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1.  Zebrafish usp39 Mutation Leads to rb1 mRNA Splicing Defect and Pituitary Lineage Expansion 
PLoS Genetics  2011;7(1):e1001271.
Loss of retinoblastoma (Rb) tumor suppressor function is associated with human malignancies. Molecular and genetic mechanisms responsible for tumorigenic Rb downregulation are not fully defined. Through a forward genetic screen and positional cloning, we identified and characterized a zebrafish ubiquitin specific peptidase 39 (usp39) mutation, the yeast and human homolog of which encodes a component of RNA splicing machinery. Zebrafish usp39 mutants exhibit microcephaly and adenohypophyseal cell lineage expansion without apparent changes in major hypothalamic hormonal and regulatory signals. Gene expression profiling of usp39 mutants revealed decreased rb1 and increased e2f4, rbl2 (p130), and cdkn1a (p21) expression. Rb1 mRNA overexpression, or antisense morpholino knockdown of e2f4, partially reversed embryonic pituitary expansion in usp39 mutants. Analysis of pre-mRNA splicing status of critical cell cycle regulators showed misspliced Rb1 pre-mRNA resulting in a premature stop codon. These studies unravel a novel mechanism for rb1 regulation by a neuronal mRNA splicing factor, usp39. Zebrafish usp39 regulates embryonic pituitary homeostasis by targeting rb1 and e2f4 expression, respectively, contributing to increased adenohypophyseal sensitivity to these altered cell cycle regulators. These results provide a mechanism for dysregulated rb1 and e2f4 pathways that may result in pituitary tumorigenesis.
Author Summary
Previous studies have shown that Rb+/− mice develop pituitary adenomas; however, RB1 mutations have not been found in human pituitary tumors. In the present study, we uncovered a novel genetic pathway that may lead to Rb downregulation through RNA splicing mediated by usp39, a gene involved in assembly of the spliceosome. Our forward genetic study in zebrafish suggests that loss of usp39 results in aberrant rb1 mRNA splicing, which likely causes elevated expression of its target e2f4, a key regulator known to have oncogenic activity when overexpressed. We established that e2f4 upregulation is a main factor responsible for the adenohypophyseal cell lineage hyperplasia observed in the zebrafish usp39 mutant. It should be of interest to investigate if mutations or downregulation of USP39 would contribute to pituitary tumorigenesis in humans.
PMCID: PMC3020934  PMID: 21249182
2.  Clinical Characteristics, Management, and Outcome of 22 Cases of Primary Hypophysitis 
Endocrinology and Metabolism  2014;29(4):470-478.
Primary hypophysitis causes varying degrees of endocrine dysfunction and mass effect. The natural course and best treatment have not been well established.
Medical records of 22 patients who had been diagnosed with primary hypophysitis between January 2001 and March 2013 were retrospectively reviewed. Based on the anatomical location, we classified the cases as adenohypophysitis (AH), infundibuloneurohypophysitis (INH), and panhypophysitis (PH). Clinical presentation, endocrine function, pathologic findings, magnetic resonance imaging findings, and treatment courses were reviewed.
Among 22 patients with primary hypophysitis, 81.8% (18/22) had involvement of the posterior pituitary lobe. Two patients of the AH (2/3, 66.6%) and three patients of the PH (3/10, 30%) groups initially underwent surgical mass reduction. Five patients, including three of the PH (3/10, 33.3%) group and one from each of the AH (1/3, 33.3%) and INH (1/9, 11.1%) groups, initially received high-dose glucocorticoid treatment. Nearly all of the patients treated with surgery or high-dose steroid treatment (9/11, 82%) required continuous hormone replacement during the follow-up period. Twelve patients received no treatment for mass reduction due to the absence of acute symptoms and signs related to a compressive mass effect. Most of them (11/12, 92%) did not show disease progression, and three patients recovered partially from hormone deficiency.
Deficits of the posterior pituitary were the most common features in our cases of primary hypophysitis. Pituitary endocrine defects responded less favorably to glucocorticoid treatment and surgery. In the absence of symptoms related to mass effect and with the mild defect of endocrine function, it may not require treatment to reduce mass except hormone replacement.
PMCID: PMC4285029  PMID: 25325267
Pituitary; Hypophysitis; Diabetes insipidus; Hypopituitarism; Steroids
3.  Pituitary Carcinoma with Mandibular Metastasis: A Case Report 
Journal of Korean Medical Science  2007;22(Suppl):S145-S148.
Pituitary carcinomas are rare primary adenohypophyseal tumors with cerebrospinal or extracranial metastasis. The present case, the first report of the disease in Korea, involved a 36-yr-old woman who presented with a 3-week history of headache. Brain magnetic resonance imaging revealed a 2.5-cm sellar and suprasellar mass showing heterogeneous enhancement with suspicious invasion of both cavernous sinuses. The patient underwent gross-total resection. The tumor cells were composed of polygonal cells singly or in variable-sized nests. The nuclei were large and round with prominent nucleoli. The cytoplasms was acidophilic and granular. Marked pleomorphism and frequent mitoses (3 per 10 HPFs) were found. By immunohistochemistry, tumor cells were strongly positive for prolactin, but negative for ACTH and GH. Additional immunostainings for cytokeratin, vimentin, and glial fibrillary acidic protein (GFAP) were negative. After the surgery, the patient received radiotherapy because of the atypical histologic features. The prolactin level fell from 123.17 ng/mL to 5.17 ng/mL after surgery. Nine months after the initial diagnosis, the patient died from mandibular metastasis associated with the pituitary carcinoma.
