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Glypican 3: a novel marker in testicular germ cell tumors.

Glypican 3 (GPC3), a membrane-bound heparin sulfate proteoglycan, may play a role in promoting embryonic cell growth and differentiation. GPC3 is mutated in Simpson-Golabi-Behmel syndrome, characterized by tissue overgrowth and an increased risk of embryonal malignancies. Recently, GPC3 was reported to be one of the over-expressed genes in testicular yolk sac tumors by gene expression microarray analysis. However, the presence of the GPC3 protein in germ cell tumors has never been investigated. The purpose of the study was to investigate the GPC3 expression in various histologic components of testicular germ cell tumors using immunohistochemistry and to assess its possible utility as a diagnostic marker. Tumors from 71 patients were examined, including components of 42 seminomas, 37 embryonal carcinomas, 24 yolk sac tumors, 20 teratomas with mature elements, 16 teratomas with immature elements, and 7 choriocarcinomas. Cytoplasmic and membranous immunoreactivity was semiquantitatively evaluated. All yolk sac tumor (24/24) and choriocarcinoma (7/7) components were immunoreactive for GPC3, whereas only 38% of teratomas with immature elements and 8% of embryonal carcinomas expressed GPC3. There was no immunoreactivity in benign testicular tissue, intratubular germ cell neoplasia, seminomas (0/42), or teratomas with mature elements (0/20). We conclude that the oncofetal protein GPC3 is a novel immunohistochemical marker in testicular germ cell tumors with differential expression in defined histologic subtypes. Our findings suggest a possible role of GPC3 in tumor cell differentiation. Furthermore, GPC immunostaining may be useful in the pathologic diagnosis of nonseminomatous germ cell tumors, particularly yolk sac tumor, and choriocarcinoma.

Adolescent↗

Magnetic resonance spectroscopic study of Alzheimer's disease and frontotemporal dementia/Pick complex.

Disease-specific metabolic changes in Alzheimer's disease and frontotemporal dementia/Pick complex were examined by proton magnetic resonance spectroscopy at 3.0 T. Spectra were acquired from posterior and anterior cingulate cortices and the parieto-occipital and frontal white matter. This study included eight Alzheimer's disease patients, 10 frontotemporal dementia/Pick complex patients and 14 healthy volunteers. N-acetylaspartate/creatine+phosphocreatine ratio was reduced in the posterior cingulate cortex in the Alzheimer's disease and frontotemporal dementia/Pick complex patients. The Alzheimer's disease patients, however, showed a posterior dominant decrease, whereas the frontotemporal dementia/Pick complex patients showed a frontal predominant decrease. These different distributions of metabolic changes may represent the underlying pathological processes in each disease. Our standardized protocol of proton magnetic resonance spectroscopy measurement may be helpful in differentiating these dementia subtypes.

Aged↗

Mucin antigens expression and Ki-67 labeling in breast cancer: the peculiarity in scirrhous carcinoma.

The expression of mucin-related antigens (Tn, T, Sialosyl-Tn [STn], DF3 [mammary-type apomucin related antigen], and intestinal-MRP [intestinal-type apomucin related antigen]) as well as Ki-67 labeling was examined in 58 mammary invasive ductal carcinomas (IDC) divided into 26 scirrhous subtype (SC) and 32 non-scirrhous subtype comprising papillotubular carcinoma and solid-tubular carcinoma (PT-ST). These data were analyzed in connection with the various pathological prognostic factors such as nodal status, tumor size, estrogen receptor status and histological grading of carcinomas. The results were as follows: (a) in SC, the expression rate of Tn was significantly higher in the cases with positive lymph node metastasis or with large tumor size (> 2 cm) than in those with negative lymph node metastasis or with small tumor size (< or = 2 cm); (b) in PT-ST, the expression rate of STn was higher in the cases with positive lymph node metastasis or with large tumor size than in those with negative lymph node metastasis or with small tumor size; (c) in SC, Ki-67 labeling was significantly higher in the cases with positive lymph node metastasis than in those with negative lymph node metastasis; and (d) in PT-ST, Ki-67 labeling was lower in the cases with positive lymph node metastasis than in those with negative lymph node metastasis. In conclusion, Tn antigen expression was correlated with pathological prognostic factors in SC but not in PT-ST, whereas STn antigen expression was correlated with pathological prognostic factors in PT-ST but not in SC.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma, Scirrhous↗

Cheilitis glandularis in an African-American woman: response to antibiotic therapy.

