Modulation of intracellular cyclic adenosine monophosphate levels and the differentiation response of human neuroblastoma cells.

We have tested the ability of various compounds to raise intracellular cyclic AMP (cAMP) levels and, either alone or in combination with retinoic acid (RA), to promote differentiation of two "RA-resistant" sublines of LA-N-5 human neuroblastoma cells, designated LA-N-5HP and LA-N-5R9. Direct activation of adenylate cyclase by forskolin and cholera toxin increased intracellular cAMP levels over 10-fold in both cell lines after 1 h of treatment, after which the levels slowly declined for the next 16 to 24 h. After 5 days of continuous treatment, cAMP levels still remained 2- to 7-fold elevated above controls and were accompanied by a decrease in cell proliferation and an increase in neurite outgrowth. All these effects were exaggerated when the agents were combined with phosphodiesterase enzyme inhibitors. Increasing cAMP levels (up to 24-fold) with N6,O2'-dibutyryl cyclic AMP (dbcAMP) or 8-bromo-cAMP also resulted in decreased proliferation and an increase in morphological differentiation. Isoproterenol and epinephrine did not alter cAMP levels and had no discernible biological effects. Of the agents that raised cAMP levels, only dbcAMP caused an increase in acetylcholinesterase activity. This effect was duplicated with sodium butyrate and prostaglandin E1 in the absence of an increase in cAMP. RA promoted differentiation but also had little effect on cAMP levels. Combination treatment of cells with RA plus agents that raised cAMP levels resulted in greater degrees of differentiation than seen with single agent treatments. We conclude that: (a) the cAMP synthetic and degradative pathways are functional in LA-N-5HP and LA-N-5R9 cells; (b) elevation of cAMP is sufficient for inhibiting proliferation and promoting neurite outgrowth from these cells, but is not a necessary condition for inducing differentiation; and (c) elevation of intracellular cAMP potentiates the differentiation-inducing activity of RA.

First year after head and neck cancer: quality of life.

PURPOSE: Treatment regimens for head and neck cancer patients profoundly affect several quality-of-life domains. Rehabilitative needs have been identified through cross-sectional analyses; however, few studies have prospectively assessed quality of life, included assessment of psychosocial variables, and identified predictors of long-term follow-up. PARTICIPANTS AND METHODS: The present study addresses these limitations through a prospective assessment of 105 patients with a newly diagnosed first primary squamous cell carcinoma of the oral cavity, pharynx, or larynx. Participants were enrolled onto a larger randomized controlled trial comparing a provider-delivered smoking cessation intervention with a usual-care-advice control condition. Participants completed a battery of self-report measures after diagnosis and before treatment and additional quality-of-life instruments at 1 and 12 months after initial smoking cessation advice. RESULTS: Participants displayed improvements at 12 months in functional status (P = .006) and in the areas of eating, diet, and speech; however, the latter three represent areas of continued dysfunction, and the changes were not statistically significant. Despite these improvements, patients reported a decline in certain quality-of-life domains, including marital (P = .002) and sexual functioning (P = .017), as well as an increase in alcohol use (P < .001). Predictors of quality of life at 12 months included treatment type, the Vigor subscale of the Profile of Mood States instrument, and quality-of-life scores obtained 1 month after initial smoking cessation advice. CONCLUSION: Results reinforce the need for rehabilitation management through the integration of psychologic and behavioral interventions in medical follow-up.

Predictors of long-term smoking cessation in head and neck cancer patients.

Cigarette smoking is a major risk factor for head and neck cancer, and individuals who continue to smoke past diagnosis and treatment are at elevated risk for further disease. In a randomized controlled trial, a state of the art provider-delivered smoking cessation intervention was compared to a usual care advice control condition. The intervention consisted of surgeon- or dentist-delivered advice to stop smoking, a contracted quit date, tailored written materials, and booster advice sessions. Subjects were 186 patients with newly diagnosed first primary squamous cell carcinomas of the upper aerodigestive tract who had smoked cigarettes within the past year. At randomization, 88.2% of subjects were current smokers. At 12-month follow-up, 70.2% of subjects completing the trial (n = 114) were continuous abstainers; among baseline smokers alone the continuous abstinence (CA) rate was 64.6%. The cotinine validation rate at 12 months was 89.6%. Modeling techniques were utilized in order to derive expected CA rates, which included noncompleter subjects (n = 72). The CA rate expected at 1 year for the entire patient population was 64.2%, and for smokers alone the expected CA rate was 59.4%. Logistic regression analysis carried out on baseline smokers identified predictors of 12-month CA status. These included medical treatment, stage of change, age, nicotine dependence, and race. The intervention effect was not significant, although the sign of the effect was positive. Based on these findings, we recommend systematic brief advice to stop smoking for head and neck cancer patients, with a stepped care approach for patients less able to quit.

