Retroperitoneal cystic mature teratoma as the presenting clinical scenario of testicular carcinoma.

OBJECTIVE: To describe a case of retroperitoneal mature teratoma presenting as metastasis of a testicular mixed germ cell tumor in a thirty year old man who had lumbar and abdominal pain and mass sensation in the left hemiabdomen. METHODS: Abdominal ultrasound and thoracic-abdominal-pelvic CT multidetector scan were performed, and then after a Doppler ultrasound study of the testicles. Surgical treatment was performed: orchiectomy and retroperitoneal lesion resection. RESULTS: Imaging studies showed a big cystic lesion in the left retroperitoneal space, 13 × 12 × 11 cm, well defined, with thin septa, displacing the kidney; and a solid-cystic 4 cm left testicular tumor, with multiple septa, solid poles and arterial flows with low resistances. Thoracic extension study did not show any finding. The histopathologic results of the orchiectomy and retroperitoneal resection pieces were, respectively, testicular mixed germ cell tumor (seminoma, with intratubular seminoma foci and teratoma) and mature cystic teratoma. CONCLUSIONS: Germ cell tumors derive from multipotencial cells with a large capacity of differentiation, and the nodal paraaortic chains are a natural way of dissemination of these neoplasms. Because of that, in the presence of a retroperitoneal lesion in a young patient we have to rule out testicular tumor metastasis. The retroperitoneal mature cystic teratoma must be considered as a lesion with malignant potential.

Urachal adenocarcinoma with late brain metastases.

OBJECTIVE: To describe a case of urachal adenocarcinoma with late brain metastases in a sixty one year old man who presented abdominal discomfort and hematuria during six months. METHODS: The clinical suspicion was bladder tumor and diagnostic studies were performed (urinary cytology, cystoscopy, abdominal ultrasound and abdominopelvic CT scan). Surgical treatment was performed. RESULTS: Negative urinary cytology. Cystoscopy showed a lesion with infiltration of the bladder dome. Ultrasound and CT scan showed a five centimeter rounded lesion, with intermediate density, internal echoes and calcifications on the anterior supravesical middle line, that infiltrated the bladder. The extension study had not findings. Partial cystectomy and lymphadenectomy were performed. The histopathologic diagnosis was mucin-secreting urachal adenocarcinoma. After five years without disease the patient suffered lung and brain metastases. CONCLUSIONS: Urachal adenocarcinoma is a tumor which must be distinguished of primary bladder adeno-carcinoma. The mucing-secreting adenocarcinoma can be associated with calcifications that can be demostrated on imaging studies. Late metastases without signs of local recurrence (after five years without disease) are an infrequent clinical-pathologic finding.

[Obstructive uropathy secondary to vesico-ureteral endometriosis: clinical, radiologic and pathologic features]. / Uropatía obstructiva secundaria a endometriosis vésico-ureteral: características clinico-radiológicas y anatomopatológicas.

OBJECTIVES: To report the case of a 37 year-old woman suffering from endometriosis of the urinary tract, that presented with lumbar and pelvic pain associated to cyclic recurrent haematuria. METHODS: Following history, physical examination, abdomino-pelvic ultrasound (USS), CT scan and cystoscopy with biopsies, surgical treatment was indicated RESULTS: Imaging (USS-CT ) revealed a protrusion of the left bladder hemi-trigone with a nodular, irregular thickening and ipsilateral grade II-III/IV uretero-hydronefrosis. Cistoscopy confirmed a swollen and oedematous lesion in left hemi-trigone that seemed extrinsic in origin. With the clinical diagnosis of a possible neoplasia of gynaecological origin, the patient underwent surgical treatment consisting in radical hysterectomy with bilateral oophorectomy, partial cystectomy and left ureteroneocystostomy. CONCLUSIONS: The frequency of endometriosis in the urinary tract is relatively low and therefore, endometriosis presenting with ureteral obstruction (uretero-hydronephrosis) has been rarely reported in the literature and should be part of the differential diagnosis in young women, especially if symptoms are cyclic. The treatment is surgery and the final diagnosis by pathology report.

A novel antagonist of prostaglandin D2 blocks the locomotion of eosinophils and basophils.

