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Cytokines as modulators of the hypothalamus-pituitary-adrenal axis.

The hypothalamus-pituitary-adrenal (HPA) axis is stimulated during the course of certain immune, inflammatory and neoplastic processes. IL-1 is an important immunologically derived cytokine mediating the stimulation of this axis, although not the only one. We have compared the relative potencies of the cytokines IL-1, IL-6 and tumor necrosis factor (TNF), which share several biological actions, for stimulating ACTH and corticosterone output in freely-moving rats. Although all three cytokines can stimulate the HPA axis, IL-1 was the most potent. This effect of IL-1 was also present during the neonatal period, when the response of the HPA axis to acute stress is reduced in rodents. The results support the existence of an immune-HPA axis circuit. The biological and clinical relevance of this circuit is discussed.

Adrenocorticotropic Hormone↗

Oestradiol synthesis from oestrone in malignant breast epithelial cells: studies on a high affinity, 80 kDa form of oestradiol dehydrogenase.

Previous studies have shown that in the breast there are multiple forms of the enzyme oestradiol dehydrogenase (E2DH), responsible for the interconversion of oestrone (E1) to oestradiol (E2). We have now re-examined oestrogen metabolism in the breast cancer cell lines (T47D and MCF-7) and have shown that steroids previously shown to inhibit the conversion of E1 to E2 in normal breast tissue failed to do so when added to growing monolayers of these malignant cells. In contrast to earlier estimates in normal breast tissues, the apparent Km for this conversion in monolayers of these malignant cells is shown here to be considerably lower, at around 50 nM. Cell free studies on these cell lines have revealed the presence of a high affinity (for E1) form of this enzyme of Mw approximately 80 kDa. The ability to detect this enzyme in soluble cell fractions appears to be critically dependent on buffer composition. Normal breast epithelial cells and adipose tissue appear to be devoid of this form of E2DH. As this form of E2DH has the highest affinity for the substrate E1 of all the forms in the breast, it is probable that this 80 kDa enzyme is responsible for the conversion of E1 to E2 in cell monolayers. If the observation holds that the 80 kDa enzyme is absent in the normal tissues, then the possibility arises that this E2DH may be linked with the neoplastic process in some breast tumours containing malignant epithelial cells of a similar type as studied here.

Adipose Tissue↗

Nodular histiocytic/mesothelial hyperplasia: a potential pitfall.

We present five cases of nodular histiocytic/mesothelial hyperplasia (two peritoneal, two pulmonary, and one pericardial) with identical microscopic features. All the lesions were biphasic and composed of cohesive monotonous epithelioid clusters of polygonal or oval cells with round or deeply grooved nuclei in association with darker cuboidal cells. Because of the increased cellularity and monotonous histologic pattern with some degree of cytologic atypia, neoplastic processes were seriously considered in the differential diagnoses. The majority of the cells marked as histiocytes by immunostain. A few scattered individual cells or small epithelial cell clusters were confirmed by calretinin stain to be mesothelial cells. The histologic patterns of the current lesions, irrespective of the location, were identical to nodular histiocytic/mesothelial hyperplasia. Histiocytic proliferations can be erroneously confused with primary mesothelial lesions or neoplasms such as granulosa cell tumor, eosinophilic granuloma, chronic myelogenous leukemia, and carcinoma. The purpose of this article is to describe the clinicopathologic features of nodular histiocytic/mesothelial hyperplasia and help familiarize pathologists with this lesion to prevent an erroneous diagnosis, particularly when it occurs in locations where mesothelial cells are not normally present.

Adult↗

Role of host genes in sporadic gastric cancer.

Gastric cancer remains a major health problem particularly in the developing world. Helicobacter pylori (H. pylori) infection is the most recognised aetiological risk factor for this malignancy. The infection causes a chronic gastritis that is the precursor to all the pathophysiological abnormalities characteristic of gastric carcinogenesis. Genetic polymorphisms have emerged in recent years as important determinants of disease susceptibility and severity. In the case of H. pylori-induced gastric cancer, host genetic polymorphisms play an important role both in the precancerous stages and in the transition to cancer. In particular, polymorphic genes of the adaptive and innate immune response are involved in all stages of the neoplastic process. This field is rapidly expanding and many other genetic determinants are currently being defined. The ultimate value of host genetics should be in understanding the pathogenesis of the disease, which would offer a true opportunity to defeat this global killer.

