Metastatic carcinoid presenting as a breast lesion.

Metastasis to the breast is a rare occurrence, constituting fewer than 2% of all breast tumours. Of all metastatic tumours in the breast, most arise from contralateral breast primaries. Other reported primary solid tumour sites include melanoma; lung, gastric, and renal cancers; and approximately 29 cases of carcinoid tumour.Ambiguous presentations and an absence of carcinoid syndrome features make accurate radiographic and histologic assessment of breast carcinoids challenging. Here, we report the case of a 52-year-old woman who presented with a mammographic abnormality in the left breast. Excisional biopsy revealed histopathology consistent with carcinoid. After an exhaustive work-up, carcinoid within the terminal ileum was ultimately identified, and the woman was diagnosed with metastatic breast carcinoid, an exceedingly rare entity. This paper describes the common mammographic, cytologic, and immunohistochemical features typical of metastatic breast carcinoid tumours, together with their common clinical features, prognosis, and treatment options.

Extraskeletal myxoid chondrosarcoma of the heart and review of current literature.

Extraskeletal myxoid chondrosarcoma (EMS) is a rare oncologic phenomenon characterized by chondroid and neurogenic differentiation in extraskeletal locations. These tumours represent fewer than 2.5% of all soft-tissue sarcomas and are most commonly found in the lower extremities, limb girdles, distal extremities, and trunk. Their presence in cardiac tissue is exceedingly unusual; just a single case of ems metastatic to the heart has been reported, and no cases of primary cardiac EMS are known.Here, we report the case of a 26-year-old man who presented to his physician with a chest wall mass. Further evaluation led to the discovery of a large intracardiac mass with multiple end-organ growths. Complete work-up of this patient included cardiac biopsy, echocardiography, magnetic resonance imaging, positron-emission tomography, computed tomography, and fluorescence in situ hybridization studies for the translocation involving the EWSR1 gene locus (22q12). Results of the foregoing studies confirmed the diagnosis of ems, but the origin of this patient's tumours remains elusive and the contention between a primary cardiac source and cardiac metastasis has yet to be resolved.This article describes the histopathology, immunohistochemistry, and chromosomal aberrations common to ems, together with the common presenting features, natural history, and prognosis.

Identification of the aromatase inhibitor letrozole in urine by gas chromatography/mass spectrometry.

Letrozole (1-(bis-(4-cyanophenyl)methyl)-1,2,4-triazole) is used therapeutically as a non-steroidal aromatase inhibitor (Femara) to treat hormone-sensitive breast cancer in postmenopausal women. For doping purposes it may be used to counteract the adverse effects of an extensive abuse of anabolic androgenic steroids (gynaecomastia) and to increase the testosterone concentration by stimulation of the testosterone biosynthesis. The use of aromatase inhibitors has been prohibited by IOC/WADA regulations for male and female athletes since September 2001 and January 2005, respectively. Spot urine samples from women suffering from metastatic breast cancer and being treated with letrozole were collected and analysed to develop/optimise the detection system for metabolites of letrozole to allow the identification of athletes who do not comply with the internationally prohibited use of this cancer drug. The assay was based on gas chromatography/mass spectrometry (GC/MS) and the main metabolite of letrozole (bis-4-cyanophenylmethanol) was identified by comparison of its mass spectrum and retention time with that of a bis-4-cyanophenylmethanol reference. The full-scan spectrum, diagnostic ions and a validation of the method for the analysis of bis-4-cyanophenylmethanol are presented.

Identification of the aromatase inhibitor aminoglutethimide in urine by gas chromatography/mass spectrometry.

Aminoglutethimide is used therapeutically as an aromatase inhibitor in the treatment of metastatic breast cancer in post-menopausal women. For doping purposes, aminoglutethimide may be used for treatment of adverse effects of an extensive abuse of anabolic androgenic steroids (gynaecomastia) and to increase the testosterone concentration and stimulation of testosterone biosynthesis. The use of aromatase inhibitors has been prohibited for male athletes since September 1, 2001. The purpose of this study was to develop methods for the identification of the parent compound or its main metabolite and the inclusion of this information into established screening procedures in doping analysis. An excretion study was conducted using oral application of one single therapeutic dose (500 mg) of Orimeten. The analysis was performed by gas chromatography/mass spectrometry (GC/MS). Aminoglutethimide is excreted almost totally as unconjugated parent compound and is detectable by different screening procedures for up to 165 h. Most suitable for the detection of aminoglutethimide is the screening procedure for heavy volatile nitrogen-containing drugs ('Screening 2'). However, since only competition samples are analysed in that screening procedure, the additional inclusion of aminoglutethimide in the screening procedure for anabolic androgenic agents ('Screening 4') is recommended. Full mass spectra and diagnostic ions for the analysis of aminoglutethimide are presented.