BACKGROUND: Chemoattractant receptor homologous molecule of Th2 cells (CRTH2) has been shown to mediate the chemotaxis of eosinophils, basophils and Th2-type T lymphocytes. The major mast cell product prostaglandin (PG) D(2) is considered to be the principal ligand of CRTH2. MATERIALS AND METHODS: We developed a novel CRTH2 antagonist, AZ11665362 [2,5-dimethyl-3-(8-methylquinolin-4-yl)-1H-indole-1-yl]acetic acid, and characterized its efficacy in binding assay in HEK293 cells, eosinophil and basophil shape change assay and migration assay, platelet aggregation and eosinophil release from guinea pig bone marrow. The effects were compared with ramatroban, the sole CRTH2 antagonist clinically available to date. RESULTS: AZ11665362 bound with high affinity to human and guinea pig CRTH2 expressed in HEK293 cells and antagonized eosinophil and basophil shape change responses to PGD(2). AZ11665362 was without effect on the PGD(2)-induced inhibition of platelet aggregation. In contrast, AZ11665362 effectively inhibited the in vitro migration of human eosinophils and basophils towards PGD(2). The release of eosinophils from the isolated perfused hind limb of the guinea pig was potently stimulated by PGD(2), and this effect was prevented by AZ11665362. In all assays tested, AZ11665362 was at least 10 times more potent than ramatroban. CONCLUSIONS: AZ11665362 is a potent CRTH2 antagonist that is capable of blocking the migration of eosinophils and basophils, and the rapid mobilization of eosinophils from bone marrow. AZ11665362 might hence be useful for the treatment of allergic diseases.

Involvement of both phosphatidylinositol 3-kinase and p44/p42 mitogen-activated protein kinase pathways in the short-term regulation of pyruvate kinase L by insulin.

Pyruvate kinase L (PK-L) is a key regulatory enzyme of the hepatic glycolytic/gluconeogenic pathway that can be dephosphorylated and activated in response to insulin. However, the signaling cascades involved in this insulin effect have not been established. In this work we have investigated the potential involvement of phosphatidylinositol 3-kinase (PI 3-K) and p44/p42 mitogen-activated protein kinase (MAPK) pathways in the short-term modulation of PK-L by insulin in primary cultures of rat hepatocytes. Wortmannin, at a concentration of 100 nM, caused a marked inhibition of the PI 3-K/protein kinase B pathway, which became complete at 500 nM wortmannin. Likewise, wortmannin at 100 and 500 nM, elicited partial and total inhibitions of insulin-mediated activation of PK-L, respectively. However, this PI 3-K inhibitor also reduced insulin-mediated phosphorylation of p44/p42 MAPK in cultured rat hepatocytes, indicating that both the PI 3-K and MAPK pathways could be involved in PK-L activation by insulin. Three facts appear to reinforce this hypothesis: 1) the selective and complete inhibition of the PI 3-K/protein kinase B pathway by LY294002 (50 microM) was accompanied by a partial blockade of insulin-induced PK-L activation; 2) when signaling through the MAPK cascade was selectively suppressed by the presence of PD98059 (50 microM), a 50% reduction of insulin-induced activation of PK-L was observed; and 3) the effect of PD98059 (50 microM) on PK-L activation was reinforced by the additional presence of 100 nM wortmannin. We also observed that the blockade of p70 S6-kinase by rapamycin did not affect the activation of PK-L by insulin. From these findings it can be concluded that both PI 3-K and MAPK pathways, but not p70 S6-kinase, are involved in the short-term activation of PK-L by insulin in rat hepatocytes.

G protein-coupled receptor fusion proteins in drug discovery.

A wide range of peptides and polypeptides can be appended to either the N- or C-terminus of G protein-coupled receptors without disrupting substantially ligand binding and signal transduction. Following fusion of fluorescent proteins, reporter gene constructs or G protein alpha subunits to the C-terminal tail of a receptor high content and G protein activation assays can be employed to identify agonist ligands. Further modification of the receptor fusions to introduce enhanced levels of constitutive activity and to physically destabilise the protein allows antagonist/inverse agonists screens to be developed in parallel. Equivalent C-terminal addition of pairs of complementary, non-functional, polypeptide fragments allows the application of enzyme complementation techniques. Introduction of N-terminal tags to receptors has also allowed the introduction of novel assay techniques based on a pH-sensitive cyanine dye. These have the capacity to overcome certain limitations of GPCR-fluorescent protein fusions.

Decreased responsiveness of gluconeogenesis to the modulation by sulfonylureas in hepatocytes isolated from obese (fa/fa) Zucker rats.

