Adrenocortical adenoma and carcinoma: histopathological and molecular comparative analysis.

We compared histomorphological features and molecular expression profiles of adrenocortical adenomas (ACAd) and carcinomas (ACCa). A critical histopathological review (mean, 11 slides per patient) was conducted of 37 ACAd and 67 ACCa. Paraffin-embedded tissue cores of ACAd (n = 33) and ACCa (n = 38) were arrayed in triplicate on tissue microarrays. Expression profiles of p53, mdm-2, p21, Bcl-2, cyclin D1, p27, and Ki-67 were investigated by immunohistochemistry and correlated with histopathology and patient outcome using standard statistical methodology. Median follow-up period was 5 years. Tumor necrosis, atypical mitoses, and >1 mitosis per 50 high-power fields were factors that were highly specific for ACCa (P <.001). Number (0 to 4) of unfavorable markers [Ki-67 (+), p21 (+), p27 (+), mdm-2(-)] expressed was significantly associated with mitotic activity and morphologic index (i.e., number of adverse morphologic features) and highly predictive of malignancy (P <.001). Ki-67 overexpression occurred in 0 ACAd and 36% ACCa (P <.001) and was significantly associated with mitotic rate and unfavorable morphologic index (P <.001). Tumor necrosis, atypical mitoses, >5 mitoses per 50 high-power fields, sinusoidal invasion, histologic index of >5, and presence of more than two unfavorable molecular markers were associated significantly with metastasis in ACCa. Well-established histopathologic criteria and Ki-67 can specifically distinguish ACCAd from ACCa. Tumor cell proliferation (Ki-67) correlates with mitotic activity and morphologic index. Tumor morphology is a better predictor of metastatic risk in ACCa than current immunohistochemistry-detected cell cycle regulatory and proliferation-associated proteins.     

Molecular cytogenetic characterization of nasopharyngeal carcinoma cell lines and xenografts by comparative genomic hybridization and spectral karyotyping

Nasopharyngeal carcinoma (NPC) cell lines and xenografts represent valuable models for functional and therapeutic studies on this common malignancy in Southeast Asia. The karyotypic information in most NPC cell lines and xenografts, however, remains largely unclear to date. We have characterized the chromosomal aberrations in six commonly used human NPC cell lines and xenografts using the molecular cytogenetic technique of comparative genomic hybridization (CGH). Genomic imbalances identified in cell lines were further correlated with structural abnormalities indicated from spectral karyotyping (SKY) analysis. CGH revealed consistent overrepresentations of 8q (six out of six cases) with a smallest overlapping region identified on 8q21.1q22. Other common gains included 7p (4/6 cases), 7q (4/6 cases), 12q (4/6), and 20q (4/6 cases), where minimal overlapping regions were suggested on 7p15p14, 7q11.2q21, and 12q22q24.1. Common losses were detected on 3p12p21 (4/6 cases) and 11q14qter (4/6 cases). Although SKY analysis on cell lines revealed predominantly unbalanced rearrangements, reciprocal translocations that involved chromosome 2 [i.e., t(1;2), t(2;3), and t(2;4)] were suggested. Furthermore, SKY examination illustrated additional breakpoints on a number of apparently balanced chromosomes. These breakpoints included 3p21, 3q26, 5q31, 6p21.1p25, 7p14p22, and 8q22. Our finding of regional gains and losses and breakpoints represents information that may contribute to NPC studies in vitro.     

Hormones increase mRNA of cyclic-nucleotide-gated cation channels in airway epithelia

Previous studies have shown that the mRNA of cyclic-nucleotide-gated nonselective cation (CNG) channels is expressed in rat airway epithelia and that these channels contribute to sodium-mediated short-circuit currents in cultured rat tracheal epithelia. Patch-clamp studies from human A549 cells indicate that these channels contribute to cGMP-stimulated L-cis-diltiazem- and dichlorobenzamil-inhibited whole-cell sodium currents. This study demonstrates that mRNA for primary and secondary subunits of CNG channels, halphaCNG1 and hbetaCNG1 respectively, are expressed in several human airway cell lines, including normal and cystic fibrosis bronchial airway cells, in normal and cystic fibrosis tracheal airway cell lines and nasal polyp tissue from a cystic fibrosis patient. The mRNA of ralphaCNG1 in rat lung increased in response to increased circulating glucocorticoids and decreased in animals with lowered circulating glucocorticoids after aminoglutethimide treatment. Likewise the mRNA of halphaCNG1 increased in the presence of glucocorticoids in cultured alveolar airway cells. The mRNA of alphaCNG1 in rat lung was also increased in response to a low-salt diet and lowered in animals fed a high-salt diet. Likewise the mRNA of alphaCNG1 was increased in response to increased aldosterone and decreased in animals given spironolactone. These results suggest that mRNA for alphaCNG1 increases in response to elevated glucocorticoids or mineralocorticoids. Because alphaCNG1 is a functional sodium entry channel in both rat and human airway epithelial cells, if channel protein is also elevated this channel could mediate an increase in sodium absorption across lung epithelia in response to circulating hormones.     