Biomarkers, Tumor↗

Extramammary Paget's disease of the breast: an unusual location with prognostic implications.

Extramammary Paget's disease is a neoplastic process of intraepidermal origin; its management and prognosis are very different from those of mammary Paget's disease. We present a case of extramammary Paget's disease located in the breast. This is an exceptional location, whose differential diagnosis is important because of its therapeutic and prognostic implications.

Breast Neoplasms↗

Bovine papillomavirus type-2 DNA and expression of E5 and E7 oncoproteins in vascular tumours of the urinary bladder in cattle.

Cattles suffering from chronic enzootic haematuria frequently develop urinary bladder tumours of both epithelial and mesenchymal origin mainly haemangioma and its malignant counterpart. The role of the bovine papillomavirus type-2 (BPV-2) and of its major transforming oncoprotein in naturally occurring urothelial carcinogenesis has been recently clarified. E5 interacts in vivo as in vitro with the beta receptor for the platelet-derived growth factor (PDGF). However, studies regarding tumours of mesenchymal origin such as those arising from blood vessels are lacking. We show that the BPV-2 is present in 100% of the vascular tumours of the urinary bladder examined. Twenty-six out of twenty-seven tumour samples (96%) expressed E5 while 20 out of 27 (74%) tumour samples expressed E7. The two viral oncoproteins were not expressed in normal endothelial cells. Additionally, they co-localize in neoplastic endothelial cells as demonstrated by confocal immunofluorescence. PDGFbeta receptor was also shown to be expressed and co-localizes with E5 in neoplastic blood vessels. Our results demonstrate, for the first time, that the BPV-2 is present in high percentage in tumours of mesenchymal origin arising in its natural host. Furthermore, the expression of the two viral oncoproteins confirm that the virus may have a causative role in the neoplastic process.

Animals↗

Diagnostic imaging of the canine and feline ear.

Radiographic evaluation of the tympanic bulla is limited. Improper obliquity or angulation of the skull for radiographs or malpositioning of the tongue can result in an inadequate study [4]. Additionally, because of the complex anatomy of the canine and feline skull, with superimposition of multiple osseous structures, radiography can result in false-negative examinations or understimation of the disease present [2]. When compared with surgical findings of 19 clinical cases of presumptive middle ear disease, false-negative radiographic findings were found in 25% of the surgically confirmed cases of otitis media [4]. Therefore, radiographs are not considered to be a highly sensitive mode of diagnosing otitis media. Radiographs may be helpful in determining lysis associated with neoplasia; however, the extent of involvement is still underestimated. In a study comparing CT and radiographic evaluation of otitis media, CT was determined to be more sensitive but less specific than radiography [11]. CT is the preferred modality for the evaluation of the tympanic bulla at our institution. This opinion may be biased by the fact that most cases are presented for recurrent or chronic otitis. Although radiography is more accessible, the availability of CT in local referral settings is increasing as opposed to being limited to university settings. After the cost (i.e., anesthesia, radiographs) and amount of time necessary to make optimum radiographic studies are taken into account, a CT study may actually be faster and more informative. Given our preference for the CT examination, the cost of the examination has been adjusted to make it more appealing to the owner and clinician. For example, a bulla CT study is only 1.3 times the cost of a radiographic bulla study. In conclusion, imaging of the ear canal can provide important information about ear disease, including unilateral or bilateral ear disease, the degree of middle or inner ear involvement, peripheral versus central vestibular disease, an infectious or inflammatory versus neoplastic process, the chronicity of the disease process, involvement of adjacent structures, and postsurgical complications.

Animals↗

Ultrahigh-resolution and 3-dimensional optical coherence tomography ex vivo imaging of the large and small intestines.