The influence of the hypoglycemic agent glipizide (0-100 microM) on the rate of gluconeogenesis from lactate, as well as on the levels of fructose 2,6-bisphosphate, has been investigated in hepatocytes isolated from genetically obese (fa/fa) Zucker rats and from their corresponding lean (Fa/-) littermates. As compared to lean rat hepatocytes, liver cells isolated from obese animals showed a lower rate of basal gluconeogenesis (0.9 +/- 0.2 vs 5.4 +/- 0.5 micromol of lactate converted to glucose/g cell x 30 min, n=4) and higher levels of fructose 2,6-bisphosphate (11.5 +/- 1.0 vs 5.9 +/- 0.4 nmol/g cell, n=8-9). In lean rat hepatocytes, the presence of glipizide in the incubation medium caused a dose-dependent inhibition of the rate of lactate conversion to glucose (maximal inhibition=46%; EC50 value=26 microM), and simultaneously raised the cellular content of fructose-2,6-bisphosphate (maximal increment=40%; EC50 value=10 microM). In contrast, in hepatocytes isolated from obese rats, the inhibition of gluconeogenesis and the increment in fructose-2,6-bisphosphate levels elicited by glipizide were significantly reduced (maximal effects of 22 and 13%, respectively). Similarly, the activation of glycogen phosphorylase and the increase in hexose 6-phosphate levels in response to glipizide were less marked in obese rat hepatocytes than in liver cells isolated from lean animals. These results demonstrate that the efficacy of sulfonylureas as inhibitors of hepatic gluconeogenesis is reduced in the genetically obese (fa/fa) Zucker rat.

'Benign' fibrous histiocytoma of the trachea.

Fibro-histiocytic neoplasms are uncommon in the respiratory tract. This paper presents a clinical and histological description of a case of fibrous histiocytoma at the level of the third tracheal ring. This cases shares some features with the four cases previously described, viz., the growth occurs mainly in young adults; recurrences are common; and all have shown similar benign histological patterns. Ultrastructural investigations confirmed the fibro-histiocytic nature of the neoplasm.

[Hepatic amyloidosis as cause of severe intrahepatic cholestasis]. / Amiloidosis hepática como causa de colestasis severa intrahepática.

The liver is frequently involved by amyloidosis, but hyperbilirubinemia and liver failure are uncommon features. A mild elevation of the serum alkaline phosphatase value and, less frequently, hepatomegaly are the most common findings. Usually the patients have no symptoms related with the liver involvement; the clinical manifestation and the long term prognosis depends on the renal and cardiac disease. We report an unusual clinical presentation of primary amyloidosis in a previously asymptomatic 65 years old woman who was admitted to the hospital because of ictericia and ascitis mimicking a drug induced acute hepatic failure.

Microsatellite abnormalities and somatic down-regulation of mismatch repair characterize nodular-trabecular muscle-invasive urothelial carcinoma of the bladder.

AIMS: To correlate histological infiltration patterns with genetic and mismatch repair (MMR) profiles in muscle-invasive bladder urothelial carcinomas (UroC). METHODS AND RESULTS: Infiltration patterns were assessed in the deep compartment of muscle-invasive UroC (nodular-trabecular, 45 cases; infiltrative, 27 cases). Tumour compartment (superficial and deep to muscularis mucosa) analysis included: microsatellite pattern of TP53, RB1, WT1 and NF1 by polymerase chain reaction/denaturing gradient gel electrophoresis; mitotic, Ki67, in situ end labelling (ISEL) indices and DNA ploidy. MMR was assessed by MLH1 and MSH2 sequencing and immunohistochemistry in UroC with two or more abnormal microsatellite loci. Statistical differences were tested using anova and Fisher's exact tests. Infiltrative UroC showed lower Ki67 index 14.94 +/- 4.28, ISEL index 14.1 +/- 10.0 and shorter median survival (20 months) than nodular-trabecular UroC (Ki67 index 20.65 +/- 4.94, ISEL 20.2 +/- 22.7, 37-month survival, respectively). The genetic profile was significantly different for RB1 (P = 0.0003) and NF1 (P = 0.0023) only, being more frequently abnormal in nodular-trabecular UroC. A significant decrease in MLH1 or MSH2 protein expression with no gene mutations was identified in UroC with microsatellite abnormalities and a nodular-trabecular growth pattern. CONCLUSIONS: Somatic down-regulation of MMR proteins in nodular-trabecular muscle-invasive UroC results in RB1/NF1 microsatellite abnormalities, correlating with higher cellular turnover and longer survival.

Differential kinetic features by tumour topography in cutaneous small-cell neuroendocrine (Merkel cell) carcinomas.

