End‐of‐life care in the head and neck cancer patient

Past the point of no longer being able to control malignancies of the oral cavity and head and neck, the decision‐making process must shift to one that essentially concerns itself with creating comfort for the patient. The role of family, physicians, and other caregivers becomes, in many ways, more directed as active neoplasia‐related concerns become less relevant. Challenges remain significant in terms of continuing management of prior treatment‐related side effects and functional impairments to providers concerning themselves with maintenance of dignity, honoring the wishes of the family, and creating full understanding of on the part of all parties concerned what the goals of treatment cessation and palliation are key as death approaches.     

Fibrinolytic properties of a human endothelial hybrid cell line (Ea.hy 926)

The fibrinolytic characteristics of the endothelial hybrid cell line EA.hy 926, established by fusing a human umbilical vein endothelial cell with a human carcinoma cell line, were studied. The hybrid cell line produced large amounts of tissue-type plasminogen activator (t- PA), plasminogen activator inhibitor type 1, and a small amount of urokinase. All plasminogen activator present in conditioned medium was complexed with inhibitor because the cells secreted plasminogen activator inhibitor in excess over plasminogen activator and no activator activity was detectable in conditioned media by direct activity assays. t-PA activator activity was, however, demonstrable in conditioned media after treatment with sodium dodecyl sulfate, in agreement with t-PA antigen determinations. Increased plasminogen activator inhibitor activity could be induced by incubating the cells in the presence of endotoxin or microtubule inhibitors, whereas increased t-PA activity could be induced by microtubule inhibitors. Interleukin-1 had no effect. The fibrinolytic characteristics of the hybrid cell line were stable for at least 30 passages. The perpetual human hybrid cell line EA.hy 926 therefore may be a useful tool for the study of fibrinolysis in cultured endothelial cells.     

Deficiency of platelet membrane glycoprotein Ia associated with a decreased platelet adhesion to subendothelium: a defect in platelet spreading

A bleeding disorder with absent collagen-induced platelet aggregation and adhesion has been described in a patient whose platelets failed to express surface glycoprotein Ia. We studied the interaction of her platelets with subendothelium in an annular perfusion chamber and the interaction with purified human collagen type III in a rectangular perfusion system under flow conditions. Platelet adherence was almost completely absent both at low and high shear rates. The few platelets which adhered remained in the contact stage without subsequent spreading and aggregate formation. Addition of a monoclonal antibody, which was directed against the von Willebrand moiety of FVIII-VWF, to the blood, completely abolished platelet adherence at high shear rates and had a partial effect at low shear rates. These data indicate that von Willebrand factor plays a role in the initial attachment (contact stage) of platelets to subendothelium. We conclude that the bleeding disorder and excessively prolonged bleeding time in our patient are caused by a new specific defect of the platelet-vessel wall interaction.     

Zinc protoporphyrin in anemia of chronic disorders

Hematofluorometric determination of zinc protoporphyrin (ZPP) is a screening method for the assessment of iron deficiency (ID). Chronic disorders are frequently accompanied by anemias of unclear origin, most probably caused by an impairment of iron metabolism. We investigated the relevance of ZPP for the detection of derangements of iron metabolism in anemias of chronic disorders (ACD). In 19 patients with ACD caused by chronic inflammatory non-neoplastic diseases, ZPP was determined and correlated with ferritin, transferrin saturation, and hemoglobin (Hb). Marrow sideroblast counts and semiquantitative grading of the marrow hemosiderin were performed in all patients to exclude ID and to show the decreased iron bioavailability. In all ACD patients who exhibited the typical laboratory findings of disturbed iron metabolism, such as hypoferremia, decreased transferrin saturation, decreased bone marrow sideroblasts, and increased marrow hemosiderin, strongly elevated ZPP levels were found (131 +/- 23 mumol/mol heme). ZPP returned to normal after successful treatment of the underlying disease. This is shown in three patients with polymyalgia rheumatica. We conclude that the fluorometric determination of ZPP allows detection and quantification of derangements of iron metabolism associated with chronic inflammatory disorders. By recording the derangements quantitatively, ZPP allows monitoring of therapy of chronic inflammatory diseases.     

The biochemical and clinical consequences of 2'-deoxycoformycin in refractory lymphoproliferative malignancy

A deficiency of adenosine deaminase, an enzyme important in purine nucleoside catabolism, is associated with a severe combined immunodeficiency disease in children. Inhibition of this enzyme in vitro and in vivo results in an impairment in lymphoblast proliferation. We have investigated the pharmacologic inhibition of this enzyme by 2'-deoxycoformycin in 15 patients with hematologic malignancies. Biochemical consequences of the administration of this agent were closely monitored in erythrocytes, nucleated peripheral blood and bone marrow cells, serum, and urine. A marked rise in erythrocyte dATP was accompanied by a depletion of ATP in those patients exhibiting toxicity. Most patients excreted large amounts of deoxyadenosine but not adenosine in the urine. Serum deoxyadenosine rose in patients demonstrating a marked decrease in cell mass. The biochemical disturbances and clinical toxicity, including hepatic, renal, and conjunctival abnormalities, were usually reversible. Central nervous system toxicity, which potentially was the most serious consequence, was associated with high erythrocyte dATP/ATP ratios and high levels of cerebrospinal fluid deoxyadenosine. In patients with lymphoma and leukemia, objective responses were observed but were short- lived. Patients with chronic lymphocytic leukemia receiving weekly low doses of the drug demonstrated minimal toxicity and some efficacy. The chemotherapeutic potential o 2'-deoxycoformycin, as either a single agent or in combination with Ara-A, merits further exploration.     

