowen, D.; Huntly, B.J.P.; Harrison, C.N.; Cross, N.C.P.; Ron, D.; Vannucchi, A.M.; Papaemmanuil, E.; Campbell, P.J.; Green, A.R.

2014-01-01

BACKGROUND Somatic mutations in the Janus kinase 2 gene (JAK2) occur in many myeloproliferative neoplasms, but the molecular pathogenesis of myeloproliferative neoplasms with nonmutated JAK2 is obscure, and the diagnosis of these neoplasms remains a challenge. METHODS We performed exome sequencing of samples obtained from 151 patients with myeloproliferative neoplasms. The mutation status of the gene encoding calreticulin (CALR) was assessed in an additional 1345 hematologic cancers, 1517 other cancers, and 550 controls. We established phylogenetic trees using hematopoietic colonies. We assessed calreticulin subcellular localization using immunofluorescence and flow cytometry. RESULTS Exome sequencing identified 1498 mutations in 151 patients, with medians of 6.5, 6.5, and 13.0 mutations per patient in samples of polycythemia vera, essential thrombocythemia, and myelofibrosis, respectively. Somatic CALR mutations were found in 70 to 84% of samples of myeloproliferative neoplasms with nonmutated JAK2, in 8% of myelodysplasia samples, in occasional samples of other myeloid cancers, and in none of the other cancers. A total of 148 CALR mutations were identified with 19 distinct variants. Mutations were located in exon 9 and generated a +1 base-pair frameshift, which would result in a mutant protein with a novel C-terminal. Mutant calreticulin was observed in the endoplasmic reticulum without increased cell-surface or Golgi accumulation. Patients with myeloproliferative neoplasms carrying CALR mutations presented with higher platelet counts and lower hemoglobin levels than patients with mutated JAK2. Mutation of CALR was detected in hematopoietic stem and progenitor cells. Clonal analyses showed CALR mutations in the earliest phylogenetic node, a finding consistent with its role as an initiating mutation in some patients. CONCLUSIONS Somatic mutations in the endoplasmic reticulum chaperone CALR were found in a majority of patients with myeloproliferative neoplasms with

Circulating tumor cells and miRNAs as prognostic markers in neuroendocrine neoplasms.

PubMed

Zatelli, Maria Chiara; Grossrubatscher, Erika Maria; Guadagno, Elia; Sciammarella, Concetta; Faggiano, Antongiulio; Colao, Annamaria

2017-06-01

The prognosis of neuroendocrine neoplasms (NENs) is widely variable and has been shown to associate with several tissue- and blood-based biomarkers in different settings. The identification of prognostic factors predicting NEN outcome is of paramount importance to select the best clinical management for these patients. Prognostic markers have been intensively investigated, also taking advantage of the most modern techniques, in the perspective of personalized medicine and appropriate resource utilization. This review summarizes the available data on the possible role of circulating tumor cells and microRNAs as prognostic markers in NENs. © 2017 Society for Endocrinology.

Tumour necrosis factor α secretion induces protease activation and acinar cell necrosis in acute experimental pancreatitis in mice.

PubMed

Sendler, Matthias; Dummer, Annegret; Weiss, Frank U; Krüger, Burkhard; Wartmann, Thomas; Scharffetter-Kochanek, Karin; van Rooijen, Nico; Malla, Sudarshan Ravi; Aghdassi, Ali; Halangk, Walter; Lerch, Markus M; Mayerle, Julia

2013-03-01

Acute pancreatitis has long been considered a disorder of pancreatic self-digestion, in which intracellular activation of digestive proteases induces tissue injury. Chemokines, released from damaged pancreatic cells then attract inflammatory cells, whose systemic action ultimately determines the disease severity. In the present work the opposite mechanism is investigated; that is, whether and how inflammatory cells can activate intracellular proteases. Using mice either deficient for the CD18-α subunit of the membrane attack complex-1 (MAC-1) complex or tumour necrosis factor (TNF)α, as well as after depletion of leucocyte subpopulations, pancreatitis was induced by 7-hourly caerulein injections (50 μg/kg, intraperitoneally). Pancreatic acini were coincubated in vitro from wild-type and cathepsin-B-deficient animals with phorbol-12-myristate-13-acetate (PMA)-activated neutrophils and macrophages, caerulein or TNFα, and activities of trypsin, cathepsin-B and caspase-3 were measured, as well as necrosis using fluorogenic substrates. TNFα was inhibited with monospecific antibodies. Deletion of CD18 prevented transmigration of leucocytes into the pancreas during pancreatitis, greatly reduced disease severity and abolished digestive protease activation. Depletion of neutrophils and macrophages equally reduced premature trypsinogen activation and disease severity. In vitro activated neutrophils and macrophages directly induced premature protease activation and cell death in pancreatic acini and stimulation of acini with TNFα induced caspase-3 activation and necrosis via a cathepsin-B and calcium-dependent mechanism. Neutralising antibodies against TNFα and genetic deletion of TNFα prevented leucocyte-induced trypsin activity and necrosis in isolated acini. The soluble inflammatory cell mediator TNFα directly induces premature protease activation and necrosis in pancreatic acinar cells. This activation depends on calcium and cathepsin-B activity. The findings

Myelodysplastic/ Myeloproliferative Neoplasms Treatment (PDQ®)—Patient Version

Cancer.gov

Myelodysplastic/myeloproliferative neoplasms treatment options include supportive care, chemotherapy, radiation therapy, surgery, biologic/targeted therapy, and stem cell transplant. Learn more about these diseases in this expert-reviewed summary.

General morphological and biological features of neoplasms: integration of molecular findings.

PubMed

Diaz-Cano, S J

2008-07-01

This review highlights the importance of morphology-molecular correlations for a proper implementation of new markers. It covers both general aspects of tumorigenesis (which are normally omitted in papers analysing molecular pathways) and the general mechanisms for the acquired capabilities of neoplasms. The mechanisms are also supported by appropriate diagrams for each acquired capability that include overlooked features such as mobilization of cellular resources and changes in chromatin, transcription and epigenetics; fully accepted oncogenes and tumour suppressor genes are highlighted, while the pathways are also presented as activating or inactivating with appropriate colour coding. Finally, the concepts and mechanisms presented enable us to understand the basic requirements for the appropriate implementation of molecular tests in clinical practice. In summary, the basic findings are presented to serve as a bridge to clinical applications. The current definition of neoplasm is descriptive and difficult to apply routinely. Biologically, neoplasms develop through acquisition of capabilities that involve tumour cell aspects and modified microenvironment interactions, resulting in unrestricted growth due to a stepwise accumulation of cooperative genetic alterations that affect key molecular pathways. The correlation of these molecular aspects with morphological changes is essential for better understanding of essential concepts as early neoplasms/precancerous lesions, progression/dedifferentiation, and intratumour heterogeneity. The acquired capabilities include self-maintained replication (cell cycle dysregulation), extended cell survival (cell cycle arrest, apoptosis dysregulation, and replicative lifespan), genetic instability (chromosomal and microsatellite), changes of chromatin, transcription and epigenetics, mobilization of cellular resources, and modified microenvironment interactions (tumour cells, stromal cells, extracellular, endothelium). The acquired

Biological and clinical characterization of recurrent 14q deletions in CLL and other mature B-cell neoplasms.

PubMed

Reindl, Lena; Bacher, Ulrike; Dicker, Frank; Alpermann, Tamara; Kern, Wolfgang; Schnittger, Susanne; Haferlach, Torsten; Haferlach, Claudia

2010-10-01

14q-deletions have been repeatedly described in mature B-cell neoplasms, but not yet characterized in a larger cohort. Based on chromosome banding analysis, the present study identified 47 del(14q) cases in 3054 mature B-cell neoplasms (1·5%) (chronic lymphocytic leukaemia [CLL]: 1·9%; CLL/prolymphocytic leukaemia [PL]: 9·0%; others: 0·2%). Interphase fluorescence in situ hybridization was performed with probes for 14q22.1, 14q24.1, 14q32.33, and IGH@ (14q32.3). The del(14q) had heterogeneous size but showed a breakpoint cluster at the centromeric site in 14q24.1 (62% of cases). At the telomeric side, the most frequent breakpoint was within the IGH@ locus (14q32.3) between IGH@ 3'-flanking and IGHV (IgVH) probes (45%). In 16 cases (34%), breakpoints occurred within 14q24.1 and 14q32.3. Eighty-one percent of del(14q) cases showed 1-3 additional cytogenetic alterations (in 45%, +12), and 56% were IGHV-unmutated. In all cases (16/16) with breakpoints in 14q24.1 and 14q32.3, a B-CLL immunophenotype was found. Clinical follow-up in 32 del(14q) patients was compared to 383 CLL and CLL/PL patients without del(14q). While 3-year-overall survival did not differ significantly, time to treatment was significantly shorter in the del(14q) cohort (21·0 months vs. 80·1 months, P = 0·015). In conclusion, the del(14q) is a rare recurrent alteration in diverse mature B-cell neoplasms, shows variable size but distinct clustering of breakpoints, and is associated with short time to treatment. © 2010 Blackwell Publishing Ltd.

Long-term survival following autologous and allogeneic stem cell transplantation for blastic plasmacytoid dendritic cell neoplasm.

PubMed

Aoki, Tomohiro; Suzuki, Ritsuro; Kuwatsuka, Yachiyo; Kako, Shinichi; Fujimoto, Katsuya; Taguchi, Jun; Kondo, Tadakazu; Ohata, Kinya; Ito, Toshiro; Kamoda, Yoshimasa; Fukuda, Takahiro; Ichinohe, Tatsuo; Takeuchi, Kengo; Izutsu, Koji; Suzumiya, Junji

2015-06-04

We sought to clarify the role of high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) and allogeneic hematopoietic stem cell transplantation (allo-HSCT) to treat blastic plasmacytoid dendritic cell neoplasm (BPDCN). We retrospectively identified 25 BPDCN patients (allo-HSCT, n = 14; auto-HSCT, n = 11) from registry data of the Japan Society for Hematopoietic Cell Transplantation and analyzed clinicopathologic data and clinical outcomes after transplantation. The median age at HSCT was 58 years (range, 17-67 years). All 11 patients who underwent auto-HSCT were in the first complete remission (CR1). With a median follow-up of 53.5 months, the overall survival rates at 4 years for patients who underwent auto-HSCT and allo-HSCT were 82% and 53% (P = .11), respectively, and progression-free survival rates were 73% and 48% (P = .14), respectively. Auto-HSCT for BPDCN in CR1 appears to provide promising results and deserves further evaluation in the setting of prospective trials. © 2015 by The American Society of Hematology.

Coupling of guanine nucleotide inhibitory protein to somatostatin receptors on pancreatic acinar membranes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sakamoto, C.; Matozaki, T.; Nagao, M.

1987-09-01

Guanine nucleotides and pertussis toxin were used to investigate whether somatostatin receptors interact with the guanine nucleotide inhibitory protein (NI) on pancreatic acinar membranes in the rat. Guanine nucleotides reduced /sup 125/I-(Tyr/sup 1/)somatostatin binding to acinar membranes up to 80%, with rank order of potency being 5'-guanylyl imidodiphosphate (Gpp(NH)p)>GTP>TDP>GMP. Scatchard analysis revealed that the decrease in somatostatin binding caused by Gpp(NH)p was due to the decrease in the maximum binding capacity without a significant change in the binding affinity. The inhibitory effect of Gpp(NH)p was partially abolished in the absence of Mg/sup 2 +/. When pancreatic acini were treated withmore » 1 ..mu..g/ml pertussis toxin for 4 h, subsequent /sup 125/I-(Tyr/sup 1/)somatostatin binding to acinar membranes was reduced. Pertussis toxin treatment also abolished the inhibitory effect of somatostatin on vasoactive intestinal peptide-stimulated increase in cellular content of adenosine 3',5'-cyclic monophosphate (cAMP) in the acini. The present results suggest that 1) somatostatin probably functions in the pancreas to regulate adenylate cyclase enzyme system via Ni, 2) the extent of modification of Ni is correlated with the ability of somatostatin to inhibit cAMP accumulation in acini, and 3) guanine nucleotides also inhibit somatostatin binding to its receptor.« less

CD22 expression on blastic plasmacytoid dendritic cell neoplasms and reactivity of anti-CD22 antibodies to peripheral blood dendritic cells.

PubMed

Reineks, Edmunds Z; Osei, Ebenezer S; Rosenberg, Arlene; Auletta, Jeffrey; Meyerson, Howard J

2009-07-01

We identified CD22 expression on a blastic plasmacytoid dendritic cell (pDC) neoplasm presenting as a leukemia in a child. CD22 expression, as determined by the antibody s-HCL-1, was also noted on the neoplastic cells from three additional patients with blastic pDC tumors identified at our institution. Subsequently we determined that peripheral blood pDCs react with the s-HCL-1 antibody demonstrating that normal pDCs express CD22. Evaluation of five additional anti-CD22 antibodies indicated that staining of pDCs with these reagents was poor except for s-HCL-1. Therefore, the detection of CD22 on pDCs is best demonstrated with the use of this specific antibody clone. All anti-CD22 antibodies stained conventional DCs. We also evaluated the reactivity of the anti-CD22 antibodies with basophils and noted that the pattern of staining was similar to that seen with pDCs. The studies demonstrate that normal DCs and pDC neoplasms express CD22, and highlight clone specific differences in anti-CD22 antibody reactivity patterns on pDCs and basophils. (c) 2009 Clinical Cytometry Society.

High mobility group box 1 induces the activation of the Janus kinase 2 and signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway in pancreatic acinar cells in rats, while AG490 and rapamycin inhibit their activation.

PubMed

Wang, Guoliang; Zhang, Jingchao; Dui, Danhua; Ren, Haoyuan; Liu, Jin

2016-11-10

The pathogenesis of severe acute pancreatitis (SAP) remains unclear. The Janus kinase and signal transducer and activator of transcription (JAK/STAT) pathway is important for various cytokines and growth factors. This study investigated the effect of the late inflammatory factor high mobility group box 1 (HMGB1) on the activation of JAK2/STAT3 in pancreatic acinar cells and the inhibitory effects of AG490 (a JAK2 inhibitor) and rapamycin (a STAT3 inhibitor) on this pathway. Rat pancreatic acinar cells were randomly divided into the control, HMGB1, AG490, and rapamycin groups. The mRNA levels of JAK2 and STAT3 at 10, 30, 60, and 120 minutes were detected using reverse transcription polymerase chain reaction (RT-PCR). The protein levels of JAK2 and STAT3 at 60 and 120 minutes were observed using Western blotting. Compared with the control group, the HMGB1 group exhibited significantly increased levels of JAK2 mRNA at each time point; STAT3 mRNA at 30, 60, and 120 minutes; and JAK2 and STAT3 proteins at 60 and 120 minutes (p < 0.01). Compared with the HMGB1 group, the AG490 and rapamycin groups both exhibited significantly decreased levels of JAK2 mRNA at each time point (p < 0.05); STAT3 mRNA at 30, 60, and 120 minutes (p < 0.01); and JAK2 and STAT3 proteins at 60 and 120 minutes (p < 0.01). HMGB1 induces the activation of the JAK2/STAT3 signaling pathway in rat pancreatic acinar cells, and this activation can be inhibited by AG490 and rapamycin. The results of this study may provide new insights for the treatment of SAP.

Role of Alpha-Smooth Muscle Actin and Fibroblast Activation Protein Alpha in Ovarian Neoplasms.

PubMed

da Silva, Ana Carolinne; Jammal, Millena Prata; Etchebehere, Renata Margarida; Murta, Eddie Fernando Candido; Nomelini, Rosekeila Simões

2018-04-05

Studies show that tumor growth is not just determined by the presence of malignant cells, since interactions between cancer cells and stromal microenvironment have important impacts on the cancer growth and progression. Cancer-associated fibroblasts play a prominent role in this process. The aims of the study were to investigate 2 cancer-associated fibroblasts markers, alpha-smooth muscle actin (α-SMA), and fibroblast activation protein alpha (FAP) in the stromal microenvironment of benign and malignant ovarian epithelial neoplasms, and to relate their tissue expression with prognostic factors in ovarian cancer. α-SMA and FAP were evaluated by immunohistochemistry in malignant (n = 28) and benign (n = 28) ovarian neoplasms. Fisher's exact test was used with a significance level lower than 0.05. FAP immunostaining was stronger in ovarian cancer when compared to benign neoplasms (p = 0.0366). There was no significant difference in relation to α-SMA expression between malignant and benign ovarian neoplasms as well as prognostic factors. In ovarian cancer, FAP stainings 2/3 was significantly related to histological grades 2 and 3 (p = 0.0183). FAP immunostaining is more intense in malignant neoplasms than in benign ovarian neoplasms, as well as in moderately differentiated and undifferentiated ovarian carcinomas compared to well-differentiated neoplasms, thus indicating that it can be used as a marker of worse prognosis. © 2018 S. Karger AG, Basel.

Treatment Options for Myelodysplastic/Myeloproliferative Neoplasms

MedlinePlus

... Myeloproliferative Neoplasms Treatment Myelodysplastic/ Myeloproliferative Neoplasms Treatment Myelodysplastic/ Myeloproliferative Neoplasms Treatment (PDQ®)–Patient Version General Information About Myelodysplastic/ ...

Treatment Option Overview (Myelodysplastic/Myeloproliferative Neoplasms)

MedlinePlus

... Myeloproliferative Neoplasms Treatment Myelodysplastic/ Myeloproliferative Neoplasms Treatment Myelodysplastic/ Myeloproliferative Neoplasms Treatment (PDQ®)–Patient Version General Information About Myelodysplastic/ ...

Genetically Modified T-cell Immunotherapy in Treating Patients With Relapsed/Refractory Acute Myeloid Leukemia and Persistent/Recurrent Blastic Plasmacytoid Dendritic Cell Neoplasm

ClinicalTrials.gov

2018-03-02

Adult Acute Myeloid Leukemia in Remission; Acute Biphenotypic Leukemia; Early Relapse of Acute Myeloid Leukemia; Late Relapse of Acute Myeloid Leukemia; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Blastic Plasmacytoid Dendritic Cell Neoplasm; Acute Myeloid Leukemia; Adult Acute Lymphoblastic Leukemia; Interleukin-3 Receptor Subunit Alpha Positive; Minimal Residual Disease; Refractory Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

HISTOPATHOLOGIC CHARACTERISTICS OF THYROID GLAND NEOPLASMS IN THOMSON'S GAZELLES ( EUDORCUS THOMSONII).

PubMed

French, Stephanie J; Garner, Michael M; Kiupel, Matti

2018-03-01

Published reports of neoplasms in Thomson's gazelles ( Eudorcas thomsonii) are very rare, but thyroid tumors were the most common neoplasm of this species, accounting for 12% of reported pathologies in a 1998-2012 retrospective study of cases submitted for histologic review of grossly enlarged thyroid glands. This report describes the histological and immunohistochemical characteristics of thyroid neoplasms in 10 Thomson's gazelles from five different zoological collections. Neoplasms were submitted as biopsies from six gazelles or collected during necropsy from four gazelles. The most common clinical findings included a palpable mass on the ventral neck and progressive weight loss. Radiographic mineral density was detected in one of the neoplastic masses. Histologically, the neoplasms were classified as microfollicular thyroid adenoma ( n = 2), solid thyroid adenoma ( n = 2), papillary thyroid adenoma ( n = 1), and solid thyroid carcinoma ( n = 5). Neoplastic cells in all 10 neoplasms were positive for thyroid transcription factor 1 and thyroglobulin, but negative for calcitonin. While five cases had histologic features of malignancy, there was no evidence of metastatic disease either clinically (biopsies) or on necropsy. Numerous concurrent diseases, including cardiomyopathies and nephropathies, were present and led to choice for euthanasia in several cases.

Bile acids induce necrosis in pancreatic stellate cells dependent on calcium entry and sodium-driven bile uptake.

PubMed

Ferdek, Pawel E; Jakubowska, Monika A; Gerasimenko, Julia V; Gerasimenko, Oleg V; Petersen, Ole H

2016-11-01

Acute biliary pancreatitis is a sudden and severe condition initiated by bile reflux into the pancreas. Bile acids are known to induce Ca 2+ signals and necrosis in isolated pancreatic acinar cells but the effects of bile acids on stellate cells are unexplored. Here we show that cholate and taurocholate elicit more dramatic Ca 2+ signals and necrosis in stellate cells compared to the adjacent acinar cells in pancreatic lobules; whereas taurolithocholic acid 3-sulfate primarily affects acinar cells. Ca 2+ signals and necrosis are strongly dependent on extracellular Ca 2+ as well as Na + ; and Na + -dependent transport plays an important role in the overall bile acid uptake in pancreatic stellate cells. Bile acid-mediated pancreatic damage can be further escalated by bradykinin-induced signals in stellate cells and thus killing of stellate cells by bile acids might have important implications in acute biliary pancreatitis. Acute biliary pancreatitis, caused by bile reflux into the pancreas, is a serious condition characterised by premature activation of digestive enzymes within acinar cells, followed by necrosis and inflammation. Bile acids are known to induce pathological Ca 2+ signals and necrosis in acinar cells. However, bile acid-elicited signalling events in stellate cells remain unexplored. This is the first study to demonstrate the pathophysiological effects of bile acids on stellate cells in two experimental models: ex vivo (mouse pancreatic lobules) and in vitro (human cells). Sodium cholate and taurocholate induced cytosolic Ca 2+ elevations in stellate cells, larger than those elicited simultaneously in the neighbouring acinar cells. In contrast, taurolithocholic acid 3-sulfate (TLC-S), known to induce Ca 2+ oscillations in acinar cells, had only minor effects on stellate cells in lobules. The dependence of the Ca 2+ signals on extracellular Na + and the presence of sodium-taurocholate cotransporting polypeptide (NTCP) indicate a Na + -dependent bile acid

Bile acids induce necrosis in pancreatic stellate cells dependent on calcium entry and sodium‐driven bile uptake

PubMed Central

Jakubowska, Monika A.; Gerasimenko, Julia V.; Gerasimenko, Oleg V.; Petersen, Ole H.

2016-01-01

Key points Acute biliary pancreatitis is a sudden and severe condition initiated by bile reflux into the pancreas.Bile acids are known to induce Ca2+ signals and necrosis in isolated pancreatic acinar cells but the effects of bile acids on stellate cells are unexplored.Here we show that cholate and taurocholate elicit more dramatic Ca2+ signals and necrosis in stellate cells compared to the adjacent acinar cells in pancreatic lobules; whereas taurolithocholic acid 3‐sulfate primarily affects acinar cells.Ca2+ signals and necrosis are strongly dependent on extracellular Ca2+ as well as Na+; and Na+‐dependent transport plays an important role in the overall bile acid uptake in pancreatic stellate cells.Bile acid‐mediated pancreatic damage can be further escalated by bradykinin‐induced signals in stellate cells and thus killing of stellate cells by bile acids might have important implications in acute biliary pancreatitis. Abstract Acute biliary pancreatitis, caused by bile reflux into the pancreas, is a serious condition characterised by premature activation of digestive enzymes within acinar cells, followed by necrosis and inflammation. Bile acids are known to induce pathological Ca2+ signals and necrosis in acinar cells. However, bile acid‐elicited signalling events in stellate cells remain unexplored. This is the first study to demonstrate the pathophysiological effects of bile acids on stellate cells in two experimental models: ex vivo (mouse pancreatic lobules) and in vitro (human cells). Sodium cholate and taurocholate induced cytosolic Ca2+ elevations in stellate cells, larger than those elicited simultaneously in the neighbouring acinar cells. In contrast, taurolithocholic acid 3‐sulfate (TLC‐S), known to induce Ca2+ oscillations in acinar cells, had only minor effects on stellate cells in lobules. The dependence of the Ca2+ signals on extracellular Na+ and the presence of sodium–taurocholate cotransporting polypeptide (NTCP) indicate a Na

A comprehensive computational human lung model incorporating inter-acinar dependencies: Application to spontaneous breathing and mechanical ventilation.

PubMed

Roth, Christian J; Ismail, Mahmoud; Yoshihara, Lena; Wall, Wolfgang A

2017-01-01

In this article, we propose a comprehensive computational model of the entire respiratory system, which allows simulating patient-specific lungs under different ventilation scenarios and provides a deeper insight into local straining and stressing of pulmonary acini. We include novel 0D inter-acinar linker elements to respect the interplay between neighboring alveoli, an essential feature especially in heterogeneously distended lungs. The model is applicable to healthy and diseased patient-specific lung geometries. Presented computations in this work are based on a patient-specific lung geometry obtained from computed tomography data and composed of 60,143 conducting airways, 30,072 acini, and 140,135 inter-acinar linkers. The conducting airways start at the trachea and end before the respiratory bronchioles. The acini are connected to the conducting airways via terminal airways and to each other via inter-acinar linkers forming a fully coupled anatomically based respiratory model. Presented numerical examples include simulation of breathing during a spirometry-like test, measurement of a quasi-static pressure-volume curve using a supersyringe maneuver, and volume-controlled mechanical ventilation. The simulations show that our model incorporating inter-acinar dependencies successfully reproduces physiological results in healthy and diseased states. Moreover, within these scenarios, a deeper insight into local pressure, volume, and flow rate distribution in the human lung is investigated and discussed. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Gemcitabine Hydrochloride With or Without Erlotinib Hydrochloride Followed by the Same Chemotherapy Regimen With or Without Radiation Therapy and Capecitabine or Fluorouracil in Treating Patients With Pancreatic Cancer That Has Been Removed by Surgery

ClinicalTrials.gov

2018-06-22

Pancreatic Acinar Cell Carcinoma; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraductal Papillary-Mucinous Neoplasm; Stage I Pancreatic Cancer AJCC v6 and v7; Stage IA Pancreatic Cancer AJCC v6 and v7; Stage IB Pancreatic Cancer AJCC v6 and v7; Stage II Pancreatic Cancer AJCC v6 and v7; Stage IIA Pancreatic Cancer AJCC v6 and v7; Stage IIB Pancreatic Cancer AJCC v6 and v7

Molecular pathology of skin neoplasms of the head and neck.

PubMed

Kraft, Stefan; Granter, Scott R

2014-06-01

Skin neoplasms include the most common malignancies affecting humans. Many show an ultraviolet (UV)-induced pathogenesis and often affect the head and neck region. To review literature on cutaneous neoplasms that show a predilection for the head and neck region and that are associated with molecular alterations. Literature review. Common nonmelanoma skin cancers, such as basal and squamous cell carcinomas, show a UV-induced pathogenesis. Basal cell carcinomas are characterized by molecular alterations of the Hedgehog pathway, affecting patched and smoothened genes. While squamous cell carcinomas show UV-induced mutations in several genes, driver mutations are only beginning to be identified. In addition, certain adnexal neoplasms also predominantly affect the head and neck region and show interesting, recently discovered molecular abnormalities, or are associated with hereditary conditions whose molecular genetic pathogenesis is well understood. Furthermore, recent advances have led to an increased understanding of the molecular pathogenesis of melanoma. Certain melanoma subtypes, such as lentigo maligna melanoma and desmoplastic melanoma, which are more often seen on the chronically sun-damaged skin of the head and neck, show differences in their molecular signature when compared to the other more common subtypes, such as superficial spreading melanoma, which are more prone to occur at sites with acute intermittent sun damage. In summary, molecular alterations in cutaneous neoplasms of the head and neck are often related to UV exposure. Their molecular footprint often reflects the histologic tumor type, and familiarity with these changes will be increasingly necessary for diagnostic and therapeutic considerations.

[Clinicopathological features of uterine neoplasms with perivascular epithelioid cell differentiation].

PubMed

Lu, Hai-zhen; Zhang, Hong-tu; Liu, Xiu-yun; Xue, Xin-hua; Xie, Yong-qiang; Liu, Shang-mei; Su, Qin

2009-03-01

To study the neoplasm with perivascular epithelioid cell differentiation (PEComa) with respect to their morphologic, immunohistochemical and clinical phenotypes. Three PEComas were included in this study, one located at the left uterine horn, and two presented as a mass in the uterine corpus. The tumors were examined by histopathology and immunohistochemistry. The lesions were composed of spindle, blunt epithelioid cells, with foci of, or scattered, cells showing adipose differentiation in two cases. The myomelanocytic differentiation was demonstrated, proving the diagnosis as PEComa. Mild nuclear atypia and focal necrosis was observed in one lesion, and the rest two showed malignant morphologic phenotypes including moderate nuclear atypia and coagulative necrosis. The mitotic and Ki67-labelling indices ranged from 0.5/10 HPF to 14/10 HPF and 0.6% to 7.0%, respectively. All of the three patients remain alive. Malignant nature of the two lesions with worrisome morphology was confirmed by occurrence of metastases after hysterectomy. PEComa is a rare tumor, occurring preferentially in the uterus. It is regarded as a tumor with uncertain malignant potential, but a minority of them shows malignant clinical behaviors. Some pathologic parameters including large tumor size, sheet-like necrosis, marked nuclear atypia, elevated mitotic index (> or = 10/10 HPF), aberrant mitotic figure and vascular invasion may help to establish a diagnosis of malignant PEComa.

Perivascular epithelioid cell neoplasm of the urinary bladder in an adolescent: a case report and review of the literature

PubMed Central

2012-01-01

Abstract Perivascular epithelioid cell neoplasms (PEComas) of the urinary bladder are extremely rare and the published cases were comprised predominantly of middle-aged patients. Herein, the authors present the first urinary bladder PEComa occurring in an adolescent. This 16-year-old Chinese girl present with a 3-year history of abdominal discomfort and a solid mass was documented in the urinary bladder by ultrasonography. Two years later, at the age of 18, the patient underwent transurethral resection of the bladder tumor. Microscopically, the tumor was composed of spindled cells mixed with epithelioid cells. Immunohistochemically, the tumor were strongly positive for HMB45, smooth muscle actin, muscle-specific actin, and H-caldesmon. Fluorescence in situ hybridization analysis revealed no evidence of EWSR1 gene rearrangement. The patient had been in a good status without evidence of recurrence 13 months after surgery. Urinary bladder PEComa is an extremely rare neoplasm and seems occur predominantly in middle-aged patients. However, this peculiar lesion can develop in pediatric population and therefore it should be rigorously distinguished from their mimickers. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1870004378817301 PMID:23276164

Perivascular epithelioid cell neoplasm of the urinary bladder in an adolescent: a case report and review of the literature.

PubMed

Yin, Lijuan; Bu, Hong; Chen, Min; Yu, Jianqun; Zhuang, Hua; Chen, Jie; Zhang, Hongying

2012-12-31

Perivascular epithelioid cell neoplasms (PEComas) of the urinary bladder are extremely rare and the published cases were comprised predominantly of middle-aged patients. Herein, the authors present the first urinary bladder PEComa occurring in an adolescent. This 16-year-old Chinese girl present with a 3-year history of abdominal discomfort and a solid mass was documented in the urinary bladder by ultrasonography. Two years later, at the age of 18, the patient underwent transurethral resection of the bladder tumor. Microscopically, the tumor was composed of spindled cells mixed with epithelioid cells. Immunohistochemically, the tumor were strongly positive for HMB45, smooth muscle actin, muscle-specific actin, and H-caldesmon. Fluorescence in situ hybridization analysis revealed no evidence of EWSR1 gene rearrangement. The patient had been in a good status without evidence of recurrence 13 months after surgery. Urinary bladder PEComa is an extremely rare neoplasm and seems occur predominantly in middle-aged patients. However, this peculiar lesion can develop in pediatric population and therefore it should be rigorously distinguished from their mimickers. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1870004378817301.

Incidence and survival patterns of rare anal canal neoplasms using the surveillance epidemiology and end results registry.

PubMed

Metildi, Cristina; McLemore, Elisabeth C; Tran, Thuy; Chang, David; Cosman, Bard; Ramamoorthy, Sonia L; Saltzstein, Sidney L; Sadler, Georgia Robins

2013-10-01

Small cell, neuroendocrine tumors, and melanoma of the anus are rare. Limited data exist on the incidence and management for these rare tumors. A large, prospective, population-based database was used to determine incidence and survival patterns of rare anal neoplasms. The Surveillance, Epidemiology and End Results registry was queried to identify patients diagnosed with anal canal neoplasms. Incidence and survival patterns were evaluated with respect to age, sex, race, histology, stage, and therapy. We identified 7078 cases of anal canal neoplasms: melanoma (n = 149), neuroendocrine (n = 61), and small cell neuroendocrine (n = 26). Squamous cell carcinoma (SCC) (n = 6842) served as the comparison group. Anal melanoma (AM) demonstrated the lowest survival rate at 2.5 per cent. Neuroendocrine tumors (NETs) demonstrated similar survival as SCC (10-year survival for regional disease of 25 and 22.3%, respectively). Ten-year survival of small cell NETs resembled AM (5.3 vs 2.5%). Age 60 years or older, sex, black race, stage, and surgery were independent predictors of survival. This study presents the largest patient series of rare anal neoplasms. NETs of the anal canal demonstrate similar survival patterns to SCC, whereas small cell NETs more closely resemble AM. Accurate histologic diagnosis is vital to determine treatment and surgical management because survival patterns can differ among rare anal neoplasms.

Chronic Myeloproliferative Neoplasms Treatment (PDQ®)—Health Professional Version

Cancer.gov

Chronic Myeloproliferative Neoplasms (MPN) treatment varies widely depending on the specific diagnosis. Treatment options may include observation, phlebotomy, steroids, chemotherapy, immunotherapy, and stem cell transplant. Get detailed information about MPNs in this summary for clinicians.

Towards a Therapeutic Reduction of Imatinib Refractory Myeloproliferative Neoplasm-Initiating Cells

PubMed Central

Philips, Steven T.; Hildenbrand, Zacariah L.; Oravecz-Wilson, Katherine I.; Foley, S. Blake; Mgbemena, Victoria E.; Ross, Theodora S.