BACKGROUND/OBJECTIVES: Merkel cell carcinomas (MCC) reveal epithelial and neuroendocrine differentiation, but its topographic cell kinetics remains unknown. This study analyses proliferation, apoptosis, and DNA ploidy by topography, features that can help planning therapeutic protocols. This study topographically analyses proliferation, apoptosis, and DNA ploidy. METHODS: We selected 27 small-cell MCCs (expressing one epithelial and two neural markers, with consistent ultrastructural findings) to evaluate mitotic figure counting, Ki-67 index, apoptosis index based on the in situ end labelling of fragmented DNA (using Escherichia coli DNA polymerase I, Klenow fragment), DNA ploidy, and BCL2 and TP53 immuno-expression. At least 50 high-power fields were screened per topographic compartment (superficial or papillary dermis, and deep or reticular dermis), recording average and standard deviation for each variable. Variables were statistically compared in each tumour compartment using analysis of variance and Student's t-test (significant if P < 0.05). RESULTS: MCCs revealed superficial aneuploid DNA content, and no topographic differences for proliferation markers. Apoptosis showed significantly lower values in the deep compartment (average, P = 0.0050, and standard deviation, P = 0.0074), correlating with increased BCL2 and TP53 immuno-expressions. CONCLUSIONS: High homogeneously distributed proliferation and superficial aneuploid DNA content defines MCCs. Apoptosis follows proliferation in superficial compartments, being less variable and proliferation independent in deep compartments, where it is inversely correlated with BCL2/TP53 expression.

Metastatic calcifications and severe hypercalcemia in a patient with parathyroid carcinoma.

Primary hyperparathyroidism is rarely produced by parathyroid carcinoma. We present the case of a 63-yr-old man who was admitted due to recent onset of constipation, weakness and progressive lethargy. At physical examination, a left cervical mass was palpated. Marked hypercalcemia (serum calcium 25 mg/dl) (6.22 mmol/l) complicated by renal insuficiency (serum creatinine 4.4 mg/dl) (388 micromol/l) was found, but both were unresponsive to conventional therapy and hemofiltration. Autopsy examination showed a carcinoma of the upper left parathyroid gland, multiple foci of metastatic calficications in the vessel walls and parenchyma of both lungs and kidneys, and the myocardium, which contributed to multi-organ failure and death. In addition to describing the clinical presentation, we review the mechanism of metastatic calcifications as well as the role of renal function and hyperphosphatemia, and the basis for therapy of hypercalcemic crisis.

Coordinated agonist regulation of receptor and G protein palmitoylation and functional rescue of palmitoylation-deficient mutants of the G protein G11alpha following fusion to the alpha1b-adrenoreceptor: palmitoylation of G11alpha is not required for interaction with beta*gamma complex.

Transfection of either the alpha(1b)-adrenoreceptor or Galpha(11) into a fibroblast cell line derived from a Galpha(q)/Galpha(11) double knockout mouse failed to produce elevation of intracellular [Ca(2+)] upon the addition of agonist. Co-expression of these two polypeptides, however, produced a significant stimulation. Co-transfection of the alpha(1b)-adrenoreceptor with the palmitoylation-resistant C9S,C10S Galpha(11) also failed to produce a signal, and much reduced and kinetically delayed signals were obtained using either C9S Galpha(11) or C10S Galpha(11). Expression of a fusion protein between the alpha(1b)-adrenoreceptor and Galpha(11) allowed [Ca(2+)](i) elevation, and this was also true for a fusion protein between the alpha(1b)-adrenoreceptor and C9S,C10S Galpha(11), since this strategy ensures proximity of the two polypeptides at the cell membrane. For both fusion proteins, co-expression of transducin alpha, as a beta.gamma-sequestering agent, fully attenuated the Ca(2+) signal. Both of these fusion proteins and one in which an acylation-resistant form of the receptor was linked to wild type Galpha(11) were also targets for agonist-regulated [(3)H]palmitoylation and bound [(35)S]guanosine 5'-3-O-(thio)triphosphate (GTPgammaS) in an agonist concentration-dependent manner. The potency of agonist to stimulate [(35)S]GTPgammaS binding was unaffected by the palmitoylation potential of either receptor or G protein. These studies provide clear evidence for coordinated, agonist-mediated regulation of the post-translational acylation of both a receptor and partner G protein and demonstrate the capacity of such fusions to bind and then release beta.gamma complex upon agonist stimulation whether or not the G protein can be palmitoylated. They also demonstrate that Ca(2+) signaling in EF88 cells by such fusion proteins is mediated via release of the G protein beta.gamma complex.

Serum activity of the key gluconeogenic enzymes in carbon-tetrachloride-induced experimental hepatotoxicity.