PMCID: PMC2694386  PMID: 17923742
Pituitary Neoplasms; Metastasis; Pitutary Carcinoma
4.  Relationship between the circulating levels of adenohypophyseal hormones in blood and in cerebrospinal fluid. 
Concentrations of prolactin, follicle stimulating hormone, luteinising hormone and growth hormone were measured simultaneously in the serum and cerebrospinal fluid of 57 patients affected by neurologic disease without any pituitary or diencephalic involvement. Prolactin secretion was stimulated in another group of 12 patients using sulpiride or metoclopramide, and the hormone concentration was measured simultaneously in serum and in CSF during the test. Basal studies showed that the concentrations of prolactin, FSH, LH and GH in serum and in CSF were directly correlated (p varying from less than 0.001 to less than 0.05). A negative correlation was found between the molecular weight of hormones reported in this and in other studies and the natural logarithm of the CSF/serum hormone concentration ratios. During prolactin stimulation the correlation between serum and CSF concentration was maintained, nevertheless a higher increase of prolactin in blood than in CSF was observed. This last finding suggests that other mechanisms in addition to filtration from blood into CSF can be responsible for the presence of adenohypophyseal hormones in CSF.
PMCID: PMC1027899  PMID: 6431056
5.  Infundibular metastasis and panhypopituitarism. 
A patient with no known history of primary neoplasia presented with panhypopituitarism secondary to metastasis. Complete anterior pituitary failure was documented by pituitary reserve testing. However, at autopsy there was extensive carcinomatous invasion of the hypothalamus and infundibulum but no adenohypophyseal involvement. The possibility of metastatic disease should be considered in patients presenting with panhypopituitarism. The literature covering this topic is reviewed.
PMCID: PMC2571626  PMID: 2540336
Indian Journal of Psychiatry  1997;39(1):29-33.
Serum levels of prolactin (PRL) and Human Growth Hormone (HGH) were assayed in 38 male alcoholics and 24 male control subjects using radioimmunoassay (RIA) technique. Biochemical parameters of hepatic function and severity of withdrawal state were also assessed. Significantly elevated values of plasma HGH were found in alcoholics as a group. Nineteen percent and eight percent of the patient had elevated serum PRL and HGH levels respectively. Evidence of advanced liver disease was scant and withdrawal symptoms were by and large mild. The findings indicate a dysfunction in hypothalamic adenohypophyseal axis in a subgroup of alcoholics.
PMCID: PMC2967078  PMID: 21584040
Prolactin; human growth hormone; alcoholics; alcohol withdrawal
7.  von Hippel-Lindau Disease-Associated Hemangioblastomas Are Derived from Embryologic Multipotent Cells 
PLoS Medicine  2007;4(2):e60.
To determine the origin of the neoplastic cell in central nervous system (CNS) hemangioblastomas in von Hippel-Lindau disease (VHL) and its role in tumor formation and distribution, we characterized and differentiated neoplastic cells from hemangioblastomas removed from VHL patients.
Methods and Findings
A total of 31 CNS hemangioblastomas from 25 VHL patients were resected and analyzed. Tumor cells from the hemangioblastomas were characterized, grown, and differentiated into multiple lineages. Resected hemangioblastomas were located in the cerebellum (11 tumors), brainstem (five tumors), and spinal cord (15 tumors). Consistent with an embryologically derived hemangioblast, the neoplastic cells demonstrated coexpression of the mesodermal markers brachyury, Flk-1 (vascular endothelial growth factor-2), and stem cell leukemia (Scl). The neoplastic cells also expressed hematopoietic stem cell antigens and receptors including CD133, CD34, c-kit, Scl, erythropoietin, and erythropoietin receptor. Under specific microenvironments, neoplastic cells (hemangioblasts) were expanded and differentiated into erythrocytic, granulocytic, and endothelial progenitors. Deletion of the wild-type VHL allele in the hematopoietic and endothelial progeny confirmed their neoplastic origin.
The neoplastic cell of origin for CNS hemangioblastomas in VHL patients is the mesoderm-derived, embryologically arrested hemangioblast. The hematopoietic and endothelial differentiation potential of these cells can be reactivated under suitable conditions. These findings may also explain the unique tissue distribution of tumor involvement.
In this study, the neoplastic cell of origin for central nervous system hemangioblastomas in patients with von Hippel-Lindau disease is shown to be the mesoderm-derived, embryologically arrested hemangioblast.
Editors' Summary
von Hippel-Lindau (VHL) disease is a rare genetic condition characterized by the development of benign and malignant tumors in multiple organ systems. All the cells of people with this disorder contain one normal copy of the VHL gene and one altered copy. This gene encodes a tumor suppressor, a protein that stops tumors growing. One functioning copy of the VHL gene is sufficient to prevent any problems, but if the remaining normal copy becomes altered (mutated) in individual cells of patients with VHL disease, tumors result. These tumors are mainly benign (noncancerous growths that do not spread around the body) and form in parts of the body that are rich in blood vessels, in particular in the retina (the back of the eye), the cerebellum (the back of the brain), the brainstem (which links the cerebellum to the spinal cord), and the spinal cord. These central nervous system (CNS) tumors are called hemangioblastomas and look like little knots of capillaries (fine blood vessels). As they grow, they can cause problems through fluid leakage or by pressing on brain tissue. There is no cure for VHL disease, but patients can be monitored and their tumors dealt with before they get too large.
Why Was This Study Done?
It is not known what sort of cells hemangioblastomas develop from or why they occur only in specific parts of the CNS. This information could help researchers develop ways to prevent or treat these hemangioblastomas. One possibility is that hemangioblastomas develop from a special kind of embryonic cell called a hemangioblast. This multipotent stem cell—a continuously dividing cell that can develop (differentiate) into several nondividing cell types—is the source of blood cells and blood vessel cells in the embryo. In this study, the researchers have examined tumor cells (so-called neoplastic stromal cells) taken from hemangioblastomas to see whether this theory is correct.
What Did the Researchers Do and Find?