A 52-year-old black woman presented with a 2-day history of lower lip swelling 5 days after starting a new medication, lisinopril. She had never experienced similar episodes in the past. She denied shortness of breath, tightening of the throat, swelling of the tongue, generalized cutaneous eruption, urticaria, or pruritus. She also denied symptoms consistent with facial paresis. Her past medical history was significant for hepatitis C infection, coronary artery disease, and hypertriglyceridemia. She had a 15 pack-year smoking history and denied both alcohol and drug abuse. She had never received a blood transfusion and was HIV negative. Physical examination disclosed a tender, swollen, and erythematous lower lip with induration, oozing, and crusting (Figure 1). Pinpoint openings evident throughout the lip surface exuded a clear, sticky, mucoid secretion. Tongue, parotid glands, and regional lymph nodes were normal. The working diagnosis was angioedema secondary to lisinopril. The presumptive offending drug was discontinued, and conservative therapy (topical clobetasol ointment, oral ranitidine, and oral fexofenadine) was initiated. Despite treatment, signs and symptoms persisted unabated. One week after initial presentation, a punch biopsy of her lower lip was taken to rule out granulomatous cheilitis and sarcoidosis. Histopathology included diffuse lymphohistiocytic infiltrate, minimal microabscess formation, and notable absence of granulomata. There was neither hypertrophy nor detectable abnormality of the salivary glands, with the exception of infiltrating mononuclear cells. Based on the clinical history and compatible pathologic findings, a diagnosis of cheilitis glandularis was made. Specifically, crusting and erosion clinically suggested a diagnosis of the superficial suppurative subtype of cheilitis glandularis. The patient received oral penicillin (dicloxacillin, 1.0 g/d) combined with oral fluoroquinolone (ciprofloxacin, 1.0 g/d). Within 2 weeks of starting the antibiotics, the lip swelling significantly decreased (Figure 2) and the patient was left with a mildly indurated nodule at the labial commissure. Following a 4-week course of continued antibiotic treatment, the lip returned to near baseline state. At both 6-month and 1-year follow-up visits, the lip remained normal.

Angiotensin-Converting Enzyme Inhibitors↗

Classification of breast cancer using genetic algorithms and tissue microarrays.

PURPOSE: A multitude of breast cancer mRNA profiling studies has stratified breast cancer and defined gene sets that correlate with outcome. However, the number of genes used to predict patient outcome or define tumor subtypes by RNA expression studies is variable, nonoverlapping, and generally requires specialized technologies that are beyond those used in the routine pathology laboratory. It would be ideal if the familiarity and streamlined nature of immunohistochemistry could be combined with the rigorously quantitative and highly specific properties of nucleic acid-based analysis to predict patient outcome. EXPERIMENTAL DESIGN: We have used AQUA-based objective quantitative analysis of tissue microarrays toward the goal of discovery of a minimal number of markers with maximal prognostic or predictive value that can be applied to the conventional formalin-fixed, paraffin-embedded tissue section. RESULTS: The minimal discovered multiplexed set of tissue biomarkers was GATA3, NAT1, and estrogen receptor. Genetic algorithms were then applied after division of our cohort into a training set of 223 breast cancer patients to discover a prospectively applicable solution that can define a subset of patients with 5-year survival of 96%. This algorithm was then validated on an internal validation set (n=223, 5-year survival=95.8%) and further validated on an independent cohort from Sweden, which showed 5-year survival of 92.7% (n=149). CONCLUSIONS: With further validation, this test has both the familiarity and specificity for widespread use in management of breast cancer. More generally, this work illustrates the potential for multiplexed biomarker discovery on the tissue microarray platform.