Serum activity has been measured in three of the key enzymes in the gluconeogenic pathway in rats subjected to experimental hepatotoxicity after intraperitoneal administration of carbon tetrachloride. The levels of phosphoenolpyruvate carboxykinase (PEPCK) and fructose-1,6-biphosphatase (FBPase) showed a similar behavior to the transaminase (AST and ALT), increasing markedly with respect to the controls at 12 h after administration of the poison, reaching their maximum peak of activity at between 24 and 36 h, and returning to normal values at 96 h. The activity of glucose-6-phosphatase was not significantly modified throughout the treatment. These results seem to demonstrate that the determination of the serum activity of PEPCK and FBPase could be a sensitive and specific marker of hepatic cytolysis.

Teratoma quístico maduro retroperitoneal como primera manifestación de carcinoma testicular. Estudio radiológico / Retroperitoneal cystic mature teratoma as the presenting clinical scenario of testicular carcinoma. Radiological study

OBJETIVO: Describir un caso de teratoma maduro retroperitoneal como metástasis de un tumor mixto de células germinales testicular en un paciente de 30 años que debutó con dolor lumbar, abdominal y sensación de masa en hemiabdomen izquierdo.MÉTODOS: Se realizó ecografía abdominal, TC multidetector tóraco-abdomino-pélvico, y ante los hallazgos apreciados ecografía-doppler testicular. Se practicó orquiectomía y resección de la lesión retroperitoneal. RESULTADOS: En las pruebas de imagen se apreció a nivel retroperitoneal izquierdo una gran lesión quística de 13x12x11 cm de diámetro, bien delimitada, con finos septos, que desplazaba el riñón; y una masa testicular de 4 cm, sólido-quística, multiseptada, con polos sólidos y flujos vasculares arteriales de baja resistencia. El estudio de extensión torácico no mostró hallazgos. Los resultados anatomopatológicos de las piezas de orquiectomía y de la lesión retroperitoneal fueron respectivamente: tumor mixto de células germinales (seminoma, con focos de seminoma intratubular y teratoma), y teratoma quístico maduro.CONCLUSIONES: Debido a que los tumores de células germinales derivan de células multipotenciales con gran capacidad de diferenciación y que las cadenas ganglionares paraaórticas constituyen una vía de diseminación natural de estas neoplasias, la presencia de una lesión retroperitoneal en un paciente joven, aún sin signos radiológicos de malignidad (en nuestro caso quística) obliga a descartar metástasis de tumor testicular. El teratoma maduro retroperitoneal postpuberal debe considerarse una lesión con potencial maligno(AU)

OBJECTIVE: To describe a case of retroperitoneal mature teratoma presenting as metastasis of a testicular mixed germ cell tumor in a thirty year old man who had lumbar and abdominal pain and mass sensation in the left hemiabdomen.METHODS: Abdominal ultrasound and thoracic-abdominal-pelvic CT multidetector scan were performed, and then after a Doppler ultrasound study of the testicles. Surgical treatment was performed: orchiectomy and retroperitoneal lesion resection.RESULTS: Imaging studies showed a big cystic lesion in the left retroperitoneal space, 13 x 12 x 11 cm, well defined, with thin septa, displacing the kidney; and a solid-cystic 4 cm left testicular tumor, with multiple septa, solid poles and arterial flows with low resistances. Thoracic extension study did not show any finding. The histopathologic results of the orchiectomy and retroperitoneal resection pieces were, respectively, testicular mixed germ cell tumor (seminoma, with intratubular seminoma foci and teratoma) and mature cystic teratoma.CONCLUSIONS: Germ cell tumors derive from multipotencial cells with a large capacity of differentiation, and the nodal paraaortic chains are a natural way of dissemination of these neoplasms. Because of that, in the presence of a retroperitoneal lesion in a young patient we have to rule out testicular tumor metastasis. The retroperitoneal mature cystic teratoma must be considered as a lesion with malignant potential(AU)

Amiloidosis hepática como causa de colestasis severa intrahepática / Primary amyloidosis as a cause of severe intrahepatic cholestasis

El hígado suele verse afectado en la amiloidosis sistémica; sin embargo, la hiperbilirrubinemia y los signos de fallo hepático son manifestaciones muy poco comunes. Una elevación ligera de las cifras de fosfatasa alcalina y, menos frecuentemente, la existencia de hepatomegalia son los hallazgos más habituales. Generalmente, los pacientes no refieren manifestaciones clínicas relacionadas con la afectación hepática; las manifestaciones clínicas y el pronóstico a largo plazo dependen de la existencia de afectación renal y cardíaca. Comunicamos un caso de amiloidosis primaria con una presentación clínica poco usual, en una mujer de 65 años de edad, que fue ingresada por un cuadro de ictericia, ascitis y fallo hepático agudo atribuído a hepatitis inducida por fármacos (AU)