The researchers obtained several CNS hemangioblastomas from patients with VHL disease and stained slices of them with antibodies that stick to proteins made only by specific types of embryonic cells. This experiment showed that the neoplastic stromal cells in the tumors contained two proteins (brachyury and Flk-1) that mark hemangioblast cells in embryos and a protein called Scl that is required for blood cell formation. The neoplastic stromal cells also made several proteins expressed by the precursors of different blood cell types. When the researchers grew neoplastic stromal cells from the hemangioblastomas in different conditions, they found that the cells differentiated into the precursors of two types of blood cell (erythrocytes and granulocytes) and of the cells that line blood vessels (endothelial cells). The researchers confirmed that these precursors had arisen from the neoplastic cells in the hemangioblastomas by showing that they did not contain a normal copy of the VHL gene.
What Do These Findings Mean?
These findings indicate that the neoplastic stromal cells in CNS hemangioblastomas in patients with VHL disease are indeed hemangioblasts. Their expression of the protein brachyury, which is normally only expressed in early development, suggests that these hemangioblasts were arrested during embryogenesis, possibly when they lost their normal VHL gene. Because VHL-related tumors usually appear in adulthood, circulating factors such as hormones might promote the growth of these pre-existing but dormant tumor cells at specific stages of life. Furthermore, the expression of Scl in the neoplastic stromal cells suggests that the specific pattern of hemangioblastomas in VHL disease is determined during development since Scl is transiently expressed in hemangioblasts in the parts of the developing brain that subsequently harbor hemangioblastomas. Because the researchers only examined VHL-associated hemangioblastomas, their findings do not explain the origin of hemangioblastomas in patients without VHL disease or the origin of VHL-associated malignant tumors. However, the identification of hemangioblasts as the source of hemangioblastomas in VHL disease suggests that it might be possible to treat these tumors by persuading the hemangioblasts to differentiate or by using their unique proteins to target toxic drugs to hemangioblastomas.
Additional Information.
Please access these Web sites via the online version of this summary at
VHL Family Alliance has information for patients and physicians on VHL disease
The US National Institute of Neurological Disorders and Stroke Web site contains information on VHL disease
Wikipedia carries pages on VHL disease (note that Wikipedia is a free online encyclopedia that anyone can edit)
The Online Mendelian Inheritance in Man (OMIM) site has detailed scientific information on VHL disease
PMCID: PMC1796910  PMID: 17298169
8.  7α-Hydroxypregnenolone, a New Key Regulator of Locomotor Activity of Vertebrates: Identification, Mode of Action, and Functional Significance 
Steroids synthesized de novo by the central and peripheral nervous systems are called neurosteroids. The formation of neurosteroids from cholesterol in the brain was originally demonstrated in mammals by Baulieu and colleagues. Our studies over the past two decades have also shown that, in birds and amphibians as in mammals, the brain expresses several kinds of steroidogenic enzymes and produces a variety of neurosteroids. Thus, de novo neurosteroidogenesis from cholesterol is a conserved property that occurs throughout vertebrates. However, the biosynthetic pathways of neurosteroids in the brain of vertebrates was considered to be still incompletely elucidated. Recently, 7α-hydroxypregnenolone was identified as a novel bioactive neurosteroid stimulating locomotor activity in the brain of newts and quail through activation of the dopaminergic system. Subsequently, diurnal and seasonal changes in synthesis of 7α-hydroxypregnenolone in the brain were demonstrated. Interestingly, melatonin derived from the pineal gland and eyes regulates 7α-hydroxypregnenolone synthesis in the brain, thus inducing diurnal locomotor changes. Prolactin, an adenohypophyseal hormone, regulates 7α-hydroxypregnenolone synthesis in the brain, and may also induce seasonal locomotor changes. This review highlights the identification, mode of action, and functional significance of 7α-hydroxypregnenolone, a new key regulator of locomotor activity of vertebrates, in terms of diurnal and seasonal changes in 7α-hydroxypregnenolone synthesis, and describes some of their regulatory mechanisms.
PMCID: PMC3356142  PMID: 22654788
neurosteroids; 7α-hydroxypregnenolone; cytochrome P4507α; dopamine; melatonin; prolactin; locomotor activity; diurnal and seasonal changes
9.  Mode of Action and Functional Significance of 7α-Hydroxypregnenolone Stimulating Locomotor Activity 
Previous studies over the past two decades have demonstrated that the brain and other nervous systems possess key steroidogenic enzymes and produces pregnenolone and other various neurosteroids in vertebrates in general. Recently, 7α-hydroxypregnenolone, a novel bioactive neurosteroid, was identified in the brain of newts and quail. Importantly, this novel neurosteroid is produced from pregnenolone through the enzymatic activity of cytochrome P4507α and acts on brain tissue as a neuronal modulator to stimulate locomotor activity in these vertebrates. Subsequently, the mode of action of 7α-hydroxypregnenolone was demonstrated. 7α-Hydroxypregnenolone stimulates locomotor activity through activation of the dopaminergic system. To understand the functional significance of 7α-hydroxypregnenolone in the regulation of locomotor activity, diurnal, and seasonal changes in 7α-hydroxypregnenolone synthesis were further characterized. Melatonin derived from the pineal gland and eyes regulates 7α-hydroxypregnenolone synthesis in the brain, thus inducing diurnal locomotor changes. Prolactin, an adenohypophyseal hormone, regulates 7α-hydroxypregnenolone synthesis in the brain, and also induces seasonal locomotor changes. In addition, 7α-hydroxypregnenolone mediates corticosterone action to modulate locomotor activity under stress. This review summarizes the current knowledge regarding the mode of action and functional significance of 7α-hydroxypregnenolone, a newly identified bioactive neurosteroid stimulating locomotor activity.