Effects of retinoic acid on the in vivo growth of human neuroblastoma cells.

We have investigated the effects of retinoic acid (RA) on the development and growth in nude mice of tumors derived from the human neuroblastoma cell line LA-N-5. When cells were treated with 4 x 10(-6) M RA in vitro there was a marked reduction in the number of mice developing tumors when compared to solvent-treated controls. In vivo treatment with RA reduced tumor formation when the retinoid was given for 5 days before tumor injection and continued for 14 days thereafter. In established tumors, RA inhibited progressive tumor growth. There was no demonstrable effect of RA in vivo on the morphologic phenotype of the tumor cells when these regimens were used. We conclude that oral retinoid administration may prove useful in inhibiting or arresting the growth of neuroblastoma, particularly when there is a small initial tumor burden.

Human neuroblastoma cell lines as models for the in vitro study of neoplastic and neuronal cell differentiation.

Neuroblastoma is a childhood solid tumor composed of primitive cells derived from precursors of the autonomic nervous system. This neoplasm has the highest rate of spontaneous regression of all cancer types and has been noted to undergo spontaneous and chemically induced differentiation into elements resembling mature nervous tissue. As such, neuroblastoma has been a prime model system for the study of neuronal differentiation and the process of cancer cell maturation. In this paper we review those agents that have been described to induce the differentiation of neuroblastoma, with an emphasis on the effects and possible mechanisms of action of a group of related compounds, the retinoids. With this model system and the availability of subclones that are both responsive and resistant to chemically induced differentiation, fundamental questions regarding the mechanisms and processes underlying cell maturation have become more amenable to in vitro study.

Insulin secretion, glucose production, and insulin sensitivity in underweight and normal-weight volunteers, and in underweight and normal-weight cancer patients: a Clinical Research Center study.

Severe malnutrition (< 65% ideal body weight [IBW]) is associated with reduced insulin secretion, decreased receptor affinity, and glucose intolerance. To characterize the abnormality of mild malnutrition in terms of insulin action, both the insulin sensitivity index and insulin secretion were measured in 15 underweight and 15 normal-weight volunteers. Ten patients had localized squamous cell carcinomas of the head and neck, and 20 were normal controls. After a 10-hour overnight fast, all volunteers were studied using Bergman's modified intravenous (IV) glucose tolerance test (IVGTT). Body weight and diagnosis were compared using a 2 x 2 ANOVA. The acute insulin response to IV glucose was reduced in normal-weight and underweight cancer patients by approximately 40% to 50% (P < .05). Both groups of cancer patients had a significantly reduced rate of glucose disposal (1.25 +/- 0.29 and 1.27 +/- 0.23 %/min) compared with the healthy volunteers (1.82 +/- 0.21 and 1.81 +/- 0.24 %/min, respectively, P < .05). Glucose production (GP) was significantly increased in the underweight cancer patients versus the weight-matched volunteers (13.9 +/- 1.3 v 10.8 +/- 0.5 micromol/kg/min, P < .05). Normal-weight and underweight cancer patients had a 32% to 44% reduction in insulin sensitivity (P < .05). In contrast to the effects of cancer, underweight controls had twice the insulin sensitivity compared with normal-weight controls (P < .01). Since insulin secretion decreased in underweight controls, the increased insulin sensitivity may have been due to an increased insulin action and to factors associated with leanness.

Hibernomas of the head and neck.

Hibernomas are rare tumors derived from brown adipose tissue, a specialized form of fat tissue found in hibernating and nonhibernating animals. Only a minority of reported hibernomas have occurred in the head and neck region. This report describes two cases of cervical hibernomas, one of which was preoperatively diagnosed by the use of fine-needle aspiration biopsy. The clinical and pathologic characteristics of this neoplasm are reviewed. In general, hibernomas are slow-growing tumors with inconclusive evidence for the existence of a malignant variant. A review of the literature supports the conclusion that excision, sparing vital structures, appears to be curative.