2014-01-01

Myeloproliferative neoplasms (MPNs) such as chronic myelogenous (CML) and chronic myelomonocytic leukemias (CMML) are frequently induced by tyrosine kinase oncogenes. Although these MPNs are sensitive to tyrosine kinase inhibitors such as imatinib, patients often relapse upon withdrawal of therapy. We used a model of MPN, which is induced by co-expression of the oncoproteins HIP1/PDGFβR (H/P) and AML1/ETO (A/E) from their endogenous loci, to examine the mechanisms of disease development and recurrence following imatinib withdrawal. Although the MPN displayed a full hematologic response to imatinib, 100% of the diseased mice relapsed upon drug withdrawal. MPN persistence was not due to imatinib resistance mutations in the H/P oncogene or massive gene expression changes. Within one week of imatinib treatment, more than 98% of gene expression changes induced by the oncogenes in isolated hematopoietic stem and progenitor cells (LSKs) normalized. Supplementation of imatinib with G-CSF or arsenic trioxide reduced MPN-initiating cell frequencies and the combination of imatinib with arsenic trioxide cured a large fraction of mice with MPNs. In contrast, no mice in the imatinib-treated control cohorts were cured. These data suggest that treatment with a combination of arsenic trioxide and imatinib can eliminate refractory MPN-initiating cells and reduce disease relapse. PMID:24240679

Cytokine Regulation of Microenvironmental Cells in Myeloproliferative Neoplasms

PubMed Central

Hoermann, Gregor; Greiner, Georg; Valent, Peter

2015-01-01

The term myeloproliferative neoplasms (MPN) refers to a heterogeneous group of diseases including not only polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), but also chronic myeloid leukemia (CML), and systemic mastocytosis (SM). Despite the clinical and biological differences between these diseases, common pathophysiological mechanisms have been identified in MPN. First, aberrant tyrosine kinase signaling due to somatic mutations in certain driver genes is common to these MPN. Second, alterations of the bone marrow microenvironment are found in all MPN types and have been implicated in the pathogenesis of the diseases. Finally, elevated levels of proinflammatory and microenvironment-regulating cytokines are commonly found in all MPN-variants. In this paper, we review the effects of MPN-related oncogenes on cytokine expression and release and describe common as well as distinct pathogenetic mechanisms underlying microenvironmental changes in various MPN. Furthermore, targeting of the microenvironment in MPN is discussed. Such novel therapies may enhance the efficacy and may overcome resistance to established tyrosine kinase inhibitor treatment in these patients. Nevertheless, additional basic studies on the complex interplay of neoplastic and stromal cells are required in order to optimize targeting strategies and to translate these concepts into clinical application. PMID:26543328

Effects of biomaterial-derived fibroblast conditioned medium on the α-amylase expression of parotid gland acinar cells.

PubMed

Chou, Ya-Shuan; Young, Tai-Horng; Lou, Pei-Jen

2015-11-01

Salivary gland cells are surrounded by a complex stromal environment, in which fibroblasts are the main cells in proximity to the gland cells. In this study, the interaction between parotid gland acinar cells (PGACs), fibroblasts, and biomaterials was investigated. We prepared different biomaterials, including chitosan, polyvinyl alcohol (PVA), poly (ethylene-co-vinyl alcohol) (EVAL), polyvinylidene fluoride (PVDF), and tissue culture polystyrene (TCPS) to culture fibroblasts and then collect their conditioned media to culture PGACs. We observed no difference in AQP3, AQP5, and E-cadherin expression among different fibroblast conditioned medium treatments. Interestingly, α-amylase expression was obviously enhanced in PGACs cultured in the presence of conditioned medium from fibroblasts cultured on PVDF. Higher neurotrophin-4 (NT-4) expression was observed in PVDF-derived fibroblast conditioned medium using a growth factor protein array assay. In addition, directly adding NT-4 into the culture medium significantly promoted α-amylase expression by PGACs. Finally, nestin and βIII-tubulin expression by fibroblasts cultured on PVDF was also enhanced. Together, these results suggest that PVDF could promote α-amylase expression by PGACs via the NT-4 produced by fibroblasts. To date, there is no effective therapy for patients with dry mouth with persistent salivary hypofunction. The study made use of different biomaterials to culture fibroblasts and then collect their conditioned media to culture PGACs. It was found that the effect of fibroblast conditioned medium from PVDF on the α-amylase expression of PGACs was obviously enhanced and higher neurotrophin-4 (NT-4) expression was found in PVDF-derived fibroblast conditioned medium. In addition, directly adding NT-4 into the culture medium significantly promoted the expression of α-amylase by PGACs and the expression of nestin and βIII-tubulin of fibroblasts after being cultured on PVDF was enhanced. Therefore, the

Enhancing Targeted Therapy for Myeloproliferative Neoplasms

DTIC Science & Technology

2013-10-01

Myeloproliferative Neoplasms PRINCIPAL INVESTIGATOR: Gary W. Reuther CONTRACTING...2. REPORT TYPE Annual 3. DATES COVERED 30 2012-2 2013 4. TITLE AND SUBTITLE Enhancing Targeted Therapy for Myeloproliferative Neoplasms ...AVAILABILITY STATEMENT Approved for Public Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Myeloproliferative neoplasms

Restricted diffusion in a model acinar labyrinth by NMR: Theoretical and numerical results

NASA Astrophysics Data System (ADS)

Grebenkov, D. S.; Guillot, G.; Sapoval, B.

2007-01-01

A branched geometrical structure of the mammal lungs is known to be crucial for rapid access of oxygen to blood. But an important pulmonary disease like emphysema results in partial destruction of the alveolar tissue and enlargement of the distal airspaces, which may reduce the total oxygen transfer. This effect has been intensively studied during the last decade by MRI of hyperpolarized gases like helium-3. The relation between geometry and signal attenuation remained obscure due to a lack of realistic geometrical model of the acinar morphology. In this paper, we use Monte Carlo simulations of restricted diffusion in a realistic model acinus to compute the signal attenuation in a diffusion-weighted NMR experiment. We demonstrate that this technique should be sensitive to destruction of the branched structure: partial removal of the interalveolar tissue creates loops in the tree-like acinar architecture that enhance diffusive motion and the consequent signal attenuation. The role of the local geometry and related practical applications are discussed.

No genetic evidence for involvement of Deltaretroviruses in adult patients with precursor and mature T-cell neoplasms

PubMed Central

Burmeister, Thomas; Schwartz, Stefan; Hummel, Michael; Hoelzer, Dieter; Thiel, Eckhard

2007-01-01

Background The Deltaretrovirus genus comprises viruses that infect humans (HTLV), various simian species (STLV) and cattle (BLV). HTLV-I is the main causative agent in adult T-cell leukemia in endemic areas and some of the simian T-cell lymphotropic viruses have been implicated in the induction of malignant lymphomas in their hosts. BLV causes enzootic bovine leukosis in infected cattle or sheep. During the past few years several new Deltaretrovirus isolates have been described in various primate species. Two new HTLV-like viruses in humans have recently been identified and provisionally termed HTLV-III and HTLV-IV. In order to identify a broad spectrum of Deltaretroviruses by a single PCR approach we have established a novel consensus PCR based on nucleotide sequence data obtained from 42 complete virus isolates (HTLV-I/-II, STLV-I/-II/-III, BLV). The primer sequences were based on highly interspecies-conserved virus genome regions. We used this PCR to detect Deltaretroviruses in samples from adult patients with a variety of rare T-cell neoplasms in Germany. Results The sensitivity of the consensus PCR was at least between 10-2 and 10-3 with 100% specificity as demonstrated by serial dilutions of cell lines infected with either HTLV-I, HTLV-II or BLV. Fifty acute T-cell lymphoblastic leukemia (T-ALL) samples and 33 samples from patients with various rare mature T-cell neoplasms (T-PLL, Sézary syndrome and other T-NHL) were subsequently investigated. There were no cases with HTLV-I, HTLV-II or any other Deltaretroviruses. Conclusion The results rule out a significant involvement of HTLV-I or HTLV-II in these disease entities and show that other related Deltaretroviruses are not likely to be involved. The newly established Deltaretrovirus PCR may be a useful tool for identifying new Deltaretroviruses. PMID:17284327

Endothelial cell markers in vascular neoplasms: an immunohistochemical study comparing factor VIII-related antigen, blood group specific antigens, 6-keto-PGF1 alpha, and Ulex europaeus 1 lectin.

PubMed

Little, D; Said, J W; Siegel, R J; Fealy, M; Fishbein, M C

1986-06-01

Markers for endothelial cells including Ulex europaeus 1 lectin, blood group A, B, and H, and the prostaglandin metabolite 6-keto-PGF1 alpha were evaluated in paraffin secretions from formalin-fixed benign and malignant vascular neoplasms using a variety of immunohistochemical techniques, and results compared with staining for factor VIII-related antigen. Staining for Ulex appeared more sensitive than factor VIII-related antigen in identifying poorly differentiated neoplasms including haemangiosarcomas and spindle cell proliferations in Kaposi's sarcoma. Staining for blood group related antigens correlated with blood group in all cases. Ulex europaeus 1 lectin was the only marker for endothelial cells in lymphangiomas.

Classification of lymphoid neoplasms: the microscope as a tool for disease discovery

PubMed Central

Harris, Nancy Lee; Stein, Harald; Isaacson, Peter G.

2008-01-01

In the past 50 years, we have witnessed explosive growth in the understanding of normal and neoplastic lymphoid cells. B-cell, T-cell, and natural killer (NK)–cell neoplasms in many respects recapitulate normal stages of lymphoid cell differentiation and function, so that they can be to some extent classified according to the corresponding normal stage. Likewise, the molecular mechanisms involved the pathogenesis of lymphomas and lymphoid leukemias are often based on the physiology of the lymphoid cells, capitalizing on deregulated normal physiology by harnessing the promoters of genes essential for lymphocyte function. The clinical manifestations of lymphomas likewise reflect the normal function of lymphoid cells in vivo. The multiparameter approach to classification adopted by the World Health Organization (WHO) classification has been validated in international studies as being highly reproducible, and enhancing the interpretation of clinical and translational studies. In addition, accurate and precise classification of disease entities facilitates the discovery of the molecular basis of lymphoid neoplasms in the basic science laboratory. PMID:19029456

Morphological and immunohistochemical characterization of spontaneous thyroid gland neoplasms in guinea pigs (Cavia porcellus).

PubMed

Gibbons, P M; Garner, M M; Kiupel, M

2013-03-01

Reports of thyroid gland neoplasms in guinea pigs (Cavia porcellus) are rare, but thyroid tumors are among the most common neoplasms seen in cases submitted to Northwest ZooPath. This report describes the histological and immunohistochemical characteristics of thyroid neoplasms and lists the concurrent conditions found in guinea pig cases submitted to Northwest ZooPath during 1998 to 2008. Of 526 guinea pig case submissions, 19 had thyroid neoplasms. The most common clinical findings included a palpable mass on the ventral neck and progressive weight loss. Neoplasms were removed as an excisional biopsy from 7 guinea pigs, and 3 of these animals died within a few days after surgery. Radiographic mineral density was detected in 2 masses. Five of the neoplasms were reported as cystic; 5 were black or a dark color. Histologically, the neoplasms were classified as macrofollicular thyroid adenoma (8), thyroid cystadenoma (1), papillary thyroid adenoma (3), follicular thyroid carcinoma (5), follicular-compact thyroid carcinoma (1), and small-cell thyroid carcinoma (1). Osseous metaplasia was present in 8 neoplasms, and myeloid hyperplasia was present in 1 neoplasm. All 19 neoplasms were positive for thyroid transcription factor 1 and thyroglobulin but negative for parathyroid hormone and calcitonin. Numerous concurrent diseases, including hepatopathies, cardiomyopathies, and nephropathies, were present and considered to be the cause of death in many cases. Research is needed to determine the appropriate modalities for antemortem diagnosis and treatment and whether thyroid disease plays a role in the pathogenesis of chronic degenerative diseases in guinea pigs.

Natural Killer/T-cell Neoplasms: Analysis of Incidence, Patient Characteristics, and Survival Outcomes in the United States.

PubMed

Kommalapati, Anuhya; Tella, Sri Harsha; Ganti, Apar Kishore; Armitage, James O

2018-05-04

Limited data are available regarding the incidence, survival patterns, and long-term outcomes of natural killer (NK)/T-cell neoplasms in the United States. We performed a retrospective study of patients with NK/T-cell neoplasms diagnosed from 2001 to 2014 using the Surveillance, Epidemiology, and End Results program database. The Kaplan-Meier method was used to estimate the overall survival difference among the subgroups. Multivariate analyses were used to determine the factors affecting survival. For the 797 patients with NK/T-cell lymphoma, nasal type, the median age at diagnosis was 53 years, and males tended to be younger at diagnosis (P < .0001). The incidence of the disease increased from 0.4 in 2001 to 0.8 in 2014 per 1,000,000 individuals. The incidence was significantly greater in Hispanic patients compared with that in non-Hispanic patients (rate ratio, 3.03; P = .0001). The median overall survival was 20 months (range, 2-73 months) and varied significantly according to the primary site (P < .0001) and the disease stage at diagnosis (P < .0001). NK/T-cell lymphoma patients had an increased risk of acute myeloid leukemia (standardized incidence ratio, 18.77; 95% confidence interval, 2.27-67.81). For the 105 NK/T-cell leukemia patients, the median age at diagnosis was 58 years (range, 4-95 years). The overall incidence of the disease was 0.09 per 1,000,000 individuals and was significantly greater in males (rate ratio, 0.41; P < .0001). Unlike NK/T-cell lymphoma, no racial disparities were found in the incidence. The median overall survival was 17 months (range, 0-36 months). The incidence of NK/T-cell lymphoma, nasal type, in the United States has at least doubled in the past decade, with the greatest predilection among Hispanics. Patients with NK/T-cell lymphoma might have an increased risk of the subsequent development of acute myeloid leukemia. Copyright © 2018 Elsevier Inc. All rights reserved.

Toward a therapeutic reduction of imatinib refractory myeloproliferative neoplasm-initiating cells.

PubMed

Philips, S T; Hildenbrand, Z L; Oravecz-Wilson, K I; Foley, S B; Mgbemena, V E; Ross, T S

2014-11-13

Myeloproliferative neoplasms (MPNs) such as chronic myelogenous (CML) and chronic myelomonocytic leukemias (CMML) are frequently induced by tyrosine kinase oncogenes. Although these MPNs are sensitive to tyrosine kinase inhibitors such as imatinib, patients often relapse upon withdrawal of therapy. We used a model of MPN, which is induced by co-expression of the oncoproteins HIP1/PDGFβR (H/P) and AML1/ETO from their endogenous loci, to examine the mechanisms of disease development and recurrence following imatinib withdrawal. Although the MPN displayed a full hematologic response to imatinib, 100% of the diseased mice relapsed upon drug withdrawal. MPN persistence was not due to imatinib resistance mutations in the H/P oncogene or massive gene expression changes. Within 1 week of imatinib treatment, more than 98% of gene expression changes induced by the oncogenes in isolated hematopoietic stem and progenitor cells (lineage(-)Sca-1(+)c-Kit(+) immunophenotype) normalized. Supplementation of imatinib with granulocyte colony-stimulating factor or arsenic trioxide reduced MPN-initiating cell frequencies and the combination of imatinib with arsenic trioxide cured a large fraction of mice with MPNs. In contrast, no mice in the imatinib-treated control cohorts were cured. These data suggest that treatment with a combination of arsenic trioxide and imatinib can eliminate refractory MPN-initiating cells and reduce disease relapse.

Effects of muscarinic, alpha-adrenergic, and substance P agonists and ionomycin on ion transport mechanisms in the rat parotid acinar cell. The dependence of ion transport on intracellular calcium

PubMed Central

1989-01-01

The relationship between receptor-mediated increases in the intracellular free calcium concentration [( Ca]i) and the stimulation of ion fluxes involved in fluid secretion was examined in the rat parotid acinar cell. Agonist-induced increases in [Ca]i caused the rapid net loss of up to 50-60% of the total content of intracellular chloride (Cli) and potassium (Ki), which is consistent with the activation of calcium-sensitive chloride and potassium channels. These ion movements were accompanied by a 25% reduction in the intracellular volume. The relative magnitudes of the losses of Ki and the net potassium fluxes promoted by carbachol (a muscarinic agonist), phenylephrine (an alpha-adrenergic agonist), and substance P were very similar to their characteristic effects on elevating [Ca]i. Carbachol stimulated the loss of Ki through multiple efflux pathways, including the large-conductance Ca-activated K channel. Carbachol and substance P increased the levels of intracellular sodium (Nai) to more than 2.5 times the normal level by stimulating the net uptake of sodium through multiple pathways; Na-K-2Cl cotransport accounted for greater than 50% of the influx, and approximately 20% was via Na-H exchange, which led to a net alkalinization of the cells. Ionomycin stimulated similar fluxes through these two pathways, but also promoted sodium influx through an additional pathway which was nearly equivalent in magnitude to the combined uptake through the other two pathways. The carbachol- induced increase in Nai and decrease in Ki stimulated the activity of the sodium pump, measured by the ouabain-sensitive rate of oxygen consumption, to nearly maximal levels. In the absence of extracellular calcium or in cells loaded with the calcium chelator BAPTA (bis[o- aminophenoxy]ethane-N,N,N',N'-tetraacetic acid) the magnitudes of agonist- or ionomycin-stimulated ion fluxes were greatly reduced. The parotid cells displayed a marked desensitization to substance P; within 10 min the

Intracholecystic papillary-tubular neoplasms (ICPN) of the gallbladder (neoplastic polyps, adenomas, and papillary neoplasms that are ≥1.0 cm): clinicopathologic and immunohistochemical analysis of 123 cases.

PubMed

Adsay, Volkan; Jang, Kee-Taek; Roa, Juan Carlos; Dursun, Nevra; Ohike, Nobuyuki; Bagci, Pelin; Basturk, Olca; Bandyopadhyay, Sudeshna; Cheng, Jeanette D; Sarmiento, Juan M; Escalona, Oscar Tapia; Goodman, Michael; Kong, So Yeon; Terry, Paul

2012-09-01

The literature on the clinicopathologic characteristics of tumoral intraepithelial neoplasms (neoplastic polyps) of the gallbladder (GB) is fairly limited, due in part to the variability in definition and terminology. Most reported adenomas (pyloric gland type and others) were microscopic and thus regarded as clinically inconsequential, whereas papillary in situ carcinomas have been largely considered a type of invasive adenocarcinoma under the heading of "papillary adenocarcinomas." In this study, 123 GB cases that have a well-defined exophytic preinvasive neoplasm measuring ≥1 cm were analyzed. The patients were predominantly female (F/M=2:1) with a mean age of 61 y and a median tumor size of 2.2 cm. Half of the patients presented with pain, and in the other half the neoplasm was detected incidentally. Other neoplasms, most being gastrointestinal tract malignancies, were present in 22% of cases. Gallstones were identified in only 20% of cases. Radiologically, almost half were diagnosed as "cancer," roughly half with polypoid tumor, and in 10% the lesion was missed. Pathologic findings: (1) The predominant configuration was papillary in 43%, tubulopapillary in 31%, tubular in 26%. (2) Each case was assigned a final lineage type on the basis of the predominant pattern (>75% of the lesion) on morphology, and supported with specific immunohistochemical cell lineage markers. The predominant cell lineage could be identified as biliary in 50% (66% of which were MUC1), gastric foveolar in 16% (all were MUC5AC), gastric pyloric in 20% (92% MUC6), intestinal in 8% (100% CK20; 75% CDX2; 50%, MUC2), and oncocytic in 6% (17% HepPar and 17% MUC6); however, 90% of cases had some amount of secondary or unclassifiable pattern and hybrid immunophenotypes. (3) Of the cases that would have qualified as "pyloric gland adenoma," 21/24 (88%) had at least focal high-grade dysplasia and 18% had associated invasive carcinoma. Conversely, 8 of 47 "papillary adenocarcinoma"-type cases

Classifying the evolutionary and ecological features of neoplasms

PubMed Central

Maley, Carlo C.; Aktipis, Athena; Graham, Trevor A.; Sottoriva, Andrea; Boddy, Amy M.; Janiszewska, Michalina; Silva, Ariosto S.; Gerlinger, Marco; Yuan, Yinyin; Pienta, Kenneth J.; Anderson, Karen S.; Gatenby, Robert; Swanton, Charles; Posada, David; Wu, Chung-I; Schiffman, Joshua D.; Hwang, E. Shelley; Polyak, Kornelia; Anderson, Alexander R. A.; Brown, Joel S.; Greaves, Mel; Shibata, Darryl

2018-01-01

Neoplasms change over time through a process of cell-level evolution, driven by genetic and epigenetic alterations. However, the ecology of the microenvironment of a neoplastic cell determines which changes provide adaptive benefits. There is widespread recognition of the importance of these evolutionary and ecological processes in cancer, but to date, no system has been proposed for drawing clinically relevant distinctions between how different tumours are evolving. On the basis of a consensus conference of experts in the fields of cancer evolution and cancer ecology, we propose a framework for classifying tumours that is based on four relevant components. These are the diversity of neoplastic cells (intratumoural heterogeneity) and changes over time in that diversity, which make up an evolutionary index (Evo-index), as well as the hazards to neoplastic cell survival and the resources available to neoplastic cells, which make up an ecological index (Eco-index). We review evidence demonstrating the importance of each of these factors and describe multiple methods that can be used to measure them. Development of this classification system holds promise for enabling clinicians to personalize optimal interventions based on the evolvability of the patient’s tumour. The Evo- and Eco-indices provide a common lexicon for communicating about how neoplasms change in response to interventions, with potential implications for clinical trials, personalized medicine and basic cancer research. PMID:28912577

Classifying the evolutionary and ecological features of neoplasms.

PubMed

Maley, Carlo C; Aktipis, Athena; Graham, Trevor A; Sottoriva, Andrea; Boddy, Amy M; Janiszewska, Michalina; Silva, Ariosto S; Gerlinger, Marco; Yuan, Yinyin; Pienta, Kenneth J; Anderson, Karen S; Gatenby, Robert; Swanton, Charles; Posada, David; Wu, Chung-I; Schiffman, Joshua D; Hwang, E Shelley; Polyak, Kornelia; Anderson, Alexander R A; Brown, Joel S; Greaves, Mel; Shibata, Darryl

2017-10-01

Neoplasms change over time through a process of cell-level evolution, driven by genetic and epigenetic alterations. However, the ecology of the microenvironment of a neoplastic cell determines which changes provide adaptive benefits. There is widespread recognition of the importance of these evolutionary and ecological processes in cancer, but to date, no system has been proposed for drawing clinically relevant distinctions between how different tumours are evolving. On the basis of a consensus conference of experts in the fields of cancer evolution and cancer ecology, we propose a framework for classifying tumours that is based on four relevant components. These are the diversity of neoplastic cells (intratumoural heterogeneity) and changes over time in that diversity, which make up an evolutionary index (Evo-index), as well as the hazards to neoplastic cell survival and the resources available to neoplastic cells, which make up an ecological index (Eco-index). We review evidence demonstrating the importance of each of these factors and describe multiple methods that can be used to measure them. Development of this classification system holds promise for enabling clinicians to personalize optimal interventions based on the evolvability of the patient's tumour. The Evo- and Eco-indices provide a common lexicon for communicating about how neoplasms change in response to interventions, with potential implications for clinical trials, personalized medicine and basic cancer research.

Nephrotic syndrome and neoplasm. The findings to date, with practical implications.

PubMed

Papper, S

1984-11-01

The following points should be kept in mind in cases of nephrotic syndrome. Neoplasm (malignant or benign) occurs in approximately 10% of adults with nephrotic syndrome (15% of those over age 60). The neoplasm may be evident before, after, or simultaneously with the development of the nephrotic syndrome. Minimal change lesion in the kidney suggests possible Hodgkin's disease, while membranous nephropathy is more suggestive of possible carcinoma, although there are many exceptions to this generalization. Membrano-proliferative and focal sclerosis renal lesions also occur with diverse tumors. Strong evidence exists that in cases of carcinoma and nephrotic syndrome, the renal lesion is generally due to immune complexes--either tumor-associated antigens, fetal antigens, or viral antigens. In cases involving Hodgkin's disease, T-cell deficiency may be relevant in the genesis of the minimal change lesion and the nephrotic syndrome. Nephrotic syndrome often responds to effective treatment of the tumor and commonly recurs with relapse of the neoplasm. Nephrotic syndrome without apparent cause in an adult compels consideration of an associated neoplasm.

Use of internal control T-cell populations in the flow cytometric evaluation for T-cell neoplasms.

PubMed

Hunt, Alicia M; Shallenberger, Wendy; Ten Eyck, Stephen P; Craig, Fiona E

2016-09-01

Flow cytometry is an important tool for identification of neoplastic T-cells, but immunophenotypic abnormalities are often subtle and must be distinguished from nonneoplastic subsets. Use of internal control (IC) T-cells in the evaluation for T-cell neoplasms was explored, both as a quality measure and as a reference for evaluating abnormal antigen expression. All peripheral blood specimens (3-month period), or those containing abnormal T-cells (29-month period), stained with CD45 V500, CD2 V450, CD3 PE-Cy7, CD7 PE, CD4 Per-CP-Cy5.5, CD8 APC-H7, CD56 APC, CD16&57 FITC, were evaluated. IC T-cells were identified (DIVA, BD Biosciences) and median fluorescence intensity (MFI) recorded. Selected files were merged and reference templates generated (Infinicyt, Cytognos). IC T-cells were present in all specimens, including those with abnormal T-cells, but subsets were less well-represented. IC T-cell CD3 MFI differed between instruments (p = 0.0007) and subsets (p < 0.001), but not specimen categories, and served as a longitudinal process control. Merged files highlighted small unusual IC-T subsets: CD2+(dim) (0.25% total), CD2- (0.03% total). An IC reference template highlighted neoplastic T-cells, but was limited by staining variability (IC CD3 MFI reference samples different from test (p = 0.003)). IC T-cells present in the majority of specimens can serve as positive and longitudinal process controls. Use of IC T-cells as an internal reference is limited by variable representation of subsets. Analysis of merged IC T-cells from previously analyzed patient samples can alert the interpreter to less-well-recognized non-neoplastic subsets. However, application of a merged file IC reference template was limited by staining variability. © 2016 Clinical Cytometry Society. © 2016 International Clinical Cytometry Society.

TP53 alterations in pancreatic acinar cell carcinoma: new insights into the molecular pathology of this rare cancer.

PubMed

La Rosa, Stefano; Bernasconi, Barbara; Frattini, Milo; Tibiletti, Maria Grazia; Molinari, Francesca; Furlan, Daniela; Sahnane, Nora; Vanoli, Alessandro; Albarello, Luca; Zhang, Lizhi; Notohara, Kenji; Casnedi, Selenia; Chenard, Marie-Pierre; Adsay, Volkan; Asioli, Sofia; Capella, Carlo; Sessa, Fausto

2016-03-01

The molecular alterations of pancreatic acinar cell carcinomas (ACCs) are poorly understood and have been reported as being different from those in ductal adenocarcinomas. Loss of TP53 gene function in the pathogenesis of ACCs is controversial since contradictory findings have been published. A comprehensive analysis of the different possible genetic and epigenetic mechanisms leading to TP53 alteration in ACC has never been reported and hence the role of TP53 in the pathogenesis and/or progression of ACC remains unclear. We investigated TP53 alterations in 54 tumor samples from 44 patients, including primary and metastatic ACC, using sequencing analysis, methylation-specific multiplex ligation probe amplification, fluorescence in situ hybridization, and immunohistochemistry. TP53 mutations were found in 13 % of primary ACCs and in 31 % of metastases. Primary ACCs and metastases showed the same mutational profile, with the exception of one case, characterized by a wild-type sequence in the primary carcinoma and a mutation in the corresponding metastasis. FISH analysis revealed deletion of the TP53 region in 53 % of primary ACCs and in 50 % of metastases. Promoter hypermethylation was found in one case. The molecular alterations correlated well with the immunohistochemical findings. A statistically significant association was found between the combination of mutation of one allele and loss of the other allele of TP53 and worse survival.

Histochemical and Immunohistochemical Study of α-SMA, Collagen, and PCNA in Epithelial Ovarian Neoplasm

PubMed

Anggorowati, Nungki; Ratna Kurniasari, Chatarina; Damayanti, Karina; Cahyanti, Titik; Widodo, Irianiwati; Ghozali, Ahmad; Romi, Muhammad Mansyur; Sari, Dwi Cahyani Ratna; Arfian, Nur

2017-03-01

Background: Alpha-smooth muscle actin (α-SMA) is an isoform of actin, positive in myofibroblasts and is an epithelial to mesenchymal transition (EMT) marker. EMT is a process by which tumor cells develop to be more hostile and able to metastasize. Progression of tumor cells is always followed by cell composition and extracellular matrix component alteration. Increased α-SMA expression and collagen alteration may predict the progressivity of ovarian neoplasms. Objective: The aim of this research was to analyse the characteristic of α-SMA and collagen in tumor cells and stroma of ovarian neoplasms. In this study, PCNA (proliferating cell nuclear antigen) expression was also investigated. Methods: Thirty samples were collected including serous, mucinous, endometrioid, and clear cell subtypes. The expression of α-SMA and PCNA were calculated in cells and stroma of ovarian tumors. Collagen was detected using Sirius Red staining and presented as area fraction. Results: The overexpressions of α-SMA in tumor cells were only detected in serous and clear cell ovarian carcinoma. The histoscore of α-SMA was higher in malignant than in benign or borderline ovarian epithelial neoplasms (105.3±129.9 vs. 17.3±17.1, P=0.011; mean±SD). Oppositely, stromal α-SMA and collagen area fractions were higher in benign than in malignant tumors (27.2±6.6 vs 20.5±8.4, P=0.028; 31.0±5.6 vs. 23.7±6.4, P=0.04). The percentages of epithelial and stromal PCNA expressions were not significantly different between benign and malignant tumors. Conclusion: Tumor cells of serous and clear cell ovarian carcinoma exhibit mesenchymal characteristic as shown by α-SMA positive expression. This expression might indicate that these subtypes were more aggressive. This research showed that collagen and α-SMA area fractions in stroma were higher in benign than in malignant neoplasms. 10.22034/APJCP.2017.18.3.667

Noncoding RNA Expression and Targeted Next-Generation Sequencing Distinguish Tubulocystic Renal Cell Carcinoma (TC-RCC) from Other Renal Neoplasms.

PubMed

Lawrie, Charles H; Armesto, María; Fernandez-Mercado, Marta; Arestín, María; Manterola, Lorea; Goicoechea, Ibai; Larrea, Erika; Caffarel, María M; Araujo, Angela M; Sole, Carla; Sperga, Maris; Alvarado-Cabrero, Isabel; Michal, Michal; Hes, Ondrej; López, José I

2018-01-01

Tubulocystic renal cell carcinoma (TC-RCC) is a rare recently described renal neoplasm characterized by gross, microscopic, and immunohistochemical differences from other renal tumor types and was recently classified as a distinct entity. However, this distinction remains controversial particularly because some genetic studies suggest a close relationship with papillary RCC (PRCC). The molecular basis of this disease remains largely unexplored. We therefore performed noncoding (nc) RNA/miRNA expression analysis and targeted next-generation sequencing mutational profiling on 13 TC-RCC cases (11 pure, two mixed TC-RCC/PRCC) and compared with other renal neoplasms. The expression profile of miRNAs and other ncRNAs in TC-RCC was distinct and validated 10 differentially expressed miRNAs by quantitative RT-PCR, including miR-155 and miR-34a, that were significantly down-regulated compared with PRCC cases (n = 22). With the use of targeted next-generation sequencing we identified mutations in 14 different genes, most frequently (>60% of TC-RCC cases) in ABL1 and PDFGRA genes. These mutations were present in <5% of clear cell RCC, PRCC, or chromophobe RCC cases (n > 600) of The Cancer Genome Atlas database. In summary, this study is by far the largest molecular study of TC-RCC cases and the first to investigate either ncRNA expression or their genomic profile. These results add molecular evidence that TC-RCC is indeed a distinct entity from PRCC and other renal neoplasms. Copyright © 2018 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

Leucine Affects α-Amylase Synthesis through PI3K/Akt-mTOR Signaling Pathways in Pancreatic Acinar Cells of Dairy Calves.

PubMed

Guo, Long; Liang, Ziqi; Zheng, Chen; Liu, Baolong; Yin, Qingyan; Cao, Yangchun; Yao, Junhu

2018-05-23

Dietary nutrient utilization, particularly starch, is potentially limited by digestion in dairy cow small intestine because of shortage of α-amylase. Leucine acts as an effective signal molecular in the mTOR signaling pathway, which regulates a series of biological processes, especially protein synthesis. It has been reported that leucine could affect α-amylase synthesis and secretion in ruminant pancreas, but mechanisms have not been elaborated. In this study, pancreatic acinar (PA) cells were used as a model to determine the cellular signal of leucine influence on α-amylase synthesis. PA cells were isolated from newborn Holstein dairy bull calves and cultured in Dulbecco's modifed Eagle's medium/nutrient mixture F12 liquid media containing four leucine treatments (0, 0.23, 0.45, and 0.90 mM, respectively), following α-amylase activity, zymogen granule, and signal pathway factor expression detection. Rapamycin, a specific inhibitor of mTOR, was also applied to PA cells. Results showed that leucine increased ( p < 0.05) synthesis of α-amylase as well as phosphorylation of PI3K, Akt, mTOR, and S6K1 while reduced ( p < 0.05) GCN2 expression. Inhibition of mTOR signaling downregulated the α-amylase synthesis. In addition, the extracellular leucine dosage significantly influenced intracellular metabolism of isoleucine ( p < 0.05). Overall, leucine regulates α-amylase synthesis through promoting the PI3K/Akt-mTOR pathway and reducing the GCN2 pathway in PA cells of dairy calves. These pathways form the signaling network that controls the protein synthesis and metabolism. It would be of great interest in future studies to explore the function of leucine in ruminant nutrition.

A Study of Varlilumab (Anti-CD27) and Sunitinib in Patients With Metastatic Clear Cell Renal Cell Carcinoma

ClinicalTrials.gov

2017-11-10

Carcinoma, Renal Cell; Kidney Diseases; Kidney Neoplasms; Urogenital Neoplasms; Urologic Diseases; Urologic Neoplasms; Neoplasms; Neoplasms by Histologic Type; Clear-cell Metastatic Renal Cell Carcinoma

Multiphoton microscopy as a diagnostic imaging modality for pancreatic neoplasms without hematoxylin and eosin stains

NASA Astrophysics Data System (ADS)

Chen, Youting; Chen, Jing; Chen, Hong; Hong, Zhipeng; Zhu, Xiaoqin; Zhuo, Shuangmu; Chen, Yanling; Chen, Jianxin

2014-09-01

Hematoxylin and eosin (H&E) staining of tissue samples is the standard approach in histopathology for imaging and diagnosing cancer. Recent reports have shown that multiphoton microscopy (MPM) provides better sample interface with single-cell resolution, which enhances traditional H&E staining and offers a powerful diagnostic tool with potential applications in oncology. The purpose of this study was to further expand the versatility of MPM by establishing the optical parameters required for imaging unstained histological sections of pancreatic neoplasms, thereby providing an efficient and environmentally sustainable alternative to H&E staining while improving the accuracy of pancreatic cancer diagnoses. We found that the high-resolution MPM images clearly distinguish between the structure of normal pancreatic tissues compared with pancreatic neoplasms in unstained histological sections, and discernable differences in tissue architecture and cell morphology between normal versus tumorigenic cells led to enhanced optical diagnosis of cancerous tissue. Moreover, quantitative assessment of the cytomorphological features visualized from MPM images showed significant differences in the nuclear-cytoplasmic ratios of pancreatic neoplasms compared with normal pancreas, as well as further distinguished pancreatic malignant tumors from benign tumors. These results indicate that the MPM could potentially serve as an optical tool for the diagnosis of pancreatic neoplasms in unstained histological sections.