[The fetlock tunnel syndrome in horses: literature review and retrospective study]. / Das Fesseltunnelsyndrom beim Pferd: Literaturübersicht und retrospektive Untersuchung.

The annular ligament constriction is characterized by a disproportion between the available space and the contents within the fetlock tunnel. The main symptoms are a persisting lameness, distention of the tendon sheath, a typical "notch" when the fetlock is viewed from the side and a hyperflexion pain in the fetlock. The surgical treatment consists of the transection of the fetlock annular ligament. The conservative management can be considered as a independent therapy or as a preparation for a subsequent desmotomy. The medical records of 75 horses suffering from fetlock tunnel syndrome presented at the Veterinary Surgery Clinic of the University of Zurich were studied. 39 horses with 41 affected limbs were reexamined clinically and ultrasonographically. 70% of the surgical cases and 82% of the conservatively treated cases were judged to be sound. Altogether it can be said that the surgical case group had a success rate of 62% while the conservatively treated group showed a success rate of 58%.

Characterization of N-glycans from mouse brain neural cell adhesion molecule.

The N-glycosylation pattern of the neural cell adhesion molecule (NCAM), isolated from brains of newborn mice, has been analyzed. Following digestion with trypsin, generated glycopeptides were fractionated by serial immunoaffinity chromatography using immobilized monoclonal antibodies specifically recognizing polysialic acid (PSA) units or the HNK1-carbohydrate epitope. Subsequent analyses of the resulting (glyco)peptides by Edman degradation and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) revealed polysialylated glycans to be exclusively linked to glycosylation sites 5 (Asn(431)) and 6 (Asn(460)), whereas glycans carrying the HNK1-epitope could be assigned to sites 2 (Asn(297)), 5, 6, and, to a lesser extent, site 3 (Asn(329)). PSA-, HNK1-, and non-PSA/HNK1-glycan fractions were characterized by carbohydrate constituent and methylation analyses as well as MALDI-TOF-MS in conjunction with chromatographic fractionation techniques. The results revealed that the core structures of PSA-glycans represented predominantly fucosylated, partially sulfated 2,6-branched isomers of triantennary as well as tetraantennary complex-type glycans, whereas carbohydrate chains bearing the HNK1-epitope were dominated by diantennary species carrying in part bisecting GlcNAc residues. Non-PSA/HNK1-glycans exhibited a highly heterogeneous pattern of partially truncated, mostly diantennary structures being characterized by the presence of additional fucose, bisecting GlcNAc and/or sulfate residues. In conclusion, our results revealed that the glycosylation pattern of murine NCAM displays high structural and regional selectivity, which might play an important role in controlling the biological activities of this molecule.

Strangulation of the duodenum by the uterus during late pregnancy in two cows.

Two Swiss Braunvieh cows in late pregnancy underwent surgery because of a rare form of ileus due to strangulation of the duodenum at its caudal flexure by the gravid uterus. The whole uterus had passed through a gap between the mesoduodenum and duodenum and with increasing weight had led to strangulation of the duodenum. This was possible since the mesoduodenum and both walls of the greater omentum adjacent to its caudal edge were not connected with the duodenum, probably due to a congenital inhibitory malformation. A transsection and an end-to-end anastomosis of the duodenum were necessary in both cases since it was impossible to retract the gravid uterus through the defect. Postoperative recovering was uneventful in both cows, which were discharged after seven and five days respectively and calved normally about two months later.

Cardiovascular effects of buccal exposure to dermal nicotine patches in the dog: a comparative evaluation.

