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PubMed1985

Effect of X-irradiation on epidermal immune function: decreased density and alloantigen-presenting capacity of Ia+ Langerhans cells and impaired production of epidermal cell-derived thymocyte activating factor (ETAF).

The mechanisms involved in the modulation of cutaneous immune responses by UV radiation have been extensively investigated; by contrast, few studies have addressed the effects of x-irradiation on epidermal immune function. We therefore investigated the effect of x-irradiation of mice on: (a) the density of epidermal Ia+ Langerhans cells (LC) in immunofluorescence studies, (b) epidermal cell (EC) allostimulatory capacity in the allogeneic EC-lymphocyte reaction (ELR), and (c) production of epidermal cell-derived thymocyte activating factor (ETAF). C3H/He and BALB/c mice were irradiated with 900, 1,800, 2,700, or 3,600 rad from a 137Cs source, and sacrificed 10 h or 3 days later. X-irradiation of mice 10 h previously only slightly decreased the density of epidermal Ia+ LC and did not affect the capacity of their EC to stimulate allogeneic responder lymphocytes in the ELR. X-irradiation of mice 3 days previously, however, resulted in a dose-dependent decrease in the density of Ia+ LC. This decrease was accompanied by a substantial reduction in EC allostimulatory capacity in the ELR at all doses of x-irradiation. ETAF production by cultured EC from mice x-irradiated 3 days previously was also found to be diminished at all doses of x-irradiation. Trypan blue exclusion studies demonstrated that the observed decreases in EC allostimulatory capacity and ETAF production were not the result of a generalized lethal effect of x-irradiation on EC. The reduction in EC allostimulatory capacity following in vivo x-irradiation could not be reversed by addition of exogenous ETAF or interleukin-1 in the ELR. Taken together, these results indicate that x-irradiation decreases the density of Ia+ LC, impairs LC alloantigen-presenting function, and reduces ETAF production. Thus cutaneous x-irradiation may affect inflammatory and neoplastic processes not only by its antimitotic activity, but also by a direct effect on EC which subserve immunologic functions.

Animals↗
PubMed1989

Porokeratosis has neoplastic clones in the epidermis: microfluorometric analysis of DNA content of epidermal cell nuclei.

Clinical evidence of malignant epithelial tumors developing on the lesions of porokeratosis has accumulated. To determine the cytologic basis for the malignant change of porokeratosis, the nuclear DNA content of epidermal cells from porokeratosis lesions was measured using microfluorometry. A total of 42% of 33 porokeratosis skin lesions in eight of the 16 patients showed DNA polyploidization in the epidermis. Most of the porokeratosis skin lesions, with or without DNA polyploidization, increased cell proportions in the S and G2/M phase range. These findings suggest that porokeratosis is undergoing the neoplastic process, and is the precursor skin manifestation of malignant tumors.

Adult↗
PubMed2005

Myxoinflammatory fibroblastic sarcoma of the neck.

BACKGROUND: Myxoinflammatory fibroblastic sarcoma (MIFS), also named inflammatory myxohyaline tumor of distal extremities with virocyte or Reed-Sternberg cells, is a rare tumor typically presenting as a painless mass in the extremities. PATIENTS: We present an unusual case of MIFS presenting as a subcutaneous neck mass. This is the first reported case of MIFS presenting in the neck. RESULTS: Therefore, this lesion must be considered in the differential diagnosis for painless subcutaneous masses presenting not only in the distal extremities, but also in the neck. CONCLUSION: MIFS has only recently been recognized. The differential diagnosis for MIFS is broad, and it can often be mistaken for several different inflammatory and neoplastic processes, which may require different treatment.

Adult↗
PubMed2006

Primary essential cutis verticis gyrata in an adult female patient: a case report.