Blastic plasmacytoid dendritic cell neoplasm is dependent on BCL-2 and sensitive to venetoclax

PubMed Central

Montero, Joan; Stephansky, Jason; Cai, Tianyu; Griffin, Gabriel K.; Cabal-Hierro, Lucia; Togami, Katsuhiro; Hogdal, Leah J.; Galinsky, Ilene; Morgan, Elizabeth A.; Aster, Jon C.; Davids, Matthew S.; LeBoeuf, Nicole R.; Stone, Richard M.; Konopleva, Marina; Pemmaraju, Naveen; Letai, Anthony; Lane, Andrew A.

2017-01-01

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematologic malignancy with dismal outcomes for which no standard therapy exists. We found that primary BPDCN cells were dependent on the anti-apoptotic protein BCL-2 and were uniformly sensitive to the BCL-2 inhibitor venetoclax, as measured by direct cytotoxicity, apoptosis assays, and dynamic BH3 profiling. Animals bearing BPDCN patient-derived xenografts had disease responses and improved survival after venetoclax treatment in vivo. Finally, we report on two patients with relapsed/refractory BPDCN who received venetoclax off-label and experienced significant disease responses. We propose that venetoclax or other BCL-2 inhibitors undergo expedited clinical evaluation in BPDCN, alone or in combination with other therapies. In addition, these data illustrate an example of precision medicine to predict treatment response using ex vivo functional assessment of primary tumor tissue, without requiring a genetic biomarker. PMID:27986708

Successful treatment with biweekly CHOP for bone marrow relapse of blastic plasmacytoid dendritic cell neoplasm.

PubMed

Ono, Keiko; Ise, Mikiko; Ikebe, Dai; Sato, Akiyasu; Wang, Xiaofei; Sugawara, Takeaki; Tsujimura, Hideki; Itami, Makiko; Kumagai, Kyoya

2017-01-01

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematological malignancy derived from precursors of plasmacytoid dendritic cells. The majority of patients initially respond to multi-agent chemotherapy, though most relapse within a year and the prognosis is very poor. We report a 67-year-old man with erythema on the right chest and a nasopharyngeal mass. Histological examination revealed a mass of tumor cells expressing CD4, CD56, and CD123, but neither CD3 nor CD20. He was diagnosed with BPDCN. Bone marrow involvement was not seen at diagnosis. He achieved complete remission (CR) with CHOP-like chemotherapy. After 1 year, he relapsed with a cutaneous tumor on the head, a nasopharyngeal tumor, and massive bone marrow involvement. Relapsed BPDCN is generally resistant to chemotherapy and the prognosis is dismal. However, he was successfully treated with biweekly CHOP therapy and achieved a second CR lasting 16 months.

Myelodysplastic/ Myeloproliferative Neoplasms Treatment (PDQ®)—Health Professional Version

Cancer.gov

Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are treated with chemotherapy or other drugs, stem cell transplant, supportive care, and targeted therapy. They include chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), and atypical chronic myeloid leukemia (aCML). Learn about the clinical features and treatment options for these leukemias.

9 CFR 311.11 - Neoplasms.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 9 Animals and Animal Products 2 2010-01-01 2010-01-01 false Neoplasms. 311.11 Section 311.11 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY... CERTIFICATION DISPOSAL OF DISEASED OR OTHERWISE ADULTERATED CARCASSES AND PARTS § 311.11 Neoplasms. (a) An...

A broad survey of cathepsin K immunoreactivity in human neoplasms.

PubMed

Zheng, Gang; Martignoni, Guido; Antonescu, Cristina; Montgomery, Elizabeth; Eberhart, Charles; Netto, George; Taube, Janis; Westra, William; Epstein, Jonathan I; Lotan, Tamara; Maitra, Anirban; Gabrielson, Edward; Torbenson, Michael; Iacobuzio-Donahue, Christine; Demarzo, Angelo; Shih, Ie Ming; Illei, Peter; Wu, T C; Argani, Pedram

2013-02-01

Cathepsin K is consistently and diffusely expressed in alveolar soft part sarcoma (ASPS) and a subset of translocation renal cell carcinomas (RCCs). However, cathepsin K expression in human neoplasms has not been systematically analyzed. We constructed tissue microarrays (TMA) from a wide variety of human neoplasms, and performed cathepsin K immunohistochemistry (IHC). Only 2.7% of 1,140 carcinomas from various sites exhibited cathepsin K labeling, thus suggesting that among carcinomas, cathepsin K labeling is highly specific for translocation RCC. In contrast to carcinomas, cathepsin K labeling was relatively common (54.6%) in the 414 mesenchymal lesions studied, including granular cell tumor, melanoma, and histiocytic lesions, but not paraganglioma, all of which are in the morphologic differential diagnosis of ASPS. Cathepsin K IHC can be helpful in distinguishing ASPS and translocation RCC from some but not all of the lesions in their differential diagnosis.

DIE-RNA: A Reproducible Strategy for the Digestion of Normal and Injured Pancreas, Isolation of Pancreatic Cells from Genetically Engineered Mouse Models and Extraction of High Quality RNA

PubMed Central

Assi, Mohamad; Dauguet, Nicolas; Jacquemin, Patrick

2018-01-01

The isolation of ribonucleic acid (RNA) suitable for gene expression studies is challenging in the pancreas, due to its high ribonuclease activity. This is even more complicated during pancreatitis, a condition associated with inflammation and fibrosis. Our aim was to implement a time-effective and reproducible protocol to isolate high quality RNA from specific pancreatic cell subtypes, in normal and inflammatory conditions. We used two genetically engineered mouse models (GEMM), Ela-CreER/YFP and Sox9-CreER/YFP, to isolate acinar and ductal cells, respectively. To induce pancreatitis, mice received a caerulein treatment (125 μg/kg) for 8 and 72 h. We alternatively used EGTA and calcium buffers that contain collagenase P (0.6 mg/mL) to rapidly digest the pancreas into individual cells. Most of the cells from normal and injured pancreas were single-dissociated, exhibited a round morphology and did not incorporate trypan blue dye. Cell suspensions from Ela- and Sox9-CreER/YFP pancreas were then sorted by flow cytometry to isolate the YFP-positive acinar and ductal cells, respectively. Sorted cells kept a round shape and emitted fluorescence detected by the 38 HE green fluorescence filter. RNA was isolated by column-based purification approach. The RNA integrity number (RIN) was high in sorted acinar cell fractions treated with or without caerulein (8.6 ± 0.17 and 8.4 ± 0.09, respectively), compared to the whole pancreas fraction (4.8 ± 1.1). Given the low number of sorted ductal cells, the RIN value was slightly lower compared to acini (7.4 ± 0.4). Quantitative-PCR experiments indicated that sorted acinar and ductal cells express the specific acinar and ductal markers, respectively. Additionally, RNA preparations from caerulein-treated acinar cells were free from significant contamination with immune cell RNA. We thus validated the DIE (Digestion, Isolation, and Extraction)-RNA tool as a reproducible and efficient protocol to isolate pure acinar and ductal cells

DIE-RNA: A Reproducible Strategy for the Digestion of Normal and Injured Pancreas, Isolation of Pancreatic Cells from Genetically Engineered Mouse Models and Extraction of High Quality RNA.

PubMed

Assi, Mohamad; Dauguet, Nicolas; Jacquemin, Patrick

2018-01-01

The isolation of ribonucleic acid (RNA) suitable for gene expression studies is challenging in the pancreas, due to its high ribonuclease activity. This is even more complicated during pancreatitis, a condition associated with inflammation and fibrosis. Our aim was to implement a time-effective and reproducible protocol to isolate high quality RNA from specific pancreatic cell subtypes, in normal and inflammatory conditions. We used two genetically engineered mouse models (GEMM), Ela-CreER/YFP and Sox9-CreER/YFP, to isolate acinar and ductal cells, respectively. To induce pancreatitis, mice received a caerulein treatment (125 μg/kg) for 8 and 72 h. We alternatively used EGTA and calcium buffers that contain collagenase P (0.6 mg/mL) to rapidly digest the pancreas into individual cells. Most of the cells from normal and injured pancreas were single-dissociated, exhibited a round morphology and did not incorporate trypan blue dye. Cell suspensions from Ela- and Sox9-CreER/YFP pancreas were then sorted by flow cytometry to isolate the YFP-positive acinar and ductal cells, respectively. Sorted cells kept a round shape and emitted fluorescence detected by the 38 HE green fluorescence filter. RNA was isolated by column-based purification approach. The RNA integrity number (RIN) was high in sorted acinar cell fractions treated with or without caerulein (8.6 ± 0.17 and 8.4 ± 0.09, respectively), compared to the whole pancreas fraction (4.8 ± 1.1). Given the low number of sorted ductal cells, the RIN value was slightly lower compared to acini (7.4 ± 0.4). Quantitative-PCR experiments indicated that sorted acinar and ductal cells express the specific acinar and ductal markers, respectively. Additionally, RNA preparations from caerulein-treated acinar cells were free from significant contamination with immune cell RNA. We thus validated the DIE (Digestion, Isolation, and Extraction)-RNA tool as a reproducible and efficient protocol to isolate pure acinar and ductal cells

Cervical embryonal rhabdomyosarcoma and ovarian Sertoli–Leydig cell tumour: a more than coincidental association of two rare neoplasms?

PubMed Central

McClean, Gareth E; Kurian, Susy; Walter, Noel; Kekre, A; McCluggage, W Glenn

2007-01-01

A case in which an embryonal rhabdomyosarcoma of the cervix and an ovarian Sertoli–Leydig cell tumour of intermediate differentiation occurred in a 13‐year‐old girl is described. Although initially considered as a chance association, a review of the literature showed the co‐occurrence of these two uncommon neoplasms in three previous cases. The reason for this association, which is thought to be more than coincidental, is not known, although an underlying genetic abnormality is a possibility. The ovarian tumour in this case was characterised by the presence of foci of cells with extremely pleomorphic nuclei, which initially raised the possibility of metastatic rhabdomyosarcoma. These were interpreted as foci of bizarre nuclei within the Sertoli–Leydig cell tumour. PMID:17347287

Fusion proteins in head and neck neoplasms: Clinical implications, genetics, and future directions for targeting

PubMed Central

Escalante, Derek A.; Wang, He; Fundakowski, Christopher E.

2016-01-01

ABSTRACT Fusion proteins resulting from chromosomal rearrangements are known to drive the pathogenesis of a variety of hematological and solid neoplasms such as chronic myeloid leukemia and non-small-cell lung cancer. Efforts to elucidate the role they play in these malignancies have led to important diagnostic and therapeutic triumphs, including the famous development of the tyrosine kinase inhibitor dasatinib targeting the BCR-ABL fusion. Until recently, there has been a paucity of research investigating fusion proteins harbored by head and neck neoplasms. The discovery and characterization of novel fusion proteins in neoplasms originating from the thyroid, nasopharynx, salivary glands, and midline head and neck structures offer substantial contributions to our understanding of the pathogenesis and biological behavior of these neoplasms, while raising new therapeutic and diagnostic opportunities. Further characterization of these fusion proteins promises to facilitate advances on par with those already achieved with regard to hematologic malignancies in the precise, molecularly guided diagnosis and treatment of head and neck neoplasms. The following is a subsite specific review of the clinical implications of fusion proteins in head and neck neoplasms and the future potential for diagnostic targeting. PMID:27636353

The oncocytic subtype is genetically distinct from other pancreatic intraductal papillary mucinous neoplasm subtypes

PubMed Central

Basturk, Olca; Tan, Marcus; Bhanot, Umesh; Allen, Peter; Adsay, Volkan; Scott, Sasinya N; Shah, Ronak; Berger, Michael F; Askan, Gokce; Dikoglu, Esra; Jobanputra, Vaidehi; Wrzeszczynski, Kazimierz O; Sigel, Carlie; Iacobuzio-Donahue, Christine; Klimstra, David S

2017-01-01

In 2010, the World Health Organization reclassified the entity originally described as intraductal oncocytic papillary neoplasm as the ‘oncocytic subtype’ of intraductal papillary mucinous neoplasm. Although several key molecular alterations of other intraductal papillary mucinous neoplasm subtypes have been discovered, including common mutations in KRAS, GNAS, and RNF3, those of oncocytic subtype have not been well characterized. We analyzed 11 pancreatic ‘oncocytic subtype’ of intraductal papillary mucinous neoplasms. Nine pancreatic ‘oncocytic subtype’ of intraductal papillary mucinous neoplasms uniformly exhibited typical entity-defining morphology of arborizing papillae lined by layers of cells with oncocytic cytoplasm, prominent, nucleoli, and intraepithelial lumina. The remaining two were atypical. One lacked the arborizing papilla and had flat oncocytic epithelium only; the other one had focal oncocytic epithelium in a background of predominantly intestinal subtype intraductal papillary mucinous neoplasm. Different components of this case were analyzed separately. Formalin-fixed, paraffin-embedded specimens of all cases were microdissected and subjected to high-depth-targeted next-generation sequencing for a panel of 300 key cancer-associated genes in a platform that enabled the identification of sequence mutations, copy number alterations, and select structural rearrangements involving all targeted genes. Fresh frozen specimens of two cases were also subjected to whole-genome sequencing. For the nine typical pancreatic ‘oncocytic subtype’ of intraductal papillary mucinous neoplasms, the number of mutations per case, identified by next-generation sequencing, ranged from 1 to 10 (median = 4). None of these cases had KRAS or GNAS mutations and only one had both RNF43 and PIK3R1 mutations. ARHGAP26, ASXL1, EPHA8, and ERBB4 genes were somatically altered in more than one of these typical ‘oncocytic subtype’ of intraductal papillary mucinous

Cystic neoplasms of the exocrine pancreas.

PubMed

Campbell, F; Azadeh, B

2008-04-01

The increasing use of radiological imaging has led to greater detection of small and asymptomatic cystic lesions of the pancreas. Most are resectable, but not all are neoplastic. This review provides an update on the histopathology, immunohistochemistry, molecular biology, pathogenesis and management of cystic neoplasms of the exocrine pancreas. These include the serous, the mucinous cystic, the intraductal papillary mucinous and the solid pseudopapillary neoplasms. Recently reported variants are described and very rare cystic variants of other pancreatic epithelial and mesenchymal neoplasms are briefly mentioned.

Perivascular epithelioid cell neoplasm (PEComa) of the uterus: A systematic review.

PubMed

Musella, Angela; De Felice, Francesca; Kyriacou, A Kyriacos; Barletta, Francesco; Di Matteo, Filippo Maria; Marchetti, Claudia; Izzo, Luciano; Monti, Marco; Benedetti Panici, Pierluigi; Redler, Adriano; D'Andrea, Vito

2015-07-01

Perivascular epithelioid cell neoplasm (PEComa) is a rare mesenchymal tumor. Gynecological PEComas account for just over one-fourth of the overall PEComa cases reported in the literature. Surgery is the most recommended primary treatment while adjuvant therapy is generally reserved for high-risk cases. However, the best management of this neoplasia has not been well established, primarily because of the paucity of cases described to date. The aim of this systematic review is to summarize what is known thus far regarding the etiopathogenesis, clinical and pathologic features of PEComas, focusing also on the most valid treatment options for uterine cases. Pubmed articles on PEComas published in various journals over the past 70 years were analyzed. Although the optimal treatment of gynecological PEComas is controversial, surgical resection remains the cornerstone. The use of adjuvant treatment is warranted in high risk patients to increase disease control. A multidisciplinary approach should be key in treatment decision-making regarding gynecological PEComas. Copyright © 2015 IJS Publishing Group Limited. Published by Elsevier Ltd. All rights reserved.

B-cell lymphomas with concurrent IGH-BCL2 and MYC rearrangements are aggressive neoplasms with clinical and pathologic features distinct from Burkitt lymphoma and diffuse large B-cell lymphoma.

PubMed

Snuderl, Matija; Kolman, Olga K; Chen, Yi-Bin; Hsu, Jessie J; Ackerman, Adam M; Dal Cin, Paola; Ferry, Judith A; Harris, Nancy Lee; Hasserjian, Robert P; Zukerberg, Lawrence R; Abramson, Jeremy S; Hochberg, Ephraim P; Lee, Hang; Lee, Alfred I; Toomey, Christiana E; Sohani, Aliyah R

2010-03-01

B-cell lymphomas with concurrent IGH-BCL2 and MYC rearrangements, also known as "double-hit" lymphomas (DHL), are rare neoplasms characterized by highly aggressive clinical behavior, complex karyotypes, and a spectrum of pathologic features overlapping with Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL) and B-lymphoblastic lymphoma/leukemia (B-LBL). The clinical and pathologic spectrum of this rare entity, including comparison to other high-grade B-cell neoplasms, has not been well defined. We conducted a retrospective analysis of clinical and pathologic features of 20 cases of DHL seen at our institution during a 5-year period. In addition, we carried out case-control comparisons of DHL with BL and International Prognostic Index (IPI)-matched DLBCL. The 11 men and 9 women had a median age of 63.5 years (range 32 to 91). Six patients had a history of grade 1 to 2 follicular lymphoma; review of the prior biopsy specimens in 2 of 5 cases revealed blastoid morphology. Eighteen patients had Ann Arbor stage 3 or 4 disease and all had elevated serum lactate dehydrogenase (LDH) levels at presentation. Extranodal disease was present in 17/20 (85%), bone marrow involvement in 10/17 (59%) and central nervous system (CNS) disease in 5/11 (45%). Nineteen patients were treated with combination chemotherapy, of whom 18 received rituximab and 14 received CNS-directed therapy. Fourteen patients (70%) died within 8 months of diagnosis. Median overall survival in the DHL group (4.5 mo) was inferior to both BL (P=0.002) and IPI-matched DLBCL (P=0.04) control patients. Twelve DHL cases (60%) were classified as B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL, 7 cases (35%) as DLBCL, not otherwise specified, and 1 case as B-LBL. Distinguishing features from BL included expression of Bcl2 (P<0.0001), Mum1/IRF4 (P=0.006), Ki-67 <95% (P<0.0001), and absence of EBV-EBER (P=0.006). DHL commonly contained the t(8;22) rather than the t(8;14) seen

Adrenal Oncocytic Neoplasm with Paradoxical Loss of Important Mitochondrial Steroidogenic Protein: The 18 kDA Translocator Protein

PubMed Central

Ciancio, Gaetano; Nielsen, Gunnlaugur Petur; Jorda, Merce

2017-01-01

The adrenal glands produce a variety of hormones that play a key role in the regulation of blood pressure, electrolyte homeostasis, metabolism, immune system suppression, and the body's physiologic response to stress. Adrenal neoplasms can be asymptomatic or can overproduce certain hormones that lead to different clinical manifestations. Oncocytic adrenal neoplasms are infrequent tumors that arise from cells in the adrenal cortex and display a characteristic increase in the number of cytoplasmic mitochondria. Since the rate-limiting step in steroidogenesis includes the transport of cholesterol across the mitochondrial membranes, in part carried out by the 18-kDa translocator protein (TSPO), we assessed the expression of TSPO in a case of adrenal oncocytic neoplasm using residual adrenal gland of the patient as internal control. We observed a significant loss of TSPO immunofluorescence expression in the adrenal oncocytic tumor cells when compared to adjacent normal adrenal tissue. We further confirmed this finding by employing Western blot analysis to semiquantify TSPO expression in tumor and normal adrenal cells. Our findings could suggest a potential role of TSPO in the tumorigenesis of this case of adrenocortical oncocytic neoplasm. PMID:29318061

Epidermal growth factor inhibits rat pancreatic cell proliferation, causes acinar cell hypertrophy, and prevents caerulein-induced desensitization of amylase release.

PubMed

Morisset, J; Larose, L; Korc, M

1989-06-01

The in vivo effects of epidermal growth factor (EGF) on pancreatic growth and digestive enzyme concentrations were compared with the actions of the pancreatic secretagogue caerulein in the adult rat. EGF (10 micrograms/kg BW) did not alter pancreatic weight or protein content. However, this concentration of EGF inhibited [3H]thymidine incorporation into DNA by 44%, decreased DNA content by 20%, and increased the concentrations of amylase, chymotrypsinogen, and protein by 106%, 232%, and 42%, respectively. Pancreatic acini prepared from EGF-treated rats exhibited a characteristic secretory response to caerulein that was superimposable to that obtained in acini from saline-treated rats. In both groups of acini half-maximal and maximal stimulation of amylase release occurred at approximately 5 pM and 50 pM caerulein, respectively. In contrast to EGF, caerulein (1 microgram/kg BW) increased pancreatic weight by 29% and protein content by 59%, and enhanced [3H]thymidine incorporation into DNA by 70%. Although caerulein increased the concentrations of pancreatic amylase and chymotrypsinogen by 38% and 297%, respectively, pancreatic acini prepared from caerulein-treated rats were less sensitive to the actions of caerulein in vitro when compared with acini from control rats. Indeed, the EC50 was shift from 4.8 pM to 9.8 pM after 4 days of treatment. EGF potentiated the actions of caerulein on pancreatic weight, protein content, and chymotrypsinogen concentration, and prevented the caerulein-induced alteration in the secretory responsiveness of the acinar cell. Conversely, caerulein reversed the inhibitory effect of EGF on thymidine incorporation. These findings suggest that EGF may modulate the trophic effects of certain gastrointestinal hormones, and may participate in the regulation of pancreatic exocrine function in vivo.

Calcified pancreatic and peripancreatic neoplasms: spectrum of pathologies.

PubMed

Verde, Franco; Fishman, Elliot K

2017-11-01

A variety of pancreatic and peripancreatic neoplasms may contain calcifications. We present a review of common to uncommon pancreatic neoplasms that may contain calcifications to include ductal adenocarcinoma, pancreatic neuroendocrine tumors, serous cystadenomas, solid pseudopapillary tumors, intraductal papillary mucinous neoplasms, mucinous cystic neoplasms, and lymphoepithelial cysts. In addition, duodenal mucinous adenocarcinoma can present as a peripancreatic mass that may contain calcification. Knowledge of the spectrum of calcification patterns can help the interpreting radiologist provide a meaningful differential.

Malignant granular cell tumors: the role of electron microscopy in the definitive diagnosis of an extremely aggressive soft tissue neoplasm.

PubMed

Knowles, Kurt J; Al-Delfi, Firas; Abdulsattar, Jehan; Lacour, Robin; Black, Destin; Chaudhery, Shabnum; Turbat-Herrera, Elba A

2018-01-01

Granular cell tumors (GCTs) are rare soft tissue neoplasms which may be multicentric. The vast majority are benign, however approximately 100 malignant GCTs have been reported, with only 8 originating in the vulva. Malignant GCTs are very aggressive with very poor survival rates. As the diagnosis of malignant GCT carries an extremely poor prognosis, the utilization of EM ensures that the most accurate diagnosis possible can be rendered.

Blastic plasmacytoid dendritic cell neoplasm: clinical features in 90 patients.

PubMed

Julia, F; Petrella, T; Beylot-Barry, M; Bagot, M; Lipsker, D; Machet, L; Joly, P; Dereure, O; Wetterwald, M; d'Incan, M; Grange, F; Cornillon, J; Tertian, G; Maubec, E; Saiag, P; Barete, S; Templier, I; Aubin, F; Dalle, S

2013-09-01

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare disease characterized by malignant proliferation of a contingent blastic plasmacytoid dendritic cell. This rare entity is recognized mostly by cutaneous spreading, or not having a leukaemic component. The prognosis is very poor. To study a large cohort of 90 patients with BPDCN, to define additional symptoms to form a correct diagnosis earlier, and to manage such patients accordingly. We retrospectively reviewed BPDCN cases registered in the French Study Group on Cutaneous Lymphoma database between November 1995 and January 2012. Ninety patients were studied. Demographic data, clinical presentation, initial staging and outcome were recorded. The group contained 62 male and 28 female patients (sex ratio 2·2). Their ages ranged from 8 to 103 years at the time of diagnosis (mean 67·2 years). Three major different clinical presentations were identified. Sixty-six patients (73%) presented with nodular lesions only, 11 patients (12%) with 'bruise-like' patches and 13 (14%) with disseminated lesions (patches and nodules). Mucosal lesions were seen in five patients (6%). The median survival in patients with BPDCN was 12 months. We here distinguish three different clinical presentations of BPDCN. A nodular pattern is a more common feature than the originally reported 'bruise-like' pattern. Despite the fact that BPDCN may initially appear as a localized skin tumour, aggressive management including allogeneic bone marrow transplantation should be considered immediately, as it is currently the only option associated with long-term survival. © 2013 The Authors BJD © 2013 British Association of Dermatologists.

Characteristics of Patients With Sertoli and Leydig Cell Testis Neoplasms From a National Population-Based Registry.

PubMed

Osbun, Nathan; Winters, Brian; Holt, Sarah K; Schade, George R; Lin, Daniel W; Wright, Jonathan L

2017-04-01

Sertoli and Leydig cell tumors (SCT and LCT) are uncommon testis neoplasms. Data regarding patient demographics and outcomes are limited to small series. We further characterized these tumors using a large cancer database. The Surveillance, Epidemiology, and End Results (SEER) database was queried from 2004 to 2012. International Classification of Diseases for Oncology (ICD-O) codes identified SCT and LCT. Common germ cell tumors (GCT) provided a reference group. Age, race, histology, tumor size, stage, and cancer-specific mortality (CSM) were compared. Thirty-one men had SCT, 76 had LCT, and 17,998 had GCTs. Median follow-up for SCT, LCT, and GCTs was 46, 38, and 50 months, respectively. Median ages for SCT and LCT were 39 and 47, respectively, which was older than those with GCT (34 years; P < .001). African American race was more common in SCT (23%) and LCT (24%) patients compared to GCT (3%, P < .001). LCT most commonly presented with stage I disease (98.5%), while patients with SCT presented at higher stages (35% with stage II/III). CSM was highest in patients with SCT (32% vs. 2% LCT and 7% GCT, P < .001). Median survival of those with CSM was similar between SCT, LCT, and GCTs (15, 12, and 14 months, respectively). Compared to GCT, SCT and LCT present at older ages and are more common in African Americans. Metastasic disease at presentation and CSM rates are higher in SCT compared to LCT and GCT, suggesting a clinically relevant distinction between these histologies. Better characterization of these rare neoplasms will continue to inform patient counseling and management. Copyright © 2016 Elsevier Inc. All rights reserved.

Oncocytic Type Intraductal Papillary Mucinous Neoplasm of the Pancreas with Unusually Low Mucin Production Mimicking Intraductal Tubulopapillary Neoplasm: A Report of a Case Diagnosed by a Preoperative Endoscopic Biopsy

PubMed Central

Yoshida, Yukinari; Endo, Takao; Tanaka, Eiichi; Kikuchi, Takefumi; Akino, Kimishige; Mita, Hiroaki; Adachi, Yasuyo; Nakamura, Masahiro; Adachi, Yasushi; Ishii, Yoshifumi; Matsumoto, Joe; Hirano, Satoshi; Nitta, Takeo; Mitsuhashi, Tomoko; Kato, Yasuo

2017-01-01

We herein report the case of a 78-year-old woman with an intraductal tumor with scant mucin production in a moderately dilated main pancreatic duct that resembled an intraductal tubulopapillary neoplasm (ITPN) on imaging. An endoscopic transpapillary forceps biopsy enabled an accurate preoperative diagnosis of the tumor as an oncocytic type intraductal papillary mucinous neoplasm (IPMN) of the pancreas microscopically showing papillary growth consisting of oncocytic cells with a typical mucin expression profile, although with few intraepithelial lumina containing mucin. This is the first case of an oncocytic type IPMN mimicking an ITPN that was able to be diagnosed preoperatively. PMID:29021473

LOXL2 induces aberrant acinar morphogenesis via ErbB2 signaling

PubMed Central

2013-01-01

Introduction Lysyl oxidase-like 2 (LOXL2) is a matrix-remodeling enzyme that has been shown to play a key role in invasion and metastasis of breast carcinoma cells. However, very little is known about its role in normal tissue homeostasis. Here, we investigated the effects of LOXL2 expression in normal mammary epithelial cells to gain insight into how LOXL2 mediates cancer progression. Methods LOXL2 was expressed in MCF10A normal human mammary epithelial cells. The 3D acinar morphogenesis of these cells was assessed, as well as the ability of the cells to form branching structures on extracellular matrix (ECM)-coated surfaces. Transwell-invasion assays were used to assess the invasive properties of the cells. Clinically relevant inhibitors of ErbB2, lapatinib and Herceptin (traztuzumab), were used to investigate the role of ErbB2 signaling in this model. A retrospective study on a previously published breast cancer patient dataset was carried out by using Disease Specific Genomic Analysis (DSGA) to investigate the correlation of LOXL2 mRNA expression level with metastasis and survival of ErbB2-positive breast cancer patients. Results Fluorescence staining of the acini revealed increased proliferation, decreased apoptosis, and disrupted polarity, leading to abnormal lumen formation in response to LOXL2 expression in MCF10A cells. When plated onto ECM, the LOXL2-expressing cells formed branching structures and displayed increased invasion. We noted that LOXL2 induced ErbB2 activation through reactive oxygen species (ROS) production, and ErbB2 inhibition by using Herceptin or lapatinib abrogated the effects of LOXL2 on MCF10A cells. Finally, we found LOXL2 expression to be correlated with decreased overall survival and metastasis-free survival in breast cancer patients with ErbB2-positive tumors. Conclusions These findings suggest that LOXL2 expression in normal epithelial cells can induce abnormal changes that resemble oncogenic transformation and cancer progression

A rare sinonasal neoplasm: fibrosarcoma.

PubMed

Bercin, Sami; Muderris, Togay; Kırıs, Muzaffer; Kanmaz, Alper; Kandemir, Olcay

2011-05-01

Sinonasal fibrosarcoma is an infrequently occurring malignant neoplasm. It usually presents with nasal obstruction and epistaxis, as do other sarcomas in this region. The final diagnosis is based on the histopathologic and immunohistochemical examination. We report a case involving a 47-year-old woman with a 2-year history of left nasal obstruction and proptosis, as well as diplopia for the 2 months preceding her visit. Computed tomography and magnetic resonance imaging showed a neoplasm occupying the left nasal cavity, ethmoid sinuses, and bilateral frontal sinuses. The neoplasm also was eroding the medial wall of the maxillary sinus, the lamina papyracea, the cribriform plate, and the anterior wall of the frontal sinus. Complete removal of the tumor was achieved both endoscopically and through a Lynch incision. Sinonasal fibrosarcoma was found on histopathologic examination.

Does prostate acinar adenocarcinoma with Gleason Score 3+3=6 have the potential to metastasize?

PubMed

Montironi, Rodolfo; Scarpelli, Marina; Mazzucchelli, Roberta; Lopez-Beltran, Antonio; Santoni, Matteo; Briganti, Alberto; Montorsi, Francesco; Cheng, Liang

2014-10-18

There is a worldwide debate involving clinicians, uropathologists as well as patients and their families on whether Gleason score 6 adenocarcinoma should be labelled as cancer. We report a case of man diagnosed with biopsy Gleason score 6 acinar adenocarcinoma and classified as low risk (based on a PSA of 5 ng/mL and stage cT2a) whose radical prostatectomy specimen initially showed organ confined Gleason score 3+3=6, WHO nuclear grade 3, acinar adenocarcinoma with lymphovascular invasion and secondary deposit in a periprostatic lymph node. When deeper sections were cut to the point that almost all the slice present in the paraffin block was sectioned, a small tumor area (<5% of the whole tumor) of Gleason pattern 4 (poorly formed glands) was found in an extraprostatic position. The epilogue was that the additional finding changed the final Gleason score to 3+3=6 with tertiary pattern 4 and the stage to pT3a. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_190.

Immunohistochemical expression of protein p53 in neoplasms of the mammary gland in bitches.

PubMed

Rodo, A; Malicka, E

2008-01-01

The aim of the study was to investigate the presence of protein p53 in correlation with other tumor traits: histological type, tumor grade and proliferative activity. Material for the investigation comprised mammary gland tumours collected from dogs, the patients of veterinary clinics, during surgical procedures, and archival samples. Alltogether 21 adenomas, 31 complex carcinomas, 35 simple carcinomas and 12 solid carcinomas were qualified for further investigation. No protein p53 expression was found in adenomas. Cancers show positive reaction in 32.5%. The highest percent of p53 positive neoplasms was observed in solid carcinomas and neoplasms with the highest degree of histological malignancy. The smallest number showing this expression was observed in adenomas and the highest was characteristic for solid carcinomas. Considering the tumour grading, it was found that an increase in neoplasm malignancy was positively correlated with the number of the cells showing the expression of protein p53. The differences were statistically significant. Statistically significant positive correlations were observed between the proliferative activity and protein p53 expression. Higher accumulation of protein p53 in more malignant neoplasms suggests that mutations of protein p53 can be responsible for higher proliferation in neoplasms with advanced progression of malignancy.

Selective Immunophenotyping for Diagnosis of B-cell Neoplasms: Immunohistochemistry and Flow Cytometry Strategies and Results

PubMed Central

Boyd, Scott D.; Natkunam, Yasodha; Allen, John R.; Warnke, Roger A.

2012-01-01

Determining the immunophenotype of hematologic malignancies is now an indispensible part of diagnostic classification, and can help to guide therapy, or to predict clinical outcome. Diagnostic workup should be guided by morphologic findings and evaluate clinically important markers, but ideally should avoid the use of overly-broad panels of immunostains that can reveal incidental findings of uncertain significance and give rise to increased costs. Here, we outline our approach to diagnosis of B cell neoplasms, combining histologic and clinical data with tailored panels of immunophenotyping reagents, in the context of the 2008 World Health Organization classification. We present data from cases seen at our institution from 2004-8 using this approach, to provide a practical reference for findings seen in daily diagnostic practice. PMID:22820658

A Druggable TCF4 and BRD4 dependent Transcriptional Network Sustains Malignancy in Blastic Plasmacytoid Dendritic Cell Neoplasm

PubMed Central

Ceribelli, Michele; Hou, Zhiying Esther; Kelly, Priscilla N.; Huang, Da Wei; Wright, George; Ganapathi, Karthik; Evbuomwan, Moses O.; Pittaluga, Stefania; Shaffer, Arthur L.; Marcucci, Guido; Forman, Stephen J.; Xiao, Wenming; Guha, Rajarshi; Zhang, Xiaohu; Ferrer, Marc; Chaperot, Laurence; Plumas, Joel; Jaffe, Elaine S.; Thomas, Craig J.; Reizis, Boris; Staudt, Louis M.