PMCID: PMC3355833  PMID: 22645507
neurosteroids; 7α-hydroxypregnenolone; dopamine; melatonin; prolactin; locomotor activity; diurnal and seasonal changes; stress
10.  Developing a sense of scents: Plasticity in olfactory placode formation 
Brain research bulletin  2007;75(2-4):340-347.
The sense organs of the vertebrate head arise predominantly from sensory placodes. The sensory placodes have traditionally been grouped as structures that share common developmental and evolutionary characteristics. In attempts to build a coherent model for development of all placodes, the fascinating differences that make placodes unique are often overlooked. Here I review olfactory placode development with special attention to the origin and cell movements that generate the olfactory placode, the derivatives of this sensory placode, and the degree to which it shows plasticity during development. Next, through comparison with adenohypophyseal, and lens placodes I suggest we revise our thinking and terminology for these anterior placodes, specifically by: 1) referring to the peripheral olfactory sensory system as neural ectoderm because it expresses the same series of genes involved in neural differentiation and differentiates in tandem with the olfactory bulb, 2) grouping the anterior placodes with their corresponding central nervous system structures and emphasizing patterning mechanisms shared between placodes and these targets. Sensory systems did not arise independent of the central nervous system; they are part of a functional unit composed of peripheral sensory structures and their targets. By expanding our analyses of sensory system development to also include cell movements, gene expression and morphological changes observed in this functional unit, we will better understand the evolution of sensory structures.
PMCID: PMC2443743  PMID: 18331896
GnRH; sensory neuron; Kallman; hypothalamus
11.  Progression on metastatic neuroendocrine carcinoma from a recurrent prolactinoma: a case report 
Journal of Clinical Pathology  2002;55(2):148-151.
A 54 year old man was referred to the department of neurosurgery for frontal headache and vomiting. The patient was known in the department because of previous multiple surgery for a locally invasive pituitary prolactinoma (eight years, three years, and one year previously). The neurological examination revealed a frontal mass, which adhered to the dura, suggesting a meningioma. One year later, a left temporal metastasis was removed. Three months later, the patient died, with spinal metastases, of massive lung embolism. Histology revealed a progression of adenohypophyseal prolactinoma on neuroendocrine carcinoma, with an increase in proliferating indexes and modification of hormone production. This study documents a 10 year history of a rare prolactin producing pituitary carcinoma, which metastasised via liquoral flow.
PMCID: PMC1769584  PMID: 11865014
pituitary carcinoma; prolactinoma; metastasis, proliferating index; electron microscopy
12.  Partial purification and characterization of a peptide with growth hormone-releasing activity from extrapituitary tumors in patients with acromegaly. 
Growth hormone (GH)-releasing activity has been detected in extracts of carcinoid and pancreatic islet tumors from three patients with GH-secreting pituitary tumors and acromegaly. Bioactivity was demonstrated in 2 N acetic acid extracts of the tumors using dispersed rat adenohypophyseal cells in primary monolayer culture and a rat anterior pituitary perifusion system. The GH-releasing effect was dose responsive and the greatest activity was present in the pancreatic islet tumor. Small amounts of activity were also found in two other tumors (carcinoid and small cell carcinoma of lung) unassociated with GH hypersecretion. Each of the tumors contained somatostatin-like immunoreactivity but the levels did not correlate with the net biologic expression of the tumor. Sephadex G-75 gel filtration indicated the GH-releasing activity to have an apparent molecular size of slightly greater than 6,000 daltons. The GH-releasing activity was adsorbed onto DEAE-cellulose at neutral pH and low ionic strength, from which it could be eluted by increasing ionic strength. The GH-releasing activity was further purified by high pressure liquid chromatography using an acetonitrile gradient on a cyanopropyl column to yield a preparation that was active at 40 ng protein/ml. Partially purified GH-releasing activity, from which most of the bioactive somatostatin had been removed, increased GH release by pituitary monolayer cultures to five times base line. Enzymatic hydrolysis studies revealed that the GH-releasing activity was resistant to carboxypeptidase, leucine-aminopeptidase, and pyroglutamate-amino-peptidase but was destroyed by trypsin and chymotrypsin, indicating that internal lysine and/or arginine and aromatic amino acid residues are required for biologic activity and that the NH2-terminus and CO9H-terminus are either blocked or not essential. The results provide an explanation for the presence of GH-secreting tumors in some patients with the multiple endocrine neoplasia syndrome, type I, and warrant the addition of GH-releasing activity to the growing list of hormones secreted by tumors of amine precursor uptake and decarboxylation cell types.
PMCID: PMC371338  PMID: 6243140
13.  Contrast-enhanced ultrasonography in peripheral lung consolidations: What’s its actual role? 
World Journal of Radiology  2013;5(10):372-380.
AIM: To evaluate the diagnostic accuracy of contrast-enhanced ultrasonography (CEUS) in the differential diagnosis between neoplastic and non-neoplastic peripheral pleuro-pulmonary lesions.
METHODS: One hundred patients with pleural or peripheral pulmonary lesions underwent thoracic CEUS. An 8 microliters/mL solution of sulfur hexafluoride microbubbles stabilized by a phospholipid shell (SonoVue®) was used as US contrast agent. The clips were stored and independently reviewed by two readers, who recorded the following parameters: presence/absence of arterial enhancement, time to enhancement (TE), extent of enhancement (EE), pattern of enhancement (PE), presence/absence of wash-out, time to wash-out, and extent of wash-out. After the final diagnosis (based on histopathologic findings or follow-up of at least 15 mo) was reached, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (PLR), negative likelihood ratio (NLR) of each CEUS parameter in the differential diagnosis between neoplastic and non-neoplastic lesions were calculated. Furthermore, an arbitrary score based on the ratio between the PPVs of each CEUS parameter was calculated, to evaluate if some relationship could exist between overall CEUS behaviour and neoplastic or non-neoplastic nature of the lesions.