OBJECTIVE: Safety concerns have been raised over the possible effects of inappropriate exposure to transdermal nicotine patches. This study was initiated to determine whether placement of these products into the mouth could affect cardiovascular function. METHODS: In a series of 10 anesthetized beagle dogs, Nicoderm, Habitrol, ProStep I (Intact), ProStep D (Damaged) transdermal nicotine products or the Skoal Bandit smokeless tobacco plug were placed in the buccal cavity for 5 minutes. Systemic arterial blood pressure and the electrocardiogram were monitored for up to 90 minutes after exposure with blood samples at intervals during the first 10 minutes for plasma nicotine concentration. RESULTS: The systolic and diastolic arterial blood pressures and heart rate increased within 2 minutes of buccal exposure to either the intact or the damaged ProStep nicotine product. Ventricular arrhythmias were observed in 6 of 10 dogs exposed to the intact patch and 7 of 10 dogs exposed to the damaged patch during the period of maximal cardiovascular response. Modest increases in systemic blood pressure and heart rate were seen with the Nicoderm and Habitrol products but not with the Skoal Bandit. The increases in systemic arterial pressure and heart rate occurring after exposure to ProStep were significantly more severe than those observed after Nicoderm and Habitrol. Mean peak nicotine levels of 9.8 microg/mL (ProStep 1), 5.4 microg/mL (ProStep D), 3.4 microg/mL (Habitrol), 2.5 microg/mL (Nicoderm), and 0.12 microg/mL (Skoal Bandit) were detected within 2 to 10 minutes after buccal placement of the product. CONCLUSIONS: Certain transdermal nicotine patches, when applied to a nondermal site such as the buccal cavity for a short period (5 minutes) can rapidly provoke significant cardiovascular alterations (hypertension, tachycardia, and ventricular arrhythmias). The magnitude of the cardiovascular responses occurring after buccal exposure to a product such as ProStep could pose a risk to susceptible individuals.

Regulatory science: a special update from the United States Food and Drug Administration: Preclinical issues and status of investigation of botanical drug products in the United States.

A recent survey was conducted across the therapeutic divisions within the CDER, U.S. FDA regarding the number of submissions related to botanical drug products over the past ten years. The overall number of botanical submissions as expressed in the parenthesis are as follows: 1990 (1), 1991 (4), 1992 (4), 1993 (5), 1994 (6), 1995 (5), 1996 (13), 1997 (16), 1998 (10). In the total of 64 counted, 50 of them are submitted in original IND and the rest (14) in pre-IND format. The therapeutic categories are focused on dermatological and topical (19), anti AIDS/antiviral (12), oncologic (13), neuropharmacologic (8), endocrine and metabolic (3), urologic (2), tobacco (2), and cardio-renal products (1). The regulatory actions taken on these submissions showed that 68% of them are evaluated as safe to proceed for the human trials, while the rest (32%) of submissions required agency's regulatory guidance. Among the submissions that required further guidance, 81% were deficient in preclinical pharmacology/toxicology information and the rest (19%) lacks information in other areas (chemistry, clinical protocols). Following agency's guidance, 93% of the submissions that were put on hold were allowed to proceed. In summary, a total of 94% of all the botanical INDs submitted to the agency were allowed to proceed without additional animal toxicity studies conducted. In conclusion, this survey indicates that the growing public interest in botanical supplements has prompted more formal evaluation of the efficacy/safety claims of these products.

Long-term detection of clenbuterol in human scalp hair by gas chromatography-high-resolution mass spectrometry.

A method for the detection of clenbuterol in human scalp hair by gas chromatography-high-resolution mass spectrometry (GC-HRMS) is described. The sample preparation involved chemical digestion of the protein structure, which was achieved by incubating the hair with 1 M KOH at 70 degrees C. A single extraction step with tert.-butyl methyl ether provided approximately 90% of the analyte, which was dried and derivatized with N-methyl-N-trimethylsilyltrifluoroacetamide (MSTFA) to yield clenbuterol N,O-bis-trimethylsilyl (TMS). Hair was collected from four pregnant women who were therapeutically treated with Spiropent (clenbuterol-HCl) and from the infant of one female patient. Hair samples were taken during the application time and two to six months after completion of clenbuterol administration. The detection limit of the method was approximately 4 ng clenbuterol/g hair when 25 mg hair material were processed and 2 ng/g for 50 mg hair samples (corresponds to 4 pg per injection). The method allows clenbuterol to be measured retrospectively for up to at least six months. The levels of clenbuterol determined in hair ranged from 2 to 236 ng/g. No clenbuterol was found in the hair of the infant, which was taken five and a half months after delivery. To improve sample preparation, an additional purification step via immuno affinity chromatography (IAC) was integrated. The IAC purified extracts showed reduced biological background interference and an improved limit of detection (0.8 ng/g).