2016-01-01

SUMMARY Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive and largely incurable hematologic malignancy originating from plasmacytoid dendritic cells (pDCs). Using RNA interference screening, we identified the E-box transcription factor TCF4 as a master regulator of the BPDCN oncogenic program. TCF4 served as a faithful diagnostic marker of BPDCN, and its downregulation caused the loss of the BPDCN-specific gene expression program and apoptosis. High-throughput drug screening revealed that bromodomain and extra-terminal domain inhibitors (BETi’s) induced BPDCN apoptosis, which was attributable to disruption of a BPDCN-specific transcriptional network controlled by TCF4-dependent super-enhancers. BETi’s retarded the growth of BPDCN xenografts, supporting their clinical evaluation in this recalcitrant malignancy. PMID:27846392

SFPQ/PSF-TFE3 renal cell carcinoma: a clinicopathologic study emphasizing extended morphology and reviewing the differences between SFPQ-TFE3 RCC and the corresponding mesenchymal neoplasm despite an identical gene fusion.

PubMed

Wang, Xiao-Tong; Xia, Qiu-Yuan; Ni, Hao; Ye, Sheng-Bing; Li, Rui; Wang, Xuan; Shi, Shan-Shan; Zhou, Xiao-Jun; Rao, Qiu

2017-05-01

Xp11 translocation renal cell carcinoma (RCC) with SFPQ/PSF-TFE3 gene fusion is a rare epithelial tumor. Of note, the appearance of the gene fusion does not necessarily mean that it is renal cell carcinoma. The corresponding mesenchymal neoplasms, including Xp11 neoplasm with melanocytic differentiation, TFE3 rearrangement-associated perivascular epithelioid cell tumor (PEComa) and melanotic Xp11 translocation renal cancer, can also harbor the identical gene fusion. However, the differences between Xp11 translocation RCC and the corresponding mesenchymal neoplasm have only recently been described. Herein, we examined 5 additional cases of SFPQ-TFE3 RCCs using clinicopathologic, immunohistochemical, and molecular analyses. One tumor had the typical morphologic features of SFPQ-TFE3 RCC, whereas other 3 cases demonstrated the unusual morphologic features associated with pseudorosettes formation or clusters of smaller cells, mimicking TFEB RCC. The remaining one showed branching tubules and papillary structure composed of clear and eosinophilic tumor cells. Immunohistochemically, all 5 cases demonstrated moderate (2+) or strong (3+) positive staining for TFE3, PAX-8 and CD10, whereas no cases demonstrated TFEB, Cathepsin K, CA-IX, CK7, Melan-A, or HMB-45 expression. Genetically, the fusion transcripts were identified in 3 cases by reverse-transcription polymerase chain reaction (RT-PCR). On the basis of fluorescence in situ hybridization (FISH) analysis, all the cases were detected with SFPQ-TFE3 gene fusion. Clinical follow-up data were available for all the patients, and no one developed tumor recurrence, progression, or metastasis. We also review the differences between SFPQ-TFE3 RCC and the corresponding mesenchymal neoplasm despite the identical gene fusion. The presence of pseudorosettes also expands the known histological features of SFPQ-TFE3 RCC. Copyright © 2017 Elsevier Inc. All rights reserved.

Involvement of mast cells by the malignant process in patients with Philadelphia chromosome negative myeloproliferative neoplasms.

PubMed

Wang, J; Ishii, T; Zhang, W; Sozer, S; Dai, Y; Mascarenhas, J; Najfeld, V; Zhao, Z J; Hoffman, R; Wisch, N; Xu, M

2009-09-01

The Philadelphia chromosome negative myeloproliferative neoplasms (MPNs) are clonal hematologic malignancies frequently characterized by a mutation in JAK2 (JAK2V617F). Peripheral blood (PB) CD34(+) cells from patients with polycythemia vera (PV) and primary myelofibrosis (PMF) generated in vitro significantly fewer mast cells (MCs) than normal PB CD34(+) cells. The numbers of MC progenitors assayed from MPN CD34(+) cells were, however, similar to that assayed from normal CD34(+) cells. A higher percentage of the cultured MPN MCs expressed FcvarepsilonRIalpha, CD63 and CD69 than normal MCs, suggesting that cultured MPN MCs are associated with an increased state of MC activation. Further analysis showed that a higher proportion of cultured PV and PMF MCs underwent apoptosis in vitro. By using JAK2V617F, MplW515L and chromosomal abnormalities as clonality markers, we showed that the malignant process involved MPN MCs. JAK2V617F-positive MC colonies were assayable from the PB CD34(+) cells of each of the 17 JAK2V617F positive MPN patients studied. Furthermore, erlotinib, a JAK2 inhibitor, was able to inhibit JAK2V617F-positive PV MC progenitor cells, indicating that malignant MC progenitor cells are a potential cellular target for such JAK2 inhibitor-directed therapy.

Endoscopic submucosal tunnel dissection for large superficial esophageal squamous cell neoplasms

PubMed Central

Zhai, Ya-Qi; Li, Hui-Kai; Linghu, En-Qiang

2016-01-01

Endoscopic submucosal dissection (ESD) is a well-established treatment for superficial esophageal squamous cell neoplasms (SESCNs) with no risk of lymphatic metastasis. However, for large SESCNs, especially when exceeding two-thirds of the esophageal circumference, conventional ESD is time-consuming and has an increased risk of adverse events. Based on the submucosal tunnel conception, endoscopic submucosal tunnel dissection (ESTD) was first introduced by us to remove large SESCNs, with excellent results. Studies from different centers also reported favorable results. Compared with conventional ESD, ESTD has a more rapid dissection speed and R0 resection rate. Currently in China, ESTD for large SESCNs is an important part of the digestive endoscopic tunnel technique, as is peroral endoscopic myotomy for achalasia and submucosal tunnel endoscopic resection for submucosal tumors of the muscularis propria. However, not all patients with SESCNs are candidates for ESTD, and postoperative esophageal strictures should also be taken into consideration, especially for lesions with a circumference greater than three-quarters. In this article, we describe our experience, review the literature of ESTD, and provide detailed information on indications, standard procedures, outcomes, and complications of ESTD. PMID:26755889

LXR agonist treatment of blastic plasmacytoid dendritic cell neoplasm restores cholesterol efflux and triggers apoptosis

PubMed Central

Ceroi, Adam; Masson, David; Roggy, Anne; Roumier, Christophe; Chagué, Cécile; Gauthier, Thierry; Philippe, Laure; Lamarthée, Baptiste; Angelot-Delettre, Fanny; Bonnefoy, Francis; Perruche, Sylvain; Biichle, Sabeha; Preudhomme, Claude; Macintyre, Elisabeth; Lagrost, Laurent; Garnache-Ottou, Francine

2016-01-01

Blastic plasmacytoid dendritic cell (PDC) neoplasm (BPDCN) is an aggressive hematological malignancy with a poor prognosis that derives from PDCs. No consensus for optimal treatment modalities is available today and the full characterization of this leukemia is still emerging. We identified here a BPDCN-specific transcriptomic profile when compared with those of acute myeloid leukemia and T-acute lymphoblastic leukemia, as well as the transcriptomic signature of primary PDCs. This BPDCN gene signature identified a dysregulation of genes involved in cholesterol homeostasis, some of them being liver X receptor (LXR) target genes. LXR agonist treatment of primary BPDCN cells and BPDCN cell lines restored LXR target gene expression and increased cholesterol efflux via the upregulation of adenosine triphosphate–binding cassette (ABC) transporters, ABCA1 and ABCG1. LXR agonist treatment was responsible for limiting BPDCN cell proliferation and inducing intrinsic apoptotic cell death. LXR activation in BPDCN cells was shown to interfere with 3 signaling pathways associated with leukemic cell survival, namely: NF-κB activation, as well as Akt and STAT5 phosphorylation in response to the BPDCN growth/survival factor interleukin-3. These effects were increased by the stimulation of cholesterol efflux through a lipid acceptor, the apolipoprotein A1. In vivo experiments using a mouse model of BPDCN cell xenograft revealed a decrease of leukemic cell infiltration and BPDCN-induced cytopenia associated with increased survival after LXR agonist treatment. This demonstrates that cholesterol homeostasis is modified in BPDCN and can be normalized by treatment with LXR agonists which can be proposed as a new therapeutic approach. PMID:27702801

Myxomatous neoplasms in the perineal region of baboons

PubMed Central

Wallace, Shannon M.; Szabo, Kathleen A.; Schlabritz-Loutsevitch, Natalia E.; Dick, Edward J.; Blanchard, Terrell W.; Hubbard, Gene B.

2012-01-01

Background In baboons, Papio sp. neoplasms tend to affect the hematopoietic system most commonly, with rare documentation of myxomatous neoplasms. In contrast, women can develop myxomatous masses within deep peripelvic tissues with some frequency during their reproductive years. Methods We have identified and examined, retrospectively, myxomatous perineal masses in twelve female baboons within one research facility and compared their histopathologic, immunohistochemical and electron microscopic features to their human variants. Results Our results indicate that these myxomatous neoplasms, in humans and non-human primates, share common features. Conclusion Further research, particularly molecular genetic analysis, may be needed to identify the baboon as a true animal model for myxomatous perineal neoplasms. PMID:19017193

Guanylyl Cyclase C Is a Specific Marker for Differentiating Primary and Metastatic Ovarian Mucinous Neoplasms

PubMed Central

Ciocca, Vincenzo; Bombonati, Alessandro; Palazzo, Juan P.; Schulz, Stephanie; Waldman, Scott A.

2011-01-01

Distinguishing primary ovarian mucinous neoplasms from metastatic mucinous adenocarcinomas with ovarian involvement can be difficult, especially when characteristic gross and microscopic features are not present. CK7/CK20 expression appears to be more useful for distinguishing metastatic gastrointestinal adenocarcinomas from the lower tract. The addition of CDX2 for distinguishing metastatic upper gastrointestinal tract adenocarcinomas from primary ovarian mucinous neoplasms offers little advantage over CK7/CK20 coordinate expression. Guanylyl cyclase C (GCC) is a brush border membrane receptor for the endogenous peptides guanylin and uroguanylin, and the homologous diarrheagenic bacterial heat-stable enterotoxins that is selectively expressed by epithelial cells from the duodenum to the rectum, but not by normal epithelia of the stomach or esophagus, or normal extramucosal cells in humans. We studied 50 ovarian tumors: 27 primary ovarian mucinous neoplasms (7 cystadenomas, 10 borderline tumors, and 10 cystadenocarcinomas) and 23 metastatic mucinous adenocarcinomas with ovarian involvement (13 colorectal adenocarcinomas, 4 gastric adenocarcinomas, 6 appendiceal mucinous tumors (4 adenocarcinomas, 1 with neuroendocrine features, and 2 appendiceal mucinous cystadenomas). For primary ovarian mucinous neoplasms, 25 of 27 were negative for GCC. Twelve of thirteen cases of colorectal adenocarcinoma (except for 1 neuroendocrine adenocarcinoma) were positive for GCC. Three of four appendiceal mucinous adenocarcinomas were positive for GCC in both the primary and metastatic tumors (except for 1 neuroendocrine adenocarcinoma). Two of two appendiceal mucinous cystadenomas were positive for GCC. Of four cases of gastric adenocarcinoma with ovarian involvement, only one (primary tumor) exhibited focal GCC staining. These findings suggest GCC may be a useful marker for differentiating primary and secondary ovarian mucinous neoplasms. PMID:19694825

Central Cemento-Ossifying Fibroma: Primary Odontogenic or Osseous Neoplasm?

PubMed

Woo, Sook-Bin

2015-12-01

Currently, central cemento-ossifying fibroma is classified by the World Health Organization as a primary bone-forming tumor of the jaws. However, histopathologically, it is often indistinguishable from cemento-osseous dysplasias in that it forms osteoid and cementicles (cementum droplets) in varying proportions. It is believed that pluripotent cells within the periodontal membrane can be stimulated to produce either osteoid or woven bone and cementicles when stimulated. If this is true, cemento-ossifying fibroma would be better classified as a primary odontogenic neoplasm arising from the periodontal ligament. Cemento-ossifying fibromas also do not occur in the long bones. The present report compares several entities that fall within the diagnostic realm of benign fibro-osseous lesions and reviews the evidence for reclassifying central cemento-ossifying fibroma as a primary odontogenic neoplasm. Copyright © 2015 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

The role of the JAK2 GGCC haplotype and the TET2 gene in familial myeloproliferative neoplasms

PubMed Central

Olcaydu, Damla; Rumi, Elisa; Harutyunyan, Ashot; Passamonti, Francesco; Pietra, Daniela; Pascutto, Cristiana; Berg, Tiina; Jäger, Roland; Hammond, Emma; Cazzola, Mario; Kralovics, Robert

2011-01-01

myeloproliferative neoplasms. As we observed an increased frequency of malignant disorders in patients with familial myeloproliferative neoplasms, we hypothesize that the germline genetic lesions that underlie familial clustering of myeloproliferative neoplasms predispose to somatic mutagenesis that is not restricted to myeloid hematopoietic cells but cause an increase in overall carcinogenesis. PMID:21173100

[CHARACTERISTICS AND INCIDENCE OF HEAD AND NECK SKIN MALIGNANT NEOPLASMS IN THE POPULATION OF THE OSIJEK-BARANYA COUNTY 2004-2012].

PubMed

Orkić, Želimir; Puntarić, Dinko; Puntarić, Eda; Puntarić, Ida; Vidosavljević, Domagoj; Gvozdić, Vlatka; Mayer, Dijana

2015-03-01

The aim of this study was to investigate the incidence and characteristics of malignant neoplasms of the skin of the head and neck region in the Osijek-Baranya County during the 2004-2012 period according to gender, age, place of residence, place of work, occupation, type and location of the neoplasm, and phenotypic characteristics of patients. The study included all subjects with the diagnosis confirmed by histopathology finding and residents of the Osijek-Baranya County. The study included a total of 2952 persons, 1487 (50.4%) male and 1465 (49.6%) female, yielding an approximate annual incidence of 104/100,000. Mean age was 72 years. Respondents were mostly from rural areas (n = 1952, 66.2%). There were 2137 (72.4%) of respondents mostly working outdoors, mainly farmers (n = 907, 42.4%) and construction workers (n = 889, 41.6%). According to the type of neoplasm, the basal cell type was most common with 2160 (73.2%) patients. Ninety-three (3.1 %) patients had malignant melanoma. According to localization, face was the most common site of malignant neoplasms with 839 (28.7%) and nose with 643 (22.0%) patients. Squamous cell carcinoma was significantly more common in men (n = 341, 56.6%) as compared with women (n = 262, (43.4%; p = 0.005). Subjects with malignant melanoma were significantly younger, with median age of 67 years. There were no significant differences according to the type of malignant neoplasms and place of residence, place of business, and occupation with regard to working outdoors or indoors. According to localization, significantly more squamous cell malignancies were found on the ears and lips (p = 0.039 and p < 0.001, respectively), malignant melanomas on the neck, head and eyes (p = 0.004, p < 0.001 and p = 0.026, respectively), and basal cell neoplasms on the nose (p = 0.002). There were no significant differences in the type and frequency of malignant neoplasms according to hair and eye color. It is obvious that the disease occurs after a

Role of leptin in modulation of Porphyromonas gingivalis lipopolysaccharide-induced up-regulation of endothelin-1 in salivary gland acinar cells.

PubMed

Slomiany, Bronislaw L; Slomiany, Amalia

2005-08-01

Leptin, a pleiotropic cytokine that regulates food intake and metabolic and endocrine responses, has emerged recently as an important regulator of mucosal inflammatory responses to bacterial infection. In this study, we report that in sublingual salivary gland acinar cells leptin plays a role in the suppression of up-regulation in endothelin-1 (ET-1), induced by the LPS of a periodontopathic bacterium P. gingivalis. We show that P. gingivalisLPS detrimental effect on salivary mucin synthesis, associated with up-regulation (3.9-fold) in ET-1 generation and the enhancement (3.2-fold) in endothelin-converting enzyme-1 (ECE-1) activity, was subject to a dose-dependent suppression by leptin. The impedance by leptin of the LPS inhibitory effect on mucin synthesis was blocked by wortmannin, an inhibitor of PI3K, as well as by ERK inhibitor, PD98059. However, while the blockade of ERK led also to amplification in the impedance by leptin of the LPS-induced expression of ECE-1 and ET-1, the effect was not observed in the presence of wortmannin. The findings are the first to demonstrate that leptin counters the pathological consequences of P. gingivalisinfection on the synthesis of salivary mucin through the involvement in signaling events of PI3K and ERK pathways. We also show that the ERK cascade represents a critical signaling target for leptin in the LPS-induced up-regulation in ET-1.

The role of immunohistochemistry, electron microscopy, and ultrastructural cytochemistry in the diagnosis of mixed carcinoma-neuroendocrine neoplasms.

PubMed

Graham, A R; Payne, C M; Nagle, R B; Angel, E

1987-02-01

We studied four mixed carcinoma-neuroendocrine neoplasms from gastrointestinal tract and pancreas by routine light microscopy (LM), immunohistochemistry (IH), electron microscopy (EM), and ultrastructural cytochemistry (UC). By LM, the individual tumors showed fairly pure neuroendocrine (carcinoid) or epithelial (papillary) patterns, mixed neuroendocrine-carcinoma features and poorly-differentiated tumor in sheets and nests which did not lend itself to morphologic characterization. IH demonstrated mixed expression, within different areas of the same neoplasm, of epithelial antigens (keratins and carcinoembryonic antigen [CEA]) and neuroendocrine markers (neuron-specific enolase [NSE], bombesin and neurohormonal peptides). By EM, each tumor showed ultrastructural features of epithelial and neuroendocrine differentiation which varied substantially in terms of number of cells involved and their distribution; two of the neoplasms showed biphasic differentiation within single cells. The nature of the neurosecretory granules was verified with the uranaffin reaction (UR). This study illustrates the value of combining LM, IH, EM and UC for the identification of mixed carcinoma-neuroendocrine lesions.

Fine needle aspiration biopsy diagnosis of metastatic neoplasms of the breast. A three-case report

PubMed Central

Raquel, Garza-Guajardo; Nora, Mendez-Olvera; Pablo, Flores-Gutierrez Juan; Silvia, Hernandez-Martinez; Michelle, Candanosa-Mc Cann; Jesús, Ancer-Rodriguez; Oralia, Barboza-Quintana

2005-01-01

Metastases to the breast are unusual lesions that make up approximately 2% of all malignant mammary neoplasms and may mimic both benign and malignant primary neoplasms from a clinical point of view, as well as in imaging studies. Arriving at a correct diagnosis is therefore essential in order to establish appropriate management. We present three cases of metastatic neoplasms diagnosed through fine needle aspiration biopsy and immunocytochemistry. The cytological diagnoses were: medulloblastoma in an 18-year-old woman, melanoma in a 26-year-old man, and an exceptional case of ovarian sarcoma originating from a granulosa cell tumor with metastases to both breasts. A metastatic disease should be considered in the differential diagnosis of a palpable mass in the breast, especially if there is a history of an extramammary malignant neoplasm. Fine needle aspiration biopsy is the method of choice for the management of these cases. Whenever possible the exam of the material obtained should be compared to the previous biopsy, which is usually enough to arrive at a correct diagnosis, thus preventing unnecessary surgical procedures. PMID:16174298

E-cadherin immunohistochemical expression in mammary gland neoplasms in bitches.

PubMed

Rodo, A; Malicka, E

2008-01-01

The aim of the study was to investigate E-cadherin expression in correlation with other neoplasm traits such as: histological type, the differentiation grade and proliferative activity. Material for the investigation comprised mammary gland tumours, collected from dogs, the patients of veterinary clinics, during surgical procedures and archival samples. All together 21 adenomas, 32 complex carcinomas, 35 simple carcinomas and 13 solid carcinomas were qualified for further investigation. E-cadherin expression was higher in adenomas as compared with carcinomas but lower in solid carcinomas as compared with simple and complex carcinomas. More over, the expression of E-cadherin decreased with the increase in the neoplasm malignancy and proliferative activity (value of the mitotic index and number of cells showing Ki67). The study has shown that the expression of E-cadherin can be used as a prognostic factor.

[Spontaneous neoplasms in guinea pigs].

PubMed

Khar'kovskaia, N A; Khrustalev, S A; Vasil'eva, N N

1977-01-01

The authors present an analysis of the data of foreign literature and the results of their personal studies of spontaneous neoplasms in 40 guinea pigs of national breeding observed during observed during a 5-year period. In 4 of them malignant tumors were diagnosed-lympholeucosis (2 cases), dermoid ovarian cysts and also cancer and adenoma of the adrenal cortex (in one animal). The neoplasms described developed in guinea pigs, aged over 4 years, and they are referred to as mostly common tumors in this species of animals.

Biliary papillary neoplasm of the liver.

PubMed

Nakanuma, Y; Sasaki, M; Ishikawa, A; Tsui, W; Chen, T C; Huang, S F

2002-01-01

Biliary papillary neoplasia of the liver characterized by intraductal papillary growth of neoplastic biliary epithelia with a fine fibrovascular stalk has been sporadically reported, and includes intraductal growing cholangiocarcinoma and biliary papillomatosis. In addition, biliary papillary dysplasia and in situ and microinvasive carcinoma with papillary configuration reported in hepatolithiasis and in other chronic biliary diseases, could be included in this category. Usually, they arise in the intrahepatic large bile ducts, and the neoplastic and non-neoplastic parts of the intrahepatic biliary tree show saccular and segmental dilatation with mucin hypersecretion. This neoplasia frequently shows intraductal spreading and peribiliary glandular involvement. Acute repeated episodes of cholangitis or obstructive jaundice are a frequent clinical manifestation. Gastroenteric metaplasia with aberrant expression of cytokeratin 20, MUC2, MUC5AC, and/or MUC6, is frequent in the neoplastic parts, and biliary epithelial dysplasia with such metaplasia may give rise to in situ and then invasive carcinoma in hepatolithiasis. Interestingly, this type tends to contain foci of mucinous carcinoma elements, and this element may be predominant (mucinous carcinoma). Some may progress to "mucinous biliary cystadenocarcinoma" without ovarian mesenchymal stroma and with intraluminal continuous growth into the neighboring bile duct lumens. Interestingly, the biliary papillary neoplasm resembles histologically, phenotypically and clinically intraductal papillary mucinous neoplasm of the pancreas which is now being established as an infrequent, slow-growing pancreatic neoplasm. Recognition of such biliary papillary neoplasm with respect to the pancreatic equivalent may lead to a better understanding and further studies of the intrahepatic biliary neoplasm.

Classification and clinical behavior of blastic plasmacytoid dendritic cell neoplasms according to their maturation-associated immunophenotypic profile

PubMed Central

Martín-Martín, Lourdes; López, Antonio; Vidriales, Belén; Caballero, María Dolores; Rodrigues, António Silva; Ferreira, Silvia Inês; Lima, Margarida; Almeida, Sérgio; Valverde, Berta; Martínez, Pilar; Ferrer, Ana; Candeias, Jorge; Ruíz-Cabello, Francisco; Buadesa, Josefa Marco; Sempere, Amparo; Villamor, Neus

2015-01-01

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare subtype of leukemia/lymphoma, whose diagnosis can be difficult to achieve due to its clinical and biological heterogeneity, as well as its overlapping features with other hematologic malignancies. In this study we investigated whether the association between the maturational stage of tumor cells and the clinico-biological and prognostic features of the disease, based on the analysis of 46 BPDCN cases classified into three maturation-associated subgroups on immunophenotypic grounds. Our results show that blasts from cases with an immature plasmacytoid dendritic cell (pDC) phenotype exhibit an uncommon CD56− phenotype, coexisting with CD34+ non-pDC tumor cells, typically in the absence of extramedullary (e.g. skin) disease at presentation. Conversely, patients with a more mature blast cell phenotype more frequently displayed skin/extramedullary involvement and spread into secondary lymphoid tissues. Despite the dismal outcome, acute lymphoblastic leukemia-type therapy (with central nervous system prophylaxis) and/or allogeneic stem cell transplantation appeared to be the only effective therapies. Overall, our findings indicate that the maturational profile of pDC blasts in BPDCN is highly heterogeneous and translates into a wide clinical spectrum -from acute leukemia to mature lymphoma-like behavior-, which may also lead to variable diagnosis and treatment. PMID:26056082

Ibrutinib inhibition of Bruton protein-tyrosine kinase (BTK) in the treatment of B cell neoplasms.

PubMed

Roskoski, Robert

2016-11-01

The Bruton non-receptor protein-tyrosine kinase (BTK), a deficiency of which leads to X-linked agammaglobulinemia, plays a central role in B cell antigen receptor signaling. Owing to the exclusivity of this enzyme in B cells, the acronym could represent B cell tyrosine kinase. BTK is activated by the Lyn and SYK protein kinases following activation of the B cell receptor. BTK in turn catalyzes the phosphorylation and activation of phospholipase Cγ2 leading to the downstream activation of the Ras/RAF/MEK/ERK pathway and the NF-κB pathways. Both pathways participate in the maturation of antibody-producing B cells. The BTK domains include a PH (pleckstrin homology) domain that interacts with membrane-associated phosphatidyl inositol trisphosphate, a TH (TEC homology) domain, which is followed by an SH3, SH2, and finally a protein kinase domain. Dysregulation of B cell receptor signaling occurs in several B cell neoplasms including mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenström macroglobulinemia. Ibrutinib is FDA-approved as first-line or second line treatment for these diseases. The drug binds tightly in the ATP-binding pocket of BTK making salt bridges with residues within the hinge that connects the two lobes of the enzyme; then its unsaturated acrylamide group forms a covalent bond with BTK cysteine 481 to form an inactive adduct. In addition to the treatment of various B cell lymphomas, ibrutinib is under clinical trials for the treatment of numerous solid tumors owing to the role of tumor-promoting inflammation in the pathogenesis of neoplastic diseases. Copyright © 2016 Elsevier Ltd. All rights reserved.

LXR agonist treatment of blastic plasmacytoid dendritic cell neoplasm restores cholesterol efflux and triggers apoptosis.

PubMed

Ceroi, Adam; Masson, David; Roggy, Anne; Roumier, Christophe; Chagué, Cécile; Gauthier, Thierry; Philippe, Laure; Lamarthée, Baptiste; Angelot-Delettre, Fanny; Bonnefoy, Francis; Perruche, Sylvain; Biichle, Sabeha; Preudhomme, Claude; Macintyre, Elisabeth; Lagrost, Laurent; Garnache-Ottou, Francine; Saas, Philippe

2016-12-08

Blastic plasmacytoid dendritic cell (PDC) neoplasm (BPDCN) is an aggressive hematological malignancy with a poor prognosis that derives from PDCs. No consensus for optimal treatment modalities is available today and the full characterization of this leukemia is still emerging. We identified here a BPDCN-specific transcriptomic profile when compared with those of acute myeloid leukemia and T-acute lymphoblastic leukemia, as well as the transcriptomic signature of primary PDCs. This BPDCN gene signature identified a dysregulation of genes involved in cholesterol homeostasis, some of them being liver X receptor (LXR) target genes. LXR agonist treatment of primary BPDCN cells and BPDCN cell lines restored LXR target gene expression and increased cholesterol efflux via the upregulation of adenosine triphosphate-binding cassette (ABC) transporters, ABCA1 and ABCG1. LXR agonist treatment was responsible for limiting BPDCN cell proliferation and inducing intrinsic apoptotic cell death. LXR activation in BPDCN cells was shown to interfere with 3 signaling pathways associated with leukemic cell survival, namely: NF-κB activation, as well as Akt and STAT5 phosphorylation in response to the BPDCN growth/survival factor interleukin-3. These effects were increased by the stimulation of cholesterol efflux through a lipid acceptor, the apolipoprotein A1. In vivo experiments using a mouse model of BPDCN cell xenograft revealed a decrease of leukemic cell infiltration and BPDCN-induced cytopenia associated with increased survival after LXR agonist treatment. This demonstrates that cholesterol homeostasis is modified in BPDCN and can be normalized by treatment with LXR agonists which can be proposed as a new therapeutic approach. © 2016 by The American Society of Hematology.

Pathological and Molecular Evaluation of Pancreatic Neoplasms

PubMed Central

Rishi, Arvind; Goggins, Michael; Wood, Laura D.; Hruban, Ralph H.

2015-01-01

Pancreatic neoplasms are morphologically and genetically heterogeneous and include wide variety of neoplasms ranging from benign to malignant with an extremely poor clinical outcome. Our understanding of these pancreatic neoplasms has improved significantly with recent advances in cancer sequencing. Awareness of molecular pathogenesis brings in new opportunities for early detection, improved prognostication, and personalized gene-specific therapies. Here we review the pathological classification of pancreatic neoplasms from their molecular and genetic perspective. All of the major tumor types that arise in the pancreas have been sequenced, and a new classification that incorporates molecular findings together with pathological findings is now possible (Table 1). This classification has significant implications for our understanding of why tumors aggregate in some families, for the development of early detection tests, and for the development of personalized therapies for patients with established cancers. Here we describe this new classification using the framework of the standard histological classification. PMID:25726050

Blastic Plasmacytoid Dendritic Cell Neoplasm Is Dependent on BCL2 and Sensitive to Venetoclax.

PubMed

Montero, Joan; Stephansky, Jason; Cai, Tianyu; Griffin, Gabriel K; Cabal-Hierro, Lucia; Togami, Katsuhiro; Hogdal, Leah J; Galinsky, Ilene; Morgan, Elizabeth A; Aster, Jon C; Davids, Matthew S; LeBoeuf, Nicole R; Stone, Richard M; Konopleva, Marina; Pemmaraju, Naveen; Letai, Anthony; Lane, Andrew A

2017-02-01

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematologic malignancy with dismal outcomes for which no standard therapy exists. We found that primary BPDCN cells were dependent on the antiapoptotic protein BCL2 and were uniformly sensitive to the BCL2 inhibitor venetoclax, as measured by direct cytotoxicity, apoptosis assays, and dynamic BH3 profiling. Animals bearing BPDCN patient-derived xenografts had disease responses and improved survival after venetoclax treatment in vivo Finally, we report on 2 patients with relapsed/refractory BPDCN who received venetoclax off-label and experienced significant disease responses. We propose that venetoclax or other BCL2 inhibitors undergo expedited clinical evaluation in BPDCN, alone or in combination with other therapies. In addition, these data illustrate an example of precision medicine to predict treatment response using ex vivo functional assessment of primary tumor tissue, without requiring a genetic biomarker. Therapy for BPDCN is inadequate, and survival in patients with the disease is poor. We used primary tumor cell functional profiling to predict BCL2 antagonist sensitivity as a common feature of BPDCN, and demonstrated in vivo clinical activity of venetoclax in patient-derived xenografts and in 2 patients with relapsed chemotherapy-refractory disease. Cancer Discov; 7(2); 156-64. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 115. ©2016 American Association for Cancer Research.

Krüppel-like Factor 5, Increased in Pancreatic Ductal Adenocarcinoma, Promotes Proliferation, Acinar-to-Ductal Metaplasia, Pancreatic Intraepithelial Neoplasia, and Tumor Growth in Mice.

PubMed

He, Ping; Yang, Jong Won; Yang, Vincent W; Bialkowska, Agnieszka B

2018-04-01

Activating mutations in KRAS are detected in most pancreatic ductal adenocarcinomas (PDACs). Expression of an activated form of KRAS (KrasG12D) in pancreata of mice is sufficient to induce formation of pancreatic intraepithelial neoplasia (PanINs)-a precursor of PDAC. Pancreatitis increases formation of PanINs in mice that express KrasG12D by promoting acinar-to-ductal metaplasia (ADM). We investigated the role of the transcription factor Krüppel-like factor 5 (KLF5) in ADM and KRAS-mediated formation of PanINs. We performed studies in adult mice with conditional disruption of Klf5 (Klf5 fl/fl ) and/or expression of Kras G12D (LSL-Kras G12D ) via Cre ERTM recombinase regulated by an acinar cell-specific promoter (Ptf1a). Activation of Kras G12D and loss of KLF5 was achieved by administration of tamoxifen. Pancreatitis was induced in mice by administration of cerulein; pancreatic tissues were collected, analyzed by histology and immunohistochemistry, and transcriptomes were compared between mice that did or did not express KLF5. We performed immunohistochemical analyses of human tissue microarrays, comparing levels of KLF5 among 96 human samples of PDAC. UN-KC-6141 cells (pancreatic cancer cells derived from Pdx1-Cre;LSL-Kras G12D mice) were incubated with inhibitors of different kinases and analyzed in proliferation assays and by immunoblots. Expression of KLF5 was knocked down with small hairpin RNAs or CRISPR/Cas9 strategies; cells were analyzed in proliferation and gene expression assays, and compared with cells expressing control vectors. Cells were subcutaneously injected into flanks of syngeneic mice and tumor growth was assessed. Of the 96 PDAC samples analyzed, 73% were positive for KLF5 (defined as nuclear staining in more than 5% of tumor cells). Pancreata from Ptf1a-Cre ERTM ;LSL-Kras G12D mice contained ADM and PanIN lesions, which contained high levels of nuclear KLF5 within these structures. In contrast, Ptf1a-Cre ERTM ;LSL-Kras G12D ;Klf5 fl

Myeloproliferative Neoplasm Animal Models

PubMed Central

Mullally, Ann; Lane, Steven W.; Brumme, Kristina; Ebert, Benjamin L.