RESULTS: Five patients were lost at follow-up before a conclusive diagnosis was reached, 53 lesions resulted neoplastic and 42 non-neoplastic. Enhancement in the arterial phase was observed in 53/53 neoplastic lesions and 30/42 non-neoplastic lesions. On the whole, 40/42 non-neoplastic lesions showed absence of enhancement or early enhancement (95.2%) vs 3/53 neoplastic lesions (5.7%). EE was marked in 29/53 (54.7%) neoplastic lesions and 25/30 (83.3%) non-neoplastic lesions, moderate in 24/53 (45.5%) and 5/30 (16.7%), respectively. PE was homogeneous in 6/53 (11.3%) neoplastic lesions and 18/30 (60%) non-neoplastic lesions, inhomogeneous in 47/53 (88.7%) and 12/30 (40%), respectively. 19/30 (63.3%) non-neoplastic lesions enhancing in the arterial phase had no wash-out in the venous phase, 11/30 (36.7%) had late and mild wash-out. Wash-out was early in 26/53 (49%) neoplastic lesions, late in 26/53 (49%), absent in 1 (2%); marked in 16/53 (30.2%), and moderate in 36/53 (67.9%). The delayed enhancement in the arterial phase showed a sensitivity of 94.32%, specificity of 95.2%, PPV of 96.2%, NPV of 93%, PLR of 19.81, and NLR of 0.06 in identifying the neoplastic lesions. All other parameters individually considered showed unsatisfactory values of sensitivity, or specificity, or both, in differentiating neoplastic from non-neoplastic lesions. The median of the overall arbitrary score was 3 (range 0-14) in non-neoplastic lesions, and 16.5 (range 7.0-17.5) in neoplastic lesions (P < 0.001). The correlation between the diagnosis of neoplastic vs non-neoplastic lesion and the score value was statistically significant (r = 0.858, P < 0.001). Based on the score distribution, a cut-off of 7.5 enabled to reach a sensitivity of 98.1%, specificity of 95.1%, PPV 96.3%, NPV 97.5%, PVR 20.1 and NVR 0.02 in differentiating neoplastic from non-neoplastic lesions.
CONCLUSION: CEUS could be useful in the diagnostic workup of pleuropulmonary lesions. A delayed TE or a score ≥ 7.5 suggest the neoplastic nature of a lesion.
PMCID: PMC3812448  PMID: 24179632
Thoracic ultrasonography; Contrast-enhanced ultrasonography; Pleuropulmonary diseases; Neoplastic lesion; Diagnostic accuracy
14.  A “field change” of inhibited apoptosis occurs in colorectal mucosa adjacent to colorectal adenocarcinoma 
Journal of Clinical Pathology  2006;59(9):942-946.
Colorectal cancer is associated with a “field change” of increased proliferation throughout the colonic and rectal mucosa. Both proliferation and apoptosis are disrupted during carcinogenesis. Whether altered apoptosis contributes to this field change of microscopic abnormality is, however, unclear. Bcl‐xL is an anti‐apoptotic protein that inhibits apoptosis by preventing release of cytochrome c, a recognised pathway to cell death.
To determine whether Bcl‐xL inhibition of apoptosis is increased in colorectal mucosa adjacent to colorectal adenocarcinoma over that in normal non‐neoplastic colorectal mucosa.
Patients undergoing surgical resection for neoplastic (adenocarcinoma) or non‐neoplastic disease of the colorectum (rectal prolapse, diverticular disease or volvulus).
Formalin‐fixed, paraffin‐wax‐embedded surgical colorectal resection specimens were immunostained for Bcl‐xL protein. Labelling indices were determined by counting the proportion of positively stained cells in mucosal crypts.
85 patients were studied. Bcl‐xL immunostaining was most marked in the upper third of mucosal crypts. It occurred in a minority of samples from non‐neoplastic colorectal mucosa, but was seen in most mucosal samples adjacent to colorectal adenocarcinoma. Significant increases (p<0.001) were observed in Bcl‐xL labelling indices in the mucosa at 1 cm (n = 46, median labelling index 31.8%, interquartile range 8.3–43.9%) and at 10 cm (n = 52, median labelling index 22.0%, interquartile range 0.0–36.3%) from colorectal carcinoma, compared with normal, non‐neoplastic colorectal mucosa (n = 22, median labelling index 0.0%, interquartile range 0.0–0.0%).
The findings are consistent with a field change of inhibited apoptosis in mucosa adjacent to colorectal carcinoma.
PMCID: PMC1860481  PMID: 16679352
15.  Fluorescence-polarization changes in mononuclear blood leucocytes after PHA incubation: differences in cells from patients with and without neoplasia. 
British Journal of Cancer  1978;37(5):797-805.
In 32 healthy blood donors, 20 patients with histologically verified cancer and 18 patients with non-neoplastic diseases, the fluorescence polarization changes of fluorescein samples incorporated in mononuclear leucotyes were measured after incubation with PHA. The leucocytes of healthy persons, and 16/18 persons with non-neoplastic diseases, responded with a decrease in the degree of fluorescence polarization by about 20% from that in non-PHA-stimulated cells. In 19/20 patients with a variety of malignant tumours, the leucotyes did not respond to PHA stimulation with such a decrease. The exceptions among the patients with neoplastic and non-neoplastic diseases are considered, and may not be "false-negative" or "false-positive" respectively, but indicative of a particular situation in that disease. The biophysical mechanisms underlying the observed changes remain to be investigated.
PMCID: PMC2009621  PMID: 656307
16.  Urinary excretion of glycosaminoglycans and hydroxyproline in Paget's disease of bone, compared with neoplastic invasion of bone 
Journal of Clinical Pathology  1981;34(10):1097-1101.
