Control of apoptosis in Epstein Barr virus-positive nasopharyngeal carcinoma cells: opposite effects of CD95 and CD40 stimulation.

The expression and function of CD95 and CD40 were investigated in malignant cells from EBV-positive undifferentiated nasopharyngeal carcinomas (NPCs). Large amounts of CD95 and CD40 expression were detected in 15 of 16 EBV-positive NPC specimens. In contrast, CD95 was not detected in two biopsies from patients with EBV-negative differentiated NPCs. We tested whether the CD95 apoptotic pathway was functional in NPC cells by treating two EBV-positive NPC tumor lines in vitro with a CD95 agonist. In both cases, NPC cells were extremely susceptible to CD95-mediated apoptosis, despite strong constitutive expression of Bcl-x. Combined CD40 and CD95 stimulation was used to investigate the possible anti-apoptotic activity mediated by CD40. The CD40 receptor was activated by incubating NPC cells with murine L cells producing CD154, the CD40 ligand. This treatment resulted in a strong inhibition of CD95-related cytotoxicity. Such an anti-apoptotic effect of CD40 is well known for B lymphocytes, but has not previously been reported for epithelial cells. These data suggest that NPC tumor-infiltrating lymphocytes, which often produce the CD40 ligand in situ, may increase the survival of malignant cells, thereby enhancing tumor growth in patients.

Chromosome 11q13 gene amplifications in oral and oropharyngeal carcinomas: no correlation with subclinical lymph node invasion and disease recurrence.

Gene amplifications in the q13 band of chromosome 11 are among the most frequent genetic alterations in head and neck squamous cell carcinomas. Previous studies have suggested that such amplification is a marker of aggressive tumor evolution. Their potential for predicting subclinical lymph node invasion or disease recurrence was investigated in a prospective series of 50 oral and oropharyngeal carcinomas. Cell DNA content was also measured in 32 tumors of this series. Gene amplifications affecting the 11q13 band were detected in 11 of 50 (20%) patients, a relatively low frequency in comparison with data reported previously for other carcinomas of the upper aerodigestive tract, especially hypopharyngeal carcinomas. These gene amplifications were preferentially associated with aneuploidy. Cervical lymph nodes of 26 clinically N0 (Tumor-Node-Metastasis staging) patients were surgically explored. The frequency of 11q13 amplifications was very similar in the presence or in the absence of histological invasion, 3 of 15 (20%) and 2 of 11 (18%), respectively. Thus, 11q13 amplifications do not appear to be a reliable marker for prediction of subclinical lymph-node invasion in oral and oropharyngeal carcinomas. The detection of 11q13 amplifications was also not associated with a higher risk of disease recurrence. These data suggest that not only the prevalence but also the prognostic significance of 11q13 amplifications varies between tumors at different sites in the upper aerodigestive tract.

Persistence of benzo[alpha]pyrenediolepoxide DNA adduct in mouse skin.

The covalently bound products of [3H]benzo[alpha]pyrene (BP) were determined in the DNA isolated from the skin of mice 3 weeks after application of the carcinogen. In the relatively rapidly proliferating skin the persistence of BP-DNA adducts was observed, 50% of which were unmodified nucleosides. Small amounts of (7R) BPDE I-dG adduct (5% from the initial formation) were found after 3 weeks. The minor adducts observed at 18 h after treatment were excised.

Chromosome-11q13 gene amplifications in head and neck squamous-cell carcinomas - relation with lymph-node invasion.

Gene amplifications occurring in the q13 band of chromosome 11 are frequently observed in head and neck squamous cell carcinomas. In order to determine the relative frequency of amplification in 5 distinct 11q13 loci and their relation with clinical data, tumor DNAs from 31 patients - including 26 who had undergone neck dissection (lymph node histology available) - were evaluated by Southern blot. Specific probes were used for the D11S833E, FGF3, CYCD1, D11S97 and GST-pi loci. The most frequently amplified loci were CYCD1 and FGF3 (each locus affected in 17 out of 19 patients with 11q13 amplifications). The range of amplification was from 2x to 9x. Seven (54%) of 13 NO patients had 11q13 amplifications versus 12 (67%) of 18 N1-N3 patients (ns). Among 26 patients for whom lymph node histology was available, 3 (33%) of 9 N- patients had 11q13 amplifications compared to 13 (76%) of 17 N+ patients (p=0.03, G2 test). Fourteen (56%) out of 25 patients staged T>N (for example T4 N1) had 11q13 amplifications versus 5 (83%) of 6 patients N greater-than-or-equal-to T (for example T2 N3) (ns). Of 21 well-differentiated HNSCC, 12 (57%) had 11q13 amplifications versus 7 (70%) of 10 moderately and poorly-differentiated tumors. Three year survival (Kaplan-Meier) was 72.9% for patients without 11q13 amplifications and 44.9% for patients with 11q13 amplifications (ns). Chromosome 11q13 gene amplifications thus appear as a potential prognostic marker, possibly related to loco-regional spread in head and neck squamous cell carcinomas.