The lack of effect of histamine on spontaneous activity in the isolated human myometrium

The effects of histamine on the spontaneous activity of the isolated human myometrium were studied. Both the frequency and force of contractions of the muscle strips were not significantly altered by histamine. The presence of either a histamine H₁-or H₂-receptor antagonist in the organ bath did not significantly change the responses of the uterine muscle to histamine. These findings suggest that histamine has negligible effects on the human myometrium, possibly due to the absence, or paucity, of histamine receptors.     

Chronic intracranial pressure monitoring by telemetry: Clinical experience

Intracranial pressure (ICP) monitoring is a critical measure for avoiding severe brain dysfunction or brain death by directing supportive therapy so as to prevent ICP increase severe enough to reduce cerebral blood perfusion. Such situations occur with brain swelling, increased cerebral vascular volume, and increase in cerebrospinal fluid (CSF) volume. Causes include ischemic stroke, subarachnoid bleeding, brain contusion, encephalitis (as in Reye's syndrome), and hydrocephalus from meningitis or neoplasm. When several days of ICP monitoring can direct resolution of the pressure crisis, the invasive direct connection of an intracranial sensor with external recording device carries only minimal infection risk. Prolonged ICP monitoring for weeks or months demands telemetry and becomes desirable in a number of chronic disease problems including both congenital and acquired hydrocephalus where enlarged and pressurized cerebral ventricles develop with reduced absorption of continuously secreted CSF. Although the primary disturbance in CSF circulation can remain incurable, its palliation by valve-regulated CSF diversions or shunting can restore normal brain function and in infants permit normal brain development. Missing this goal can result from failure to maintain a sufficiently normal pattern of CSF dynamics and ICP. Monitoring of the CSF pressure fluctuations transmitted through an intraventricular catheter provides the most accurate record of ICP pulsations. Therefore, a pressure sensing module can be “T'd” into an existing shunt system in continuity with the already placed ventricular tube. The capacity to monitor ICP accurately by telemetry was first established in dogs made hydrocephalic to assure free CSF pulse through a ventricular catheter (1,2,3, 4,5). The subsequent use of ICP monitoring by telemetry in three patients will be described.     

Norepinephrine and amino acids in prepyriform cortex of rats fed imbalanced amino acid diets

Monoamines and amino acids were measured in anterior prepyriform cortex (PPC) and anterior cingulate cortex (CC) of male Sprague-Dawley rats after they were offered basal, imbalanced (IMB) or corrected amino acid diets, limited in threonine (THR) or isoleucine (ILE). In the THR study, brains were taken after 2.5 hr of feeding, when intake of THR-IMB was just depressed. In the ILE study the brains were taken after 3.5 hr on ILE-IMB, a less severely imbalanced ration, before the onset of food intake depression. The PPC has been shown to be involved in the acute response of animals to imbalanced amino acid diets. In the PPC from the IMB diet groups, NE was reduced by 30%, but the other monoamines were unchanged. In CC, an area involved in the adaptive, but not the acute feeding response to imbalanced diets, the monoamines were unchanged in the IMB diet groups. In both studies, in both tissues, the limiting amino acids were decreased in the IMB groups, although the decrease of ILE in the CC failed to reach significance. The remaining indispensable amino acids, added to create the imbalance, were slightly reduced in the THR-IMB group, but not in the ILE-IMB group in both tissues. Thus, the amino acid patterns were altered in the PPC and CC, as they are in whole brains from animals fed imbalanced amino acid diets. These results also suggest that the concentration of NE in the PPC may be associated with the initial food intake response of animals to imbalanced amino acid diets.