Algorithms↗

Human B cell lymphomas: in vitro and in vivo studies on growth factors and cell growth.

The B cell non-Hodgkin's lymphomas (NHL-B) are a common, but heterogeneous group of human lymphoid neoplasms, consisting of monoclonal populations of neoplastic B lymphocytes demonstrating non-random chromosomal abnormalities, often associated with proto-oncogene translocations. Clinically and pathologically, these lymphomas are classified as low, intermediate, or high grade, according to the clinical aggressiveness of the NHL-B subtype. The clinical behavior can also be correlated with biological function regarding proliferative capabilities of the tumor cells. Our studies have shown that the low grade B cell lymphomas have low constitutive proliferative capacity in vitro and do not respond to cytokine growth factors (CGF), while the high grade NHL-B respond to the B cell growth factor (BCGF) family of CGFs. The high grade NHL-B also secrete BCGFs both in vitro and in vivo, as autocrine growth factors that may provide a target for new therapeutic approaches to therapy.

Animals↗

Endothelial and myocyte apoptosis--role of angiotensin II.

Recent studies have assessed the role of angiotensin II in apoptosis and the effects of the angiotensin II type 1 (AT1) and type 2 (AT2) receptor subtypes. A complex picture is emerging with cell-specific effects of AT1 and AT2 receptors, and differential effects dependent on pathology. In vitro studies have shown that angiotensin II mediated apoptosis in myocytes and endothelium. More recent in vivo studies have shown the prevention and regression of vascular lesions by apoptosis induction with medications (including AT1 receptor inhibitor).

Angiotensin II↗

Trends in breast cancer at a county hospital.

Breast cancer mortality has changed dramatically with improvements in screening techniques. Mammography is essential for early detection; however, its contribution to the survival benefit in young women is questionable. We report our experience in breast biopsies at a county teaching hospital with a traditionally younger patient population. Institutional review board approval was obtained prior to data collection. A total of 550 breast biopsies were conducted between 1995 and 2000. Data regarding age, method of breast biopsy, and pathology was reviewed. One hundred twenty of 550 patients (21.8%) had breast carcinoma detected on breast biopsies with the predominant histologic subtype being invasive ductal carcinoma. The mean age of patients with carcinoma was 52.8 years, whereas that of patients with benign breast disease was 43.6 years (P < 0.05). Forty-three per cent of all breast cancers occurred in women under the age of 50 years. During the study period, there was neither an increase in the number of breast biopsies performed per year nor a decrease in the average age of women with breast cancer. However, observing a significant percentage of breast cancer patients under 50 years old, our data suggest the importance of strict adherence to current screening recommendations including self-breast examination and yearly mammography.

Adolescent↗

[Clinical study of acute low-tone sensorineural hearing loss].

OBJECTIVE: To explore the etiology, clinical aspects, diagnosis and therapeutic strategies of acute low-tone sensorineural hearing loss (ALHL). METHODS: Thirty patients (31 ears) with ALHL were selected for this study. Detailed history collection, otological examination and systematic audiological evaluations were conducted. The hearing tests included pure tone audiometry, acoustic immittance, auditory brainstem response (ABR) and otoacoustic emissions (OAE). All cases received therapeutic trial of corticosteroid for 15 days with 6 to 14 months' following-up. RESULTS: ALHL mainly affected young people. Low-tone tinnitus, a sensation of ear fullness and hearing impairment were the frequent complains. Otological examinations showed normal results. Mild to moderate sensorineural hearing loss at low frequencies and type "A" tympanograms were found in all patients. Acoustic stapedial reflexes were elicited in 26 of 31 affected ears, and 14 of them had positive results on the Metz test. ABR responses were normal in all 20 tested ears. In 14 out of 20 ears, TEOAEs were absent and DPOAE grams at low frequencies (0.5, 0.75 kHz) were abnormal on the first visit. After steroid therapy, 24 ears demonstrated complete recovery, but 4 ears showed partial recovery and 3 ears unchanged. The total improvement rate was 90.3%. CONCLUSIONS: ALHL patients are clinically characterized by low-tone tinnitus, aural fullness and hearing loss, which mainly involved unilateral ear. Audiological findings indicate a cochlear impairment, which only invades low frequency region. The basic pathological feature may be endolymphatic hydrops involves immune response. Conflicting data exist on whether ALHL is an independent disorder or a subtype of Meniere's disease. Ideal therapeutic strategy has not been established by now and corticosteroid is probably an effective agent.