2012-01-01

Synopsis Myeloproliferative neoplasm (MPN) animal models accurately re-capitulate human disease in mice and have been an important tool for the study of MPN biology and therapy. Transplantation of BCR-ABL transduced bone marrow cells into irradiated syngeneic mice established the field of MPN animal modeling and the retroviral bone marrow transplantation (BMT) assay has been used extensively since. Genetically engineered MPN animal models have enabled detailed characterization of the effects of specific MPN associated genetic abnormalities on the hematopoietic stem and progenitor cell (HSPC) compartment and xenograft models have allowed the study of primary human MPN-propagating cells in vivo. All models have facilitated the pre-clinical development of MPN therapies. JAK2V617F, the most common molecular abnormality in BCR-ABL negative MPN, has been extensively studied using retroviral, transgenic, knock-in and xenograft models. MPN animal models have also been used to investigate additional genetic lesions found in human MPN and to evaluate the bone marrow microenvironment in these diseases. Finally, several genetic lesions, although not common, somatically mutated drivers of MPN in humans induce a MPN phenotype in mice. Future uses for MPN animal models will include modeling compound genetic lesions in MPN and studying myelofibrotic transformation. PMID:23009938

Philadelphia-negative chronic myeloproliferative neoplasms

PubMed Central

Bittencourt, Rosane Isabel; Vassallo, Jose; Chauffaille, Maria de Lourdes Lopes Ferrari; Xavier, Sandra Guerra; Pagnano, Katia Borgia; Nascimento, Ana Clara Kneese; De Souza, Carmino Antonio; Chiattone, Carlos Sergio

2012-01-01

Chronic myeloproliferative diseases without the Philadelphia chromosome marker (Ph-), although first described 60 years ago, only became the subject of interest after the turn of the millennium. In 2001, the World Health Organization (WHO) defined the classification of this group of diseases and in 2008 they were renamed myeloproliferative neoplasms based on morphological, cytogenetic and molecular features. In 2005, the identification of a recurrent molecular abnormality characterized by a gain of function with a mutation in the gene encoding Janus kinase 2 (JAK2) paved the way for greater knowledge of the pathophysiology of myeloproliferative neoplasms. The JAK2 mutation is found in 90-98% of polycythemia vera and in about 50% essential thrombocytosis and primary myelofibrosis. In addition to the JAK2 mutation, other mutations involving TET2 (ten-eleven translocation), LNK (a membrane-bound adaptor protein); IDH1/2 (isocitrate dehydrogenase 1/2 enzyme); ASXL1 (additional sex combs-like 1) genes were found in myeloproliferative neoplasms thus showing the importance of identifying molecular genetic alterations to confirm diagnosis, guide treatment and improve our understanding of the biology of these diseases. Currently, polycythemia vera, essential thrombocytosis, myelofibrosis, chronic neutrophilic leukemia, chronic eosinophilic leukemia and mastocytosis are included in this group of myeloproliferative neoplasms, but are considered different situations with individualized diagnostic methods and treatment. This review updates pathogenic aspects, molecular genetic alterations, the fundamental criteria for diagnosis and the best approach for each of these entities. PMID:23049404

Altered glutamyl-aminopeptidase activity and expression in renal neoplasms

PubMed Central

2014-01-01

Background Advances in the knowledge of renal neoplasms have demonstrated the implication of several proteases in their genesis, growth and dissemination. Glutamyl-aminopeptidase (GAP) (EC. 3.4.11.7) is a zinc metallopeptidase with angiotensinase activity highly expressed in kidney tissues and its expression and activity have been associated wtih tumour development. Methods In this prospective study, GAP spectrofluorometric activity and immunohistochemical expression were analysed in clear-cell (CCRCC), papillary (PRCC) and chromophobe (ChRCC) renal cell carcinomas, and in renal oncocytoma (RO). Data obtained in tumour tissue were compared with those from the surrounding uninvolved kidney tissue. In CCRCC, classic pathological parameters such as grade, stage and tumour size were stratified following GAP data and analyzed for 5-year survival. Results GAP activity in both the membrane-bound and soluble fractions was sharply decreased and its immunohistochemical expression showed mild staining in the four histological types of renal tumours. Soluble and membrane-bound GAP activities correlated with tumour grade and size in CCRCCs. Conclusions This study suggests a role for GAP in the neoplastic development of renal tumours and provides additional data for considering the activity and expression of this enzyme of interest in the diagnosis and prognosis of renal neoplasms. PMID:24885240

Circulating Tumor Cell Count Correlates with Colorectal Neoplasm Progression and Is a Prognostic Marker for Distant Metastasis in Non-Metastatic Patients

NASA Astrophysics Data System (ADS)

Tsai, Wen-Sy; Chen, Jinn-Shiun; Shao, Hung-Jen; Wu, Jen-Chia; Lai-Ming, Jr.; Lu, Si-Hong; Hung, Tsung-Fu; Chiu, Yen-Chi; You, Jeng-Fu; Hsieh, Pao-Shiu; Yeh, Chien-Yuh; Hung, Hsin-Yuan; Chiang, Sum-Fu; Lin, Geng-Ping; Tang, Reiping; Chang, Ying-Chih

2016-04-01

Enumeration of circulating tumor cells (CTCs) has been proven as a prognostic marker for metastatic colorectal cancer (m-CRC) patients. However, the currently available techniques for capturing and enumerating CTCs lack of required sensitivity to be applicable as a prognostic marker for non-metastatic patients as CTCs are even more rare. We have developed a microfluidic device utilizing antibody-conjugated non-fouling coating to eliminate nonspecific binding and to promote the multivalent binding of target cells. We then established the correlation of CTC counts and neoplasm progression through applying this platform to capture and enumerate CTCs in 2 mL of peripheral blood from healthy (n = 27), benign (n = 21), non-metastatic (n = 95), and m-CRC (n = 15) patients. The results showed that the CTC counts progressed from 0, 1, 5, to 36. Importantly, after 2-year follow-up on the non-metastatic CRC patients, we found that those who had ≥5 CTCs were 8 times more likely to develop distant metastasis within one year after curable surgery than those who had <5. In conclusion, by employing a sensitive device, CTC counts show good correlation with colorectal neoplasm, thus CTC may be as a simple, independent prognostic marker for the non-metastatic CRC patients who are at high risk of early recurrence.

The myeloproliferative neoplasms, unclassifiable: clinical and pathological considerations.

PubMed

Gianelli, Umberto; Cattaneo, Daniele; Bossi, Anna; Cortinovis, Ivan; Boiocchi, Leonardo; Liu, Yen-Chun; Augello, Claudia; Bonometti, Arturo; Fiori, Stefano; Orofino, Nicola; Guidotti, Francesca; Orazi, Attilio; Iurlo, Alessandra

2017-02-01

In this study, we investigate in detail the morphological, clinical and molecular features of 71 consecutive patients with a diagnosis of myeloproliferative neoplasms, unclassifiable. We performed a meticulous morphological analysis and found that most of the cases displayed a hypercellular bone marrow (70%) with normal erythropoiesis without left-shifting (59%), increased granulopoiesis with left-shifting (73%) and increased megakaryocytes with loose clustering (96%). Megakaryocytes displayed frequent giant forms with hyperlobulated or bulbous nuclei and/or other maturation defects. Interestingly, more than half of the cases displayed severe bone marrow fibrosis (59%). Median values of hemoglobin level and white blood cells count were all within the normal range; in contrast, median platelets count and lactate dehydrogenase were increased. Little less than half of the patients (44%) showed splenomegaly. JAK2V617F mutation was detected in 72% of all patients. Among the JAK2-negative cases, MPLW515L mutation was found in 17% and CALR mutations in 67% of the investigated cases, respectively. Finally, by multiple correspondence analysis of the morphological profiles, we found that all but four of the cases could be grouped in three morphological clusters with some features similar to those of the classic BCR-ABL1-negative myeloproliferative neoplasms. Analysis of the clinical parameters in these three clusters revealed discrepancies with the morphological profile in about 55% of the patients. In conclusion, we found that the category of myeloproliferative neoplasm, unclassifiable is heterogeneous but identification of different subgroups is possible and should be recommended for a better management of these patients.

Smad2/3 Linker Phosphorylation Is a Possible Marker of Pancreatic Stem/Progenitor Cells in the Regenerative Phase of Acute Pancreatitis.

PubMed

Sakao, Masayuki; Sakaguchi, Yutaku; Suzuki, Ryo; Takahashi, Yu; Kishimoto, Masanobu; Fukui, Toshiro; Uchida, Kazushige; Nishio, Akiyoshi; Matsuzaki, Koichi; Okazaki, Kazuichi

The aims of this study are to characterize cell proliferation and differentiation during regeneration after pancreatitis and pancreatic buds during development to evaluate the role of Smad2/3, phosphorylated at the specific linker threonine residues (pSmad2/3L-Thr) in positive cells. Male C57BL/6 mice received hourly intraperitoneal injections of cerulein and were analyzed after induced pancreatitis. Pancreatitis-affected tissue sections and pancreatic buds were immunostained for pSmad2/3L-Thr, with other markers thought to be stem/progenitor markers of the pancreas. pSmad2/3L-Thr immunostaining-positive cells increased as the pancreatitis progressed. The expression of pSmad2/3L-Thr was seen in acinar cells and ductlike tubular complexes. These results suggest that pSmad2/3L-Thr is expressed during acinar-ductal metaplasia. Immunohistochemical colocalization of pSmad2/3L-Thr with Ki67 was never observed. pSmad2/3L-Thr-positive cells may remain in an undifferentiated state. During the pancreatic development process, pSmad2/3L-Thr was expressed as other markers. pSmad2/3L-Thr develops in duct structure of the undifferentiated cell population in the last part of viviparity that acinar structure is formed clearly. pSmad2/3L-Thr expression occurs during acinar-ductal metaplasia after pancreatitis and may represent the contribution of stem cells and/or progenitor cells to the differentiation of the pancreas.

Incidence of lymphoid neoplasms by subtype among six Asian ethnic groups in the United States, 1996-2004.

PubMed

Carreon, J Daniel; Morton, Lindsay M; Devesa, Susan S; Clarke, Christina A; Gomez, Scarlett L; Glaser, Sally L; Sakoda, Lori C; Linet, Martha S; Wang, Sophia S

2008-12-01

To establish baseline data for lymphoid neoplasm incidence by subtype for six Asian-American ethnic groups. Incident rates were estimated by age and sex for six Asian ethnic groups--Asian Indian/Pakistani, Chinese, Filipino, Japanese, Korean, Vietnamese--in five United States cancer registry areas during 1996-2004. For comparison, rates for non-Hispanic Whites were also estimated. During 1996-2004, Filipinos had the highest (24.0) and Koreans had the lowest incidence (12.7) of total lymphoid neoplasms. By subtype, Vietnamese and Filipinos had the highest incidence for diffuse large B-cell lymphoma (DLBCL) (8.0 and 7.2); Japanese had the highest incidence of follicular lymphoma (2.3). Although a general male predominance of lymphoid neoplasms was observed, this pattern varied by lymphoid neoplasm subtype. Whites generally had higher rates than all Asian ethnic groups for all lymphoid neoplasms and most lymphoma subtypes, although the magnitude of the difference varied by both ethnicity and lymphoma subtype. The observed variations in incidence patterns among Asian ethnic groups in the United States suggest that it may be fruitful to pursue studies that compare Asian populations for postulated environmental and genetic risk factors.

[New features in the 2014 WHO classification of uterine neoplasms].

PubMed

Lax, S F

2016-11-01

The 2014 World Health Organization (WHO) classification of uterine tumors revealed simplification of the classification by fusion of several entities and the introduction of novel entities. Among the multitude of alterations, the following are named: a simplified classification for precursor lesions of endometrial carcinoma now distinguishes between hyperplasia without atypia and atypical hyperplasia, the latter also known as endometrioid intraepithelial neoplasia (EIN). For endometrial carcinoma a differentiation is made between type 1 (endometrioid carcinoma with variants and mucinous carcinoma) and type 2 (serous and clear cell carcinoma). Besides a papillary architecture serous carcinomas may show solid and glandular features and TP53 immunohistochemistry with an "all or null pattern" assists in the diagnosis of serous carcinoma with ambiguous features. Neuroendocrine neoplasms are categorized in a similar way to the gastrointestinal tract into well differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas (small cell and large cell types). Leiomyosarcomas of the uterus are typically high grade and characterized by marked nuclear atypia and lively mitotic activity. Low grade stromal neoplasms frequently show gene fusions, such as JAZF1/SUZ12. High grade endometrial stromal sarcoma is newly defined by cyclin D1 overexpression and the presence of the fusion gene YWHAE/FAM22 and must be distinguished from undifferentiated uterine sarcoma. Carcinosarcomas (malignant mixed Mullerian tumors MMMT) show biological and molecular similarities to high-grade carcinomas.

Collecting and Storing Malignant, Borderline Malignant Neoplasms, and Related Samples From Young Patients With Cancer

ClinicalTrials.gov

2017-12-11

Acute Undifferentiated Leukemia; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Childhood Acute Lymphoblastic Leukemia; Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies; Childhood Chronic Myelogenous Leukemia; Chronic Lymphocytic Leukemia; Hairy Cell Leukemia; Juvenile Myelomonocytic Leukemia; Mast Cell Leukemia; Neoplasm of Uncertain Malignant Potential; Prolymphocytic Leukemia; Secondary Acute Myeloid Leukemia; T-cell Large Granular Lymphocyte Leukemia; Unspecified Childhood Solid Tumor, Protocol Specific

Gorlin-Goltz syndrome and neoplasms: a case study.

PubMed

Lopes, Nilza N F; Caran, Eliana M; Lee, Maria Lucia; Silva, Nasjla Saba; Rocha, André Caroli; Macedo, Carla R D

2010-01-01

Gorlin syndrome is a rare autosomal dominant disorder exhibiting high penetrance and variable expressivity. It is characterized by facial dysmorphism, skeletal anomalies, multiple basal cell carcinomas, odontogenic keratocysts (OKC), palmar and plantar pits, bifid ribs, vertebral anomalies and a variety of other malformations. Various neoplasms, such as medulloblastomas, meningiomas, ovarian and cardiac fibromas are also found in this syndrome. To describe a twelve-year-old patient with Gorlin-Goltz syndrome, with basal cell carcinomas and promyelocytic leukemia developed after receiving craniospinal radiation for a medulloblastoma. Bifid ribs as well as mandibular and maxillar OKC were also diagnosed Conclusion: The patient with Gorlin-Goltz syndrome should receive close follow-up for early detection of malformations nd malignant neoplasias.

Mouse pancreas tissue slice culture facilitates long-term studies of exocrine and endocrine cell physiology in situ.

PubMed

Marciniak, Anja; Selck, Claudia; Friedrich, Betty; Speier, Stephan

2013-01-01

Studies on pancreatic cell physiology rely on the investigation of exocrine and endocrine cells in vitro. Particularly, in the case of the exocrine tissue these studies have suffered from a reduced functional viability of acinar cells in culture. As a result not only investigations on dispersed acinar cells and isolated acini were limited in their potential, but also prolonged studies on pancreatic exocrine and endocrine cells in an intact pancreatic tissue environment were unfeasible. To overcome these limitations, we aimed to establish a pancreas tissue slice culture platform to allow long-term studies on exocrine and endocrine cells in the intact pancreatic environment. Mouse pancreas tissue slice morphology was assessed to determine optimal long-term culture settings for intact pancreatic tissue. Utilizing optimized culture conditions, cell specificity and function of exocrine acinar cells and endocrine beta cells were characterized over a culture period of 7 days. We found pancreas tissue slices cultured under optimized conditions to have intact tissue specific morphology for the entire culture period. Amylase positive intact acini were present at all time points of culture and acinar cells displayed a typical strong cell polarity. Amylase release from pancreas tissue slices decreased during culture, but maintained the characteristic bell-shaped dose-response curve to increasing caerulein concentrations and a ca. 4-fold maximal over basal release. Additionally, endocrine beta cell viability and function was well preserved until the end of the observation period. Our results show that the tissue slice culture platform provides unprecedented maintenance of pancreatic tissue specific morphology and function over a culture period for at least 4 days and in part even up to 1 week. This analytical advancement now allows mid -to long-term studies on the cell biology of pancreatic disorder pathogenesis and therapy in an intact surrounding in situ.

Mouse Pancreas Tissue Slice Culture Facilitates Long-Term Studies of Exocrine and Endocrine Cell Physiology in situ

PubMed Central

Marciniak, Anja; Selck, Claudia; Friedrich, Betty; Speier, Stephan

2013-01-01

Studies on pancreatic cell physiology rely on the investigation of exocrine and endocrine cells in vitro. Particularly, in the case of the exocrine tissue these studies have suffered from a reduced functional viability of acinar cells in culture. As a result not only investigations on dispersed acinar cells and isolated acini were limited in their potential, but also prolonged studies on pancreatic exocrine and endocrine cells in an intact pancreatic tissue environment were unfeasible. To overcome these limitations, we aimed to establish a pancreas tissue slice culture platform to allow long-term studies on exocrine and endocrine cells in the intact pancreatic environment. Mouse pancreas tissue slice morphology was assessed to determine optimal long-term culture settings for intact pancreatic tissue. Utilizing optimized culture conditions, cell specificity and function of exocrine acinar cells and endocrine beta cells were characterized over a culture period of 7 days. We found pancreas tissue slices cultured under optimized conditions to have intact tissue specific morphology for the entire culture period. Amylase positive intact acini were present at all time points of culture and acinar cells displayed a typical strong cell polarity. Amylase release from pancreas tissue slices decreased during culture, but maintained the characteristic bell-shaped dose-response curve to increasing caerulein concentrations and a ca. 4-fold maximal over basal release. Additionally, endocrine beta cell viability and function was well preserved until the end of the observation period. Our results show that the tissue slice culture platform provides unprecedented maintenance of pancreatic tissue specific morphology and function over a culture period for at least 4 days and in part even up to 1 week. This analytical advancement now allows mid -to long-term studies on the cell biology of pancreatic disorder pathogenesis and therapy in an intact surrounding in situ. PMID:24223842

Deactylase inhibition in myeloproliferative neoplasms

PubMed Central

Mithraprabhu, Sridurga; Grigoriadis, George; Khong, Tiffany

2010-01-01

Summary Myeloproliferative neoplasms (MPN) are clonal haemopoietic progenitor cell disorders characterized by the proliferation of one or more of the haemopoietic lineages (myeloid, erythroid and/or megakaryocytic). The MPNs include eight haematological disorders: chronic myelogenous leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), systemic mastocytosis (SM), chronic eosinophilic leukemia, not otherwise specified (CEL, NOS), chronic neutrophilic leukemia (CNL), and unclassifiable MPN (MPN, U). Therapeutic interventions for MPNs include the use of tyrosine kinase inhibitors (TKIs) for BCR-ABL1+ CML and JAK2 inhibitors for PV, ET and PMF. Histone deacetylase inhibitors (HDACi) are a novel class of drugs capable of altering the acetylation status of both histone and non-histone proteins, thereby affecting a repertoire of cellular functions in neoplastic cells including proliferation, differentiation, immune responses, angiogenesis and survival. Preliminary studies indicate that HDACi when used in combination with tyrosine kinase or JAK2 inhibitors may overcome resistance to the latter agents and enhance the pro-apoptotic effects on MPN cells. This review provides a review of pre-clinical and clinical studies that have explored the use of HDACi as potential therapeutics for MPNs. PMID:21127942

Serum of myeloproliferative neoplasms stimulates hematopoietic stem and progenitor cells.

PubMed

Lubberich, Richard K; Walenda, Thomas; Goecke, Tamme W; Strathmann, Klaus; Isfort, Susanne; Brümmendorf, Tim H; Koschmieder, Steffen; Wagner, Wolfgang

2018-01-01

Myeloproliferative neoplasms (MPN)-such as polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF)-are typically diseases of the elderly caused by acquired somatic mutations. However, it is largely unknown how the malignant clone interferes with normal hematopoiesis. In this study, we analyzed if serum of MPN patients comprises soluble factors that impact on hematopoietic stem and progenitor cells (HPCs). CD34+ HPCs were cultured in medium supplemented with serum samples of PV, ET, or MF patients, or healthy controls. The impact on proliferation, maintenance of immature hematopoietic surface markers, and colony forming unit (CFU) potential was systematically analyzed. In addition, we compared serum of healthy young (<25 years) and elderly donors (>50 years) to determine how normal aging impacts on the hematopoiesis-supportive function of serum. Serum from MF, PV and ET patients significantly increased proliferation as compared to controls. In addition, serum from MF and ET patients attenuated the loss of a primitive immunophenotype during in vitro culture. The CFU counts were significantly higher if HPCs were cultured with serum of MPN patients as compared to controls. Furthermore, serum of healthy young versus old donors did not evoke significant differences in proliferation or immunophenotype of HPCs, whereas the CFU frequency was significantly increased by serum from elderly patients. Our results indicate that serum derived from patients with MPN comprises activating feedback signals that stimulate the HPCs-and this stimulatory signal may result in a viscous circle that further accelerates development of the disease.

The clinical and molecular diversity of mast cell leukemia with or without associated hematologic neoplasm

PubMed Central

Jawhar, Mohamad; Schwaab, Juliana; Meggendorfer, Manja; Naumann, Nicole; Horny, Hans-Peter; Sotlar, Karl; Haferlach, Torsten; Schmitt, Karla; Fabarius, Alice; Valent, Peter; Hofmann, Wolf-Karsten; Cross, Nicholas C.P.; Metzgeroth, Georgia; Reiter, Andreas

2017-01-01

Mast cell leukemia is a rare variant of advanced systemic mastocytosis characterized by at least 20% of mast cells in a bone marrow smear. We evaluated clinical and molecular characteristics of 28 patients with (n=20, 71%) or without an associated hematologic neoplasm. De novo mast cell leukemia was diagnosed in 16 of 28 (57%) patients and secondary mast cell leukemia evolving from other advanced systemic mastocytosis subtypes in 12 of 28 (43%) patients, of which 7 patients progressed while on cytoreductive treatment. Median bone marrow mast cell infiltration was 65% and median serum tryptase was 520 μg/L. C-findings were identified in 26 of 28 (93%) patients. Mutations in KIT (D816V, n=19; D816H/Y, n=5; F522C, n=1) were detected in 25 of 28 (89%) patients and prognostically relevant additional mutations in SRSF2, ASXL1 or RUNX1 (S/A/Rpos) in 13 of 25 (52%) patients. Overall response rate in 18 treatment-naïve patients was 5 of 12 (42%) on midostaurin and 1 of 6 (17%) on cladribine, and after switch 1 of 4 (25%) on midostaurin and 0 of 3 on cladribine, respectively. S/A/Rpos adversely affected response to treatment and progression to secondary mast cell leukemia (n=6) or acute myeloid leukemia (n=3) while on treatment (P<0.05). The median overall survival from mast cell leukemia diagnosis was 17 months as compared to 44 months in a control group of 124 patients with advanced systemic mastocytosis but without mast cell leukemia (P=0.03). In multivariate analyses, S/A/Rpos remained the only independent poor prognostic variable predicting overall survival (P=0.007). In conclusion, the molecular signature should be determined in all patients with mast cell leukemia because of its significant clinical and prognostic relevance. PMID:28255023

[Cystic renal neoplasms. New entities and molecular findings].

PubMed

Moch, H

2010-10-01

Renal neoplasms with dominant cysts represent a broad spectrum of known as well as novel renal tumor entities. Established renal tumors with dominant cysts include cystic nephroma, mixed epithelial and stromal tumor, synovial sarcoma and multilocular cystic renal cancer (WHO classification 2004). Novel tumor types have recently been reported, which are also characterized by marked cyst formation. Examples are tubulocystic renal cancer and renal cancer in end-stage renal disease. These tumors are very likely to be included in a future WHO classification due to their characteristic phenotype and molecular features. Cysts and clear cell renal cell carcinoma frequently coexist in the kidneys of patients with von Hippel-Lindau disease. Cysts are also a component of many sporadic clear cell renal cell carcinomas. Multilocular cystic renal cell carcinoma is composed almost exclusively of cysts and is regarded as a specific subtype of clear cell renal cancer. Recent molecular findings suggest that clear cell renal cancer may develop via a cyst-dependent mechanism in von Hippel-Lindau syndrome as well as via cyst-independent molecular pathways in sporadic clear cell renal cancer.

Urgent Chemotherapy for Life-Threatening Complications Related to Solid Neoplasms.

PubMed

Zerbib, Yoann; Rabbat, Antoine; Fartoukh, Muriel; Bigé, Naïke; Andréjak, Claire; Mayaux, Julien; De Prost, Nicolas; Misset, Benoît; Lemiale, Virginie; Bruneel, Fabrice; Maizel, Julien; Ricome, Sylvie; Jacobs, Frédéric; Bornstain, Caroline; Dupont, Hervé; Baudin, François; Azoulay, Elie; Pène, Frédéric

2017-07-01

Solid neoplasms can be directly responsible for organ failures at the time of diagnosis or relapse. The management of such specific complications relies on urgent chemotherapy and eventual instrumental or surgical procedures, combined with advanced life support. We conducted a multicenter study to address the prognosis of this condition. A multicenter retrospective (2001-2015) chart review. Medical and respiratory ICUs. Adult patients who received urgent chemotherapy in the ICU for organ failure related to solid neoplasms were included. The modalities of chemotherapy, requirements of adjuvant instrumental or surgical procedures, and organ supports were collected. Endpoints were short- and long-term survival rates. None. One hundred thirty-six patients were included. Lung cancer was the most common malignancy distributed into small cell lung cancer (n = 57) and non-small cell lung cancer (n = 33). The main reason for ICU admission was acute respiratory failure in 111 patients (81.6%), of whom 89 required invasive mechanical ventilation. Compression and tissue infiltration by tumor cells were the leading mechanisms resulting in organ involvement in 78 (57.4%) and 47 (34.6%) patients. The overall in-ICU, in-hospital, 6-month, and 1-year mortality rates were 37%, 58%, 74%, and 88%, respectively. Small cell lung cancer was identified as an independent predictor of hospital survival. However, this gain in survival was not sustained since the 1-year survival rates of small cell lung cancer, non-small cell lung cancer, and non-lung cancer patients all dropped below 20%. Urgent chemotherapy along with aggressive management of organ failures in the ICU can be lifesaving in very selected cancer patients, most especially with small cell lung cancer, although the long-term survival is hardly sustainable.

Blastic plasmacytoid dendritic cell neoplasm frequently shows occult central nervous system involvement at diagnosis and benefits from intrathecal therapy.

PubMed

Martín-Martín, Lourdes; Almeida, Julia; Pomares, Helena; González-Barca, Eva; Bravo, Pilar; Giménez, Teresa; Heras, Cecilia; Queizán, José-Antonio; Pérez-Ceballos, Elena; Martínez, Violeta; Alonso, Natalia; Calvo, Carlota; Álvarez, Rodolfo; Caballero, María Dolores; Orfao, Alberto

2016-03-01

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare aggressive myeloid neoplasm which shows a high rate of central nervous system (CNS) recurrence and overall survival (OS) of <1 year. Despite this, screening for CNS involvement is not routinely performed at diagnosis and intrathecal (IT) prophylaxis is not regularly administered in BPDCN. Here, we prospectively evaluated 13 consecutive BPDCN patients for the presence of CNS involvement by flow cytometry. Despite none of the patients presented with neurological symptoms, occult CNS involvement was detected in 6/10 cases evaluated at diagnosis and 3/3 studied at relapse/progression. BPDCN patients evaluated at diagnosis received IT treatment -either CNS prophylaxis (n = 4) or active therapy (n = 6)- and all but one remain alive (median follow-up of 20 months). In contrast, all three patients assessed at relapse/progression died. The potential benefit of IT treatment administered early at diagnosis on OS and CNS recurrence-free survival of BPDCN was further confirmed in a retrospective cohort of another 23 BPDCN patients. Our results show that BPDCN patients studied at diagnosis frequently display occult CNS involvement; moreover, they also indicate that treatment of occult CNS disease might lead to a dramatically improved outcome of BPDCN.

Blastic plasmacytoid dendritic cell neoplasm frequently shows occult central nervous system involvement at diagnosis and benefits from intrathecal therapy

PubMed Central

Martín-Martín, Lourdes; Almeida, Julia; Pomares, Helena; González-Barca, Eva; Bravo, Pilar; Giménez, Teresa; Heras, Cecilia; Queizán, José-Antonio; Pérez-Ceballos, Elena; Martínez, Violeta; Alonso, Natalia; Calvo, Carlota; Álvarez, Rodolfo; Caballero, María Dolores; Orfao, Alberto

2016-01-01

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare aggressive myeloid neoplasm which shows a high rate of central nervous system (CNS) recurrence and overall survival (OS) of <1 year. Despite this, screening for CNS involvement is not routinely performed at diagnosis and intrathecal (IT) prophylaxis is not regularly administered in BPDCN. Here, we prospectively evaluated 13 consecutive BPDCN patients for the presence of CNS involvement by flow cytometry. Despite none of the patients presented with neurological symptoms, occult CNS involvement was detected in 6/10 cases evaluated at diagnosis and 3/3 studied at relapse/progression. BPDCN patients evaluated at diagnosis received IT treatment -either CNS prophylaxis (n = 4) or active therapy (n = 6)- and all but one remain alive (median follow-up of 20 months). In contrast, all three patients assessed at relapse/progression died. The potential benefit of IT treatment administered early at diagnosis on OS and CNS recurrence-free survival of BPDCN was further confirmed in a retrospective cohort of another 23 BPDCN patients. Our results show that BPDCN patients studied at diagnosis frequently display occult CNS involvement; moreover, they also indicate that treatment of occult CNS disease might lead to a dramatically improved outcome of BPDCN. PMID:26840087

Primary malignant perivascular epithelioid cell neoplasm (PEComa) of the bone mimicking granular cell tumor in core biopsy: A case report and literature review

PubMed Central

Sadigh, Sam; Shah, Preya; Weber, Kristy; Sebro, Ronnie; Zhang, Paul J.

2018-01-01

The present study investigated the case of a 46-year-old female with primary malignant perivascular epithelioid cell neoplasm (PEComa) of the femur. The patient presented with a 5-month history of right distal thigh pain following trauma. Radiographs of the right distal femur revealed a mixed lytic and sclerotic lesion with subtle areas of cortical destruction and soft tissue extension, consistent with an aggressive tumor. A core biopsy revealed an epithelioid tumor with granular cell features, but a definitive diagnosis could not be made. Due to the aggressive features on radiologic evaluation, the patient underwent a resection of the distal femur and reconstruction with a distal femoral megaprosthesis and hinged knee replacement. The post-resection pathology led to a final diagnosis of primary bone PEComa, with histologic features including epithelioid, granular cell and spindled cell morphologies and biphasic immunoreactivity for melanocytic and smooth muscle markers. The large tumor size (>5 cm), rapid mitotic rate, infiltrative growth pattern, high nuclear grade and cellularity, and the presence of necrosis rendered this a malignant PEComa. The present study discussed the case, including radiographic (radiographs, magnetic resonance imaging and positron emission tomography scans) and histologic appearance and a literature review. PMID:29435023

Identification of Prognostic Biomarkers for Progression of Invasive Squamous Cell Carcinoma

ClinicalTrials.gov

2017-10-09

Carcinoma, Squamous Cell; Carcinoma, Squamous; Squamous Cell Carcinoma; Lung Neoplasms; Cancer of Lung; Cancer of the Lung; Lung Cancer; Neoplasms, Lung; Neoplasms, Pulmonary; Pulmonary Cancer; Pulmonary Neoplasms

Role of intraoperative imprint cytology in diagnosis of suspected ovarian neoplasms.

PubMed

Dey, Soumit; Misra, Vatsala; Singh, P A; Mishra, Sanjay; Sharma, Nishant

2010-01-01

The present study was conducted to assess whether cytology can help in rapid diagnosis of ovarian neoplasms and thus facilitate individualised treatment. A prospective investigation was performed on 30 cases of suspected ovarian neoplasms. Imprint smears were made intraperatively from fresh samples from various representative areas, and stained with Leishman Giemsa for air-dried smears, and with hematoxylin and eosin and Papanicolaou for alcohol-fixed smears. A rapid opinion regarding the benign or malignant nature of the lesion and the type of tumour was given. The overall sensitivity was 96.2%, specificity 75%, positive predictive value 96.3%, and diagnostic accuracy of 83.3%. Characteristic cytological patterns were noted in various epithelial and germ cell tumours. Imprint cytology can be used as an adjunct to histopathology for rapid and early diagnosis in the operation theatre, thus helping better management of patients.

Chronic Myeloproliferative Neoplasms Treatment

MedlinePlus

... are described below. Chronic myeloproliferative neoplasms sometimes become acute leukemia , in which too many abnormal white blood ... higher. Patients also have an increased risk of acute myeloid leukemia or primary myelofibrosis . Symptoms of polycythemia ...

Histomorphologic spectrum of BAP1 negative melanocytic neoplasms in a family with BAP1-associated cancer susceptibility syndrome.

PubMed

Marušić, Zlatko; Buljan, Marija; Busam, Klaus J

2015-06-01

Multiple BAP1 negative melanocytic neoplasms are a hallmark of familial cancer susceptibility syndrome caused by BAP1 germline mutation. The syndrome is characterized by increased incidence of renal cell carcinoma, mesothelioma, cholangiocarcinoma, cutaneous and uveal melanoma and some other neoplasms. We report histomorphologic characteristics of six cutaneous melanocytic neoplasms with loss of BAP1 expression in two members of a family with BAP1-associated cancer susceptibility syndrome. The neoplasms were dermal melanocytic nevi characterized by a proliferation of large epithelioid (spitzoid) melanocytes, and adipocytic metaplasia. Nuclear pseudoinclusions and multinucleated melanocytes were present in most neoplasms. In two of the cases, a nodular melanoma was found associated with a dermal nevus. None of the melanomas recurred or metastasized after 6 and 3 years of follow up. We report two new cases of melanoma arising in a BAP1-deficient melanocytic nevus in the setting of familial tumor predisposition syndrome. Adipocytic metaplasia and nuclear pseudoinclusions may be additional morphologic clues to a BAP1-deficient nevus. It remains to be seen whether these features are more common in familial than sporadic lesions. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The quest for tissue stem cells in the pancreas and other organs, and their application in beta-cell replacement.

PubMed

Houbracken, Isabelle; Bouwens, Luc

2010-01-01

Adult stem cell research has drawn a lot of attention by many researchers, due to its medical hope of cell replacement or regenerative therapy for diabetes patients. Despite the many research efforts to date, there is no consensus on the existence of stem cells in adult pancreas. Genetic lineage tracing experiments have put into serious doubt whether β-cell neogenesis from stem/progenitor cells takes place postnatally. Different in vitro experiments have suggested centroacinar, ductal, acinar, stellate, or yet unidentified clonigenic cells as candidate β-cell progenitors. As in the rest of the adult stem cell field, sound and promising observations have been made. However, these observations still need to be replicated. As an alternative to committed stem/progenitor cells in the pancreas, transdifferentiation or lineage reprogramming of exocrine acinar and endocrine α-cells may be used to generate new β-cells. At present, it is unclear which approach is most medically promising. This article highlights the progress being made in knowledge about tissue stem cells, their existence and availability for therapy in diabetes. Particular attention is given to the assessment of methods to verify the existence of tissue stem cells.

Primary Neoplasms of Bones in Mice: Retrospective Study and Review of Literature

PubMed Central

Kavirayani, A. M.; Sundberg, J. P.; Foreman, O.

2011-01-01

To compare and summarize the mechanisms, frequencies of occurrence, and classification schemes of spontaneous, experimental, and genetically engineered, mouse skeletal neoplasms, the literature was reviewed and archived case material at The Jackson Laboratory examined. The frequency of occurrence of spontaneous bone neoplasms was less than 1% for most strains, with the exceptions of osteomas in CF-1 (5.5% and 10% in two studies) and OF-1 outbred strains (35%), and osteosarcomas in NOD/ShiLtJ (11.5%) and NOD derived (7.1%) mice. The frequency was 100% for osteochondromas induced by conditional inactivation of exostoses (multiple) 1 (Ext1) in chondrocytes, osteosarcomas induced by tibial intramedullary inoculation of Moloney’s murine sarcoma virus, and osteosarcomas induced by conditional inactivation of Trp53-with or without inactivation of Rb1-in osteoblast precursors. Spontaneous osteogenic neoplasms were more frequent than spontaneous cartilaginous and vascular types. Malignant neoplasms were more frequent than benign ones. The age of occurrence for spontaneous neoplasms ranged from 37 to 720 (Mean 316.35) days for benign, and 35 to 990 (Mean 299.28) days for malignant neoplasms. In genetically engineered mice, the average age of occurrence ranged from 28 to 70 days for benign, and from 35 to 690 days for malignant neoplasms. Histologically, non-osteogenic neoplasms were similar across strains and mutant stocks; osteogenic neoplasms exhibited greater diversity. This comparison and summarization of mouse bone neoplasms provides valuable information for the selection of strains to create, compare, and validate models of bone neoplasms. PMID:21343597

Targeted therapy by combined inhibition of the RAF and mTOR kinases in malignant spindle cell neoplasm harboring the KIAA1549-BRAF fusion protein.