Choroidal Osteoma.

Choroidal osteomas caused visual symptoms in four healthy young women. A positive 32P test led to enucleation and histopathologic confirmation of the diagnosis in one patient. The characteristic ophthalmoscopic findings in these patients included the following: (1) slightly and irregularly elevated, yellow-white, juxtapapillary, choroidal tumor and well-defined geographic borders; (2) diffuse and mottled depigmentation of the overlying pigment epithelium; and (3) multiple small vascular networks on the tumor surface. A diffuse mottled pattern of hyperfluorescence in the area of the tumor occurred during the early and later stages of angiography. The tumors were ultrasonically dense, and the orbital tissue behind them was rendered silent. The tumors were visible on routine orbital x-ray films and computerized tomograms. The latter study demonstrated the tumors as having the consistency of normal bone.

Normal intraocular pressure during enucleation for choroidal melanoma.

A simple surgical technique for maintaining normal intraocular pressure during enucleation of eyes with a malignant melanoma of the choroid consists of making an incision into the anterior chamber through clear cornea with a microvitreo-retinal blade, followed by the introduction of a No. 21-gauge scalp vein needle or a No. 23-gauge sidewall-holed needle attached to a closed system filled with balanced salt solution. Measurements of pressure fluctuations during five enucleations are given. Such a system maintains the anterior chamber and keeps fluctuations in IOP to a minimum. This may be important in preventing hematogenous dissemination of tumor cells, resulting in metastatic disease.

Paranasal sinus carcinoma causing orbital mucocele.

Three patients presented with typical orbital mucoceles. However, subsequent histopathologic study revealed paranasal sinus concomitant squamous cell carcinoma in all three cases. Careful histologic investigation is necessary before considering orbital mucocele a benign process.

Action spectrum for retinal injury from near-ultraviolet radiation in the aphakic monkey.

We found that the action spectrum for retinal damage (determined by the fundus photographic appearance of a minimal lesion immediately after exposure) extends into the near-ultraviolet by exposing three aphakic eyes from rhesus monkeys to 405-, 380-, 350-, and 320-nm wavelengths produced by a 2,500-W xenon lamp equipped with quartz optics and 10-nm interference filters. Exposure times were 100 and 1,000 seconds and the spot diameter on the retina was 500 micrometers. The retina was six times more sensitive to 350- and 325-nm wavelengths than to blue light (441 nm). Both ophthalmoscopic and histologic data showed that near-ultraviolet lesions differed in important respects from blue-light lesions. Near-ultraviolet produced irreparable damage to rod and cone photoreceptors.

Basic mechanisms underlying the production of photochemical lesions in the mammalian retina.

Extended exposure (100s) of the macaque retina to blue light (400-500nm) produces a photochemical type or types of lesion. The basic mechanisms responsible for such photic damage are unknown but the toxic combination of light and oxygen leading to the free radicals O-.2, H2O2, OH., and O2(1 delta) have been suggested as a possible source of the phototoxicity. To test this hypothesis, the radiant exposure (J. cm-2) to short wavelength light (435-445nm) required for minimal damage in the macaque retina is under investigation as a function of oxygenation and after administration of substances known to either inhibit/scavenge radicals or act as anti-inflammatory/anti-oxidant agents. Substances under study include beta-carotene, steroids, catalase and SOD. Here we report radiant exposure in J.cm-2 needed to produce a minimal lesion vs oxygenation as measured by partial pressure of O2 in arterial blood (Po2). There is a sharp drop in the radiant exposure threshold with increase in the partial pressure of O2 in arterial blood, e.g. 30 J.cm-2 at 75 torr to 10 J.cm-2 at 271 torr, a factor of 3. Methylprednisolone injected intravenously one hour before exposure (125 mg) has been shown to raise the threshold for retinal damage in two macaques by a factor of approximately 2. Another animal fed beta-carotene (7.5 mg daily) over a period of 3 months has been exposed to blue light at several levels of oxygenation. The results suggest a protective effect.