Urinary glycosaminoglycan and hydroxyproline excretion was studied in 11 patients with clear evidence of Paget's disease of bone. Urinary hydroxyproline, cetyl pyridinium chloride (CPC)-precipitable uronic acid and CPC-precipitable hexosamine were expressed as ratios to urinary creatinine. Urine samples were concentrated × 1000 by vacuum dialysis and the glycosaminoglycans examined by electrophoresis on cellulose acetate followed by staining with alcian blue. All the cases studied showed markedly raised hydroxyproline excretion, whereas the uronic acid excretion was normal or only slightly raised in 10 of the 11 cases studied. One patient who had a raised uronic acid and raised hydroxyproline concentration was shown to have osteosarcoma as a complication of Paget's disease.
The very high hydroxyproline: creatinine ratio in all cases of Paget's disease (mean 241·8 mmol hydroxyproline/mol creatinine) contrasted sharply with the cases of disseminated neoplasm, where the ratio was either normal or slightly raised (mean 29·3 mmol hydroxyproline/mol creatinine). The ratio of hydroxyproline to CPC-precipitable uronic acid was also markedly raised in cases of Paget's disease (mean 77·3 mmol hydroxyproline/mmol uronic acid) and was lower in the neoplastic group (mean 14·1 mmol hydroxyproline/mmol uronic acid) but showed no advantage over the hydroxyproline: creatinine ratio in differentiating the two groups.
The urinary hydroxyproline: creatinine ratio promises to be of value in differentiating between Paget's disease of bone and neoplastic invasion of bone. A marked rise in CPC-precipitable uronic acid excretion alone is more suggestive of neoplastic invasion of bone, and if associated with a marked increase in hydroxyproline excretion, it raises the possibility of neoplastic change in Paget's disease of bone. The results of this study also suggest that bone collagen, rather than bone tissue in general, is primarily affected in Paget's disease.
PMCID: PMC494372  PMID: 7309892
17.  Rare Nonneoplastic Cysts of Pancreas 
Clinical Endoscopy  2015;48(1):31-38.
Pancreatic cysts represent a small proportion of pancreatic diseases, but their incidence has been recently increasing. Most pancreatic cysts are identified incidentally, causing a dilemma for both clinicians and patients. In contrast to ductal adenocarcinoma, neoplastic pancreatic cysts may be cured by resection. In general, pancreatic cysts are classified as neoplastic or non-neoplastic cysts. The predominant types of neoplastic cysts include intraductal papillary mucinous neoplasms, mucinous cystic neoplasms, serous cystic neoplasms, and solid pseudopapillary neoplasms. With the exception of serous type, neoplastic cysts, have malignant potential, and in most cases requires resection. Non-neoplastic cysts include pseudocyst, retention cyst, benign epithelial cysts, lymphoepithelial cysts, squamous lined cysts (dermoid cyst and epidermal cyst in intrapancreatic accessory spleen), mucinous nonneoplastic cysts, and lymphangiomas. The incidence of nonneoplastic, noninflammatory cysts is about 6.3% of all pancreatic cysts. Despite the use of high-resolution imaging technologies and cytologic tissue acquisition with endosonography, distinguishing nonneoplastic from neoplastic cysts remains difficult with most differentiations made postoperatively. Nonetheless, the definitive distinction between non-neoplastic and neoplastic cysts is crucial as unnecessary surgery could be avoided with proper diagnosis. Therefore, consideration of these rare disease entities should be entertained before deciding on surgery.
PMCID: PMC4323429
Pancreatic cyst; Neoplastic cyst; Nonneoplastic cyst
18.  Probiotics against neoplastic transformation of gastric mucosa: Effects on cell proliferation and polyamine metabolism 
World Journal of Gastroenterology : WJG  2014;20(37):13258-13272.
Gastric cancer is still the second leading cause of cancer death worldwide, accounting for about 10% of newly diagnosed neoplasms. In the last decades, an emerging role has been attributed to the relations between the intestinal microbiota and the onset of both gastrointestinal and non-gastrointestinal neoplasms. Thus, exogenous microbial administration of peculiar bacterial strains (probiotics) has been suggested as having a profound influence on multiple processes associated with a change in cancer risk. The internationally accepted definition of probiotics is live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. The possible effects on the gastrointestinal tract following probiotic administration have been investigated in vitro and in animal models, as well as in healthy volunteers and in patients suffering from different human gastrointestinal diseases. Although several evidences are available on the use of probiotics against the carcinogen Helicobacter pylori, little is still known about the potential cross-interactions among probiotics, the composition and quality of intestinal flora and the neoplastic transformation of gastric mucosa. In this connection, a significant role in cell proliferation is played by polyamines (putrescine, spermidine, and spermine). These small amines are required in both pre-neoplastic and neoplastic tissue to sustain the cell growth and the evidences here provided suggest that probiotics may act as antineoplastic agents in the stomach by affecting also the polyamine content and functions. This review will summarize data on the most widely recognized effects of probiotics against neoplastic transformation of gastric mucosa and in particular on their ability in modulating cell proliferation, paying attention to the polyamine metabolism.
PMCID: PMC4188884  PMID: 25309063
Cell proliferation; Gastric cancer; Microbiota; Polyamines; Probiotics
19.  Diagnostic Accuracy of High Resolution Ultrasound to Differentiate Neoplastic and Non Neoplastic Causes of Cervical Lymphadenopathy 
Introduction: Lymph nodes are normal structures distributed throughout the human body and are enlarged in various disease entities. Identifying the relevant lymph nodes is important in treating these patients. High resolution sonography (HRSG) and fine needle aspiration cytology (FNAC) play crucial role in planning the treatment.