PubMed

Subbiah, Vivek; Westin, Shannon N; Wang, Kai; Araujo, Dejka; Wang, Wei-Lien; Miller, Vincent A; Ross, Jeffrey S; Stephens, Phillip J; Palmer, Gary A; Ali, Siraj M

2014-01-14

Oncologic patients who are extreme responders to molecularly targeted therapy provide an important opportunity to better understand the biologic basis of response and, in turn, inform clinical decision making. Malignant neoplasms with an uncertain histologic and immunohistochemical characterization present challenges both on initial diagnostic workups and then later in management, as current treatment algorithms are based on a morphologic diagnosis. Herein, we report a case of a difficult to characterize sarcoma-like lesion for which genomic profiling with clinical next generation sequencing (NGS) identified the molecular underpinnings of arrested progression(stable disease) under combination targeted therapy within a phase I clinical trial. Genomic profiling with clinical next generation sequencing was performed on the FoundationOne™ platform (Foundation Medicine, Cambridge MA). Histopathology and immunohistochemical studies were performed in the Department of Pathology, MD Anderson Cancer Center (Houston, TX). Treatment was administered in the context of a phase I clinical trial ClinicalTrials.gov Identifier: (NCT01187199). The histology of the tumor was that of a spindle cell neoplasm, grade 2 by FNCLCC standards. Immunohistochemical staining was positive for S100 and CD34. Genomic profiling identified the following alterations: a KIAA1549-BRAF gene fusion resulting from a tandem duplication event, a homozygous deletion of PTEN, and frameshift insertion/deletions in CDKN2A A68fs*51, SUFU E283fs*3, and MAP3K1 N325fs*3. The patient had a 25% reduction in tumor (RECIST v1.1) following combination therapy consisting of sorafenib, temsirolimus, and bevazicumab within a phase I clinical trial. The patient responded to combination targeted therapy that fortuitously targeted KIAA1549-BRAF and PTEN loss within a spindle cell neoplasm, as revealed by genomic profiling based on NGS. This is the first report of a tumor driven by a KIAA1549-BRAF fusion responding to

CYTOLOGY ASSESSMENT CAN PREDICT SURVIVAL FOR PATIENTS WITH METASTATIC PANCREATIC NEUROENDOCRINE NEOPLASMS

PubMed Central

Sigel, Carlie S.; Guo, Huimin; Sigel, Keith M.; Zhang, Ming; Rekhtman, Natasha; Lin, Oscar; Klimstra, David S.; Jungbluth, Achim A.; Tang, Laura K.

2017-01-01

Background Histological features and Ki67 index have known utility for predicting prognosis and guiding therapy for metastatic pancreatic neuroendocrine neoplasms. Fine needle aspiration (FNA) may offer advantages for Ki67 assessment because the technique obtains highly cellular, well-preserved specimens with potential for broader tumor sampling. We evaluated concordance for grade and differentiation between concurrent core biopsy and cytology preparations. Secondly, cytological features and grade were correlated with survival. Methods Differentiation, grade by Ki67 index, and correlation of these features with survival were compared between concurrent core biopsy and cytology from 44 metastatic pancreatic neuroendocrine neoplasms. Results Differentiation by cytology smear was 38 (86%) well and 6 (14%) poor. Agreement for differentiation between smear and cell block, smear and biopsy, and cell block and biopsy was: 88%, 94%, and 83%, respectively and agreement for grade were: 68%, 54%, and 22%, respectively. Cytology differentiation and cytology grade were strong predictors of outcome with respective hazard ratio of 8.3 (95% CI: 3.1–22.1; p<0.001) and 1.9 (95% CI: 1.2–2.9) for each ascending grade. Cytology median disease specific survival projections (months) were G1= 121 (95% CI: 57–185 (estimated)); G2= 45 (95% CI 29–87); and G3=19 (95% CI 1–44) and WD=45; PD= 3; (P<.001)). Conclusions Pancreatic neuroendocrine neoplasm grading on cytology may not exactly correlate with concurrent core biopsy, but cytology differentiation and grade are predictive of survival based on stage-adjusted analysis. PMID:28094897

Perspectives on testicular sex cord-stromal tumors and those composed of both germ cells and sex cord-stromal derivatives with a comparison to corresponding ovarian neoplasms.

PubMed

Roth, Lawrence M; Lyu, Bingjian; Cheng, Liang

2017-07-01

Sex cord-stromal tumors (SCSTs) are the second most frequent category of testicular neoplasms, accounting for approximately 2% to 5% of cases. Both genetic and epigenetic factors account for the differences in frequency and histologic composition between testicular and ovarian SCSTs. For example, large cell calcifying Sertoli cell tumor and intratubular large cell hyalinizing Sertoli cell neoplasia occur in the testis but have not been described in the ovary. In this article, we discuss recently described diagnostic entities as well as inconsistencies in nomenclature used in the recent World Health Organization classifications of SCSTs in the testis and ovary. We also thoroughly review the topic of neoplasms composed of both germ cells and sex cord derivatives with an emphasis on controversial aspects. These include "dissecting gonadoblastoma" and testicular mixed germ cell-sex cord stromal tumor (MGC-SCST). The former is a recently described variant of gonadoblastoma that sometimes is an immediate precursor of germinoma in the dysgenetic gonads of patients with a disorder of sex development. Although the relationship of dissecting gonadoblastoma to the previously described undifferentiated gonadal tissue is complex and not entirely resolved, we believe that it is preferable to continue to use the term undifferentiated gonadal tissue for those cases that are not neoplastic and are considered to be the precursor of classical gonadoblastoma. Although the existence of testicular MGC-SCST has been challenged, the most recent evidence supports its existence; however, testicular MGC-SCST differs significantly from ovarian examples due to both genetic and epigenetic factors. Copyright © 2017 Elsevier Inc. All rights reserved.

Transcription factor mutations in myelodysplastic/myeloproliferative neoplasms

PubMed Central

Ernst, Thomas; Chase, Andrew; Zoi, Katerina; Waghorn, Katherine; Hidalgo-Curtis, Claire; Score, Joannah; Jones, Amy; Grand, Francis; Reiter, Andreas; Hochhaus, Andreas; Cross, Nicholas C.P.

2010-01-01

Background Aberrant activation of tyrosine kinases, caused by either mutation or gene fusion, is of major importance for the development of many hematologic malignancies, particularly myeloproliferative neoplasms. We hypothesized that hitherto unrecognized, cytogenetically cryptic tyrosine kinase fusions may be common in non-classical or atypical myeloproliferative neoplasms and related myelodysplastic/myeloproliferative neoplasms. Design and Methods To detect genomic copy number changes associated with such fusions, we performed a systematic search in 68 patients using custom designed, targeted, high-resolution array comparative genomic hybridization. Arrays contained 44,000 oligonucleotide probes that targeted 500 genes including all 90 tyrosine kinases plus downstream tyrosine kinase signaling components, other translocation targets, transcription factors, and other factors known to be important for myelopoiesis. Results No abnormalities involving tyrosine kinases were detected; however, nine cytogenetically cryptic copy number imbalances were detected in seven patients, including hemizygous deletions of RUNX1 or CEBPA in two cases with atypical chronic myeloid leukemia. Mutation analysis of the remaining alleles revealed non-mutated RUNX1 and a frameshift insertion within CEBPA. A further mutation screen of 187 patients with myelodysplastic/myeloproliferative neoplasms identified RUNX1 mutations in 27 (14%) and CEBPA mutations in seven (4%) patients. Analysis of other transcription factors known to be frequently mutated in acute myeloid leukemia revealed NPM1 mutations in six (3%) and WT1 mutations in two (1%) patients with myelodysplastic/myeloproliferative neoplasms. Univariate analysis indicated that patients with mutations had a shorter overall survival (28 versus 44 months, P=0.019) compared with patients without mutations, with the prognosis for cases with CEBPA, NPM1 or WT1 mutations being particularly poor. Conclusions We conclude that mutations of

Effects of cardiac oscillations and lung volume on acinar gas mixing during apnea

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mackenzie, C.F.; Skacel, M.; Barnas, G.M.

1990-05-01

We evaluated the importance of cardiogenic gas mixing in the acini of 13 dogs during 2 min of apnea. 133Xe (1-2 mCi in 4 ml of saline) was injected into an alveolar region through an occluded pulmonary artery branch, and washout was measured by gamma scintillation scanning during continued occlusion or with blood flow reinstated. The monoexponential rate constant for Xe washout (XeW) was -0.4 +/- 0.08 (SE) min-1 at functional residual capacity (FRC) with no blood flow in the injected region. It decreased by more than half at lung volumes 500 ml above and 392 ml below FRC. Withmore » intact pulmonary blood flow, XeW was -1.0 +/- 0.08 (SE) min-1 at FRC, and it increased with decreasing lung volume. However, if calculated Xe uptake by the blood was subtracted from the XeW measured with blood flow intact, resulting values at FRC and at FRC + 500 ml were not different from XeW with no blood flow. Reasonable calculation of Xe blood uptake at 392 ml below FRC was not possible because airway closure, increased shunt, and other factors affect XeW. After death, no significant XeW could be measured, which suggests that XeW caused by molecular diffusion was small. We conclude that (1) the effect of heart motion on the lung parenchyma increases acinar gas mixing during apnea, (2) this effect diminishes above or below FRC, and (3) there is probably no direct effect of pulmonary vascular pulsatility on acinar gas mixing.« less

Reticulated acanthoma with sebaceous differentiation: another sebaceous neoplasm associated with Muir-Torre syndrome?

PubMed

Shon, Wonwoo; Wolz, Michael M; Newman, Catherine C; Bridges, Alina G

2014-11-01

Reticulated acanthoma with sebaceous differentiation (RASD) represents a rare benign cutaneous epithelial neoplasm with sebaceous differentiation. There has been much speculation about the relationship between RASD and Muir-Torre syndrome (MTS). We report a 53 year-old man who presented with RASD in addition to a prior history of sebaceous adenomas. Immunohistochemically, the tumour cells in the RASD and sebaceous adenomas showed a significantly reduced MSH6 protein expression, whereas there was no loss of MLH1, MSH2 and PMS2. This benign neoplasm, which can be mistaken for various other cutaneous lesions with sebaceous differentiation, deserves wider recognition for its possible association with MTS. © 2013 The Authors. Australasian Journal of Dermatology © 2013 The Australasian College of Dermatologists.

Malignant neoplasms of the nasal cavity and paranasal sinuses: a series of 256 patients in Mexico City and Monterrey. Is air pollution the missing link?

PubMed

Calderón-Garcidueñas, L; Delgado, R; Calderón-Garcidueñas, A; Meneses, A; Ruiz, L M; De La Garza, J; Acuna, H; Villarreal-Calderón, A; Raab-Traub, N; Devlin, R

2000-04-01

Air pollution is a serious health problem in major cities in Mexico. The concentrations of monitored criteria pollutants have been above the US National Ambient Air Quality Standards for the last decade. To determine whether the number of primary malignant nasal and paranasal neoplasms has increased, we surveyed 256 such cases admitted to a major adult oncology hospital located in metropolitan Mexico City (MMC) for the period from 1976-1997 and to a tertiary hospital in Monterrey, an industrial city, for the period from 1993-1998. The clinical histories and histopathologic material were reviewed, and a brief clinical summary was written for each case. In the MMC hospital the number of newly diagnosed nasal and paranasal neoplasms per year for the period from 1976-1986 averaged 5.1, whereas for the next 11 years it increased to 12.5. The maximal increase was observed in 1995-1997, with an average of 20.3 new cases per year (P = 0.0006). The predominant neoplasms in these series were non-Hodgkin's lymphoma, squamous cell carcinoma, melanoma, adenocarcinoma, Schneiderian carcinoma, and nasopharyngeal carcinoma. In the Monterrey hospital a 2-fold increase in the numbers of newly diagnosed nasal and paranasal neoplasms was recorded between 1993 and 1998. The predominant MMC neoplasm in this series, namely nasal T-cell/natural killer cell non-Hodgkin's lymphoma, is potentially Epstein-Barr virus related. Nasal and paranasal malignant neoplasms are generally rare. Environmental causative factors include exposure in industries such as nickel refining, leather, and wood furniture manufacturing. Although epidemiologic studies have not addressed the relationship between outdoor air pollution and sinonasal malignant neoplasms, there is strong evidence for the nasal and paranasal carcinogenic effect of occupational aerosol complex chemical mixtures. General practitioners and ear, nose, and throat physicians working in highly polluted cities should be aware of the clinical

HDAC8 overexpression in mesenchymal stromal cells from JAK2+ myeloproliferative neoplasms: a new therapeutic target?

PubMed Central

Ramos, Teresa L.; Sánchez-Abarca, Luis Ignacio; Redondo, Alba; Hernández-Hernández, Ángel; Almeida, Antonio M.; Puig, Noemí; Rodríguez, Concepción; Ortega, Rebeca; Preciado, Silvia; Rico, Ana; Muntión, Sandra; González Porras, José Ramón; Cañizo, Consuelo Del; Sánchez-Guijo, Fermín

2017-01-01

Histone deacetylases (HDACs) are involved in epigenetic modulation and their aberrant expression has been demonstrated in myeloproliferative neoplasms (MPN). HDAC8 inhibition has been shown to inhibit JAK2/STAT5 signaling in hematopoietic cells from MPN. Nevertheless, the role of HDAC8 expression in bone marrow-mesenchymal stromal cells (BM-MSC) has not been assessed. In the current work we describe that HDAC8 is significantly over-expressed in MSC from in JAK-2 positive MPN compared to those from healthy-donors (HD-MSC). Using a selective HDAC8 inhibitor (PCI34051), we verified that the subsequent decrease in the protein and mRNA expression of HDAC8 is linked with an increased apoptosis of malignant MSC whereas it has no effects on normal MSC. In addition, HDAC8 inhibition in MPN-MSC also decreased their capacity to maintain neoplastic hematopoiesis, by increasing the apoptosis, cell-cycle arrest and colony formation of JAK2+-hematopoietic cells. Mechanistic studies using different MPN cell lines revealed that PCI34051 induced their apoptosis, which is enhanced when were co-cultured with JAK2V617F-MSC, decreased their colony formation and the phosphorylation of STAT3 and STAT5. In summary, we show for the first time that the inhibition of HDAC8 in MSC from JAK2+ MPN patients selectively decreases their hematopoietic-supporting ability, suggesting that HDAC8 may be a potential therapeutic target in this setting by acting not only on hematopoietic cells but also on the malignant microenvironment. PMID:28390197

Targeting glutamine metabolism in myeloproliferative neoplasms

PubMed Central

Zhan, Huichun; Ciano, Kristen; Dong, Katherine; Zucker, Stanley

2016-01-01

JAK2V617F mutation can be detected in the majority of myeloproliferative neoplasm (MPN) patients. The JAK2 inhibitor Ruxolitinib is the first FDA-approved treatment for MPNs. However, its use is limited by various dose related toxicities. Here, we studied the metabolic state and glutamine metabolism of BaF3-hEPOR-JAK2V617F and BaF3-hEPOR-JAK2WT cells. We found that the JAK2V617F-mutant cells were associated with increased oxygen consumption rate and extracellular acidification rate than the JAK2WT cells and there was an increased glutamine metabolism in JAK2V617F-mutant cells compared to wild-type cells. Glutaminase (GLS), the key enzyme in gluta-mine metabolism, was upregulated in the JAK2V617F-mutant BaF3 cells compared to the JAK2WT BaF3 cells. In MPN patient peripheral blood CD34+ cells, GLS expression was increased in JAK2V617F-mutant progenitor cells compared to JAK2 wild-type progenitor cells from the same patients and GLS levels were increased at the time of disease progression compared to at earlier time points. Moreover, GLS inhibitor increased the growth inhibitory effect of Ruxolitinib in both JAK2V617F-mutant cell lines and peripheral blood CD34+ cells from MPN patients. Therefore, GLS inhibitor should be further explored to enhance the therapeutic effectiveness of JAK2 inhibitor and allow the administration of lower doses of the drug to avoid its toxicity. PMID:26227854

Pancreatic cystic neoplasms: Review of current knowledge, diagnostic challenges, and management options

PubMed Central

Jana, Tanima; Shroff, Jennifer; Bhutani, Manoop S.

2015-01-01

Pancreatic cystic lesions are being detected with increasing frequency, largely due to advances in cross-sectional imaging. The most common neoplasms include serous cystadenomas, mucinous cystic neoplasms, intraductal papillary mucinous neoplasms, solid pseudopapillary neoplasms, and cystic pancreatic endocrine neoplasms. Computed tomography (CT), magnetic resonance imaging (MRI), and endoscopic ultrasound (EUS) are currently used as imaging modalities. EUS-guided fine needle aspiration has proved to be a useful diagnostic tool, and enables an assessment of tumor markers, cytology, chemistries, and DNA analysis. Here, we review the current literature on pancreatic cystic neoplasms, including classification, diagnosis, treatment, and recommendations for surveillance. Data for this manuscript was acquired via searching the literature from inception to December 2014 on PubMed and Ovid MEDLINE. PMID:25821410

APC alterations are frequently involved in the pathogenesis of acinar cell carcinoma of the pancreas, mainly through gene loss and promoter hypermethylation.

PubMed

Furlan, Daniela; Sahnane, Nora; Bernasconi, Barbara; Frattini, Milo; Tibiletti, Maria Grazia; Molinari, Francesca; Marando, Alessandro; Zhang, Lizhi; Vanoli, Alessandro; Casnedi, Selenia; Adsay, Volkan; Notohara, Kenji; Albarello, Luca; Asioli, Sofia; Sessa, Fausto; Capella, Carlo; La Rosa, Stefano

2014-05-01

Genetic and epigenetic alterations involved in the pathogenesis of pancreatic acinar cell carcinomas (ACCs) are poorly characterized, including the frequency and role of gene-specific hypermethylation, chromosome aberrations, and copy number alterations (CNAs). A subset of ACCs is known to show alterations in the APC/β-catenin pathway which includes mutations of APC gene. However, it is not known whether, in addition to mutation, loss of APC gene function can occur through alternative genetic and epigenetic mechanisms such as gene loss or promoter methylation. We investigated the global methylation profile of 34 tumor suppressor genes, CNAs of 52 chromosomal regions, and APC gene alterations (mutation, methylation, and loss) together with APC mRNA level in 45 ACCs and related peritumoral pancreatic tissues using methylation-specific multiplex ligation probe amplification (MS-MLPA), fluorescence in situ hybridization (FISH), mutation analysis, and reverse transcription-droplet digital PCR. ACCs did not show an extensive global gene hypermethylation profile. RASSF1 and APC were the only two genes frequently methylated. APC mutations were found in only 7 % of cases, while APC loss and methylation were more frequently observed (48 and 56 % of ACCs, respectively). APC mRNA low levels were found in 58 % of cases and correlated with CNAs. In conclusion, ACCs do not show extensive global gene hypermethylation. APC alterations are frequently involved in the pathogenesis of ACCs mainly through gene loss and promoter hypermethylation, along with reduction of APC mRNA levels.

Margins for Benign Salivary Gland Neoplasms of the Head and Neck.

PubMed

Carlson, Eric R; McCoy, James Michael

2017-08-01

The proper ablation of any neoplasm of the head and neck requires the inclusion of linear and anatomic barrier margins surrounding the neoplasm. Extirpative surgery of the major and minor salivary glands is certainly no exception to this surgical principle. To this end, the selection and execution of the most appropriate ablative surgical procedure for a major or minor benign salivary gland neoplasm is an essential exercise in oral and maxillofacial surgery. Of equal importance is the intraoperative identification and preservation of the pseudocapsule surrounding the benign neoplasm. This article reviews these important elements specifically related to ablative surgery of benign neoplasms of the parotid, submandibular and minor salivary glands with strict attention to observed nomenclature. Copyright © 2017 Elsevier Inc. All rights reserved.

Epithelial-type and neural-type cadherin expression in malignant noncarcinomatous neoplasms with epithelioid features that involve the soft tissues.

PubMed

Laskin, William B; Miettinen, Markku

2002-04-01

Transmembrane adhesion molecules, epithelial-type cadherin (ECAD) and neural-type cadherin (NCAD), help in regulating transformations between epithelial and mesenchymal cells in the developing embryo and in maintaining the epithelioid phenotype. Consequently, the presence of epithelioid cells in certain malignant noncarcinomatous neoplasms raises speculation that the expression of ECAD and NCAD in these neoplasms may have diagnostic significance. To investigate the utility of ECAD and NCAD immunoexpression in distinguishing malignant (noncarcinomatous) neoplasms with epithelioid features that involve the soft tissues. Membranous immunoreactivity of anti-ECAD and anti-NCAD was evaluated on archived cases selected from the files of the Armed Forces Institute of Pathology. Epithelial-type cadherin was found in biphasic synovial sarcoma (35 of 35 cases), malignant melanoma (13/21), monophasic fibrous synovial sarcoma (13/26), clear cell sarcoma (4/9), poorly differentiated synovial sarcoma (3/13), diffuse mesothelioma (4/20), malignant epithelioid peripheral nerve sheath tumor (1/6), and epithelioid sarcoma (5/62). Neural-type cadherin was observed in chordoma (11/11), biphasic synovial sarcoma (30/35), diffuse mesothelioma (14/20), malignant melanoma (14/25), epithelioid sarcoma (24/63), epithelioid angiosarcoma (1/4), poorly differentiated synovial sarcoma (2/13), clear cell sarcoma (1/10), and monophasic fibrous synovial sarcoma (1/26). Eighteen cases of primary cutaneous squamous cell carcinomas all tested positive for ECAD, whereas NCAD was focally observed in 5 cases. No expression of either molecule was observed in cases of epithelioid hemangioendothelioma (n = 9), alveolar soft part sarcoma (n = 8), and extraskeletal myxoid chondrosarcoma (n = 7). Epithelial-type and neural-type cadherins are found in a variety of noncarcinomatous neoplasms with epithelioid features that involve the soft tissues and can be utilized, in association with other immunomarkers, in

Aberrant let7a/HMGA2 signaling activity with unique clinical phenotype in JAK2-mutated myeloproliferative neoplasms

PubMed Central

Chen, Chih-Cheng; You, Jie-Yu; Lung, Jrhau; Huang, Cih-En; Chen, Yi-Yang; Leu, Yu-Wei; Ho, Hsing-Ying; Li, Chian-Pei; Lu, Chang-Hsien; Lee, Kuan-Der; Hsu, Chia-Chen; Gau, Jyh-Pyng

2017-01-01

High mobility group AT-hook 2 (HMGA2) is an architectural transcription factor that is negatively regulated by let-7 microRNA through binding to it’s 3′-untranslated region. Transgenic mice expressing Hmga2 with a truncation of its 3′-untranslated region has been shown to exhibit a myeloproliferative phenotype. To decipher the let-7-HMGA2 axis in myeloproliferative neoplasms, we employed an in vitro model supplemented with clinical correlation. Ba/F3 cells with inducible JAK2V617F expression (Ton.JAK2.V617F cells) showed upregulation of HMGA2 with concurrent let-7a repression. Ton.JAK2.V617F cells treated with a let-7a inhibitor exhibited further escalation of Hmga2 expression, while a let-7a mimic diminished the Hmga2 transcript level. Hmga2 overexpression conferred JAK2-mutated cells with a survival advantage through inhibited apoptosis. A pan-JAK inhibitor, INC424, increased the expression of let-7a, downregulated the level of Hmga2, and led to increased apoptosis in Ton.JAK2.V617F cells in a dose-dependent manner. In samples from 151 patients with myeloproliferative neoplasms, there was a modest inverse correlation between the expression levels of let-7a and HMGA2. Overexpression of HMGA2 was detected in 29 (19.2%) of the cases, and it was more commonly seen in patients with essential thrombocythemia than in those with polycythemia vera (26.9% vs. 12.7%, P=0.044). Patients with upregulated HMGA2 showed an increased propensity for developing major thrombotic events, and they were more likely to harbor one of the 3 driver myeloproliferative neoplasm mutations in JAK2, MPL and CALR. Our findings suggest that, in a subset of myeloproliferative neoplasm patients, the let-7-HMGA2 axis plays a prominent role in the pathogenesis of the disease that leads to unique clinical phenotypes. PMID:28057739

[Incidence of haematological neoplasms in Castilla y León, Spain].

PubMed

Rodríguez-García, José Antonio; Vázquez, Lourdes; Ramos, Fernando; Cuevas, Beatriz; Martín, Alejandro; Smucler, Alicia; Guerola, Dulce Nombre; Cantalapiedra, Alberto; Alonso, José María; Fernández, Silvia; Díez, Eva; Rodríguez, María Jesús; Calmuntia, María José; Aguilar, Carlos; Sierra, Magdalena; Gracia, José Antonio; Cebeira, María José; Cantalejo, Rosa

2015-06-08

We aimed to assess the incidence of haematological neoplasms (HNs) in Castilla y León (2,5 million inhabitants) and its distribution by age, gender and histological type. The epidemiological profile based on the described variables of the 10,943 HNs diagnosed during a 10-years period was analyzed, compared with other studies. The overall age-adjusted incidence was 29.4 cases/10(5) inhabitants-year, with some geographical differences. The mean age was 67.3 years, with a turning point between the 6th-7th decades of life from which there was a very significant increase of incidence. Two relevant facts where simultaneous with advancing age: decreased lymphoid neoplasms incidence and increased low degree neoplasms incidence. Lymphoid low degree neoplasms accounted for half of the registered processes, showed the greatest preference for male and reached the mode before the rest of neoplasms. Myeloid neoplasms incidence (9.5) was higher than that reported in other European registries, specially compared to southern European countries, opposite to lymphoid neoplasms incidence (20.0). A higher myeloid neoplasms incidence and lower lymphoid one than expected was observed. The turning point of incidence is between the 6th-7th decades of life, with a preference for male that decreases with age. There is an increased incidence of HNs in the area where a higher density of potentially polluting facilities is concentrated. Copyright © 2013 Elsevier España, S.L.U. All rights reserved.

New advances in cell physiology and pathophysiology of the exocrine pancreas.

PubMed

Mössner, Joachim

2010-01-01

This review provides some aspects on the physiology of stimulation and inhibition of pancreatic digestive enzyme secretion and the pathophysiology of pancreatic acinar cell function leading to pancreatitis. Cholecystokinin (CCK) stimulates both directly via CCK-A receptors on acinar cells and indirectly via CCK-B receptors on nerves, followed by acetylcholine release, pancreatic enzyme secretion. It is still not known whether CCK-A receptors exist in human acinar cells, in contrast to acinar cells of rodents where CCK-A receptors have been well described. CCK has numerous actions both in the periphery and in the central nervous systems. CCK inhibits gastric motility and regulates satiety. Another major function of CCK is stimulation of gallbladder contraction. This function enables that bile acids act simultaneously with pancreatic lipolytic enzymes. Secretin is a major stimulator of bicarbonate secretion. Trypsinogen is activated by the gut mucosal enzyme enterokinase. The other pancreatic proenzymes are activated by trypsin. Termination of enzyme secretion may be regulated by negative feedback mechanisms via destruction of CCK-releasing peptides by trypsin. Furthermore, the ileum may act as a brake by release of inhibitory hormones such as PYY and somatostatin. In the pathophysiology of acute pancreatitis, fusion of zymogen granules with lysosomes leading to intracellular activation of trypsinogen is regarded as an initiation step. This activation of trypsinogen may be caused by the lysosomal enzyme cathepsin B. However, autoactivation of trypsinogen itself may be a possibility in pathogenesis. Autoactivation is enhanced in certain mutations of trypsinogen. Furthermore, an imbalance of protease inhibitors and active proteases may be involved. The role of pancreatic lipolytic enzymes, the role of bicarbonate secretion, and toxic Ca(2+) signals by excessive liberation from the endoplasmic reticulum have to be discussed in the pathogenesis of acute pancreatitis

Pathology and Molecular Genetics of Pancreatic Neoplasms

PubMed Central

Wood, Laura D.; Hruban, Ralph H.

2014-01-01

Cancer is fundamentally a genetic disease caused by the ac cumulation of somatic mutations in oncogenes and tumor suppressor genes. In the last decade, rapid advances in sequencing and bioinformatic technology led to an explosion in sequencing studies of cancer genomes, greatly expanding our knowledge of the genetic changes underlying a variety of tumor types. Several of these studies of cancer genomes have focused on pancreatic neoplasms, and cancers from the pancreas are some of the best characterized tumors at the genetic level. Pancreatic neoplasms encompass a wide array of clinical diseases, from benign cysts to deadly cancers, and the genetic alterations underlying neoplasms of the pancreas are similarly diverse. This new knowledge of pancreatic cancer genomes has deepened our understanding of tumorigenesis in the pancreas and has opened several promising new avenues for novel diagnostics and therapeutics. PMID:23187835

[Closed needle-biopsy in the diagnosis of neoplasms].

PubMed

Sforza, M; Perelli Ercolini, M; Beani, G

1979-04-01

The AA. demonstrate with this communication the validity of the needle biopsie for the diagnosis of neoplasms. They had used it for the breast, thyroid, flg and some other superficial tumefactions. In the mass-screening for the feminine neoplasms the clinical examination and the needle biopsy are very good method for a careful diagnosis.

Reconstructing human pancreatic differentiation by mapping specific cell populations during development.

PubMed

Ramond, Cyrille; Glaser, Nicolas; Berthault, Claire; Ameri, Jacqueline; Kirkegaard, Jeannette Schlichting; Hansson, Mattias; Honoré, Christian; Semb, Henrik; Scharfmann, Raphaël

2017-07-21

Information remains scarce on human development compared to animal models. Here, we reconstructed human fetal pancreatic differentiation using cell surface markers. We demonstrate that at 7weeks of development, the glycoprotein 2 (GP2) marks a multipotent cell population that will differentiate into the acinar, ductal or endocrine lineages. Development towards the acinar lineage is paralleled by an increase in GP2 expression. Conversely, a subset of the GP2 + population undergoes endocrine differentiation by down-regulating GP2 and CD142 and turning on NEUROG3 , a marker of endocrine differentiation. Endocrine maturation progresses by up-regulating SUSD2 and lowering ECAD levels. Finally, in vitro differentiation of pancreatic endocrine cells derived from human pluripotent stem cells mimics key in vivo events. Our work paves the way to extend our understanding of the origin of mature human pancreatic cell types and how such lineage decisions are regulated.

Comparative analysis of cytokeratin 15, TDAG51, cytokeratin 20 and androgen receptor in sclerosing adnexal neoplasms and variants of basal cell carcinoma.

PubMed

Evangelista, Mara Therese P; North, Jeffrey P

2015-11-01

Desmoplastic trichoepithelioma (DTE), morpheaform basal cell carcinoma (BCC) and microcystic adnexal carcinoma (MAC) are sclerosing adnexal neoplasms with overlapping histopathologic features. We compared cytokeratin 15, (CK15), T-cell death-associated gene 51 (TDAG51), cytokeratin 20 (CK20) and androgen receptor (AR) in differentiating these tumors and assessed their expression in BCC subtypes. Fifteen DTE, 15 infundibulocystic BCC, 18 micronodular BCC, 18 morpheaform BCC and 6 MAC were assessed for CK15, TDAG51, CK20 and AR expression. Quantitative CK15 staining was higher in DTE compared with BCC (p < 0.0001) and MAC (p = 0.02). Quantitative TDAG51 staining was higher in DTE than BCC (p < 0.0001). The CK20+AR- immunophenotype was 100% sensitive and specific in diagnosing DTE. The CK20-AR+ immunophenotype was 95.24% specific and 83.33% sensitive for BCC. The CK20-AR- immunophenotype was 83.33% sensitive and 90.91% specific for MAC. CK15, CK20 and AR were positive in 87, 53 and 67% of infundibulocystic BCC cases, respectively. Combination of CK20 and AR best differentiated these sclerosing adnexal neoplasms. Greater positivity for CK15 and TDAG51 generally favors benign lesions. Infundibulocystic BCC has higher CK20 and lower AR immunopositivity than other BCC variants and a high degree of CK15 and TDAG51 positivity. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Helicobacter pylori-related chronic gastritis as a risk factor for colonic neoplasms.

PubMed

Inoue, Izumi; Kato, Jun; Tamai, Hideyuki; Iguchi, Mikitaka; Maekita, Takao; Yoshimura, Noriko; Ichinose, Masao

2014-02-14

To summarize the current views and insights on associations between Helicobacter pylori (H. pylori)-related chronic gastritis and colorectal neoplasm, we reviewed recent studies to clarify whether H. pylori infection/H. pylori-related chronic gastritis is associated with an elevated risk of colorectal neoplasm. Recent studies based on large databases with careful control for confounding variables have clearly demonstrated an increased risk of colorectal neoplasm associated with H. pylori infection. The correlation between H. pylori-related chronic atrophic gastritis (CAG) and colorectal neoplasm has only been examined in a limited number of studies. A recent large study using a national histopathological database, and our study based on the stage of H. pylori-related chronic gastritis as determined by serum levels of H. pylori antibody titer and pepsinogen, indicated that H. pylori-related CAG confers an increased risk of colorectal neoplasm, and more extensive atrophic gastritis will probably be associated with even higher risk of neoplasm. In addition, our study suggested that the activity of H. pylori-related chronic gastritis is correlated with colorectal neoplasm risk. H. pylori-related chronic gastritis could be involved in an increased risk of colorectal neoplasm that appears to be enhanced by the progression of gastric atrophy and the presence of active inflammation.