Erysipelas and elephantiasis of the scrotum--surgery and drug therapy.

Elephantiasis of the scrotum is the terminal stage of persistent refractory lymphedema. Its debilitating functional and cosmetic effects have significant psychological, emotional and social consequences for the affected patient. The causal relationship between etiology and recurrent disease is illustrated here by 2 cases. Therapy options are also discussed. Primary therapeutic success is determined by radical surgery, since chronic inflammation and chronic oedema mutually foster one another. Metabolic stability, sanitization of infected cutaneous areas and the prophylactic administration of antibiotics are essential to ensure that the treatment of recurrent erysipelas is successful in the long term.

Long-term detection and identification of metandienone and stanozolol abuse in athletes by gas chromatography-high-resolution mass spectrometry.

The misuse of anabolic androgenic steroids (AAS) in human sports is controlled by gas chromatography-mass spectrometric analysis of urine specimens obtained from athletes. The analysis is improved with modern high-resolution mass spectrometry (HRMS). The detection and identification of metabolites of stanozolol (I) [3'-hydroxystanozolol (II) and 4 beta-hydroxystanozolol (III)] and metandienone (IV) I17 beta-methyl-5 beta-androst-1-ene-3 alpha,17 alpha-diol (V) and 18-nor-17,17-dimethyl-5 beta-androsta-1,13-dien-3 alpha-ol (VI)] with GC-HRMS at 3000 resolution yielded a large increase in the number of positive specimens. A total of 116 anabolic steroid positives were found in this laboratory in 1995 via GC-MS and GC-HRMS screening of 6700 human urine specimens collected at national and international sporting events and at out-of-competition testing. Of the 116 positive cases, 41 were detected using conventional (quadrupole) GC-MS screening. The other 75 positives were identified via GC-HRMS screening. To confirm the HRMS screening result, the urine sample was reanalyzed using a specific sample workup procedure to selectively isolate the metabolites of the identified substance. II and III were selectively isolated via immunoaffinity chromatography (IAC) using an antibody which was prepared for methyltestosterone and shows high cross reactivity to II and III. V and VI were isolated using high-performance liquid chromatography (HPLC) fractionation.

[Erysipelas and elephantiasis of the scrotum. Surgical and drug therapy]. / Erysipel und Elephantiasis des Skrotums. Operative und medikamentöse Therapie.

Elephantiasis is the outcome of persistent lymphedema. It is refractory to different therapy modalities. The social approachability of patients with this disease is impaired by severe functional and cosmetic disturbances. The causal relationship between etiology and recurrent disease is demonstrated by two cases. Treatment options are discussed. Radical surgery is decisive for primary success since chronic inflammation and chronic edema support each other. Metabolic equilibrium, disinfecting skin areas and antibiotic prophylaxis are urgent steps in the successful treatment of Erysipelas disease.

Oligosaccharide profiles of HIV-2 external envelope glycoprotein: dependence on host cells and virus isolates.

The glycosylation pattern of the external envelope glycoprotein of human immunodeficiency virus type 2 (HIV-2) was studied in dependence on host cells and virus isolates. Strains HIV-2ALT, HIV-2ROD and HIV-2D194, differing in their biological properties and in the amino acid sequences of their env genes, were propagated in MOLT4, HUT78 and U937 cells, in human peripheral blood lymphocytes and monocytes/macrophages in the presence of [6-3H]glucosamine. Radiolabelled viral glycoproteins were isolated from the cell-free supernatants and digested with trypsin. Glycans were sequentially liberated by endo-beta-N-acetylglucosaminidase H and peptide-N4-(N-acetyl-beta-glucosaminyl) asparagine amidase F, and fractionated according to charge and size. Comparison of the oligosaccharide profiles revealed that the envelope glycoproteins of different virus isolates, propagated in the same host cells, yielded very similar glycan patterns, whereas cultivation of an isolate in different host cells resulted in markedly divergent oligosaccharide maps. Variations concerned the proportion of high-mannose-, hybrid- and complex-type substituents, as well as the state of charge and structural parameters of the complex-type species. As a characteristic feature, complex-type glycans of macrophage-derived viral glycoprotein were almost exclusively substituted by lactosamine repeats. Hence, glycosylation of the HIV-2 external envelope glycoprotein seems to be primarily governed by host cell-specific factors rather than by the amino acid sequence of the corresponding polypeptide backbone.