Acute Disease↗

Expression of class II major histocompatibility complex antigens (HLA-DR) and lymphocyte subset immunotyping in chronic pulmonary transplant rejection.

OBJECTIVE: Currently, the bronchiolitis obliterans syndrome (BOS) of chronic airway rejection represents the most significant obstacle to the long-term function of isolated pulmonary allografts in humans. Between 20% and 30% of recipients are affected by this condition. To define the possible pathogenetic role of altered expression of class II major histocompatibility complex antigens (ie, HLA-DR) in BOS, the authors studied well-characterized examples of this process immunohistologically. DESIGN: Eleven BOS specimens were compared with seven controls, represented by allografts with no pathologic abnormalities taken from patients with normal posttransplant respiratory function, as well as 14 biopsies showing acute rejection. In addition, immunophenotypic subtyping of lymphocytes in all specimens was undertaken. RESULTS: Control tissues exhibited variable but weak expression of HLA-DR in bronchiolar epithelium and alveolar pneumocytes. In comparison, immunostaining for class II major histocompatibility complex antigens in BOS showed no statistically significant differences, whereas the 14 examples of acute rejection manifested intense HLA-DR expression in epithelia and endothelial cells. The numbers of intrabronchiolar and peribronchiolar lymphocytes were clearly higher in both acute rejection and BOS than in controls, but these cells differed in lineage in the two rejection states. Acute rejection showed an obvious preponderance of CD43-positive T lymphocytes, whereas lymphoid cells in BOS were a relatively equal mixture of CD20-positive B cells and CD43-positive T cells. Moreover, incipient peribronchiolar B-cell follicles were observed in BOS. Natural killer (CD57-positive) lymphocytes were rare in all specimens. CONCLUSIONS: These data suggest that alterations in HLA-DR expression probably do not play a central role in the genesis of BOS, as they do in acute rejection. In contrast, the results of lymphocyte immunophenotyping and correlative histologic findings in BOS suggest that both T cells and B lymphocytes may be involved in the mechanism of chronic airway rejection.

Adult↗

Myelodysplastic syndrome. A clinical and pathological analysis of 88 patients.

Eighty eight patients with myelodysplastic syndromes were studied to determine the clinical and pathological features and the prognosis. All the patients had anemia. Neutropenia was seen in 44% and thrombocytopenia in 78% patients. The subtypes included refractory anemia in six, refractory anemia with ringed sideroblasts in three, refractory anemia with excess blasts in 30, refractory anemia with excess blasts in transformation in 32 and chronic myelomonocytic anemia in 17 patients. Forty four patients who received chemotherapy were evaluable for response. Three of the 15 patients treated with hydroxyurea achieved partial remission. Eighteen patients were treated with low dose cytosine arabinoside and complete remission was achieved in five and partial response in six patients. Aggressive chemotherapy was given to 11 patients at the onset of the illness resulting in complete remission in six and partial response in two patients. Nineteen of the 88 patients transformed to acute myeloid leukemia. The crude survival of all the patients ranged from 15 days to 22.5 months. The mortality was due to hemorrhage in 15% and septicemia in 85%. Our data reveals ineffectiveness of the current therapy and emphasizes on the need to develop newer therapeutic approaches.