BACKGROUND: Ultrahigh-resolution optical coherence tomography (OCT) has an axial resolution of <5 microm, 2 to 3 times finer than standard OCT. This study investigates ultrahigh-resolution and three-dimensional OCT for ex vivo imaging of the large and small intestines and correlates images with histology. METHODS: Ultrahigh-resolution OCT imaging was performed on fresh surgical specimens from the large and small intestines in the pathology laboratory, and images were correlated with histology. OCT was performed at 1.3-microm wavelength with 4.5-microm axial x 11-microm transverse resolution and at 1.1-microm wavelength with 3.5-microm axial x 6-microm transverse resolution. Three-dimensional OCT also was investigated. RESULTS: Normal and pathologic areas from 23 surgical specimens of the large and small intestines were imaged. Ultrahigh-resolution OCT distinguished the epithelial layer of the mucosa and visualized individual villi, glands, and crypts. Finer transverse resolutions improved visualization of features, e.g., the epithelium, but reduced the depth of field. Architectural distortion of glands from inflammatory and neoplastic processes was observed. Three-dimensional rendering enabled visualization of surface pit pattern and mucosal folds as well as subsurface crypt microstructure. CONCLUSIONS: This study evaluates new OCT technology and can provide a baseline for interpreting future ultrahigh-resolution endoscopic OCT studies.

Adult↗

Genotypic analysis of pulmonary Langerhans cell histiocytosis.

Reported studies show that the systemic form of Langerhans cell histiocytosis (LCH) is a clonal expansion of Langerhans cells (LC) associated with aberrant expression of several oncogenes or tumor-suppressor genes. LCH of the lung is a heterogenous group of lesions thought to be a reactive rather than neoplastic process. The histogenesis of the LCH of the lung is uncertain, and to date there are no studies investigating its underlying molecular abnormalities. We performed comparative genotypic analysis by using allelic loss (LOH) of polymorphic microsatellite markers associated with tumor suppressor genes. Fourteen cases of formalin-fixed, paraffin-embedded LCH of the lung were studied. Microdissection of a total of 26 nodules from 14 patients and paired reference lung tissue was performed under stereomicroscopic visualization. To evaluate allelic loss, we used a panel of 11 polymorphic microsatellite markers that were situated at or near tumor suppressor genes on chromosomes 1p, 1q, 3p, 5p, 9p, 17p, and 22q. The PCR products were analyzed by using capillary electrophoresis to identify germline heterozygous alleles and LOH. Allelic loss at 1 or more tumor suppressor gene loci was identified in 19 of 24 nodules. The total fractional allelic loss (FAL) ranged from 6% (1q) to 41% (22q), with a mean of 22%. The FAL in individual cases ranged from 0 (7 nodules) to 57% (1 nodule). Fifteen discordant allelic losses at 1 to 3 chromosomal loci were identified in 8 patients with multiple synchronous nodules. Our results show that LOH of tumor suppressor genes is present in the LCH of the lung, and they indicate that the putative tumor suppressor genes situated on chromosomes 9p and 22q may play a role in the development of a subset of the LCH of the lung.

Adult↗

p16INK4A expression as biomarker for HPV 16-related vulvar neoplasias.

Up-regulation of p16INK4A is associated with high-risk human papillomavirus (HPV) in preinvasive and invasive cervical neoplasia. However, its expression in vulvar carcinomas, which have a diverse pathogenesis, has not been extensively studied. One hundred seventy-seven vulvar intraepithelial neoplasms (VIN), squamous cell carcinomas (SCC), and benign squamous epithelia were analyzed for p16 expression. RNA/RNA in situ hybridization was used to detect HPV 16 E6/E7 transcripts in 112. Ninety-five percent of VIN 3 and basaloid or warty SCCs (76/80) and 4% of keratinizing SCC (2/48) were moderately to strongly immunopositive for p16, which localized to nucleus and cytoplasm; 52/58 analyzed (90%) contained HPV 16 transcripts. The positive predictive value (PPV) of moderate to strong diffuse p16 immunostaining and HPV positivity for the diagnosis of VIN 3 and of basaloid or warty SCC was 97% and 95%, respectively. Conversely, 94% of keratinizing SCC contained heterogeneous staining, and when present, it was strictly cytoplasmic and frequently localized to the cells at the epithelial-stromal interface. Benign squamous epithelia were p16 negative, with the exception of lichen sclerosus, which contained focal and heterogeneously p16 positive in 42%. As in the cervix, intense diffuse p16 expression supports an HPV-related neoplastic process in vulvar neoplasia, irrespective of the level of differentiation. Up-regulation of p16 at the epithelial-stromal interface in HPV negative keratinizing SCCs is consistent with an HPV-independent response to alterations associated with invasion. These disparate patterns of p16 expression underscore 2 different mechanisms for p16 expression in HPV-related and HPV-unrelated vulvar carcinomas.