Helicobacter pylori-related chronic gastritis as a risk factor for colonic neoplasms

PubMed Central

Inoue, Izumi; Kato, Jun; Tamai, Hideyuki; Iguchi, Mikitaka; Maekita, Takao; Yoshimura, Noriko; Ichinose, Masao

2014-01-01

To summarize the current views and insights on associations between Helicobacter pylori (H. pylori)-related chronic gastritis and colorectal neoplasm, we reviewed recent studies to clarify whether H. pylori infection/H. pylori-related chronic gastritis is associated with an elevated risk of colorectal neoplasm. Recent studies based on large databases with careful control for confounding variables have clearly demonstrated an increased risk of colorectal neoplasm associated with H. pylori infection. The correlation between H. pylori-related chronic atrophic gastritis (CAG) and colorectal neoplasm has only been examined in a limited number of studies. A recent large study using a national histopathological database, and our study based on the stage of H. pylori-related chronic gastritis as determined by serum levels of H. pylori antibody titer and pepsinogen, indicated that H. pylori-related CAG confers an increased risk of colorectal neoplasm, and more extensive atrophic gastritis will probably be associated with even higher risk of neoplasm. In addition, our study suggested that the activity of H. pylori-related chronic gastritis is correlated with colorectal neoplasm risk. H. pylori-related chronic gastritis could be involved in an increased risk of colorectal neoplasm that appears to be enhanced by the progression of gastric atrophy and the presence of active inflammation. PMID:24587623

Improved detection rate of cytogenetic abnormalities in chronic lymphocytic leukemia and other mature B-cell neoplasms with use of CpG-oligonucleotide DSP30 and interleukin 2 stimulation.

PubMed

Shi, Min; Cipollini, Matthew J; Crowley-Bish, Patricia A; Higgins, Anne W; Yu, Hongbo; Miron, Patricia M

2013-05-01

Detection of cytogenetic abnormalities requires successful culture of the clonal population to obtain metaphase chromosomes for study, and as such, has been hampered by low mitotic indices of mature B cells in culture. Our study presents data on the improved abnormality detection rate with the use of a CpG-oligonucleotide/interleukin 2 (OL/IL-2) culture protocol for mature B-cell neoplasms, including chronic lymphocytic leukemia (CLL) and non-CLL specimens. The increased detection rate of abnormalities, compared with unstimulated culture and traditional pokeweed mitogen culture, was statistically significant for both CLL and non-CLL neoplasms. For CLL specimens, our data also showed that for cytogenetically visible aberrations, OL/IL-2 was as, if not more, sensitive than detection with interphase fluorescence in situ hybridization (iFISH). Use of OL/IL-2 allowed a number of abnormalities to be detected, which were not covered by specific iFISH panels, especially balanced translocations. Therefore, OL/IL-2 stimulation improves diagnostic sensitivity and increases discovery rate of novel prognostic findings.

Limb Preservation With Isolated Limb Infusion for Locally Advanced Nonmelanoma Cutaneous and Soft-Tissue Malignant Neoplasms

PubMed Central

Turaga, Kiran K.; Beasley, Georgia M.; Kane, John M.; Delman, Keith A.; Grobmyer, Stephen R.; Gonzalez, Ricardo J.; Letson, G. Douglas; Cheong, David; Tyler, Douglas S.; Zager, Jonathan S.

2015-01-01

Objective To demonstrate the efficacy of isolated limb infusion (ILI) in limb preservation for patients with locally advanced soft-tissue sarcomas and nonmelanoma cutaneous malignant neoplasms. Background Locally advanced nonmelanoma cutaneous and soft-tissue malignant neoplasms, including soft-tissue sarcomas of the extremities, can pose significant treatment challenges. We report our experience, including responses and limb preservation rates, using ILI in cutaneous and soft-tissue malignant neoplasms. Methods We identified 22 patients with cutaneous and soft-tissue malignant neoplasms who underwent 26 ILIs with melphalan and actinomycin from January 1, 2004, through December 31, 2009, from 5 institutions. Outcome measures included limb preservation and in-field response rates. Toxicity was measured using the Wieberdink scale and serum creatinine phosphokinase levels. Results The median age was 70 years (range, 19-92 years), and 12 patients (55%) were women. Fourteen patients (64%) had sarcomas, 7 (32%) had Merkel cell carcinoma, and 1 (5%) had squamous cell carcinoma. The median length of stay was 5.5 days (interquartile range, 4-8 days). Twenty-five of the 26 ILIs (96%) resulted in Wieberdink grade III or less toxicity, and 1 patient (4%) developed grade IV toxicity. The median serum creatinine phosphokinase level was 127 U/L for upper extremity ILIs and 93 U/L for lower extremity ILIs. Nineteen of 22 patients (86%) underwent successful limb preservation. The 3-month in-field response rate was 79% (21% complete and 58% partial), and the median follow-up was 8.6 months (range, 1-63 months). Five patients underwent resection of disease after an ILI, of whom 80% are disease free at a median of 8.6 months. Conclusions Isolated limb infusion provides an attractive alternative therapy for regional disease control and limb preservation in patients with limb-threatening cutaneous and soft-tissue malignant neoplasms. Short-term response rates appear encouraging, yet

T Cells in Predicting Acute Graft-Versus-Host Disease in Patients Undergoing Donor Stem Cell Transplant

ClinicalTrials.gov

2017-06-26

Breast Cancer; Chronic Myeloproliferative Disorders; Gestational Trophoblastic Tumor; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Neuroblastoma; Ovarian Cancer; Testicular Germ Cell Tumor

Myeloproliferative Neoplasms (MPNs) Patient Registry

ClinicalTrials.gov

2017-10-27

Primary Myelofibrosis; Polycythemia Vera; Essential Thrombocythemia; Mastocytosis; Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative; Leukemia, Myelomonocytic, Juvenile; Chronic Eosinophilic Leukemia-not Otherwise Specified; Myelodysplastic-Myeloproliferative Diseases; Neoplasms; Leukemia, Myelomonocytic, Chronic

Radiology of pancreatic neoplasms: An update

PubMed Central

de la Santa, Luis Gijón; Retortillo, José Antonio Pérez; Miguel, Ainhoa Camarero; Klein, Lea Marie

2014-01-01

Diagnostic imaging is an important tool to evaluate pancreatic neoplasms. We describe the imaging features of pancreatic malignancies and their benign mimics. Accurate detection and staging are essential for ensuring appropriate selection of patients who will benefit from surgery and for preventing unnecessary surgeries in patients with unresectable disease. Ultrasound, multidetector computed tomography with multiplanar reconstruction and magnetic resonance imaging can help to do a correct diagnosis. Radiologists should be aware of the wide variety of anatomic variants and pathologic conditions that may mimic pancreatic neoplasms. The knowledge of the most important characteristic key findings may facilitate the right diagnosis. PMID:25232458

Radiology of pancreatic neoplasms: An update.

PubMed

de la Santa, Luis Gijón; Retortillo, José Antonio Pérez; Miguel, Ainhoa Camarero; Klein, Lea Marie

2014-09-15

Diagnostic imaging is an important tool to evaluate pancreatic neoplasms. We describe the imaging features of pancreatic malignancies and their benign mimics. Accurate detection and staging are essential for ensuring appropriate selection of patients who will benefit from surgery and for preventing unnecessary surgeries in patients with unresectable disease. Ultrasound, multidetector computed tomography with multiplanar reconstruction and magnetic resonance imaging can help to do a correct diagnosis. Radiologists should be aware of the wide variety of anatomic variants and pathologic conditions that may mimic pancreatic neoplasms. The knowledge of the most important characteristic key findings may facilitate the right diagnosis.

Lymph node staging of oral and maxillofacial neoplasms in 31 dogs and cats.

PubMed

Herring, Erin S; Smith, Mark M; Robertson, John L

2002-09-01

A retrospective study was performed to report the histologic examination results of regional lymph nodes of dogs and cats with oral or maxillofacial neoplasms. Twenty-eight dogs and 3 cats were evaluated. Histologic examination results of standard and serial tissue sectioning of regional lymph nodes were recorded. When available, other clinical parameters including mandibular lymph node palpation, thoracic radiographs, and pre- and postoperative fine needle aspiration of lymph nodes were compared with the histologic results. Squamous cell carcinoma, fibrosarcoma, and melanoma were the most common neoplasms diagnosed in dogs. Squamous cell carcinoma and fibrosarcoma were diagnosed in cats. Of the palpably enlarged mandibular lymph nodes, 17.0% had metastatic disease histologically. Radiographically evident thoracic metastatic disease was present in 7.4% of cases. Preoperative cytologic evaluation of the mandibular lymph node based on fine needle aspiration concurred with the histologic results in 90.5% of lymph nodes examined. Postoperative cytologic evaluation of fine needle aspirates of regional lymph nodes concurred with the histologic results in 80.6% of lymph nodes examined. Only 54.5% of cases with metastatic disease to regional lymph nodes had metastasis that included the mandibular lymph node. Serial lymph node sectioning provided additional information or metastasis detection. Cytologic evaluation of the mandibular lymph node correlates positively with histology, however results may fail to indicate the presence of regional metastasis. Assessment of all regional lymph nodes in dogs and cats with oral or maxillofacial neoplasms will detect more metastatic disease than assessing the mandibular lymph node only.

Pleomorphic dermal sarcoma: a more aggressive neoplasm than previously estimated.

PubMed

Tardío, Juan C; Pinedo, Fernando; Aramburu, José A; Suárez-Massa, Dolores; Pampín, Ana; Requena, Luis; Santonja, Carlos

2016-02-01

Pleomorphic dermal sarcoma (PDS) is a rare neoplasm sharing pathological features with atypical fibroxanthoma, but adding tumor necrosis, invasion beyond superficial subcutis or vascular or perineural infiltration. Although its metastatic risk has been estimated to be less than 5%, its real outcome is presently uncertain because of its rarity and to the lack of homogeneous criteria used in reported cases. Retrospective clinicopathological study of 18 cases of PDS. The lesions presented as tumors or plaques (size: 7-70 mm) on the head of elderly patients (median: 81 years), without a gender predominance. Histopathologically, they consisted of spindle cells arranged in a fascicular pattern, containing pleomorphic epithelioid and giant multinucleated cells in varying proportions, and usually exhibiting numerous mitotic figures and infiltrative tumor margins. No immunoexpression for cytokeratins, S100 protein, desmin or CD34 was observed. Necrosis and venous invasion were found in three tumors each (17%). Follow-up was available in 15 cases (median: 33 months). Three patients (20%) had local recurrences, all with incomplete primary surgical resections. Three patients (20%) developed distant metastases in the skin, regional lymph nodes and/or lungs and died from the disease. Our data suggest that PDS may be a more aggressive neoplasm than previously estimated. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Encapsulated papillary oncocytic neoplasms of the thyroid: morphologic, immunohistochemical, and molecular analysis of 18 cases.

PubMed

Woodford, Randall Lyndon; Nikiforov, Yuri E; Hunt, Jennifer L; Bellizzi, Andrew M; Zhang, Xiaotang; Mills, Stacey E; Stelow, Edward B

2010-11-01

Encapsulated papillary oncocytic neoplasms (EPONs) of the thyroid are rare tumors, whose relationship to other thyroid tumors has not been thoroughly elucidated. Earlier, they have been regarded as variants of papillary thyroid carcinoma (PTC), hyperplastic lesions, and follicular neoplasms. Eighteen EPONs were retrieved from our surgical pathology files and reviewed for defining morphologic features. Cases having the typical nuclear features of PTC were excluded. Immunohistochemistry (IHC) for CK19, HBME1, and CD56 was carried out. Microdissection, polymerase chain reaction, and sequencing of exon 15 of the BRAF gene were completed. Cases were evaluated for rearranged in transformation/papillary thyroid carcinoma RET/PTC rearrangement by fluorescent in situ hybridization (FISH). The majority of the tumors exhibited a distinctive histologic appearance. They were composed of true papillae lined by a single layer of predominantly cuboidal cells with oncocytic cytoplasm; hobnailing was typically prominent. Three tumors showed taller cells with uniformly apical nuclei and no hobnailing. Ten of 18 cases showed vascular and/or capsular invasion; hence, if the diagnostic criteria used to evaluate follicular neoplasms are applied, more than half of the tumors would be considered minimally invasive carcinomas. No cases were immunoreactive with antibodies to HBME1, whereas only 1 of 13 was immunoreactive for CK19. Six of 7 interpretable cases were immunoreactive for CD56. No BRAF point mutations or RET/PTC rearrangements were identified in the examined cases. All patients were alive at the time of last follow-up and no locally recurrent disease had been reported; however, 1 case was remarkable for a lymph node metastasis. Our results confirm that EPONs are histologically, immunohistochemically, and molecularly distinct from papillary thyroid carcinoma and seem to be most related to follicular neoplasms.

Diffusion-weighted magnetic resonance imaging in the characterization of testicular germ cell neoplasms: Effect of ROI methods on apparent diffusion coefficient values and interobserver variability.

PubMed

Tsili, Athina C; Ntorkou, Alexandra; Astrakas, Loukas; Xydis, Vasilis; Tsampalas, Stavros; Sofikitis, Nikolaos; Argyropoulou, Maria I

2017-04-01

To evaluate the difference in apparent diffusion coefficient (ADC) measurements at diffusion-weighted (DW) magnetic resonance imaging of differently shaped regions-of-interest (ROIs) in testicular germ cell neoplasms (TGCNS), the diagnostic ability of differently shaped ROIs in differentiating seminomas from nonseminomatous germ cell neoplasms (NSGCNs) and the interobserver variability. Thirty-three TGCNs were retrospectively evaluated. Patients underwent MR examinations, including DWI on a 1.5-T MR system. Two observers measured mean tumor ADCs using four distinct ROI methods: round, square, freehand and multiple small, round ROIs. The interclass correlation coefficient was analyzed to assess interobserver variability. Statistical analysis was used to compare mean ADC measurements among observers, methods and histologic types. All ROI methods showed excellent interobserver agreement, with excellent correlation (P<0.001). Multiple, small ROIs provided the lower mean ADC in TGCNs. Seminomas had lower mean ADC compared to NSGCNs for each ROI method (P<0.001). Round ROI proved the most accurate method in characterizing TGCNS. Interobserver variability in ADC measurement is excellent, irrespective of the ROI shape. Multiple, small round ROIs and round ROI proved the more accurate methods for ADC measurement in the characterization of TGCNs and in the differentiation between seminomas and NSGCNs, respectively. Copyright © 2017 Elsevier B.V. All rights reserved.

A case report of mixed acinar-endocrine carcinoma of the pancreas treated with S-1 chemotherapy: Does it work or induce endocrine differentiation?

PubMed

Yokode, Masataka; Itai, Ryosuke; Yamashita, Yukimasa; Zen, Yoh

2017-11-01

Acinar cell carcinomas (ACCs) and mixed acinar-endocrine carcinomas (MAECs) of the pancreas are rare, accounting for only 1% of pancreatic tumors. Although both typically present at an advanced stage, chemotherapeutic regimes have not yet been standardized. A 65-year-old man presented with a large mass in the pancreatic tail with multiple liver metastases. He was initially treated with gemcitabine for suspected ductal carcinoma of the pancreas, but no response was observed. S-1, administered as second-line chemotherapy, showed an approximately 38% reduction in the size of the primary tumor and metastatic deposits with therapeutic effects being maintained for 12 months. When the tumor progressed again, he underwent a percutaneous liver biopsy, which led to the diagnosis of MAEC. Combination therapy with cisplatin and etoposide targeting the endocrine component was administered, and this was based on the endocrine component potentially being less sensitive to S-1 than the ACC element. However, therapy was stopped due to the development of neutropenia, and the patient is currently receiving best supportive care. Given the previous studies suggested that S-1 is more effective for ACCs than gemcitabine, MAECs may also respond to S-1 chemotherapy, similar to ACCs. Another potential interpretation is that S-1 was effective when the condition was ACC, and eventually showed decreased effectiveness when the condition shifted to MAEC. Future studies are needed to conclude whether S-1 chemotherapy truly works against MAECs or induces endocrine differentiation in ACCs as a part of the drug-resistance process.

"Pseudomyxoma Endometrii": Endometrial Deposition of Acellular Mucin from a Low-Grade Appendiceal Mucinous Neoplasm as a Rare Mimic of Myxoid Uterine Tumors.

PubMed

Shaw, Kristin C; Kokh, Dina; Ioffe, Olga B; Staats, Paul N

2015-07-01

Low-grade appendiceal mucinous neoplasms (LAMNs) are commonly associated with deposition of mucin, with or without admixed low-grade epithelium, on peritoneal surfaces (pseudomyxoma peritonei). We describe a very rare presentation of LAMN as extensive mucin deposition in the endometrium of a 43-yr-old woman initially mistaken for a primary uterine myxoid neoplasm. The patient underwent endometrial curettage that demonstrated abundant myxoid/mucoid material interspersed with small vessels, bland eosinophilic spindled cells, scattered foci of typical endometrial stroma, and occasional endometrioid glands. The endometrial stroma was positive for CD10, and the eosinophilic spindled cells were positive for actin. The lesion was interpreted as "myxoid/mucinous neoplasm, most likely of smooth muscle/endometrial stromal origin." Subsequent laparotomy revealed peritoneal mucin in the anterior cul-de-sac and a dilated appendix. Pathologic review confirmed appendiceal LAMN and multifocal peritoneal mucinosis. The uterus contained scant residual mucoid material. On review of all pathologic material at our institution, the endometrial lesion was consistent with organizing mucin derived from the LAMN with entrapped benign endometrium. "Pseudomyxoma endometrii" is readily mistaken for a primary uterine myxoid neoplasm, particularly myxoid endometrial stromal tumor. A key to diagnosis is recognition that the material is mucin rather than myxoid stroma. This is evidenced by the absence of embedded stromal cells and presence of myofibroblastic, vascular, and macrophage infiltration associated with organization. Epithelium containing goblet cells is an important clue if present. The presence of rare endometrial glands within the endometrial stroma suggests that the latter is entrapped rather than neoplastic.

TFE3 Translocation Associated Perivascular Epithelioid Cell Neoplasm (PEComa) of the Gynecologic Tract: Morphology, Immunophenotype, Differential Diagnosis

PubMed Central

Schoolmeester, J. Kenneth; Dao, Linda N.; Sukov, William R.; Park, Kay J.; Murali, Rajmohan; Hameed, Meera R.; Soslow, Robert A.

2016-01-01

TFE3 translocation associated PEComa is a distinct form of perivascular epithelioid cell neoplasm, the features of which are poorly defined owing to their general infrequency and limited prior reports with confirmed rearrangement or fusion totaling nine cases. Recent investigation has found a lack of TSC gene mutation in these tumors compared to their nonrearranged counterparts which underscores the importance of recognizing the translocated variant due to hypothetical ineffectiveness of targeted mTOR inhibitor therapy. Six cases were identified and TFE3 rearrangement was confirmed by FISH. Patient age ranged 46 to 66 years (median 50) and none had a history of tuberous sclerosis complex. Three cases arose in the uterine corpus, one in the vagina, and one pelvic tumor and one pulmonary tumor were likely a recurrence/metastasis from a probable uterine primary. Five cases had purely clear cell epithelioid morphology that showed a spectrum of atypia while one case had a mixture of clear cell epithelioid and spindle cells. A mostly consistent immunophenotype was observed in the purely clear cell epithelioid cases: each demonstrated diffuse TFE3, HMB45, CathepsinK labeling, either focal or no melanA staining and variably weak reactivity to smooth muscle markers. The mixed clear cell epithelioid and spindle cell case had a similar pattern in its epithelioid component, but strong muscle marker positivity in its spindle cell component. Follow up ranged 1 to 57 months. Three cases demonstrated aggressive behavior and three cases had no evidence of recurrence. Both GYN-specific and traditional sets of criteria for malignancy were evaluated. The GYN model showed improved inclusion and specificity in comparison to the traditional model. PMID:25517951

TFE3 translocation-associated perivascular epithelioid cell neoplasm (PEComa) of the gynecologic tract: morphology, immunophenotype, differential diagnosis.

PubMed

Schoolmeester, J Kenneth; Dao, Linda N; Sukov, William R; Wang, Lu; Park, Kay J; Murali, Rajmohan; Hameed, Meera R; Soslow, Robert A

2015-03-01

TFE3 translocation-associated PEComa is a distinct form of perivascular epithelioid cell neoplasm, the features of which are poorly defined owing to their general infrequency and limited prior reports with confirmed rearrangement or fusion. Recent investigation has found a lack of TSC gene mutation in these tumors compared with their nonrearranged counterparts, which underscores the importance of recognizing the translocated variant because of hypothetical ineffectiveness of targeted mTOR inhibitor therapy. Six cases were identified, and TFE3 rearrangement was confirmed by fluorescence in situ hybridization. Patient age ranged from 46 to 66 years (median 50 y), and none had a history of a tuberous sclerosis complex. Three cases arose in the uterine corpus, 1 in the vagina, 1 pelvic tumor, and 1 pulmonary tumor that was likely a recurrence/metastasis from a probable uterine primary. Five cases had clear cell epithelioid morphology that showed a spectrum of atypia, while 1 case had a mixture of clear cell epithelioid and spindle cells. A mostly consistent immunophenotype was observed in the clear cell epithelioid cases: each demonstrated diffuse TFE3, HMB45, cathepsinK labeling, either focal or no melanA staining, and variably weak reactivity to smooth muscle markers. The mixed clear cell epithelioid and spindle cell case had a similar expression pattern in its epithelioid component but strong muscle marker positivity in its spindle cell component. Follow-up ranged from 1 to 57 months. Three cases demonstrated aggressive behavior, and 3 cases had no evidence of recurrence. Both GYN-specific and traditional sets of criteria for malignancy were evaluated. The GYN model showed improved inclusion and specificity in comparison to the traditional model.

Age-specific incidence of all neoplasms after colorectal cancer.

PubMed

Levi, Fabio; Randimbison, Lalao; Blanc-Moya, Rafael; La Vecchia, Carlo

2014-10-01

Patients diagnosed with a specific neoplasm tend to have a subsequent excess risk of the same neoplasm. The age incidence of a second neoplasm at the same site is approximately constant with age, and consequently the relative risk is greater at younger age. It is unclear whether such a line of reasoning can be extended from a specific neoplasm to the incidence of all neoplasms in subjects diagnosed with a defined neoplasm. We considered the age-specific incidence of all non-hormone-related epithelial neoplasms after a first primary colorectal cancer (n = 9542) in the Vaud Cancer Registry data set. In subjects with a previous colorectal cancer, the incidence rate of all other epithelial non-hormone-related cancers was stable around 800 per 100,000 between age 30 and 60 years, and rose only about twofold to reach 1685 at age 70 to 79 years and 1826 per 100,000 at age 80 years or older. After excluding synchronous cancers, the rise was only about 1.5-fold, that is, from about 700 to 1000. In the general population, the incidence rate of all epithelial non-hormone-related cancers was 29 per 100,000 at age 30 to 39 years, and rose 30-fold to 883 per 100,000 at age 70 to 79 years. Excluding colorectal cancers, the rise of all non-hormone-related cancers was from 360 per 100,000 at age 40 to 49 years to 940 at age 70 to 79 years after colorectal cancer, and from 90 to 636 per 100,000 in the general population (i.e., 2.6- vs. 7.1-fold). The rise of incidence with age of all epithelial non-hormone-related second cancers after colorectal cancer is much smaller than in the general population. This can possibly be related to the occurrence of a single mutational event in a population of susceptible individuals, although alternative models are plausible within the complexity of the process of carcinogenesis. Copyright © 2014 Elsevier Inc. All rights reserved.

Saccular aortic aneurysm that resembled a mediastinal neoplasm

PubMed Central

Nose, Naohiro; Kataoka, Hiroumi; Hamada, Masakatsu; Kosako, Yukio; Matsuno, Yasuji; Ishii, Takahiro

2012-01-01

INTRODUCTION Saccular aortic arch aneurysms in unusual sites may be misdiagnosed as a neoplasm. We present the case of a rare saccular aortic arch aneurysm between trachea and esophagus that resembled a mediastinal neoplasm in the preoperative findings. PRESENTATION OF CASE A 63-year-old male with an abnormal mediastinal shadow on chest X-ray was referred to the hospital. An axial plain computed tomogram of the chest revealed mediastinal soft tissue next to the right side of the aortic arch resembling a neoplasm originating from the gap between the trachea and the esophagus. The coronal view constructed by enhanced 64-row multi detector computed tomography revealed the soft tissue was an aneurysm arising from the inner side of the aortic arch. An aortic arch replacement was performed via a median sternotomy. DISCUSSION A thoracic aortic aneurysm sometimes behaves like a mediastinal neoplasm. The multiple cross-sectional image from multidetector computed tomography was useful for the correct diagnosis of such an aneurysm. CONCLUSION The possibility of an aneurysm should be considered whenever a mass in contact with the aortic wall is identified. PMID:22995656

Solute carrier transporters: potential targets for digestive system neoplasms.

PubMed

Xie, Jing; Zhu, Xiao Yan; Liu, Lu Ming; Meng, Zhi Qiang

2018-01-01

Digestive system neoplasms are the leading causes of cancer-related death all over the world. Solute carrier (SLC) superfamily is composed of a series of transporters that are ubiquitously expressed in organs and tissues of digestive systems and mediate specific uptake of small molecule substrates in facilitative manner. Given the important role of SLC proteins in maintaining normal functions of digestive system, dysregulation of these protein in digestive system neoplasms may deliver biological and clinical significance that deserves systemic studies. In this review, we critically summarized the recent advances in understanding the role of SLC proteins in digestive system neoplasms. We highlighted that several SLC subfamilies, including metal ion transporters, transporters of glucose and other sugars, transporters of urea, neurotransmitters and biogenic amines, ammonium and choline, inorganic cation/anion transporters, transporters of nucleotide, amino acid and oligopeptide organic anion transporters, transporters of vitamins and cofactors and mitochondrial carrier, may play important roles in mediating the initiation, progression, metastasis, and chemoresistance of digestive system neoplasms. Proteins in these SLC subfamilies may also have diagnostic and prognostic values to particular cancer types. Differential expression of SLC proteins in tumors of digestive system was analyzed by extracting data from human cancer database, which revealed that the roles of SLC proteins may either be dependent on the substrates they transport or be tissue specific. In addition, small molecule modulators that pharmacologically regulate the functions of SLC proteins were discussed for their possible application in the treatment of digestive system neoplasms. This review highlighted the potential of SLC family proteins as drug target for the treatment of digestive system neoplasms.

Solute carrier transporters: potential targets for digestive system neoplasms

PubMed Central

Xie, Jing; Zhu, Xiao Yan; Liu, Lu Ming; Meng, Zhi Qiang

2018-01-01

Digestive system neoplasms are the leading causes of cancer-related death all over the world. Solute carrier (SLC) superfamily is composed of a series of transporters that are ubiquitously expressed in organs and tissues of digestive systems and mediate specific uptake of small molecule substrates in facilitative manner. Given the important role of SLC proteins in maintaining normal functions of digestive system, dysregulation of these protein in digestive system neoplasms may deliver biological and clinical significance that deserves systemic studies. In this review, we critically summarized the recent advances in understanding the role of SLC proteins in digestive system neoplasms. We highlighted that several SLC subfamilies, including metal ion transporters, transporters of glucose and other sugars, transporters of urea, neurotransmitters and biogenic amines, ammonium and choline, inorganic cation/anion transporters, transporters of nucleotide, amino acid and oligopeptide organic anion transporters, transporters of vitamins and cofactors and mitochondrial carrier, may play important roles in mediating the initiation, progression, metastasis, and chemoresistance of digestive system neoplasms. Proteins in these SLC subfamilies may also have diagnostic and prognostic values to particular cancer types. Differential expression of SLC proteins in tumors of digestive system was analyzed by extracting data from human cancer database, which revealed that the roles of SLC proteins may either be dependent on the substrates they transport or be tissue specific. In addition, small molecule modulators that pharmacologically regulate the functions of SLC proteins were discussed for their possible application in the treatment of digestive system neoplasms. This review highlighted the potential of SLC family proteins as drug target for the treatment of digestive system neoplasms. PMID:29416375

Reconstructing human pancreatic differentiation by mapping specific cell populations during development

PubMed Central

Ramond, Cyrille; Glaser, Nicolas; Berthault, Claire; Ameri, Jacqueline; Kirkegaard, Jeannette Schlichting; Hansson, Mattias; Honoré, Christian; Semb, Henrik; Scharfmann, Raphaël

2017-01-01

Information remains scarce on human development compared to animal models. Here, we reconstructed human fetal pancreatic differentiation using cell surface markers. We demonstrate that at 7weeks of development, the glycoprotein 2 (GP2) marks a multipotent cell population that will differentiate into the acinar, ductal or endocrine lineages. Development towards the acinar lineage is paralleled by an increase in GP2 expression. Conversely, a subset of the GP2+ population undergoes endocrine differentiation by down-regulating GP2 and CD142 and turning on NEUROG3, a marker of endocrine differentiation. Endocrine maturation progresses by up-regulating SUSD2 and lowering ECAD levels. Finally, in vitro differentiation of pancreatic endocrine cells derived from human pluripotent stem cells mimics key in vivo events. Our work paves the way to extend our understanding of the origin of mature human pancreatic cell types and how such lineage decisions are regulated. DOI: http://dx.doi.org/10.7554/eLife.27564.001 PMID:28731406

Chronic myeloproliferative neoplasms in the elderly.

PubMed

Maffioli, Margherita; Orlandi, Ester; Passamonti, Francesco

2018-05-22

This review focuses on the management of elderly patients with chronic myeloid leukemia and chronic myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia and primary myelofibrosis. Median age in these neoplasms is within the 6th decades of age. All new therapies can be done at any age without absolute contraindication. However, the selection of the precise therapy for the single patient is mandatory. For these reasons, an accurate definition of diagnosis and prognostication is necessary. Precision in disease definition and prognostication is definitively helpful for personalizing therapeutic approach. Copyright © 2018 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

BRAF/KRAS gene sequencing of sebaceous neoplasms after mismatch repair protein analysis.

PubMed

Cornejo, Kristine M; Hutchinson, Lloyd; Deng, April; Tomaszewicz, Keith; Welch, Matthew; Lyle, Stephen; Dresser, Karen; Cosar, Ediz F

2014-06-01

Sebaceous neoplasms are cutaneous markers for the autosomal-dominant Muir-Torre syndrome (MTS). This phenotypic variant of Lynch syndrome (LS) is caused by germline mutations in DNA mismatch repair (MMR) genes. Microsatellite instability or loss of protein expression suggests a mutation or promoter hypermethylation in 1 of the MMR genes. BRAF gene sequencing may help to distinguish between patients with sporadic and LS-associated colorectal carcinomas with loss of MLH1 expression. LS-associated carcinomas are virtually negative for BRAF mutations, but a subset harbors KRAS mutations. The aim of our study was to test sebaceous neoplasms for V600E BRAF or KRAS mutations to determine if these mutations are associated with somatic or germline MMR defects, analogous to colorectal carcinomas. Over a 4-year period, 32 cases comprising 21 sebaceous adenomas, 3 sebaceomas, and 8 sebaceous carcinomas with sufficient material for testing were collected. MMR immunohistochemistry showed that 7 neoplasms had combined loss of MLH1-PMS2, 16 neoplasms had combined loss of MSH2-MSH6, 2 neoplasms had solitary loss of MSH6, and 7 sebaceous neoplasms had intact protein expression. BRAF/KRAS testing revealed all sebaceous neoplasms contained a wild-type BRAF gene. Two (15%) of 13 patients with MTS were found to harbor a KRAS mutation and loss of MLH1 expression. We conclude that a V600E BRAF mutation may not be helpful in distinguishing sporadic from MTS-associated sebaceous neoplasms. Further studies are needed to determine if KRAS mutations are restricted to patients with MTS or are also present in sporadic sebaceous neoplasms. Copyright © 2014 Elsevier Inc. All rights reserved.

Blood Stem Cell Transplant in Treating Patients With Hematologic Cancer

ClinicalTrials.gov

2014-06-05

Adult Langerhans Cell Histiocytosis; Childhood Langerhans Cell Histiocytosis; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms

P14.06 Central nervous system symptoms as the first manifestation of malignant neoplasm

PubMed Central

Espírito Santo, V.; Almendra, R.; Mendes, M.; Veiga, A.; Velon, A.; Guimarães, P.

2017-01-01

Abstract Introduction: Neurological involvement is a frequent complication of systemic neoplasm, but not all secondary lesions have clinical manifestations, and there are fewer cases in which first symptom is neurological. Materials and Methods: Retrospective study between January 2006 through November 2016 of patients in whom neurological manifestations due to metastases were the inaugural manifestation of systemic neoplasm. Results: Twenty-six patients (19 male, 7 female) between the ages of 48 and 85 were identified. The main complaints were motor deficit (n = 10), headache (n = 7), behaviour change (n = 3), sensory deficit (n = 2), language disorder (n=1), visual disorder (n=1), syncope (n = 1) and dizziness (n = 1), with 11 patients presenting with symptoms other than the main complaint. Twenty-four patients had brain metastases, in 9 patients, it was solitary, in 5 patients, 2 lesions were found and in the remaining 9, 3 or more lesions were found. Two patients had multiple spinal metastases and 1 patient presented meningeal carcinomatosis. The primary neoplasm were of pulmonary origin (n = 17), gastric (n = 1), prostatic (n = 1), rectal (n = 1) and skin (n=1). In 5 patients the primary lesion remained hidden. Histology results were available in 19 patients: adenocarcinoma (n = 13), small cell carcinoma (n = 3), spinous cell carcinoma (n = 1), melanoma (n = 1) and linitis plastica (n=1). The treatment consisted in corticosteroid treatment (n = 23), chemotherapy (n = 11), radiotherapy (n = 11), surgery (n = 2) and hormonal treatment (n = 1). The mean survival was 225 days, ranging from 9 to 801 days. Conclusions: With this work we verified a broad spectrum of central nervous system symptoms as clinical presentation of malignant neoplasm. In these cases, a detailed investigation is essential for the treatment and prognosis of these patients.

Hepatobiliary and Pancreatic neoplasms in patients with McCune-Albright syndrome.

PubMed

Gaujoux, Sébastien; Salenave, Sylvie; Ronot, Maxime; Rangheard, Anne-Sophie; Cros, Jérôme; Belghiti, Jacques; Sauvanet, Alain; Ruszniewski, Philippe; Chanson, Philippe

2014-01-01

McCune-Albright syndrome (MAS), which includes polycystic fibrous dysplasia, precocious puberty, and café au lait spots, is a rare disorder caused by somatic activating mutations of the GNAS gene. GNAS mutations have also been implicated in various sporadic tumors, including hepatobiliary and pancreatic neoplasms. The aim of this study was to assess the prevalence of hepatobiliary and pancreatic neoplasms in patients with McCune-Albright syndrome. Nineteen patients diagnosed between 1995 and 2012 with MAS in a tertiary referral center for rare growth disorders were screened with dedicated gadolinium-enhanced magnetic resonance imaging for hepatobiliary and pancreatic neoplasms between June 2011 and December 2012. Six (32%) of the 19 screened patients were found to have hepatic, pancreatic, or biliary lesions, excluding liver hemangiomas, liver cysts, and focal nodular hyperplasia. This includes pancreatic ductal lesions observed in 4 patients, including numerous branch-duct intraductal papillary mucinous neoplasms in 3 patients. Biliary lesions were observed in 1 patient, with a large choledochal cyst also involving the left biliary branch. Finally, multiple inflammatory/telangiectatic hepatic adenomas were observed in 2 patients, including 1 with proven somatic GNAS mutation. We describe the first observation of syndromic intraductal papillary mucinous neoplasms and the new association between MAS and pancreatic neoplasms, namely intraductal papillary mucinous neoplasms of the pancreas but also rare hepatobiliary neoplasms including liver adenomas and choledochal cysts. These findings strongly suggest that somatic activating GNAS mutations, possibly through cAMP pathway disorders, are involved in the tumorigenesis of hepatobiliary and pancreatic tissues originating from the foregut endoderm and have led us to use a routine screening by dedicated magnetic resonance imaging including both pancreatobiliary and liver sequences in patients with MAS.