Objective: To assess the diagnostic accuracy of HRSG differentiate neoplastic and non neoplastic causes of enlarged cervical lymph nodes.
Materials and Methods: HRSG evaluation of enlarged cervical lymph nodes were performed to differentiate neoplastic from non neoplastic lymph nodes followed by FNAC correlation and the accuracy of HRSG was studied.
Results: One hundred and fourteen lymph nodes of 106 patients were analysed to accomplish the study objective. In our study, HRSG had 96% sensitivity and 90.6% specificity for differentiating between neoplatic and non-neoplastic cervical lymphadenopathy. Similarly positive and negative predictive values were 88.9% and 96.7% respectively. Overall accuracy of HRSG was 93%.
Conclusion: Owing to high sensitivity and negative predictive value, HRSG with Doppler is an excellent first line investigating tool for enlarged lymph nodes and avoids invasive procedures like FNAC in cases of reactive/ inflammatory (non-neoplastic) lymph nodes. However, neoplastic diagnosis of HRSG needs further confirmation by FNAC.
PMCID: PMC4225953  PMID: 25386501
Cervical lymphadenopathy; High resolution ultrasound; Neoplastic
20.  Microsatellite instability in inflamed and neoplastic epithelium in ulcerative colitis 
Journal of Clinical Pathology  2001;54(7):526-532.
Background—Several genetic alterations have been documented in dysplasia and cancer developing in ulcerative colitis (UC). However, the microsatellite instability (MSI) status has rarely been described, especially in the inflamed epithelium of UC.
Aims—To study MSI status during neoplastic and inflammatory changes in UC.
Methods—Seventy five surgically resected samples of colorectal mucosa, taken from 16 colectomy specimens of patients with UC were examined: five patients had a long duration with dysplasia or cancer (UC-LD with neoplasm), seven patients had a long duration without neoplastic changes (UC-LD without neoplasm), and four patients had a short duration without neoplastic changes (UC-SD). In addition to MSI status examined by six microsatellite markers, p53 expression was compared among the three groups.
Results—With regard to non-neoplastic inflamed epithelium, MSI in two or more loci (MSI≥2) was seen more frequently in the UC-LD without neoplasm group than in the UC-SD group (six of 14 v one of 12; p = 0.060), and significantly more often than in the UC-LD with neoplasm group (six of 14 v two of 23; p = 0.016). In the UC-LD without neoplasm group, MSI≥2 was detected significantly more frequently in patients with severe inflammation than in those with mild inflammation (six of nine v none of five; p = 0.028). With regard to neoplastic epithelium in the UC-LD with neoplasm group, MSI in two or more loci was found in three of 17, and p53 overexpression was seen in 11 of 17 of the neoplastic lesions.
Conclusions—A high incidence of MSI in long standing UC with severe inflammation probably reflects genomic instability caused by repeated inflammatory stress. Thus, the influence of inflammation should be considered when estimating MSI in UC. It is possible that changes in p53 expression are important in the development of cancer in UC.
Key Words: microsatellite instability • p53 • ulcerative colitis
PMCID: PMC1731482  PMID: 11429424
21.  Silencing of RASSF3 by DNA Hypermethylation Is Associated with Tumorigenesis in Somatotroph Adenomas 
PLoS ONE  2013;8(3):e59024.
The pathogenic mechanisms underlying pituitary somatotroph adenoma formation, progression are poorly understood. To identify candidate tumor suppressor genes involved in pituitary somatotroph adenoma tumorigenesis, we used HG18 CpG plus Promoter Microarray in 27 human somatotroph adenomas and 4 normal human adenohypophyses. RASSF3 was found with frequent methylation of CpG island in its promoter region in somatotroph adenomas but rarely in adenohypophyses. This result was confirmed by pyrosequencing analysis. We also found that RASSF3 mRNA level correlated negatively to its gene promoter methylation level. RASSF3 hypermethylation and downregulation was also observed in rat GH3 and mouse GT1.1 somatotroph adenoma cell lines. 5-Aza-2′ deoxycytidine and trichostatin-A treatment induced RASSF3 promoter demethylation, and restored its expression in GH3 and GT1.1 cell lines. RASSF3 overexpression in GH3 and GT1.1 cells inhibited proliferation, induced apoptosis accompanied by increased Bax, p53, and caspase-3 protein and decreased Bcl-2 protein expression. We also found that the antitumor effect of RASSF3 was p53 dependent, and p53 knockdown blocked RASSF3-induced apoptosis and growth inhibition. Taken together, our results suggest that hypermethylation-induced RASSF3 silencing plays an important role in the tumorigenesis of pituitary somatotroph adenomas.
PMCID: PMC3610897  PMID: 23555615
22.  Pituitary-directed leukemia inhibitory factor transgene forms Rathke's cleft cysts and impairs adult pituitary function. A model for human pituitary Rathke's cysts. 
Journal of Clinical Investigation  1997;99(10):2462-2469.
Leukemia inhibitory factor (LIF) and LIF receptors are expressed in adenohypophyseal cells and LIF regulates pituitary hormone transcription and cell replication in vitro. Therefore, transgenic mice expressing pituitary-directed LIF driven by the rat growth hormone (GH) promoter were generated to evaluate the impact of LIF on pituitary development. Three founders were established with diminished linear growth and body weight (57-65% of wild type [WT]), and intense anterior pituitary LIF immunoreactivity. Cystic cavities observed in pituitary anterior lobes were lined by cuboidal, ciliated epithelial cells, focally immunopositive for cytokeratin and S-100 protein and immunonegative for adenohypophyseal hormones. Transgenic pituitaries showed decreased GH (40%) and prolactin (PRL) (26%) cells, and decreased GH and PRL mRNAs by in situ hybridization. ACTH cells increased 2.2-fold, whereas gonadotrophs and thyrotrophs were unchanged. Serum GH was undetectable (< 0.78 ng/ml), PRL levels were one third of WT (P < 0.05), IGF-I levels were 30% of WT (P < 0. 001), and T4 was normal. 10 human pituitary Rathke's cysts studied all showed conclusive LIF immunoreactivity in cyst-lining cells. Thus, intrapituitary murine LIF overexpression causes cystic invaginations from the anterior wall of Rathke's cleft, suggesting failed differentiation of Rathke's epithelium to hormone-secreting cells. Arrested murine pituitary maturation with formation of pituitary Rathke's cleft cysts, GH deficiency, and short stature provide a model to study human Rathke's cyst pathogenesis.