Glycosylation of glycoprotein 55 encoded by the anaemia-inducing strain of Friend spleen focus-forming virus.

Normal rat kidney cells, non-productively infected with the anaemia-inducing variant of Friend spleen focus-forming virus (F-SFFVA), were metabolically labelled with [2-3H]mannose. The primary translation product of the viral envelope gene (env), representing a glycoprotein with an apparent molecular M(r) of 55,000 (gp55), was isolated from cell lysates by immunoaffinity chromatography and purified by preparative SDS/PAGE. Radiolabelled oligosaccharides, released from tryptic glycopeptides by treatment with endo-beta-N-acetylglucosaminidase H, were characterized chromatographically, by enzymic digestion and by acetolysis. The results revealed that F-SFFVA gp55 obtained from this source carried predominantly oligomannose type sugar chains with five to nine mannoses. As a characteristic feature, glycans with seven to nine mannoses contained, in part, an additional glucose residue. Although the amount of glucosylated species found was higher in F-SFFVA gp55 (about 25% of total endo-H-sensitive oligosaccharides) than in gp55 of the corresponding polycythaemia-inducing variant (F-SFFVP, 16.3%), the overall glycosylation pattern of the F-SFFVA env product closely resembled that of F-SFFVP gp55 [Strube et al. (1988) J Biol Chem 263:3762-71]. Hence, our results demonstrate that the different intracellular processing and transport of the primary F-SFFVA env product cannot be attributed to aberrant trimming of its oligomannose type glycans.

Metabolism of metandienone in man: identification and synthesis of conjugated excreted urinary metabolites, determination of excretion rates and gas chromatographic-mass spectrometric identification of bis-hydroxylated metabolites.

After oral administration of metandienone (17 alpha-methyl-androsta-1,4-dien-17 beta-ol-3-one) to male volunteers conjugated metabolites are isolated from urine via XAD-2-adsorption, enzymatic hydrolysis and preparative high-performance liquid chromatography (HPLC). Four conjugated metabolites are identified by gas chromatography-mass spectrometry (GC/MS) with electron impact (EI)-ionization after derivatization with N-methyl-N-trimethyl-silyl-trifluoroacetamide/trimethylsilyl-imidazole (MSTFA/TMS-Imi) and comparison with synthesized reference compounds: 17 alpha-methyl-5 beta-androst-1-en-17 beta-ol-3-one (II), 17 alpha-methyl-5 beta-androst-1-ene-3 alpha,17 beta-diol (III), 17 beta-methyl-5 beta-androst-1-ene-3 alpha,17 alpha-diol (IV) and 17 alpha-methyl-5 beta-androstane-3 alpha,17 beta-diol (V). After administration of 40 mg of metandienone four bis-hydroxy-metabolites--6 beta,12-dihydroxy-metandienone (IX), 6 beta,16 beta-dihydroxy-metandienone (X), 6 beta,16 alpha-dihydroxy-metandienone (XI) and 6 beta,16 beta-dihydroxy-17-epimetandienone (XII)--were detected in the unconjugated fraction. The metabolites III, IV and V are excreted in a comparable amount to the unconjugated excreted metabolites 17-epimetandienone (VI), 6 beta-hydroxy-metandienone (VII) and 6 beta-hydroxy-17-epimetandienone (VIII). Whereas the unconjugated excreted metabolites show maximum excretion rates between 4 and 12 h after administration the conjugated metabolites III, IV and V are excreted with maximum rates between 12 and 34 h.

[Involution and redevelopment of the mammary gland in goats. Histological-histochemical studies after a lactation time of 8-10 months]. / Rück- und Anbildung der Milchdrüse bei Ziegen. Histologisch-Histochemische Untersuchungen nach einer Melkzeit von 8-10 Monaten.