Adolescent↗

Pathology of esophageal cancers: local experience and current insights.

Esophageal cancer is very popular in Hong Kong. The tumor is often prevalent in males and has a modal peak of occurrence in the 7th decade. The pathogenesis of the esophageal neoplasm is still uncertain but likely to be multi-factorial. The commonest histological subtype is squamous cell carcinoma. Besides, mucoepidermoid carcinoma/adenosquamous carcinoma, adenocarcinoma, small cell carcinoma, sarcomatoid carcinoma, adenoid cystic carcinoma, undifferentiated carcinoma, melanoma and gastrointestinal autonomic nerve tumor are also found in a minority of patients. The proportion of various histologic subtypes is different from the Western populations. Concerning the genetic alternation, P53 mutation is common in esophageal squamous cell carcinoma. Esophageal cancer has its unique pattern of P53 mutations in Hong Kong. In addition, intramural metastasis and multiple lesions are characteristic features in esophageal squamous cell carcinoma. Important pathologic factors in determining the prognosis of patients with esophageal cancer includes completeness of surgical resection, stages, tumor dimension as well as MIB-1 scores and the presence of P53 mutations.

Carcinoma, Adenosquamous↗

A comparative study of three methods for the visualization of von Willebrand factor (vWF) multimers.

This study was performed to compare three visualization methods for the detection of vWF multimers: autoradiography (125I), electroblot with a horseradish peroxidase system (BLOT-HRP), and an avidin-biotin peroxidase system (AV-BIO). Each method was evaluated according to: 1) ability to visually detect bands and subbands thereby identifying von Willebrand's disease (vWD) subtypes and normals, 2) reagent availability, 3) cost, and 4) time requirements. Additionally, resolvability was evaluated utilizing low, intermediate, and high resolution gels prepared with both low and high gelling temperature agaroses with subsequent visualization by the three detecting systems. With intermediate resolution gels, our results showed that all three visualization methods could discern pathologic patterns from normal. In addition, the avidin-biotin peroxidase system demonstrated the best band discreteness with low resolution gels used to detect unusually high molecular weight multimers. With high resolution gels used for subtyping type II vWD, we found the internal band structure was best demonstrated using LGT agarose and the electroblot horseradish peroxidase system.

Autoradiography↗

Residual or recurrent chest mass in pediatric Hodgkin's disease. A surgical problem?

Controversy surrounds the management of a residual chest mass in patients treated for Hodgkin's disease. Between 1971 and 1985, we treated 22 children, aged 7-18 years, with pathologically proven Hodgkin's disease. Nine had radiographic evidence of mediastinal and/or pulmonary involvement. Following treatment, a residual or new chest mass occurred in three patients, prompting surgical exploration. No histologic subtype of Hodgkin's disease predominated in this group. Two patients had received radiotherapy and chemotherapy, and one had received chemotherapy alone. The erythrocyte sedimentation rate (ESR), uniformly elevated at diagnosis, was normal prior to surgery in all three patients. Gallium scans, also uniformly positive at diagnosis, were negative in two patients but positive in a third, suggesting possible relapse. At operation, however, no patient had recurrent Hodgkin's disease. Pathologic findings were thymic fibrosis, mediastinal pseudocyst, and normal thymus, respectively. We conclude that a chest mass following treatment for Hodgkin's disease may be benign, particularly if disease markers such as ESR have normalized. Moreover, a positive gallium scan does not necessarily indicate recurrent Hodgkin's disease. Although surgical exploration is a prudent policy when there is persistent evidence of residual or recurrent chest mass, our experience suggests that immediate exploration is not mandatory and may be deferred for a period of close continued observation.

Adolescent↗

Alpha 1-adrenergic receptor regulation: basic science and clinical implications.