Myocardial infarct size quantification by MR imaging early after coronary artery occlusion in dogs

The feasibility of using magnetic resonance (MR) imaging to estimate myocardial infarct size was explored in an in vitro model using only the inherent differences in contrast between infarcted and noninfarcted myocardium. Eight dogs underwent coronary occlusion; their hearts were removed 6 hours later. Estimates of T2 for normal and infarcted myocardium were derived from MR images. Infarct size was quantified anatomically using triphenyltetrazolium-chloride (TTC) staining and compared with MR estimates. The T2 values derived from the images clearly discriminated between infarcted (126 +/- 22 msec) and normal myocardium (88 +/- 10 msec, P less than .05), providing images with good contrast between normal and infarcted myocardium. Comparable differences in T2 values were also noted from spectrometric determinations. Estimates of infarct size by MR imaging compared well with TTC estimates (r = 0.98) over a wide range of infarct sizes from 3% to 29% of the left ventricular mass. These results suggest the potential for in vivo quantification of infarct size based on the inherent contrast difference between infarcted and normal myocardium.     

US diagnosis of choledocholithiasis: a reappraisal

Sonographic detectability of choledocholithiasis using real-time sector scanners appears to be improved in comparison with series previously reported. To establish this premise, 78 consecutive patients with choledocholithiasis were evaluated prospectively by ultrasound (US) prior to surgery or endoscopic retrograde cholangiopancreatography. Preoperative US analysis yielded a 55% sensitivity for detection of choledocholithiasis (43 patients), representing more than a threefold increase over previous series. Dilated extrahepatic ducts were seen in 52 patients (67%), 40 of whom (77%) were seen to have an intraluminal stone. Extrahepatic ducts were normal in size in 26 patients (33%), only three of whom were seen to have a stone. This marked improvement in detection rate probably is related to improvements in imaging technology as well as to increased diagnostic efforts based on cognizance of the difficulty in making the diagnosis of choledocholithiasis sonographically.     

The N-terminal domain of human urokinase receptor contains two distinct regions critical for ligand recognition

The high-affinity receptor that binds human urokinase-type plasminogen activator (hu-PAR) is a glycosyl-phosphatidylinositol (GPI)-anchored cell-surface glycoprotein that belongs to the Ly-6 superfamily of T- cell-activating receptors. Binding of urokinase (u-PA) to u-PAR is species-specific, since neither murine (mu-PAR) nor hu-PAR binds u-PA from the other species. I designed and analyzed a series of exchanges between hu-PAR and mu-PAR in the N-terminal first domain to which ligand-binding function had been independently mapped. Introduction of as few as 13 murine residues (six of 13 variables) into the N-terminal region of hu-PAR abrogated binding to recombinant human pro-u-PA, whereas the opposite chimera, a mu-PAR carrying six of 13 human residues, was positive for binding. Within this region, the mu-PAR domain 1 could be minimally humanized to bind human pro-u-PA by a substitution of as few as four of the six nonconserved residues, thereby identifying the residues arginine-2, lysine-7, threonine-8, and glycine-10 as important in determining binding specificity. By alanine- scanning mutagenesis, a second recognition site within domain 1 was discovered between residues 47 and 53, a segment that is fully conserved between the human and the mouse receptors. Taken together, these results provide identification of two confined subregions within the N-terminal domain of hu-PAR critically involved in pro-u-PA recognition.     

Chronic radiodermatitis following percutaneous coronary interventions: a report of two cases

We describe two patients in whom chronic radiodermatitis with therapy-resistant ulceration of the right scapular region developed, following percutaneous coronary intervention with fluoroscopic imaging. Contrary to most reported cases in the literature, which involve numerous cardiac catheterization procedures, in both patients described here the total radiation dose was given during two successive procedures, involving difficult and prolonged coronary intervention with stent implantation. In both cases, local treatment of the ulcerative lesions was insufficient, necessitating excision of the radiodermatitis area and replacement with a skin graft, with good therapeutic result. The incidence of radiodermatitis after percutaneous coronary interventions is rising with the increasing number and complexity of these procedures. The main risk factor is a long duration of fluoroscopy using the same incidence. The skin lesions encompass a wide spectrum, ranging from erythema, telangiectasia, atrophy, hyperpigmentation and hypopigmentation to necrosis, chronic ulceration and squamous cell carcinoma. The lesions can appear from 15 days to 10 years after the procedure. To prevent radiation-induced injury, the radiation dose has to be limited and monitored. Also, careful inspection of the skin at the site of exposure is necessary and the radiographic beam has to be restricted to the smallest field size. A good clinical follow-up at regular intervals is important after long and complicated procedures.