Sinus surgery in bone marrow transplantation patients.

Bone marrow transplantation (BMT) is used in the treatment of a wide range of malignancies. It involves immunosuppression and increased risk of infections such as sinusitis. However, the risk of infection is much higher in allogeneic transplants than those who are replaced with their own bone marrow (autologous). Immunodeficient patients may develop fungal sinusitis with a high mortality rate. An aggressive approach to evaluation and surgical intervention for fungal sinusitis in BMT patients at the Indiana University Medical Center was used for 2 years (from 1991 through 1992). This approach encouraged surgery on any BMT patient who was clinically septic or had any changes on a sinus CT scan. In 1993, a more medically oriented approach with radiologic and nasal endoscopic monitoring was adopted. During 1991 to 1992, 12 of the 21 allogeneic transplant patients (57%) who had sinus surgery died. The four autologous BMT patients operated on during this period all survived. Three allogeneic transplant recipients had surgery in 1993 and survived. No autologous cases had sinus procedures in 1993. No fungal sinus infection occurred in any BMT patient during the 3-year review. Careful patient selection, evaluation, and preventative measures can be successful in dealing with this rare but potentially fatal complication without performing unnecessary surgery on patients who have a poor prognosis unrelated to their sinuses.

Antileukotriene therapy for the relief of sinus symptoms in aspirin triad disease.

We studied the effect of antileukotriene therapy for the relief of sinus symptoms in patients with aspirin triad disease (ATD). We reviewed the charts of 18 ATD patients who had received antileukotriene therapy. All patients had undergone previous sinus surgery. We then designed a questionnaire to determine the level of each patient's symptoms of chronic rhinosinusitis before and after antileukotriene therapy. Responses were converted to symptom scores. For each patient, the role of therapy in the relief of sinus symptoms was evaluated in three ways: by total symptom scores, by self-reports of overall benefit, and by findings on endoscopic nasal examination. Fifteen of the 18 patients completed the questionnaire. Symptom scores for both major and minor symptoms indicated that nine patients had improved following antileukotriene therapy; three other patients reported some overall benefit from therapy, despite no improvement in their symptom scores. Endoscopic nasal examination findings were consistent with the reports of overall benefit. We conclude that antileukotriene therapy is an effective treatment for most patients whose symptoms of chronic rhinosinusitis persist following sinus surgery.

Factors influencing survival in ethmoid sinus cancer.

Nineteen patients with primary ethmoid sinus malignancies were treated at the Cleveland (Ohio) Clinic Foundation between 1976 and 1989. Pathologic diagnoses included adenocarcinoma (eight), sarcoma (four), squamous cell carcinoma (three), mucoepidermoid carcinoma (two), adenoid cystic carcinoma (one), and undifferentiated carcinoma (one). All patients underwent surgical resection: 13 had craniofacial resection, four had craniofacial resection/orbital exenteration, one had radical ethmoidectomy/maxillectomy/orbital exenteration, and one had transantral ethmoidectomy. Twelve patients had combined treatment with radiation therapy. Ten patients were alive with no evidence of disease. A trend toward improved prognosis is associated with negative surgical margins. Preservation of the globe was not associated with local recurrence at this site. A poor prognosis was noted with involvement of the dura, brain, nasopharynx, or sphenoid sinus.

Carotid body tumors.

The surgical management of carotid body tumors requires identification and preservation of neural and vascular structures without compromising resection of the neoplasm. Fifteen patients were examined and treated for carotid body tumors at the Cleveland (Ohio) Clinic Foundation from 1979 through 1987. The benchmark of diagnosis is bilateral carotid angiography. When neural structures are free of tumor, meticulous dissection facilitates their preservation. Large tumor size increases risk for arterial resection necessitating reconstruction. The use of a vascular shunt minimizes the risk of cerebral ischemia. Postoperative intravenous digital subtraction angiography allows for evaluation of arterial repair. A retrospective review of 15 carotid body tumor resections performed in 14 patients revealed no evidence of tumor recurrence, no mortality associated with surgical intervention, no postoperative cerebrovascular accident, and limited morbidity associated with unavoidable sacrifice of neural elements.