PMCID: PMC508087  PMID: 9153290
23.  Immunohistochemical and morphological features of a small bowel leiomyoma in a black crested macaque (Macaca nigra) 
Spontaneous gastrointestinal neoplasms in non-human primates are commonly seen in aged individuals. Due to genetic similarities between human and non-human primates, scientists have shown increasing interest in terms of comparative oncology studies.
Case presentation
The present study is related to a case of an intestinal leiomyoma in a black crested macaque (Macaca nigra), kept on captivity by Matecaña Zoo, Pereira City, Colombia. The animal had abdominal distension, anorexia, vomiting, diarrhea and behavioral changes. Clinical examination showed an increased volume in the upper right abdominal quadrant caused by a neoplastic mass. The patient died during the surgical procedure. Necropsy revealed several small nodules in the peritoneum with adhesion to different portions of the small and large intestines, liver, stomach and diaphragm. Tissue samples were collected, routinely processed and stained by H&E. Microscopic examination revealed a mesenchymal tumor limited to tunica muscularis, resembling normal smooth muscle cells. Neoplastic cells were positive for alpha-smooth muscle actin and vimentin, and negative for cytokeratin AE1/AE3 by immunohistochemistry. Those morphological and immunohistochemical findings allowed to diagnose the intestinal leiomyoma referred above.
Neoplastic diseases in primates have multifaceted causes. Their manifestations are understudied, leading to a greater difficulty in detection and measurement of the real impact provides by this disease.
PMCID: PMC3488556  PMID: 22747606
Neoplasm; Small bowel; Macaca; Monkey; Leiomyoma; Intestine
24.  AB 29. Malignant mediastinal tumor: restrictions in immunohistochemical evaluation 
Journal of Thoracic Disease  2012;4(Suppl 1):AB29.
It is common ground that immunohistochemistry’s contribution in neoplasm’s origin identification is invaluable. However, in some cases there seem to exist certain limitations raising differential diagnosis problems.
Patients and methods
A young 23-year old woman, who was recently pregnant and breastfeeding, presented to our hospital with dyspnea and superior vena cava syndrome. A month ago she suffered from upper respiratory tract infection, which was treated with antibiotics. Axial computed tomography showed several mediastinal masses and right lower lobe lung invasion. This was followed by bronchoscopy and samples were taken for biopsy.
Upon histological evaluation a malignant neoplasm with extensive necrosis was revealed. Diffuse distribution of oval, middle to large size cells, with conspicuous nucleoli and mitoses, tend to lead to the diagnosis of a lymphoproliferative neoplasm. During to gradual and extensive immunohistochemical examination, the neoplastic cells were found negative to stains specific for hemopoietic system diseases as well as other malignant neoplasm such as sarcoma, mesothelioma, germ cell tumor, melanoma and neuroendocrine carcinoma. On the other hand, they were strongly positive for p63 (squamous cell differentiation index), CD138 and only weak and focally for keratins (CKAE1/AE3, CK8/18, CK7, CK5/6). Morphological and immunohistochemical findings consisted with undifferentiated carcinoma, with squamous cell differentiation. The patient deceased 20 days later.
Neoplastic morphological features tend to lead to a correct diagnosis which should always be certified by immunohistochemical findings. However, in some cases immunohistochemistry’s role is diminished due to tumor specific factors as neoplastic cells’ poor differentiation or dedifferentiation and degenerative changes.
PMCID: PMC3537357
25.  Value of ultrasonography-guided fine needle aspiration cytology in the investigative sequence of hepatic lesions with an emphasis on hepatocellular carcinoma 
The evaluation and management of various hepatic lesions is a common clinical problem and their appropriate clinical management depends on accurate diagnoses.
To study the cytomorphological features of distinctive non-neoplastic and neoplastic lesions of the liver and to evaluate the sensitivity, specificity and diagnostic accuracy of ultrasonography (USG)-guided fine needle aspiration cytology (FNAC) in the diagnosis of liver diseases.
Materials and Methods:
Seventy-two patients with evidence of liver diseases underwent USG-guided, percutaneous FNAC. Cytomorphological diagnoses were correlated with clinical, biochemical and radiological findings, histopathological diagnoses and follow-up information.
The age of the patients ranged from eight months to 90 years with 48 males (66.67%) and 24 females (33.33%). Of the 72 cases, the cytological diagnosis was rendered in 71 patients and smears were inadequate for interpretation in one case. Neoplastic lesions (68.06%) were more common than non-neoplastic lesions (30.56%). The majority of the neoplastic lesions were hepatocellular carcinomas (36.12%) followed by metastatic adenocarcinomas (19.45%). Among non-neoplastic lesions, cirrhosis was the commonest lesion (8.34%). The overall diagnostic accuracy of FNAC was 97.82% with a sensitivity and specificity of 96.87 and 100% respectively.
USG-guided FNAC of the liver is a safe, simple, cost-effective and accurate method for cytological diagnosis of hepatic diffuse, focal/nodular and cystic lesions with good sensitivity and specificity.
PMCID: PMC3214462  PMID: 22090691
Fine needle aspiration cytology; hepatic lesions; ultrasonography

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