Extrafacial lentigo maligna melanoma: analysis of 71 cases and comparison with lentigo maligna melanoma of the head and neck

We report a retrospective analysis of extrafacial lentigo maligna melanoma (LMM), and a comparison with patients with LMM of the head and neck. Seventy-one patients (22 men, 49 women) with extrafacial LMM were identified from the Scottish Melanoma Group database for January 1979-March 1996. Their mean age (63 years) was significantly less than that of 335 patients with head and neck LMM (mean 72 years, P < 0.001), with a significantly greater difference among women than men. Extrafacial sites comprised 17.5% of LMMs. There was a marked body site distribution difference between the sexes (P = 0. 001): 68% of extrafacial LMMs in men were on the trunk while 80% in women were on the limbs, particularly the lower leg. Extrafacial LMMs were thinner at presentation than head and neck LMMs (P < 0.05) in both sexes, but this was not simply explained by the younger age of these patients as there was no significant correlation between age and tumour thickness at either extrafacial or at head and neck sites. Although the female lower leg is a site of chronic solar exposure in older women, the other extrafacial sites are habitually covered in the temperate Scottish climate. The significantly younger age group of patients with LMM at extrafacial compared with head and neck sites therefore suggests that the relationship between LMM and sunlight is not simply related to cumulative solar exposure. The demonstration that head and neck LMMs were thicker at presentation compared with extrafacial sites, despite being at a more routinely visible part of the body, suggests that there are still opportunities for targeted pigmented lesion public education.     

Glomangioma of the ankle simulating injury to the flexor hallucis longus: a case report

The glomangioma is one of a group of benign tumors of glomus body origin. Commonly found in the distal extremities, they may present with pain, tenderness to palpation, and sensitivity to temperature. Histologically, varying proportions of glomus cells, as well as vascular and smooth muscle elements, are found. Complete surgical excision is usually curative. We report on a glomangioma of the ankle in a 12-year-old male patient that simulated injury to the flexor hallucis longus tendon.     

Chemotherapy for spinal cord astrocytoma

A combined retrospective and prospective study of 129 beta-thalassaemia major patients seen between 1965 and 1995 in Sabah Hospital, Kuwait has been carried out. The age range at diagnosis was 2 to 84 months, median 9 months. In approximately 80 per cent, the patients were outcomes of first- or second-cousin marriages. Nine (7 per cent) of the patients were HBsAg positive, while 42 (33 per cent) were hepatitis C seropositive. Eleven (9 per cent) patients had had bone marrow transplantation (BMT). There was no BMT-related mortality, but there were three graft rejections and two cases of chronic graft-versus-host disease (GVHD).     

An in vitro model of human red blood cell production from hematopoietic progenitor cells

Hemoglobinopathies, such as beta-thalassemias and sickle cell anemia (SCA), are among the most common inherited gene defects. Novel models of human erythropoiesis that result in terminally differentiated red blood cells (RBCs) would be able to address the pathophysiological abnormalities in erythrocytes in congenital RBC disorders and to test the potential of reversing these problems by gene therapy. We have developed an in vitro model of production of human RBCs from normal CD34(+) hematopoietic progenitor cells, using recombinant growth factors to promote terminal RBC differentiation. Enucleated RBCs were then isolated to a pure population by flow cytometry in sufficient numbers for physiological studies. Morphologically, the RBCs derived in vitro ranged from early polylobulated forms, resembling normal reticulocytes to smooth biconcave discocytes. The hemoglobin pattern in the in vitro-derived RBCs mimicked the in vivo adult or postnatal pattern of beta-globin production, with negligible gamma-globin synthesis. To test the gene therapy potential using this model, CD34(+) cells were genetically marked with a retroviral vector carrying a cell-surface reporter. Gene transfer into CD34(+) cells followed by erythroid differentiation resulted in expression of the marker gene on the surface of the enucleated RBC progeny. This model of human erythropoiesis will allow studies on pathophysiology of congenital RBC disorders and test effective therapeutic strategies.     

Age-dependent inaccuracy of asthma death certification in Northern England, 1991-1992

OBJECTIVE: To test the usefulness of a commercial DNA hybridization assay for the detection of high-risk (HR) human papillomavirus (HPV) types in archival cervical smears and to compare the sensitivity with that of polymerase chain reaction (PCR) using consensus primers. STUDY DESIGN: Stained material was scraped from archival slides and the pellet volume noted. DNA was extracted using silica/guanidinium isothiocyanate and the quality checked by amplification of the beta-globin gene. HR-HPV DNA was detected using a commercial hybrid capture assay (HCA) and the results compared with an in-house amplification system with consensus primers. RESULTS: Of 156 archival smears stored for 12-13 years, 20 were positive by HCA using an HR probe cocktail. Ninety-eight were also tested by PCR, and 35 were positive. The percentage of HPV-positive samples increased with the increasing size of the pellet. HR-HCA detected more positives in samples with high grade squamous intraepithelial lesion (moderate/severe dyskaryosis). CONCLUSION: Both hybridization by HCA and amplification by PCR could be used to detect genital HPV in archival smears. The general primers PCR detected more positives than HR-HCA but included HPV 6/11. While variation in sample size and prolonged storage may reduce the quality of DNA, the use of archival material for longitudinal studies of HPV presence is potentially worthwhile.     