A high molecular weight cytotoxic lymphokine in supernatants of lymphokine-activated killer cells cross-reacts with transforming growth factor beta.

Supernatants of lymphokine-activated killer (LAK) cells were highly cytotoxic for melanoma A375 cells. A high-molecular-weight fraction was isolated from such supernatants by gel filtration on an S-300 Sephacryl column (Fraction 1; Fr1). The cytotoxic activity in Fr1 was heat- and acid-resistant and was completely abolished by a rabbit antibody against TGF-beta. We conclude that Fr1 contains TGF-beta or a cross-reactive molecule, associated with a high-molecular-weight carrier.

Primary squamous cell carcinoma of the parotid gland.

Primary squamous cell carcinoma of the parotid gland is an uncommon malignancy. It can be diagnosed only after squamous cell carcinoma metastatic to the parotid gland has been excluded. Histologic evaluation must differentiate primary squamous cell carcinoma from high-grade mucoepidermoid carcinoma or adenocarcinoma. Retrospective review of parotid gland neoplasms seen in the Department of Otolaryngology and Communicative Disorders between 1972 and 1987 identified eight cases for an incidence of 1.8%. The majority of these patients had advanced disease and were treated with both surgery and radiation therapy. Fifty percent of the cases demonstrated no evidence of disease at an average follow-up of 29 months.

Culture supernatants of lymphokine-activated killer (LAK) cells contain a high-molecular-weight cytotoxic lymphokine.

Supernatants of human lymphokine-activated killer (LAK) cells grown in vitro were tested for cytotoxic activity against several mouse and human neoplastic cell lines. All LAK preparations tested (14/14) exhibited cytotoxic activity (40-90% killing of the target cells). Sephacryl S-300 Gel filtration experiments indicated that the biological activity of the LAK supernatant is associated with molecular moieties ranging from 800 kDa or more, to less than 10 kDa. The finding of strong cytotoxic activity in LAK supernatants against several tumor lines points to the possibility of employing soluble products of these cells, rather than the living cells themselves, for therapeutic purposes.

Histiocytic necrotizing lymphadenitis (Kikuchi's disease).

Histiocytic necrotizing lymphadenitis (Kikuchi's disease) is a benign disorder predominantly of young women who present with cervical adenopathy. It has, on occasion, been misdiagnosed as a malignant neoplasm. Little mention of this condition has appeared in the otolaryngologic literature. A patient with Kikuchi's disease is reported and the pertinent literature is reviewed. Because both the clinical and pathological aspects of Kikuchi's disease are important in establishing the diagnosis, effective consultation between the head and neck surgeon and the pathologist is crucial.

Off-axis folded laser beam trajectories in a strip-line CO(2) laser.

Using an rf-excited strip-line CO(2) laser with large lateral dimensions (a high Fresnel number) in a hemiconfocal optical cavity configuration, we observe modes that are distinctively off axial. They can be viewed as folded Gaussian beams with trajectories in the shapes of the letters M and W. Either of these modes can be isolated by suppressing the other mode through the introduction of a suitably positioned obstacle into the cavity. Computer simulations of the radiation propagation in the cavity yielded field distributions conforming to the observed pattern.

An adhesion-defective variant of F9 embryonal carcinoma cells fails to differentiate into visceral endoderm.