Cutis verticis gyrata (CVG) is a very rare morphological condition of the scalp characterized by ridges and furrows resembling the surface of the brain. Primary or idiopathic CVG occurs in the absence of underlying soft-tissue abnormalities and is often associated with neuropsychiatric disorders. Secondary CVG occurs as a result of a local inflammatory or neoplastic process of the scalp or a systemic illness that produce pathologic changes in the scalp structure. The choice of treatment of CVG is surgical repair which depends on the size and location of the lesion, the underlying disorder, and the wishes of the patient, including primary repair, serial excision, skin grafting, local flaps and tissue expansion. In this case report, we describe the first female patient in the published work with primary essential CVG that appeared at 30 years of age. Because the patient had no cosmetic or functional complaint, no surgical intervention was attempted. Primary essential CVG, a very uncommon disorder, may be encountered in females after the third decade. The classification of CVG is essential to properly diagnose and treat patients who present with these unusual scalp lesions.

Female↗
PubMed1996

p53 mutations in two patients with intraductal papillary adenoma of the pancreas.

There has been no report on p53 gene mutation in benign human pancreatic intraductal tumors. We examined pancreatic juice and tissue specimens from two patients with intraductal papillary adenoma of the pancreas by polymerase chain reaction-single-strand conformation polymorphism analysis and direct sequencing and found point mutations of p53 gene resulting in amino acid substitutions in exons 6 and 8. Thus, p53 gene mutation may be an early event in the neoplastic process of some pancreatic intraductal tumors and may play an important role in tumorigenesis.

Adenoma↗
PubMed2004

DNA hypermethylation in gastric cancer.

BACKGROUND: Transcriptional silencing of tumour suppressor genes by DNA hypermethylation plays a crucial role in the progression of gastric cancer. Many genes involved in the regulation of cell cycle, tissue invasion, DNA repair and apoptosis have been shown to be inactivated by this type of epigenetic mechanism. RESULTS: Recent studies have demonstrated that DNA hypermethylation begins early in cancer progression, and in some cases, may precede the neoplastic process. Ageing is associated with DNA hypermethylation, and may provide a mechanistic link between ageing and cancer. Several reports have indicated that Epstein-Barr virus-related gastric cancer is associated with a high frequency of DNA hypermethylation, suggesting that viral oncogenesis might involve DNA hypermethylation with inactivation of tumour suppressor genes. Hypermethylation of hMLH1 with the resulting loss of its expression is known to cause microsatellite instability, which reflects genomic instability associated with defective DNA mismatch repair genes in the tumour. CONCLUSIONS: In conclusion, recent studies demonstrate that DNA hypermethylation is a crucial mechanism of inactivation of tumour suppressor genes in gastric cancer. A better understanding of DNA hypermethylation will provide us with new opportunities in the diagnosis and therapy of gastric cancer.

Cadherins↗
PubMed1984

Platelet factor-4 excretion in myeloproliferative disease: implications for the aetiology of myelofibrosis.

Experimental evidence suggests that the fibroblastic proliferation often associated with the myeloproliferative disorders is not part of the neoplastic process, but is secondary to an unknown stimulus. This stimulus may be a factor derived from platelets which promotes the proliferation of fibroblasts in vitro (PDGF). Platelet-derived growth factor is localized to platelet alpha-granules together with PF4 and beta-TG. As an indicator of alpha-granule release, we have measured PF4 levels in plasma, platelets and urine in 46 normal subjects and 49 patients with myeloproliferative disorders, secondary thrombocytosis and miscellaneous malignancies. All 11 patients with elevated urinary PF4 excretion exhibited myelofibrosis, whereas 11 of 22 patients with documented myelofibrosis had urinary PF4 excretion in the normal range. No correlation was seen between marrow fibrosis and plasma levels or the platelet content of PF4. The data are consistent with the possibility that release of mitogen(s) from platelet or megakaryocyte alpha-granules in some patients with myeloproliferative disorders is pathogenetically related to the development of marrow fibrosis.