Adult↗

Recurrent pulmonary embolism with non-mobile thrombus in a patient with leiomyosarcoma of the left renal vein.

We describe the case of a man who suffered recurrent pulmonary embolisms despite well-conducted oral anticoagulant therapy. Echocardiography and helical computed tomography revealed a non-mobile right atrial mass related to a leiomyosarcoma of the left renal vein. The prognosis of such a disease is bad and the patient died at 1-year follow-up. Recurrent pulmonary embolism with well-conducted oral anticoagulant therapy requires further appropriate investigations, because of high suspicion of neoplastic process.

Anticoagulants↗

Suppression of macrophage function in AK-5 tumor transplanted animals: role of TGF-beta1.

Transforming growth factor-beta 1 (TGF-beta1), a multifunctional cytokine secreted by various cell types has been implicated in diverse physiologic and pathophysiologic functions, including immunological, inflammatory, and neoplastic processes. AK-5 tumor cells when injected intraperitoneally grow as ascites, causing 100% mortality. Peritoneal macrophages cocultured with AK-5 cells, in vitro showed specific suppression of tumoricidal function. We report that AK-5 cells secrete the latent form of TGF-beta1, which is converted to its active homodimeric form, causing suppression of the secretion of cytocidal molecule by macrophages thereby inhibiting their cytotoxic capabilities. When macrophages are cocultured with AK-5 cells in the presence of antibodies against TGF-beta1 or the receptor II for TGF-beta, there is significant recovery in the secretion of nitric oxide and macrophage cytotoxic potential. These results suggest a major role for TGF-beta produced by the tumor cells, in the immune escape mechanisms adopted by the AK-5 tumor cells.

Animals↗

The role of interleukin 10 in the pathogenesis and potential treatment of skin diseases.

UNLABELLED: Interleukin 10 (IL-10) is a key cytokine produced by a multitude of immune effector cells and possesses distinct regulatory effects on immune functioning in the skin. In this article we report the current understanding of the immunobiology of IL-10 and identify the role of IL-10 in cutaneous infection as well as in autoimmune and neoplastic processes. We reviewed the literature to examine the function of IL-10 in different cutaneous disorders. IL-10 can influence and potentially treat T1/T2 differentiation, antigen-presenting cell functioning, antigen-presenting cell-mediated T-cell activation, and T-cell, B-cell, and mast cell growth and differentiation that is aberrant in various disease processes. The literature consensus is that the multitude of effects of IL-10 contribute to the pathogenesis of different skin disorders. In certain circumstances IL-10 could represent novel therapeutic approaches to treating cutaneous diseases. LEARNING OBJECTIVE: At the conclusion of this learning activity, participants should be acquainted with the role of IL-10 in many infectious diseases, autoimmune skin disease, inflammatory processes, and malignancy. Its possible role in the resolution of various skin diseases should be better understood.

Animals↗

Transient clonal expansion of T-large granular lymphocytes during primary cytomegalovirus infection.

Clonal immunoglobulin and T-cell receptor gene rearrangements are useful in distinguishing reactive lymphoproliferations from neoplastic processes. Here, we report a case of transient clonal expansion of CD8+ CD57- T-large granular lymphocytes (T-LGL) during primary cytomegalovirus infection. This case underlines that clonal expansion of T-LGL could be a reactive phenomenon related to an acute infectious disease and is not specific for lymphoid malignancy.

CD8-Positive T-Lymphocytes↗

Inflammatory pseudotumor of the ureter.

Inflammatory myofibroblastic pseudotumors are rare solid tumors found in most soft tissue locations although mainly in the lung. Their etiology is uncertain, and they are generally considered benign although some have a potential for recurrence and dissemination. Recent studies have suggested, however, that some of these tumors are in fact neoplastic processes that harbor chromosomal aberrations similar to those seen in certain lymphomas. The authors report a case of inflammatory pseudotumor of the ureter in a child and discuss recent reports.

Actins↗

Carotid atherosclerotic plaques from symptomatic stroke patients share the molecular fingerprints to develop in a neoplastic fashion: a microarray analysis study.