AKT2, a member of the protein kinase B family, is activated by growth factors, v-Ha-ras, and v-src through phosphatidylinositol 3-kinase in human ovarian epithelial cancer cells

Three members have been identified in the protein kinase B (PKB) family, i.e., Akt/PKB alpha, AKT2/PKB beta, and AKT3/PKB gamma. Previous studies have demonstrated that only AKT2 is predominantly involved in human malignancies and has oncogenic activity. However, the mechanism of transforming activity of AKT2 is still not well understood. Here, we demonstrate the activation of AKT2 with several growth factors, including epidermal growth factor, insulin-like growth factor 1, insulin-like growth factor II, basic fibroblast growth factor, platelet-derived growth factor, and insulin, in human ovarian epithelial cancer cells. The kinase activity and the phosphorylation of AKT2 were induced by the growth factors and blocked by the phosphatidylinositol (PI) 3-kinase inhibitor, wortmannin, and dominant-negative Ras (N17Ras). Moreover, the activated Ras and v-Src, two proteins that transduce growth factor-generated signals, also activated AKT2, and this activation was not significantly enhanced by growth factor stimulation but was abrogated by wortmannin. These results indicate that AKT2 is a downstream target of PI 3-kinase and that Ras and Src function upstream of PI 3-kinase and mediate the activation of AKT2 by growth factors. The findings also provide further evidence that AKT2, in cooperation with Ras and Src, is important in the development of some human malignancies.     

PLA2 activity regulates Ca2+ storage-dependent cellular proliferation

The objective of this study is to determine the role of arachidonic acid (AA) in cell proliferation by inhibiting AA synthetic enzyme phospholipase A2 (PLA2) and to determine its involvement in the role of the second messenger intracellular calcium (Ca2+). Methods used to determine the effects on proliferation of cell cultures of primary meningioma and astrocytoma U373-MG included treatment with micromolar concentrations of PLA2 inhibitors 4-bromophenacylbromide and quinacrine. Effects of these drugs on proliferation were further investigated by the application of concentrations that inhibit growth by 50% while antagonizing these agents with AA replacement. Free cytosolic Ca2+ was measured with the use of fluorescent dye Fura-2 during PLA2 agonist/antagonist studies. These Ca2+ measurements were performed in the absence of extracellular Ca2+ to identify the contribution of intracellular Ca2+ sources. PLA2 inhibition resulted in decreased growth of cultured astrocytoma and meningioma cells in a dose-dependent manner in the micromolar range. This inhibitory effect was antagonized by the addition of AA. PLA2 inhibition caused an elevation of basal-cytosolic-free [Ca2+] while depleting internal Ca2+ stores. These Ca2+ changes were also antagonized by the addition of AA. In conclusion, these results demonstrate that AA, a PLA2 enzyme product, is involved in regulating the growth rate of these cell types. The PLA2 pathway also regulates the maintenance of the internal Ca2+ stores. Ca2+ is known to be a growth-related intracellular second messenger. These results suggest that the growth regulatory functions of AA are mediated by Ca2+-dependent mechanisms.     

Noniatrogenic esophageal trauma

Few guidelines are available with which to facilitate treatment in patients with noniatrogenic injuries of the esophagus. Early diagnosis and proper management are essential if a good outcome is to be expected. In an effort to define better the treatment of patients with penetrating and blunt injuries of the esophagus, we report our recent 5-year experience at an urban trauma center. From July 1988 to June 1993, nineteen patients with esophageal perforations from penetrating (18) and blunt (1) trauma were identified by our trauma registry. There was no mortality in this group of patients and morbidity was mostly due to associated injuries. Eleven cervical esophageal injuries were repaired. One cervical injury was treated by stopping oral intake and giving intravenous antibiotics. The neck was not drained in 10 of the surgical cases. In 1 patient a tracheoesophageal fistula developed, which later was repaired with a pectoralis muscle flap. Seven perforations were identified in the thoracic (2) and abdominal (5) portions of the esophagus. All were due to gunshot wounds. In 4 cases, a fundal wrap was used to reinforce the repairs. Postoperative contrast studies confirmed that all repairs were intact. We conclude that penetrating and blunt tears of the esophagus can be repaired safely with minimal mortality. Morbidity is usually from associated injuries such as to the spinal cord and trachea. When identified early, cervical esophageal injuries do not need to be drained routinely.     

CVT-313, a specific and potent inhibitor of CDK2 that prevents neointimal proliferation

The activity of cyclin-dependent kinase 2 (CDK2) is essential for progression of cells from G1 to the S phase of the mammalian cell cycle. CVT-313 is a potent CDK2 inhibitor, which was identified from a purine analog library with an IC50 of 0.5 microM in vitro. Inhibition was competitive with respect to ATP (Ki = 95 nM), and selective CVT-313 had no effect on other, nonrelated ATP-dependent serine/threonine kinases. When added to CDK1 or CDK4, a 8.5- and 430-fold higher concentration of CVT-313 was required for half-maximal inhibition of the enzyme activity. In cells exposed to CVT-313, hyperphosphorylation of the retinoblastoma gene product was inhibited, and progression through the cell cycle was arrested at the G1/S boundary. The growth of mouse, rat, and human cells in culture was also inhibited by CVT-313 with the IC50 for growth arrest ranging from 1.25 to 20 microM. To evaluate the effects of CVT-313 in vivo, we tested this agent in a rat carotid artery model of restenosis. A brief intraluminal exposure of CVT-313 to a denuded rat carotid artery resulted in more than 80% inhibition of neointima formation. These observations suggest that CVT-313 is a promising candidate for evaluation in other disease models related to aberrant cell proliferation.