Blood Platelets↗
PubMed1990

Contrasting patterns of neoplastic cell behaviour in long-term culture of bone marrow from patients with acute leukaemia and myelodysplastic disorders. A survey of responses in 31 cases with cytogenetic determination of neoplastic status of cultured cells in 17 studies.

Alterations in neoplastic cell behaviour responsible for increased production of terminally-differentiated granulocytes during long-term culture of bone marrow in different categories of acute leukaemia and myelodysplasia have been investigated. An increase in neutrophils associated with transition to a morphological picture identical to normal control cultures occurred in 15 of 25 studies on acute leukaemia in contrast to one of six studies on myelodysplastic disorders. An abnormal neoplastic karyotype was employed as a marker for monitoring the course of the neoplastic cell population in 11 studies in which there was progression towards a normal pattern of differentiation. An increase in differentiation was shown by this means to represent increased maturation of cells of the neoplastic process in one study on a myelodysplastic disorder, demonstrating domination of proliferative activity in culture by all of the myelodysplastic disorders examined. Transition towards normal differentiation in nine studies on acute leukaemia, however, correlated with partial or complete replacement of the acute leukaemic cells by normal haemopoietic series in de novo acute leukaemia, and by Ph positive cells in blast crisis of CML. Conversion to morphologically and cytogenetically normal cell populations in five studies on de novo acute leukaemia occurred in four cases which failed to respond to remission-induction therapy, suggesting the selective toxic effect capable of purging acute leukaemic cells from bone marrow operated by a mechanism which lacked cross-resistance to currently-employed cytotoxic agents.

Adult↗
PubMed1993

Detection of clonal platelet antibodies in immunologically-mediated thrombocytopenias: association with circulating clonal/oligoclonal B cells.

Aware that T and B cells in autoimmune thrombocytopenia are abnormal, including the existence of clonal B cell populations, we sought to characterize this clonal phenomenon in various immunological thrombocytopenias using platelet antibody light chain analysis, flow cytometry, Southern blot analysis, and PCR. Using a monoclonal antibody-antigen capture ELISA, we analysed sera from 21 of 26 patients with autoimmune, alloimmune, or drug-induced immunological thrombocytopenia for the light chain phenotypes of their platelet antibodies. Alloantibodies and drug-dependent antibodies from four and 14 patients, respectively, were found that expressed a predominant type of light chain, suggesting that these platelet-reactive antibodies were monoclonal or oligoclonal in nature. 14 of the 26 patients were available for light chain B cell phenotyping studies. Of these 14 patients, thrombocytopenia was due to autoimmunity in two, drug-induced immunity in four, and alloimmunity in eight. We detected clonal populations of B cells in all 14 patients by flow cytometry. Although six of these latter patients possessed platelet antibodies with clonal characteristics, light chain phenotypes of antibodies in five patients were opposite to those of their B cells. Eight of these patients were further examined for immunoglobulin gene rearrangement using Southern and/or polymerase chain reaction analysis. In all eight patients we detected clonal or oligoclonal B cell populations. Only two of these patients had malignancies (chronic lymphocytic leukaemia) that would be expected to have detectable clonal B cells, and thus the mechanism for clonal expansion in the other six patients did not appear to be related to an obvious neoplastic process. Prior to these studies, detection of clonal B cells in thrombocytopenic patients without known malignancies was limited to individuals with autoimmune thrombocytopenia, prompting the speculation that this particular autoimmune disorder arises from B cell dysregulation, rather than from expansion of specific autoantibody producing B cell clones. In contrast, the current studies provide evidence that clonal B cells are common to patients with any form of immunologically-mediated thrombocytopenia. Moreover, the majority of the platelet antibodies (86%) present in these disorders exhibited monoclonal characteristics in that there was an apparent restriction in light chain usage.

Adult↗
PubMed2004

Impaired generation of bone marrow CD34-derived dendritic cells with low peripheral blood subsets in patients with myelodysplastic syndrome.