Adrenergic receptors (ARs) are members of the G-protein-coupled receptor family, which includes alpha 1ARs, alpha 2ARs, beta 1ARs, beta 2ARs, beta 3ARs, adenosine, muscarinic, angiotensin, endothelin receptors, and many others that are responsible for a large variety of physiologic effects through G-protein coupling. This review focuses on alpha 1ARs and their regulation at both the mRNA and protein levels. Currently, three alpha 1AR subtypes have been characterized both pharmacologically and at the gene level: alpha 1aAR, alpha 1bAR, and alpha 1dAR. These are expressed in a species- and tissue-dependent manner. Mutagenesis approaches have been extremely valuable in the identification of key residues that govern alpha 1AR ligand binding and signaling. These studies reveal that alpha 1ARs have evolved an exquisitely sensitive regulation of their activity in which any disruption of the native structure has profound effects on subsequent function and effector coupling. Significant advances have also been made in the elucidation of signaling pathway components, resulting in the identification of novel pathways that can lead to pathologic conditions. Specific topics include mitogen-activated protein kinase, phosphatidylinositol 3-kinase, and G-protein-coupled receptor cross-talk pathways. Within this context, recent studies identifying underlying transcriptional mechanisms involved in the regulation of the alpha 1AR subtypes are also discussed. Finally, given the potentially important role of alpha 1ARs in the vasculature, as well as in the pathology of many diseases, such as myocardial hypertrophy and benign prostatic hyperplasia, the clinical relevance of alpha 1AR distribution, pharmacology, and therapeutic intervention is reviewed.

Cardiomyopathy, Hypertrophic↗

New subtype of salmonid alphavirus (SAV), Togaviridae, from Atlantic salmon Salmo salar and rainbow trout Oncorhynchus mykiss in Norway.

In Europe, 2 closely related alphaviruses (Togaviridae) are regarded as the causative agents of sleeping disease (SD) and salmon pancreas disease (SPD): SD virus (SDV) has been isolated from rainbow trout Oncorhynchus mykiss in France and the UK, while SPD virus (SPDV) has been isolated from salmon Salmo salar in Ireland and the UK. Farmed salmonids in western Norway also suffer from a disease called pancreas disease (PD), and this disease is also believed to be caused by an alphavirus. However, this virus has not yet been characterised at the molecular level. We have cultured a Norwegian salmonid alphavirus from moribund fishes diagnosed with cardiac myopathy syndrome (CMS) and fishes diagnosed with PD. The virus has also been found in salmon suffering from haemorrhagic smolt syndrome in the fresh water phase. The genomic organisation of the Norwegian salmonid alphavirus is identical to that in SPDV and SDV, and the nucleotide sequence similarity to the other 2 alphaviruses is 91.6 and 92.9%, respectively. Based on the pathological changes, host species and the nucleotide sequence, we suggest naming this virus Norwegian salmonid alphavirus (NSAV). Together with SPDV and SDV it constitutes a third subtype of salmonid alphavirus (SAV) species within the genus Alphavirus, family Togaviridae.

Alphavirus↗

A thyroidectomy case with a surprising pathologic result: three different birds in one nest.

Neoplasms of the thyroid include types that range from indolent, localized papillary carcinomas to lethal anaplastic disease. Hurthle cell neoplasm is a histopathologic subtype that signals poor prognosis. Herein, we present the case of a 72-year-old female patient with multinodular goiter who, although fine needle aspiration biopsy revealed a benign result, underwent thyroid surgery because of the diameter of the largest nodule. Histopathologically, the neoplasm was diagnosed as papillary thyroid microcarcinoma on one lobe and Hurthle cell neoplasm on the other, whereas the remainder of the thyroid showed a typical pattern of colloidal goiter, all of which are not commonly encountered in one patient. Although multinodular goiter is usually acknowledged as a sign of a benign process, its risk of malignancy is no less than that of a solitary thyroid nodule. The age of the patient, the duration of the disease, or the number of the nodules should not mislead the physician, nor affect the therapeutic approach.

Adenocarcinoma, Papillary↗