Adhesion-defective EC cells were isolated from a population of mutagenized F9 cells by serial transfer of cells that did not adhere to gelatin-coated dishes. The variant cells grew in suspension as multicellular clusters of loosely aggregated cells. The cells adhered to, but did not flatten on, fibroblast monolayers and extracellular matrix produced by parietal-like endoderm. Two different mutant cell lines exhibited increased sensitivity to the lectin abrin and decreased sensitivity to wheat germ agglutinin, suggesting that changes in cell surface glycosylation are associated with the mutant phenotype. These adhesion-defective mutants were used to study the relationship between cell-cell adhesion and endodermal differentiation. Unlike wild-type cells, when cultured with low concentrations of retinoic acid (RA) in suspension culture, the mutant cells did not form embryoid bodies but remained as loosely adhering strings of cells. Electron microscopic examination revealed that most of the differentiated variant cells resembled parietal endoderm, and this was confirmed by immunofluorescent staining for TROMA-3 marker. The levels of some of the markers that characterize the differentiative pathways were examined by immunoprecipitation and by enzyme-linked immunosorbent assay (ELISA). The variant line produced higher levels of laminin and type IV collagen compared to the wild-type cells. alpha-Fetoprotein (AFP) was produced at a significantly lower level by the variant compared to wild-type F9 cells during the differentiative process. The results show that variant cells differentiated toward parietal endoderm but have a very much restricted ability to differentiate to visceral endoderm. We conclude that aggregation and/or compaction provide some essential signals during the differentiation of F9 cells into epithelial layers of visceral endoderm.

Metabolism, distribution, seminal excretion and pharmacokinetics of caffeine in the rabbit.

The pharmacokinetics, tissue distribution and metabolism of caffeine were studied in male New Zealand White rabbits after an i.v. dose of 4 mg/kg. The mean (n = 4) distribution half-life was 0.2 hr and the mean elimination half-life was 3.8 hr. The mean clearance was 0.20 liters/kg/hr and the mean volume of distribution was 0.82 liters/kg. Concurrent samples of blood and semen from three rabbits, trained to ejaculate into an artificial vagina, were analyzed. The mean semen/blood concentration ratio of caffeine was 1.0. The concentrations of caffeine in the tissues of three rabbits were examined at 1 hr after an i.v. dose of 4 mg/kg. Most tissues exhibited a tissue/blood concentration ratio of approximately 1.0. Exceptions to this included fat, adrenals, liver and bile in which the ratios were 0.2, 0.6, 1.5 and 2.7, respectively. Urinary metabolites were investigated after an i.v. dose of 4 mg/kg of [14C]caffeine. The metabolites of caffeine were separated by high-pressure liquid chromatography and quantified by liquid scintillation counting. The major urinary metabolites of caffeine in the rabbit were 1-methylxanthine (22%), 1-methyluric acid (19%), 7-methylxanthine (16%) and 1,7-dimethylxanthine (14%).

Variant embryonal carcinoma cells lacking SSEA-1 and Forsmann antigens remain developmentally pluripotent.

Six embryonal carcinoma (EC) cell lines that are resistant to the cytotoxic, galactose-specific lectin abrin were isolated from mutagenized populations of either PSA-1 or F9 cells. The LD10 for each of the variant lines was at least 150-fold greater than that for parental cells. Indirect cytotoxicity tests demonstrated that all of the variant cell lines lacked both Stage Specific Embryonic Antigen-1 (SSEA-1, less than 1% of wild-type levels) and Forsmann antigen (less than 5% of wild-type levels). When abrin-resistant cells were fused to previously isolated SSEA-1-negative cells (M. J. Rosenstraus (1983), Dev. Biol. 99, 318-323) that express Forsmann antigen, the resulting hybrids expressed SSEA-1. This implies the mutation conferring abrin resistance is in a different gene than that defined by the previously isolated mutation. Thus, we have identified two genes that are required for SSEA-1 expression, one of which also appears to be required for Forsmann antigen expression. The F9-derived variants differentiated into visceral-like or parietal-like endoderm when treated with retinoic acid in the absence or presence of 8-bromo-cAMP, respectively. PSA-1-derived variants formed differentiated teratocarcinomas containing derivatives of all three germ layers. Thus the SSEA-1 and Forsmann haptenic determinants are not required for EC cells to differentiate into a broad spectrum of cell types; nor do they appear to be involved in the cell-cell interactions that are postulated to regulate visceral versus parietal endoderm differentiation.

Modulation of hepatic protein kinase activity by indomethacin.