Myelodysplastic syndrome (MDS) is a stem cell disorder characterized by ineffective haematopoiesis and blood cytopenias. The present study investigated the potential of bone marrow CD34(+) progenitors in MDS patients to proliferate and differentiate into dendritic cells (DCs) in a cytokine-supplemented liquid culture system and analysed the status of blood DC subsets in these patients. CD34(+) progenitors had low potential to generate DCs in vitro, as the number of DCs obtained from one CD34(+) cell was significantly lower compared with controls (median value 0.2 vs. 4, P = 0.003). In patients, the survival and proliferation of CD34(+) cells in culture was not correlated to the degree of apoptosis. Phenotypically and functionally CD34(+)-derived DCs were similar in MDS patients and normal subjects. The percentage of both circulating DC subsets in patients was extremely diminished compared with controls (myeloid DC: 0.10 +/- 0.10% vs. 0.35 +/- 0.13%, P < 0.001; plasmacytoid DC: 0.11 +/- 0.10% vs. 0.37 +/- 0.14%, P < 0.001). In cases with the 5q deletion both CD34-derived DCs and blood DCs harboured the cytogenetic abnormality. Our results indicate that, in MDS, the production of DCs is affected by the neoplastic process resulting in ineffective 'dendritopoiesis' with low blood DC precursor numbers. This quantitative DC defect probably contributes to the poor immune response against infectious agents and to the escape of the malignant clone from immune recognition with disease progression towards acute leukaemia.

Adult↗
PubMed1991

Langerhans-cell histiocytosis--excellent response to etoposide.

We describe an adult with progressive LCH who received oral etoposide as primary treatment. The response is documented and the strategical implications of this drug in Langerhans-cell histiocytosis discussed. Langerhans-cell histiocytosis (LCH) is the term recognized since 1987 for the group of diseases previously designated histiocytosis X. It is not now regarded as a malignant neoplastic process and there is some evidence to suggest that it is due to abnormal immunity, but cytotoxic drugs and steroids are still the mainstay of systemic treatment. Etoposide (VP16) is a semisynthetic epipodophyllotoxin derivative effective in the treatment of malignancies of the monocyte-macrophage lineage and used in resistant or relapsed childhood LCH. There are no previous reports of its use as firstline monotherapy in adults with LCH.

Adult↗
PubMed2004

Ductal carcinoma in situ with spindle cells: a potential diagnostic pitfall in the evaluation of breast lesions.

AIMS: To evaluate the morphological features of 11 cases of breast ductal carcinoma in situ (DCIS) with spindle cells and to propose an approach to distinguish it from benign mimics. The association with neuroendocrine differentiation was also investigated. METHODS: Cases of breast DCIS with a spindle cell component diagnosed in the Department of Pathology, Singapore General Hospital, between June 1996 and January 2003, were included in the study. The histological characteristics were documented, and immunohistochemistry for neuroendocrine markers, hormone receptors, cerbB2, smooth muscle actin (SMA) and high-molecular-weight (HMW) cytokeratins, was carried out. Electron microscopy was carried out on reprocessed paraffin-embedded material in three cases. RESULTS: Of 11 women diagnosed with DCIS with spindle cells, four presented with nipple discharge, six with a breast lump, while one was discovered to have a screen detected density. The tumour size ranged from 3 to 41 mm. The proportion of spindle cells varied from 10% to 80% of the in-situ tumour cell population. Nuclear grade was low in seven cases and intermediate in four. Necrosis was observed in two cases. Architectural pattern was papillary in six cases, and mixed in the rest. Microinvasion was present in two cases, with possible microinvasion in another two. Immunohistochemistry for neuroendocrine markers synaptophysin and chromogranin showed positive reactivity for at least one marker in all but three cases; one of these latter cases demonstrated ultrastructural neurosecretory granules. Oestrogen and progesterone receptors were expressed in 10 and nine cases, respectively, while cerbB2 was positive in only one case. HMW cytokeratin immunoprofile revealed a general lack of immunostaining within the abnormal cell population; likewise, no positivity for SMA of the cellular proliferation was detected. CONCLUSIONS: Almost all DCIS lesions with spindle cells disclose neuroendocrine differentiation. Although the distinction from benign florid usual hyperplasia may pose a diagnostic histological problem, the presence of diffuse neuroendocrine expression, in conjunction with the pattern of HMW keratin profile on immunohistochemistry, supports an in-situ neoplastic process. The absence of SMA immunostaining, in conjunction with negative reactivity for cytokeratins 5/6 and 14, makes the possibility of a myoepithelial proliferation unlikely.