Transforming growth factor (TGF)beta, fibroblast growth factor (FGF) and retinoid signalling pathways promote pancreatic exocrine gene expression in mouse embryonic stem cells.

PubMed Central

Skoudy, Anouchka; Rovira, Meritxell; Savatier, Pierre; Martin, Franz; León-Quinto, Trinidad; Soria, Bernat; Real, Francisco X

2004-01-01

Extracellular signalling cues play a major role in the activation of differentiation programmes. Mouse embryonic stem (ES) cells are pluripotent and can differentiate into a wide variety of specialized cells. Recently, protocols designed to induce endocrine pancreatic differentiation in vitro have been designed but little information is currently available concerning the potential of ES cells to differentiate into acinar pancreatic cells. By using conditioned media of cultured foetal pancreatic rudiments, we demonstrate that ES cells can respond in vitro to signalling pathways involved in exocrine development and differentiation. In particular, modulation of the hedgehog, transforming growth factor beta, retinoid, and fibroblast growth factor pathways in ES cell-derived embryoid bodies (EB) resulted in increased levels of transcripts encoding pancreatic transcription factors and cytodifferentiation markers, as demonstrated by RT-PCR. In EB undergoing spontaneous differentiation, expression of the majority of the acinar genes (i.e. amylase, carboxypeptidase A and elastase) was induced after the expression of endocrine genes, as occurs in vivo during development. These data indicate that ES cells can undergo exocrine pancreatic differentiation with a kinetic pattern of expression reminiscent of pancreas development in vivo and that ES cells can be coaxed to express an acinar phenotype by activation of signalling pathways known to play a role in pancreatic development and differentiation. PMID:14733613

Natural killer T-cell lymphoma of the tongue.

PubMed

Cho, Kwang-Jae; Cho, Seok-Goo; Lee, Dong-Hee

2005-01-01

Lymphoma, which represents about 5.4% of all neoplasms and, more significantly, 19% to 28% of malignant neoplasms, is the most common nonepithelial malignancy of the head and neck area in Koreans. Natural killer T-cell (NK/T-cell) lymphoma is a lymphoma of putative natural killer cell lineage. NK/T-cell neoplasms are generally rare, but they are more common in people of East Asian, Mexican, or South American descent. These neoplasms are highly aggressive and show a strong association with Epstein-Barr virus. The preferential site of extranodal NK/T-cell lymphoma is the nasal cavity, and there has been no report of NK/T-cell lymphoma developing from the tongue. We encountered a rare case of NK/T-cell lymphoma of the tongue, which we report with a review of the literature.

Use of CBL exon 8 and 9 mutations in diagnosis of myeloproliferative neoplasms and myelodysplastic/myeloproliferative disorders: an analysis of 636 cases

PubMed Central

Schnittger, Susanne; Bacher, Ulrike; Alpermann, Tamara; Reiter, Andreas; Ulke, Madlen; Dicker, Frank; Eder, Christiane; Kohlmann, Alexander; Grossmann, Vera; Kowarsch, Andreas; Kern, Wolfgang; Haferlach, Claudia; Haferlach, Torsten

2012-01-01

We analyzed 636 patients with diverse myeloproliferative neoplasms or myelodysplastic/myeloproliferative neoplasms for mutations of the Casitas B-cell lymphoma gene (CBLmut) in exons 8 and 9 and performed correlations to other genetic alterations. CBLmut were detected in 63 of 636 (9.9%) of these selected patients. CBLmut were more frequent in myelodysplastic/myeloproliferative neoplasms than myeloproliferative neoplasms (51 of 328, 15.5% vs. 12 of 291, 4.1%; P<0.001). Frequency was 48 of 278 (17.3%) in chronic myelomonocytic leukemia and 3 of 33 (9.1%) in unclassifiable myelodysplastic/myeloproliferative neoplasms. CBLmut was not detected in polycythemia vera, primary myelofibrosis, essential thrombocythemia, or refractory anemia with ring sideroblasts and marked thrombocytosis. CBLmut were underrepresented in JAK2V617F mutated as compared to JAK2V617wt cases (P<0.001), and mutually exclusive of JAK2exon12mut and MPLW515mut. CBLmut were associated with monosomy 7 (P=0.008) and TET2mut (P=0.003). In chronic myelomonocytic leukemia, CBLmut had no significant impact on survival outcomes. Therefore, CBLmut are frequent in chronic myelomonocytic leukemia, absent in classical myeloproliferative neoplasms, and are only exceptionally found in coincidence with JAK-STAT pathway activating mutations. PMID:22733026

The incidence of hematological neoplasms morbidity on radiation-contaminated territories in Cherkasy region.

PubMed

Paramonov, V V

2017-12-01

The main goal was to analyze the incidence of the morbidity in 1980, 1989, 2001, 2014 years and the structures of the absolute number of hematopoietic and lymphoid neoplasms cases during the period 1980-2014 on radiation contaminated and not contaminated territories in Cherkasy region. The epidemiological indecies of hematological neoplasms were analyzed on radiation con taminated and not contaminated territories in Cherkasy region during the period from 1980 to 2014. Referring the territory in Cherkasy region to radiation contaminated is based on settlements dosimetry certification of Ukraine after the Chornobyl accident. 63 settlements were enrolled to radiation contaminated areas in Cherkasy region and 11 settlements assigned as not contaminated areas. The first positions in the list of the hematological neoplasms structure and frequency among new cases during 1980-2014 on not contaminated territories in Cherkasy region occupied by lymphoid leukemia, Hodgkin's lymphoma and myeloid leukemia and on the radiation contaminated territories - chronic, acute lymphoid and myeloid leukemia and lymphoma, diffuse large cell lymphoma. In the structure of hematological neoplasms record ed on the contaminated territories in Cherkasy region, there is a smaller proportion of Hodgkin's lymphoma cases (C81) than 0.84 fold (RR = 0.84; 95 % CI = 0.75-0.93) and more than 1.15 times (RR = 1.15; 95 % CI = 1.02-1.30) other unspecified malignant lymphoid and hematopoietic neoplasms. In 2001 on the radiation contaminated terri tories in Cherkasy region increase the incidence of acute and chronic myeloid leukemia in 2.46 times (p = 0.024) observed compared to non contaminated areas there (5.30 per 100 000, 95% CI = 3.03-8.33 versus 2.15 per 100,000, 95 % CI = 0.66-3.64). It was calculated that RR of acute and chronic myeloid leukemia (C92) in 2001 on radiation contaminated areas in Cherkasy region is 1.40 (95 % CI = 1.12-1.17) and Hodgkin's lymphoma (C81) on condition ally clean areas

Reliability of store and forward teledermatology for skin neoplasms.

PubMed

Warshaw, Erin M; Gravely, Amy A; Nelson, David B

2015-03-01

Teledermatology may be less optimal for skin neoplasms than for rashes. We sought to determine agreement for skin neoplasms. This was a repeated measures study. Each lesion was examined by a clinic dermatologist and a teledermatologist; both generated a primary diagnosis, up to 2 differential diagnoses, and management. Macro images and polarized light dermoscopy images were obtained; for pigmented lesions only, contact immersion dermoscopy image was obtained. There were 3021 lesions in 2152 patients. Of 1685 biopsied lesions, there were 410 basal cell carcinomas (24%), 240 squamous cell carcinomas (14%), and 41 melanomas (2.4%). Agreement was fair to substantial for primary diagnosis (45.7%-80.1%; kappa 0.32-0.62), substantial to almost perfect for aggregated diagnoses (primary plus differential; 78.6%-93.9%; kappa 0.77-0.90), and fair for management (66.7%-86.1%; kappa 0.28-0.41). Diagnostic agreement rates were higher for pigmented lesions (52.8%-93.9%; kappa 0.44-0.90) than nonpigmented lesions (47.7%-87.3%; kappa 0.32-0.86), whereas the reverse was found for management agreement (pigmented: 66.7%-79.8%, kappa 0.19-0.35 vs nonpigmented: 72.0%-86.1%, kappa 0.38-0.41). Agreement rates using macro images were similar to polarized light dermoscopy; contact immersion dermoscopy, however, significantly improved rates for pigmented lesions. We studied a homogeneous population. Diagnostic agreement was moderate to almost perfect whereas management agreement was fair. Polarized light dermoscopy increased rates modestly whereas contact immersion dermoscopy significantly increased rates for pigmented lesions. Published by Elsevier Inc.

Multiple neoplasms among cervical cancer patients in the material of the lower Silesian cancer registry.

PubMed

Izmajłowicz, Barbara; Kornafel, Jan; Błaszczyk, Jerzy

2014-01-01

According to the definition by the International Agency for Research on Cancer (IARC), primary multiple neoplasms are two or more neoplasms of different histopathological build in one organ, or two or more tumors occurring in one patient, regardless of the time of their occurrence (synchronic - up to 6 months, metachronous - after 6 months), coming from an organ or a tissue and not being an infiltration from another neoplasm, a relapse or a metastasis. It was the aim of the study to analyze the frequency of the occurrence of multiple neoplasms among patients suffering from uterine cervix cancer, with a special interest in coexistent neoplasms, the time of their occurrence and total 5-year survivals. The data from the Lower Silesian Cancer Registry concerning the years 1984-2009 formed the material of the present study. 5.3% of all cervix neoplasms occurred as multiple cancers. Cervix neoplasms were 13.4% of multiple neoplasms. On average, cervical cancer occurred as a subsequent cancer in 6 patients yearly (60.7% of the occurrences of cervical cancer were in the period of 5 years following treatment for the first neoplasm). 5-year survival in patients suffering from primarily multiple cervix neoplasms constituted 57% and was convergent with the results for all patients suffering from cervical cancer. Cervical cancer as the first neoplasm occurred in 287 patients, on average in 11 patients annually. In the period of the first 5 years after the treatment of cervical cancer, there were 42.8% occurrences of other cancers. Cervical neoplasms most frequently coexisted with cancers of the breast, lung and large intestine. The frequency of the occurrence of multiple neoplasm among cervical cancer patients is increasing. Most frequently they coexist with other tobacco-related neoplasms, those related to HPV infections and with secondary post-radiation neoplasms. These facts should be taken into consideration during post-treatment observation and when directing diagnostic

Second neoplasms in adult patients submitted to haematopoietic stem cell transplantation.

PubMed

Torrent, Anna; Ferrá, Christelle; Morgades, Mireia; Jiménez, María-José; Sancho, Juan-Manuel; Vives, Susana; Batlle, Montserrat; Moreno, Miriam; Xicoy, Blanca; Oriol, Albert; Ibarra, Gladys; Ribera, Josep-Maria

2018-06-08

Patients submitted to haematopoietic stem cell transplantation (HSCT) are at increased risk of late complications, such as second neoplasm (SN). The incidence and risk factors of SN in patients receiving HSCT at a single centre were analysed. The follow-up of adult patients who received a first HSCT (autologous [auto-HSCT] or allogeneic [allo-HSCT]) between January 2000 and December 2015 was reviewed. We collected their demographic characteristics, the primary disease and type of HSCT, and analysed the cumulative incidence of SN and their risk factors. Of 699 transplanted patients (auto-HSCT, n=451; allo-HSCT, n=248), 42 (6%) developed SN (17 haematological and 25 solid), 31 post-auto-HSCT and 11 post-allo-HSCT. Haematologic SN were more frequent after auto-HSCT than after allo-HSCT. The median time between HSCT and SN was 4.09 years [range 0.07-13.15], with no differences between auto-HSCT and allo-HSCT. The cumulative incidence of SN was 5% (95% CI 3-6) at 5 years, 7% (95% CI 5-10) at 10 years and 11% (95% CI 8-15) at 15 years, without differences according to the type of HSCT. Only the age over 40 years correlated with an increased risk of SN. In this series, the incidence of post-HSCT SN was similar to that previously described. Patients submitted to an auto-HSCT showed a higher frequency of haematologic SN. A higher incidence of SN was detected in patients older than 40 at the time of HSCT. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

Characterization of IDH1 p.R132H Mutant Clones Using Mutation-specific Antibody in Myeloid Neoplasms.

PubMed

Kurt, Habibe; Bueso-Ramos, Carlos E; Khoury, Joseph D; Routbort, Mark J; Kanagal-Shamanna, Rashmi; Patel, Umang V; Jorgensen, Jeffrey L; Wang, Sa A; Ravandi, Farhad; DiNardo, Courtney; Luthra, Rajyalakshmi; Medeiros, L Jeffrey; Patel, Keyur P

2018-05-01

Isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations occur in a variety of myeloid neoplasms. Immunohistochemistry (IHC)-based direct visualization of mutant clones of hematopoietic cells can be useful for rapid diagnostic screening and for monitoring treatment response. In this study, we first evaluated the sensitivity and specificity of the IDH1 p.R132H mutation-specific antibody by IHC. All IDH1 wild type cases (n=11) and IDH1 mutant cases with a non-p.R132H mutation (n=30) were negative by IHC, demonstrating 100% antibody specificity. All the initial diagnostic specimens with IDH1 p.R132H mutation including acute myeloid leukemia (n=30), myelodysplastic syndromes (MDS) (n=10), MDS/myeloproliferative neoplasms (MPN) (n=4), and MPN (n=5) were positive by IHC, demonstrating 100% antibody sensitivity. Both immature and mature myeloid cells showed immunoreactivity. Erythroid precursors, lymphoid cells, endothelial cells, and osteoblasts were consistently negative by IHC. We then evaluated the follow-up specimens with a known IDH1 mutation status including acute myeloid leukemia (n=23), MDS (n=2), MDS/MPN (n=2), and MPN (n=2). Thirty-three IDH1 p.R132H mutant cases were positive by IHC and 12 IDH1 mutation negative cases were negative by IHC. However, IHC reactivity in up to 25% of bone marrow cells was noted in 8 of 20 polymerase chain reaction-negative cases, all from patients with a known history of IDH1 p.R132H mutation indicating sampling error or a sensitivity issue with molecular tests. These data indicate that IHC is a highly specific and sensitive tool to detect IDH1 p.R132H mutation in bone marrow involved by myeloid neoplasms. In addition, IDH1 p.R132H IHC also allows localization and assessment of the maturation stage of the clones carrying the mutation.

The Synchronous Prevalence of Colorectal Neoplasms in Patients with Stomach Cancer

PubMed Central

Lee, Sang Su; Kim, Cha Young; Ha, Chang Yoon; Min, Hyun Ju; Kim, Hyun Jin; Kim, Tae Hyo

2011-01-01

Purpose The association between stomach cancer and colorectal cancer is controversial. The purpose of this study was to determine the synchronous prevalence of colorectal neoplasms in patients with stomach cancer. Methods A total of 123 patients with stomach cancer (86 male) and 246 consecutive, age- and sex-matched persons without stomach cancer were analyzed from July 2005 to June 2010. All of them underwent colonoscopy within 6 months after undergoing gastroscopy. Results The prevalence of colorectal neoplasms was significantly higher in the stomach cancer group (35.8%) than in the control group (17.9%) (P < 0.001). Colorectal neoplasms were more prevalent in the patients with stomach cancer (odds ratio [OR], 3.10; 95% confidence interval [CI], 1.71 to 5.63). In particular, the difference in the prevalence of colorectal neoplasms was more prominent in the patients above 50 years old (OR, 3.54; 95% CI, 1.80 to 6.98). Conclusion The results showed that the synchronous prevalence of colorectal neoplasms was higher in patients with stomach cancer than in those without stomach cancer. Therefore, patients with stomach cancer should be regarded as a high-risk group for colorectal neoplasms, and colonoscopy should be recommended for screening. PMID:22102975

Second neoplasms after invasive and borderline ovarian cancer.

PubMed

Levi, Fabio; Randimbison, Lalao; Blanc-Moya, Rafael; La Vecchia, Carlo

2009-06-01

Excess risk of subsequent cancers has been documented in women diagnosed with ovarian cancer. We updated to 2006 data on second cancers in women diagnosed with invasive and borderline ovarian cancer in the Swiss canton of Vaud. Between 1974 and 2006, 304 borderline and 1530 invasive first ovarian tumours were abstracted from the Vaud Cancer Registry database and followed up till the end of 2006. Calculation of expected numbers of tumours in the cohorts was based on site-specific, age-specific and calendar-year-specific incidence rates. We computed the standardized incidence ratios (SIRs) of second cancers, and the corresponding 95% confidence intervals (CI). There was no change in the incidence of malignant cancers, but that of borderline tumours increased over more recent years. Overall, 110 second neoplasms were observed versus 49.7 expected after invasive ovarian cancer (SIR 2.21; 95% CI: 1.82-2.67). Significant excess risks were observed for cancers of the breast, corpus uteri and leukaemias. When synchronous cancers were excluded, the overall SIR for all sites declined to 1.05. Thirty-one second neoplasms were observed after borderline tumours compared with 21.1 expected (SIR=1.47; 95% CI: 1.00-2.09). SIRs were above unity for ovary, colorectum and uterus. After exclusion of synchronous neoplasms, SIR for all neoplasms declined to 1.09, and remained significant only for second ovarian cancers (SIR=4.93). The present record linkage cohort study shows an excess risk for selected synchronous neoplasms in women diagnosed with both borderline and invasive ovarian cancer, likely because of shared genetic and perhaps environmental factors.

Myeloproliferative Neoplasms: Molecular Drivers and Therapeutics.

PubMed

Reuther, G W

2016-01-01

Activating mutations in genes that drive neoplastic cell growth are numerous and widespread in cancer, and specific genetic alterations are associated with certain types of cancer. For example, classic myeloproliferative neoplasms (MPNs) are hematopoietic stem cell disorders that affect cells of the myeloid lineage, including erythrocytes, platelets, and granulocytes. An activating mutation in the JAK2 tyrosine kinase is prevalent in these diseases. In MPN patients that lack such a mutation, other genetic changes that lead to activation of the JAK2 signaling pathway are present, indicating deregulation of JAK2 signaling plays an etiological driving role in MPNs, a concept supported by significant evidence from in vivo experimental MPN systems. Thus, small molecules that inhibit JAK2 activity are ideal drugs to impede the progression of disease in MPN patients. However, even though JAK inhibitors provide significant symptomatic relief, they have failed as a remission-inducing therapy. Nonetheless, the progress made understanding the molecular etiology of MPNs since 2005 is significant and has provided insight for the development and testing of novel molecular targeted therapeutic approaches. The current understanding of driver mutations in MPNs and an overview of current and potential therapeutic strategies for MPN patients will be discussed. © 2016 Elsevier Inc. All rights reserved.

Pancreas-Sparing Distal Duodenectomy for Infrapapillary Neoplasms

PubMed Central

Spalding, DRC; Isla, AM; Thompson, JN; Williamson, RCN

2007-01-01

INTRODUCTION For neoplasms that arise in the third and fourth parts of the duodenum (D3, D4), a duodenectomy that preserves the pancreas can provide adequate tumour clearance while avoiding the additional dissection and risk of the common alternative, pancreatoduodenectomy. PATIENTS AND METHODS Pancreas-sparing distal duodenectomy (PSDD) was performed in 14 patients with infrapapillary duodenal neoplasms between 1991–2002, and the clinical outcome is reviewed. The operation entails careful separation of the lower pancreatic head from D3, complete mobilisation of the ligament of Treitz and end-to-end duodenojejunal anastomosis 1–3 cm below the major duodenal papilla. RESULTS There were 9 men and 5 women of median age 56 years, who presented with iron-deficiency anaemia (n = 8), gastric outlet obstruction (n = 4), anaemia and gastric outlet obstruction (n = 1), epigastric pain or mass (1 each). There were 11 malignant neoplasms (adenocarcinoma 5, stromal tumour 4, recurrent seminoma 1, plasmacytoma 1), 2 benign neoplasms (villous adenoma, lipoma) and 1 patient with steroid-induced ulceration. In addition to D3 and D4, resection included the distal part of D2 in 5 patients, while 4 required concomitant partial colectomy. Median operation time was 240 min and median blood loss 1197 ml, being greater for malignant than benign lesions (1500 ml versus 700 ml). There was one death from gangrenous cholecystitis, one early re-operation for anastomotic bleeding and one late re-operation for delayed gastric emptying secondary to anastomotic stricture, but no pancreatic complications. At a median follow-up of 47 months, three patients had died of recurrent disease while the other 10 were alive and well with no upper gastrointestinal symptoms. CONCLUSIONS Provided there is a minimum 1-cm clearance at the papilla, PSDD is a useful alternative to formal pancreatoduodenectomy in patients with unusual neoplasms arising from the third and fourth parts of the duodenum. Although a

Pancreatic Lipomatous Hamartoma: A Hitherto Unrecognized Variant.

PubMed

Tanaka, Mariko; Ushiku, Tetsuo; Ikemura, Masako; Takazawa, Yutaka; Igari, Toru; Shimizu, Michio; Yamaguchi, Hiroshi; Fukushima, Noriyoshi; Sakuma, Kei; Arita, Junichi; Sakamoto, Yoshihiro; Hasegawa, Kiyoshi; Watadani, Takeyuki; Nakai, Yousuke; Koike, Kazuhiko; Fukayama, Masashi

2018-05-04

Pancreatic masses consisting of lipomatous components clinically include lipoma, liposarcoma, lipomatous pseudohypertrophy of the pancreas, fat-containing neoplasms such as perivascular epithelioid cell tumor, and malignant neoplasm with lipoid degeneration. We present pancreatic lipomatous hamartoma, which has not been reported hitherto. A solid pancreatic mass was detected from a computed tomographic scan check-up in each of 3 cases of Japanese men. Macroscopically, well-demarcated solid lipomatous masses were detected at the uncus, body, and tail of the pancreas, respectively. Microscopically, the masses predominantly consisted of mature adipocytes with no atypia, but contained characteristics components of pancreatic hamartoma, such as small ducts, a well-preserved acinar structure, and/or fibrous stroma. On the basis of the unique features, lack of islets and absence of periductal elastic fibers, these tumors are a distinct variant of pancreatic hamartoma. Furthermore, high-mobility group AT-hook 2 expression in the fibro-adipocytes of this tumor indicated that these cells are an integral component of the pancreatic lipomatous hamartoma. Consequently, the unique tumors described herein are pancreatic lipomatous hamartoma, which must be discriminated from other lipomatous lesions of the pancreas.

PIK3CA Mutations in Mucinous Cystic Neoplasms of the Pancreas

PubMed Central

Garcia-Carracedo, Dario; Chen, Zong-Ming; Qiu, Wanglong; Huang, Alicia S.; Tang, Sophia M.; Hruban, Ralph H.; Su, Gloria H.

2014-01-01

Objectives Mucinous cystic neoplasms (MCNs) are rare, potentially curable, mucin-producing neoplasms of the pancreas. We have previously reported PIK3CA (phosphoinositide-3-kinase catalytic subunit, p110α) mutations in intraductal papillary mucinous neoplasms, another mucin-producing neoplasm of the pancreas. In this study, we analyzed the presence of PIK3CA and AKT1/PKB (V-akt murine thymoma viral oncogene homolog 1) hot-spot mutations in MCN specimens. Methods Using the genomic DNA sequencing of tumor tissues isolated by laser capture microdissection, we evaluated 15 well-characterized MCNs for the E542K, E545K(exon 9), and H1047R (exon 20) hot-spotmutations in the PIK3CA gene and the E17K mutation in the AKT1 gene. Results A hot-spotmutation (E545K) of the PIK3CA gene was detected in 1 of the 15 MCNs and further confirmed by a mutant-enriched method. Interestingly, this mutation was found to be present only in the high-grade but not in low-grade dysplastic epithelium obtained from this neoplasm and coexisted with a KRASG12D mutation. No mutations were identified in the AKT1 gene. Conclusions Our data, when combined with previous reports on intraductal papillary mucinous neoplasms, indicate that oncogenic activation of the PI3K pathway involving PIK3CA gene mutations can contribute to the progression of mucin-producing neoplasms but not pancreatic intraepithelial neoplasia. PIK3CA status could be useful for understanding their progression to malignancy. PMID:24518503

Oxidative stress alters mitochondrial bioenergetics and modifies pancreatic cell death independently of cyclophilin D, resulting in an apoptosis-to-necrosis shift

PubMed Central

Armstrong, Jane A.; Cash, Nicole J.; Ouyang, Yulin; Morton, Jack C.; Chvanov, Michael; Latawiec, Diane; Awais, Muhammad; Tepikin, Alexei V.; Sutton, Robert; Criddle, David N.

2018-01-01

Mitochondrial dysfunction lies at the core of acute pancreatitis (AP). Diverse AP stimuli induce Ca2+-dependent formation of the mitochondrial permeability transition pore (MPTP), a solute channel modulated by cyclophilin D (CypD), the formation of which causes ATP depletion and necrosis. Oxidative stress reportedly triggers MPTP formation and is elevated in clinical AP, but how reactive oxygen species influence cell death is unclear. Here, we assessed potential MPTP involvement in oxidant-induced effects on pancreatic acinar cell bioenergetics and fate. H2O2 application promoted acinar cell apoptosis at low concentrations (1–10 μm), whereas higher levels (0.5–1 mm) elicited rapid necrosis. H2O2 also decreased the mitochondrial NADH/FAD+ redox ratio and ΔΨm in a concentration-dependent manner (10 μm to 1 mm H2O2), with maximal effects at 500 μm H2O2. H2O2 decreased the basal O2 consumption rate of acinar cells, with no alteration of ATP turnover at <50 μm H2O2. However, higher H2O2 levels (≥50 μm) diminished spare respiratory capacity and ATP turnover, and bioenergetic collapse, ATP depletion, and cell death ensued. Menadione exerted detrimental bioenergetic effects similar to those of H2O2, which were inhibited by the antioxidant N-acetylcysteine. Oxidant-induced bioenergetic changes, loss of ΔΨm, and cell death were not ameliorated by genetic deletion of CypD or by its acute inhibition with cyclosporine A. These results indicate that oxidative stress alters mitochondrial bioenergetics and modifies pancreatic acinar cell death. A shift from apoptosis to necrosis appears to be associated with decreased mitochondrial spare respiratory capacity and ATP production, effects that are independent of CypD-sensitive MPTP formation. PMID:29626097

Role of Axumin PET Scan in Germ Cell Tumor

ClinicalTrials.gov

2018-05-01

Testis Cancer; Germ Cell Tumor; Testicular Cancer; Germ Cell Tumor of Testis; Germ Cell Tumor, Testicular, Childhood; Testicular Neoplasms; Testicular Germ Cell Tumor; Testicular Yolk Sac Tumor; Testicular Choriocarcinoma; Testicular Diseases; Germ Cell Cancer Metastatic; Germ Cell Neoplasm of Retroperitoneum; Germ Cell Cancer, Nos

Stem Cell-Soluble Signals Enhance Multilumen Formation in SMG Cell Clusters.

PubMed

Maruyama, C L M; Leigh, N J; Nelson, J W; McCall, A D; Mellas, R E; Lei, P; Andreadis, S T; Baker, O J

2015-11-01

Saliva plays a major role in maintaining oral health. Patients with salivary hypofunction exhibit difficulty in chewing and swallowing foods, tooth decay, periodontal disease, and microbial infections. At this time, treatments for hyposalivation are limited to medications (e.g., muscarinic receptor agonists: pilocarpine and cevimeline) that induce saliva secretion from residual acinar cells as well as artificial salivary substitutes. Therefore, advancement of restorative treatments is necessary to improve the quality of life in these patients. Our previous studies indicated that salivary cells are able to form polarized 3-dimensional structures when grown on growth factor-reduced Matrigel. This basement membrane is rich in laminin-III (L1), which plays a critical role in salivary gland formation. Mitotically inactive feeder layers have been used previously to support the growth of many different cell types, as they provide factors necessary for cell growth and organization. The goal of this study was to improve salivary gland cell differentiation in primary cultures by using a combination of L1 and a feeder layer of human hair follicle-derived mesenchymal stem cells (hHF-MSCs). Our results indicated that the direct contact of mouse submandibular (mSMG) cell clusters and hHF-MSCs was not required for mSMG cells to form acinar and ductal structures. However, the hHF-MSC conditioned medium enhanced cell organization and multilumen formation, indicating that soluble signals secreted by hHF-MSCs play a role in promoting these features. © International & American Associations for Dental Research 2015.

Optimizing reduced-intensity conditioning regimens for myeloproliferative neoplasms

PubMed Central

Ramakrishnan, Aravind; Sandmaier, Brenda M

2010-01-01

The myeloproliferative neoplasms (MPNs) are a group of clonal disorders that arise from a pluripotent hematopoietic stem cell and are characterized by excess cellular proliferation. These disorders tend to be chronic in nature and can terminate over time into a bone marrow failure syndrome characterized by marrow fibrosis or transform into a leukemic phase. MPNs are predominantly diseases of the elderly and this is one reason why until very recently the standard treatment was supportive care. The only curative modality for these disorders is allogeneic hematopoietic cell transplantation. The introduction of reduced-intensity conditioning regimens now allows this life-saving therapy to be offered to elderly patients who were previously considered ineligible for high-dose conditioning owing to age or comorbidity. In this review, we will summarize the current strategies and future directions regarding the use of reduced-intensity conditioning regimens in the treatment of MPNs. PMID:20383269

Donor Stem Cell Transplant or Donor White Blood Cell Infusions in Treating Patients With Hematologic Cancer

ClinicalTrials.gov

2017-09-25

Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Unusual Cancers of Childhood

The role of JAK2 abnormalities in hematologic neoplasms

PubMed Central

Alabdulaali, Mohammed K.

2009-01-01

In 2005, an activating mutation in the Janus kinase 2 (JAK2) was identified in a significant proportion of patients with myeloproliferative neoplasms, mainly polycythemia vera, essential thrombocythemia and primary myelofibrosis. Many types of mutations in the JAK-STAT pathway have been identified, the majority are related to JAK2. Currently JAK2 mutations are important in the area of diagnosis of myeloid neoplasms, but its role beyond the confirmation of clonality is growing and widening our knowledge about these disorders. In addition to that, clinical trials to target JAK2-STAT pathway will widen our knowledge and hopefully will offer more therapeutic options. In this review, we will discuss the role of JAK2 abnormalities in the pathogenesis, diagnosis, classification, severity and management of hematologic neoplasms.

Drugs Approved for Myeloproliferative Neoplasms

Cancer.gov

This page lists cancer drugs approved by the Food and Drug Administration (FDA) for myeloproliferative neoplasms. The list includes generic names, brand names, and common drug combinations, which are shown in capital letters. The drug names link to NCI's Cancer Drug Information summaries.

European evidence-based guidelines on pancreatic cystic neoplasms

PubMed Central

Del Chiaro, Marco

2018-01-01

Evidence-based guidelines on the management of pancreatic cystic neoplasms (PCN) are lacking. This guideline is a joint initiative of the European Study Group on Cystic Tumours of the Pancreas, United European Gastroenterology, European Pancreatic Club, European-African Hepato-Pancreato-Biliary Association, European Digestive Surgery, and the European Society of Gastrointestinal Endoscopy. It replaces the 2013 European consensus statement guidelines on PCN. European and non-European experts performed systematic reviews and used GRADE methodology to answer relevant clinical questions on nine topics (biomarkers, radiology, endoscopy, intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm (MCN), serous cystic neoplasm, rare cysts, (neo)adjuvant treatment, and pathology). Recommendations include conservative management, relative and absolute indications for surgery. A conservative approach is recommended for asymptomatic MCN and IPMN measuring <40 mm without an enhancing nodule. Relative indications for surgery in IPMN include a main pancreatic duct (MPD) diameter between 5 and 9.9 mm or a cyst diameter ≥40 mm. Absolute indications for surgery in IPMN, due to the high-risk of malignant transformation, include jaundice, an enhancing mural nodule >5 mm, and MPD diameter >10 mm. Lifelong follow-up of IPMN is recommended in patients who are fit for surgery. The European evidence-based guidelines on PCN aim to improve the diagnosis and management of PCN. PMID:29574408

Long-term risks of subsequent primary neoplasms among survivors of childhood cancer.

PubMed

Reulen, Raoul C; Frobisher, Clare; Winter, David L; Kelly, Julie; Lancashire, Emma R; Stiller, Charles A; Pritchard-Jones, Kathryn; Jenkinson, Helen C; Hawkins, Michael M

2011-06-08

Survivors of childhood cancer are at excess risk of developing subsequent primary neoplasms but the long-term risks are uncertain. To investigate long-term risks of subsequent primary neoplasms in survivors of childhood cancer, to identify the types that contribute most to long-term excess risk, and to identify subgroups of survivors at substantially increased risk of particular subsequent primary neoplasms that may require specific interventions. British Childhood Cancer Survivor Study--a population-based cohort of 17,981 5-year survivors of childhood cancer diagnosed with cancer at younger than 15 years between 1940 and 1991 in Great Britain, followed up through December 2006. Standardized incidence ratios (SIRs), absolute excess risks (AERs), and cumulative incidence of subsequent primary neoplasms. After a median follow-up time of 24.3 years (mean = 25.6 years), 1354 subsequent primary neoplasms were ascertained; the most frequently observed being central nervous system (n = 344), nonmelanoma skin cancer (n = 278), digestive (n = 105), genitourinary (n = 100), breast (n = 97), and bone (n = 94). The overall SIR was 4 times more than expected (SIR, 3.9; 95% confidence interval [CI], 3.6-4.2; AER, 16.8 per 10,000 person-years). The AER at older than 40 years was highest for digestive and genitourinary subsequent primary neoplasms (AER, 5.9 [95% CI, 2.5-9.3]; and AER, 6.0 [95%CI, 2.3-9.6] per 10,000 person-years, respectively); 36% of the total AER was attributable to these 2 subsequent primary neoplasm sites. The cumulative incidence of colorectal cancer for survivors treated with direct abdominopelvic irradiation was 1.4% (95% CI, 0.7%-2.6%) by age 50 years, comparable with the 1.2% risk in individuals with at least 2 first-degree relatives affected by colorectal cancer. Among a cohort of British childhood cancer survivors, the greatest excess risk associated with subsequent primary neoplasms at older than 40 years was for digestive and genitourinary neoplasms.

Myeloproliferative Neoplasms in Children.

PubMed