7 chamois-coloured mountain goats were used to investigate histologically and histochemically the processes of involution and redevelopment of the mammary gland after a lactation period of 8 to 10 months. Tissue specimens were obtained by incision biopsy at drying-off two months prepartum and afterwards in intervals of 8-16 days up to parturition. The findings of this investigation were compared with results of two former investigations, in which involution and proliferation of the gland were studied separately, thus precluding an overlapping of the two processes. At drying-off, after an 8 to 10 month-lactation, sections indicative of active lactation occurred concomitantly with sections at various stages of involution, as well as early stages of redeveloping alveoli. At 16 days post drying-off, the sections indicating lactation at first examination were in a stage of maximum involution and transformation. Thus, the time required for involution was reduced by half compared to drying-off at peak lactation. At 32 days post drying-off, stages of proliferation predominated with only a few involuting glands. Specimens obtained thereafter contained only redeveloping glands. The histological and histochemical differentiation between areas of involution and those of proliferation may present difficulties during the mid-portion of the dry period. There appears to be an association between the length of the time interval from drying-off to parturition and the rate of tissue transformation in the caprine mammary gland; the rate is increased when the duration of the dry period is reduced.

Glycosylation of the envelope glycoprotein from a polytropic murine retrovirus in two different host cells.

A polytropic recombinant retrovirus containing the envelope gene of Friend mink cell focus-inducing virus plus the remainder of the genome of an amphoropic murine leukemia virus was propagated on mouse embryo fibroblasts and mink lung cells. Virus particles, metabolically labeled with [2-3H]mannose, were harvested from the culture supernatants and lysed with detergents. The viral envelope glycoprotein was isolated from the lysates by immunoaffinity chromatography and purified by preparative SDS/PAGE. Oligosaccharides were liberated by sequential treatment of tryptic glycopeptides with endo-beta-N-acetylglucosaminidase H and peptide-N4-(N-acetyl-beta-glucosaminyl) asparagine amidase F and fractionated by high-performance liquid chromatography. Individual glycans were characterized chromatographically, by methylation analyses and in part, by enzymic microsequencing. The results demonstrated that viral glycoproteins, synthesized in mouse embryo fibroblasts, carried as major constituents partially fucosylated diantennary, 2,4- and 2,6-branched triantennary and tetraantennary complex type N-glycans with 0-4 sialic acid residues and only small amounts of high-mannose type species with 5-9 mannose residues. As a characteristic feature, part of the complex type glycans contained additional Gal(alpha 1-3) substituents. Glycoprotein obtained from virions propagated on mink lung cells, contained partially fucosylated diantennary and 2,4-branched triantennary oligosaccharides with 1-3 sialic acid residues, in addition to trace amounts of high-mannose type species with 8 or 9 mannose residues. Thus, the results reveal that predominantly, the complex type N-glycans of the retroviral envelope glycoprotein display cell-specific variations including differences in oligosaccharide branching, sialylation and substitution by additional Gal(alpha 1-3) residues.

Estrogen and progesterone receptors in endometrial cancer and their prognostic relevance.

Three hundred and nine malignant endometrial tumors were biochemically analyzed with respect to estrogen (ER) and progesterone (PR) receptors. Fifty-seven percent of endometrial carcinomas were ER and PR positive (greater than or equal to 50 fmole/mg of cytosol protein); 24% were negative for both receptors. Five sarcomas and 16 of 21 mixed müllerian tumors were receptor negative. Receptor status correlated with clinical stage and grade of histological differentiation, but not with myometrial invasion. Anamnestic data on patients showed no differences between those with receptor-negative and receptor-positive tumors. Five-year survival rate (stage I) and median survival time (stages II-IV, recurrences) for patients with ER+/PR+ and ER-/PR+ endometrial cancer were significantly better than for ER-/PR- and ER+/PR- patients. A multivariate analysis demonstrated progesterone receptor as a significant prognostic factor next to clinical stage. Estrogen receptor had no significant prognostic relevance. A retrospective analysis of gestagen treatment and progesterone receptor status confirms the importance of PR, possibly independent of hormonal treatment.