Aged↗
PubMed1978

Cutaneous manifestation of internal malignancies (I). Acanthosis nigricans.

Skin changes may be the first clue to a neoplastic process at a stage when it still is treatable (Such as the development of Acanthosis Nigrican (AN) in an otherwise healthy adult). Ninety percent of the neoplasm responsible for the development of AN originate in the abdomen. The tumor, even in a subclinical state, seems to possess unidentified properties that activate the dermatosis.

Acanthosis Nigricans↗
PubMed1995

Synthetic Tyr-phospho and non-hydrolyzable phosphonopeptides as PTKs and TC-PTP inhibitors.

Tyrosine-specific protein kinases and phosphatases are important signal transducing enzymes in normal cellular growth and differentiation and have been implicated in the etiology of a number of human neoplastic processes. In order to develop agents which inhibits the function of these two classes of enzymes by interfering with the binding of their substrates, we synthesized analogs derived from the peptide EDNEYTA. This sequence reproduces the main autophosphorylation site of Src tyrosine kinases. In this work we report the synthesis, by classical solution methods, of the phosphotyrosyl peptide EDNEYpTA as well as of three analogs in which the phosphotyrosine is replaced by a phosphinotyrosine and by two unnatural, non-hydrolyzable amino acids 4-phosphonomethyl-L-phenylalanine and 4-phosphono-L-phenylalanine. The Src peptide and its derivatives were tested as inhibitors of three non-receptor tyrosine kinases (Lyn, belonging to the Src family, CSK and PTK-IIB) and a non-receptor protein tyrosine phosphatase obtained from human T-cell (TC-PTP). The biomimetic analogues, which do not significantly affect the activity of CSK, PTK-IIB and TC-PTP, act as efficient inhibitors on Lyn, influencing both the exogenous phosphorylation and, especially, its autophosphorylation. In particular, the Pphe derivative may provide a basis for the design of a class of inhibitors specific for Lyn and possibly Src tyrosine kinases, capable of being used in vivo and in vitro conditions.

Enzyme Inhibitors↗
PubMed1987

Fetoacinar pancreatic protein in the developing human pancreas.

The distribution of the 110-kilodalton fetoacinar pancreatic (FAP) protein was examined in 56 pancreases obtained from human embryos and fetuses (ranging 6 from weeks of gestation to full term) and 10 normal adult pancreases. This recently discovered protein is a concanavalin-A-binding glycoprotein that is specific for acinar cells of the pancreas. Using a murine monoclonal antibody for either immunoperoxidase or immunofluorescence procedures, FAP-protein expression was not found in embryos at less than 9 weeks of gestation. At 9-10 weeks, a clear staining was observed in the terminal portions of dilated buds in primitive pancreatic tubular structures (i.e., the site of the first development of the future acinus). At 11-12 weeks, acinar structuration began, and FAP-protein expression increased as shown by the higher number of stained acini and the greater staining intensity. Maximal expression occurred at 15-22 weeks and then gradually decreased; from 28 to 32 weeks until full term, the pancreas was almost negative for this protein. In the adult pancreases, the protein was either absent or only present in acinar cells surrounding the islets of Langerhans. The pancreatic ducts and endocrine cells remained negative throughout gestation and in adults. FAP-protein thus appears to be a marker of acinar-cell differentiation. Its function remains unknown at present. Its close association with the growth and development of the pancreas together with the fact that, in a previous study, it was found to be re-expressed in pancreatitis and in cancer, suggest that it may play a role in developmental regenerative and neoplastic processes in the pancreas.