Identification of genetic mechanisms that promote the onset of stroke and transient cerebral ischemic attack symptoms in carotid atherosclerotic patients would further our understanding of the pathophysiology of this disease and could lead to new pharmacological and molecular therapies. Using Affymetrix Human Genome 230 GeneChip set, the present study evaluated the gene expression differences in geometrically similar carotid artery plaque samples extricated from six symptomatic stroke patients and four asymptomatic patients. There was no significant difference in the degree of stenosis between the two groups. Of the 44,860 transcripts analyzed, 289 (approximately 0.6% of the total transcripts) were differentially expressed between the plaques from the symptomatic and asymptomatic groups (236 were expressed more abundantly and 53 were expressed less abundantly in the symptomatic group). Of the 236 transcripts expressed more abundantly in the symptomatic plaques, 71% (167 transcripts) indicate an active cell proliferation and neoplastic process. These include oncogenes, growth factors, tumor promoters, tumor markers, angiogenesis promoters, transcription factors, RNA splicing factors, RNA processing proteins, signal transduction mediators and those that control the metabolism. Real-time polymerase chain reaction confirmed the increased expression of 63 transcripts in the symptomatic plaques. The other groups of transcripts expressed more abundantly in the symptomatic plaques are those that control ionic homeostasis, those that participate in the progression of degenerative neurological diseases (Alzheimer's disease, amyotrophic lateral sclerosis and Huntington's disease) and epilepsy. This indicates that symptomatic plaques are molecularly and biochemically more active than the asymptomatic plaques, or active plaque growth precipitates stroke symptoms.

Aged↗

Facial nerve paralysis secondary to occult malignant neoplasms.

OBJECTIVE: This study reviewed patients with unilateral facial paralysis and normal clinical and imaging findings who underwent diagnostic facial nerve exploration. Study design and setting Fifteen patients with facial paralysis and normal findings were seen in the Mayo Clinic Department of Otorhinolaryngology. RESULTS: Eleven patients were misdiagnosed as having Bell palsy or idiopathic paralysis. Progressive facial paralysis with sequential involvement of adjacent facial nerve branches occurred in all 15 patients. Seven patients had a history of regional skin squamous cell carcinoma, 13 patients had surgical exploration to rule out a neoplastic process, and 2 patients had negative exploration. At last follow-up, 5 patients were alive. CONCLUSIONS: Patients with facial paralysis and normal clinical and imaging findings should be considered for facial nerve exploration when the patient has a history of pain or regional skin cancer, involvement of other cranial nerves, and prolonged facial paralysis. SIGNIFICANCE: Occult malignancy of the facial nerve may cause unilateral facial paralysis in patients with normal clinical and imaging findings.

Aged↗

Increased urinary coproporphyrin excretion observed in patients with differently staged Hodgkin's disease treated with chemotherapy.

It has been reported that patients with Hodgkin's disease (HD) show altered porphyrin metabolism, and suggested that the cause is the neoplastic process itself. If this is true, disease progression should be associated with higher levels of porphyrin excretion. The aim of this study was to evaluate urinary coproporphyrin levels in patients with Hodgkin's disease at different stages. As many of the patients received chemotherapy, another aim was to verify experimentally whether chemotherapeutic agents might increase porphyrin levels in rabbits. All of the patients had above-normal urinary coproporphyrin levels. On the other hand, rabbits receiving the porphyrin precursor 5-aminolevulinic acid (5-ALA), and also treated with doxorubicin, showed very high plasma porphyrin levels. The increased levels of urinary coproporphyrins seem to be due to the disease itself, since the patients in stages III and IV had higher excretion values, presumably due to biochemical heme synthesis lesions that lead to the availability of the porphyrin precursor, as well as coproporphyrin accumulation and excretion. The altered porphyrin synthesis may be attributable to the cytotoxic oxygen species generated in the presence of NADH and iron. As the patients also received extensive chemotherapy regimes, the altered porphyrin metabolism may be affected by antineoplastic treatment generating oxygen reactive radicals. The alterations in porphyrin metabolism induced by chemotherapeutic agents appear to be demonstrated in rabbits in which doxorubicin increases porphyrin synthesis after porphyrin precursor treatment.

Adolescent↗