We previously demonstrated that treatment with indomethacin in vivo significantly blunted the glucagon-induced glycemic response in the rat. This prostaglandin synthetase (cyclo-oxygenase) inhibitor also accentuated the evanescent effect of glucagon on hepatic glucose output in the intact, anesthetized rat. In this report, we present evidence that impairment of glucagon action in the rat liver by indomethacin is mediated through its inhibitory effect on both cAMP-dependent and cAMP-independent hepatic protein kinase. Indomethacin treatment did not have a measurable effect on any of the other components of the glucagon transducer system. Furthermore, infusion with glucagon for two hours that maintained plasma glucagon values at high physiological levels significantly reduced hepatic cAMP-dependent protein kinase activity without altering its Km. Glucagon infusion also down-regulated its own hepatic receptors and glucagon-stimulated cAMP production; prostaglandin E1-stimulated cAMP production was not affected. We concluded that prostaglandins may play a role in the regulation of hepatic protein kinases involved in the glucagon-stimulated glycogenolytic response and that glucagon-induced down-regulation extends at least to the hepatic protein kinases. However, a direct effect of indomethacin or protein kinase and the adenylate cyclase complex cannot be ruled out.

Fibroblast feeder layers inhibit differentiation of retinoic acid-treated embryonal carcinoma cells by increasing the probability of stem cell renewal.

The appearance of differentiated cells in embryonal carcinoma (EC) cultures can be inhibited by culturing the cells on fibroblast feeder layers. To determine whether or not feeder layers act by increasing the probability of stem cell renewal, growth and differentiation were monitored in cultures of F9 (subclone OTF9 -63) EC cells exposed to retinoic acid (RA) in either the presence or absence of feeder layers. By measuring the fraction of laminin-positive TROMA 1-positive or alkaline phosphatase-negative cells, it was determined that the frequency of differentiated cells in RA-treated F9 cultures was reduced by 70-80% when cells were cultured on fibroblast feeder layers instead of gelatin-coated dishes. Experiments in which EC cells were cultured in close proximity to a feeder layer demonstrated that cell-cell contact was required for maximal inhibition of differentiation. The probability of stem cell renewal was determined by measuring the number of colony-forming cells in RA-treated cultures as a function of time. Analysis of the data demonstrated that the probabilities of stem cell renewal were 0.5 and 0.25 during the first and second 48 h periods, respectively, following addition of RA for cells cultured without feeder layers. Cultures maintained on feeder layers exhibited a stem cell renewal probability of 0.72. Thus, feeder layers reduce the frequency of differentiated cells in RA-treated cultures by increasing the probability of stem cell renewal. Determining the mechanism by which feeder layers counteract the effect of a chemically defined differentiation inducer should help to uncover the processes that regulate the probability of stem cell renewal.

Ontogeny of hepatic insulin and glucagon receptors and adenylate cyclase in rabbit.

In rabbit liver plasma membranes (LPM), specific binding of 125I-insulin rapidly increased in late gestation and peaked at birth, declining thereafter. In contrast, 125I-glucagon binding was lowest in late gestation, somewhat higher at birth, and increased by 48 h although only to 20-25% of adult. These changes in binding were due to changing numbers of receptors involving predominantly high affinity sites for insulin and low affinity sites for glucagon, with only minor changes in affinity. Despite measurable glucagon receptors by birth, fetal LPM produced no increment above basal in cAMP production with maximal doses of glucagon (10(-6) M), prostaglandin E1 (10(-4) M), or epinephrine (10(-4) M). Near birth only NaF (10 mM) produced a modest but significant increment in cAMP. By 2 h postbirth, all stimuli evoked significant increments in cAMP production that increased progressively but was still only 15-20% of adult at 48 h. Furthermore, although specific binding of cholera toxin was greater in fetal LPM (11 +/- 1 vs. 6 +/- 1%), cholera toxin-stimulated cAMP production increased by only 12-26% above basal in the fetus compared with 220% in adult. Markers of membrane purity including 5'-nucleotidase, phosphodiesterase, and insulin or glucagon degradation were not different in fetus and adult. We conclude that receptors and components of the adenylate cyclase complex mature independently; initial coupling occurs between the G/F regulatory protein and the catalytic unit (NaF but not hormonal activation) followed within hours of birth by coupling to the hormone receptor.