Adult↗
PubMed1996

Systemic, metastatic, eu- and heterotope tumours of the heart in necropsied dogs.

10,090 dissections of dogs exhibited 2631 neoplastic processes of which 309 involved the heart in the form of eu- and heteropic tumours. The most common primary and/or secondary heart tumour type was hemangiosarcoma (n = 187), followed by paraganglioma (n = 46), carcinoma (n = 33), malignant lymphoma (n = 12), thyroid heart base tumour (n = 9), melanoma (n = 7), mast cell tumour (n = 3) and blastoma (n = 2). The tumour diagnoses were immunohistochemically proved by various antibodies to cytokeratins, vimentin, GFAP, NSE, von Willebrand factor, CD3, CD45RA, S100, thyroglobulin as well as histochemically with argyrophilic, Fontana-Masson and heterochromatic reactions. The odds ratio (OR) for breed and tumour prevalences were determined: German shepherds showed the highest OR for hemangiosarcomas and boxers for paragangliomas.

Animals↗
PubMed1997

Intestinal-type tumour in resected gastric remnant cancer.

Lauren's intestinal type of gastric cancer was proposed to be dependent on long-term environmental factors and is always preceded by chronic premalignant change. A cohort study was performed and demonstrated an increased cancer risk of gastric remnant after gastric surgery for benign disease. It is generally believed that after gastrectomy the residual stomach has an environmental change and, thus, enters a neoplastic process. Based on the carcinogenic theory of intestinal-type tumour, it would be of interest to know whether the intestinal-type tumour is more common in gastric remnant cancer. Forty patients with gastric remnant cancer had gastrectomy in the Veterans General Hospital-Taipei. Another 683 patients with primary gastric carcinoma underwent resection and were used as controls. The clinical characteristics, tumour stage and intestinal-type tumour were analysed in gastric remnant cancer and were compared with the various portions of primary gastric carcinoma. Although the overall distribution of intestinal-type carcinoma in gastric remnant (45%) was no different to that of any other portion of stomach cancer, intestinal-type carcinoma was more common in the early stage of gastric remnant (73%) and distal stomach (73%), but not in the proximal stomach (50%), which was supposed to have the same characteristics as the gastric remnant because of identical anatomic location. More than expected, intestinal-type carcinoma in early gastric remnant cancer together with a long incubation interval between primary surgery and later tumour occurrence were compatible with the theory of carcinogenesis of intestinal-type carcinoma.

Adenocarcinoma↗
PubMed1989

Myoid cells in the human thymus and thymoma revealed by three different immunohistochemical markers for striated muscle.

Specimens of human thymus and thymoma obtained from 81 patients including 22 with myasthenia gravis (MG), ranging in age from 10 weeks of gestation to 75 years were examine by the indirect immunoperoxidase technique using three different striated muscle markers: myoglobin, CPK-mm and beta-enolase. Myoid cells ovoid or elongated in shape were distributed in the medulla and showed positive immunoreactions for myoglobin, CPK-mm and beta-enolase by light and electron microscopy. The antigens were first detectable immunohistochemically in the fetus at the 10th week of gestation and showed a relative increase in number and varying distribution patterns with age involution in non-myasthenic thymuses. In MG cases, the number of myoid cells was smaller than in non-myasthenic cases, especially in markedly involuted thymuses. Myoid cells were occasionally observed within thymomas in areas showing medullary differentiation. Small numbers of cells showing a positive immunoreaction for beta-enolase but not for myoglobin and CPK-mm were scattered in the area predominantly composed of epithelial cells. These cells were occasionally positive for keratin and showed desmosome-like structures but no apparent myofilaments, suggesting that muscle-like differentiation of epithelial cells might occur in the neoplastic process of thymoma.

Adolescent↗