Multiple sequential pulmonary resections for metastatic pheochromocytoma with long-term survival.

Pheochromocytoma is not rare; indeed, it was discovered in 0.1 percent of consecutive autopsies and in 0.64 percent of a large group of patients screened for hypertension. A patient who underwent excision of a pheochromocytoma at age 7 years is presented. Seven years later, bilateral metastatic pulmonary nodules were excised. Fourteen years later, two metastatic pulmonary nodules were again excised. The patient is doing well 1 year after discharge. Surgical resection of multiple metastatic pheochromocytoma nodules is recommended.

The effects of retinoic acid on the in vitro and in vivo growth of neuroblastoma cells.

In large part, malignancy is the end result of aberrant cell growth and differentiation. Control of these processes is anticipated to result in a suppression of oncogenicity. Retinoic acid (RA), a derivative of vitamin A, has been shown to inhibit proliferation, induce cell differentiation and reverse the malignant phenotype of a variety of tumor cell types. In order to further characterize the antitumor potential of RA, this study examined the in vitro and in vivo effects of this retinoid on cell lines derived from human neuroblastoma (NB). The in vitro phase of this study tested the ability of various compounds to raise intracellular cyclic adenosine 3':5'-monophosphate (cAMP) levels and either alone or in combination with RA, to promote differentiation of two relatively RA-resistant cell lines. Direct activation of the synthetic enzyme adenylate cyclase by forskolin or cholera toxin increased intracellular cAMP levels over 10-fold after 1 hour of treatment, declining over the next 16 to 24 hours. After 5 days of continuous growth in the presence of these agents, cAMP levels remained elevated 2- to 7-fold above control values and were accompanied by a decrease in cell proliferation and an increase in cell differentiation. All these effects were exaggerated in the presence of phosphodiesterase inhibitors. Isoproterenol and epinephrine did not alter cAMP levels and had no discernible biological effects. RA promoted differentiation with little effect on cAMP levels. Combination treatment of cells with RA plus agents that raised cAMP levels resulted in greater degrees of differentiation than seen with single-agent treatment. From these data, it was concluded that: 1. the cAMP synthetic and degradative pathways are functional in the NB cell lines studied; 2. elevation of cAMP is a sufficient but not necessary condition for inhibiting proliferation and promoting differentiation in these cells; 3. elevation of intracellular cAMP potentiates the differentiation-inducing activity of RA; and 4. overcoming retinoid resistance in some tumor cell lines may be feasible by alterations in the cAMP system. This would be of particular value in treating tumors that have lost retinoid responsiveness. The in vivo phase of this study examined the effects of single-agent treatment using RA on the development and growth in nude mice of tumors derived from a NB cell line.(ABSTRACT TRUNCATED AT 400 WORDS)

Merkel cell carcinoma: an aggressive skin neoplasm.

Merkel cell carcinoma (MCC) is an aggressive skin neoplasm of neuroendocrine origin. To clarify those factors important in improving survival, we retrospectively reviewed the charts of all patients with Merkel cell carcinoma treated at two tertiary referral centers. Eighty percent of the patients with stage I disease were initially treated with local therapy alone, while all of the patients with stage II disease were treated with local and regional therapy. The overall survival rate for all patients was 64%. Regardless of stage, patients treated with local excision alone had a 52% 5-year survival rate, while patients treated with local excision and lymph node dissection had an 87% survival rate. We conclude that the aggressive nature of this tumor warrants radical therapy.

Juvenile nasopharyngeal angiofibroma: an update of the UCLA experience, 1960-1985.

The UCLA experience with juvenile angiofibroma (JNA) over a 25-year period is reviewed. There were 83 patients, the majority being adolescent males. Surgery was the primary method of treatment for disease not extending intracranially; 63 of 68 patients (92.5%) became asymptomatic with this modality. In patients treated with a single course of primary radiation, 10 of 14 (78.5%) became asymptomatic. Trends in diagnosis and treatment were evaluated. Contrast computerized tomography reliably assesses tumor extent. Preoperative arteriography is essential for the evaluation and embolization of feeding vessels; this in turn significantly reduces operative blood loss and the need for transfusions. Radiotherapy should be reserved for disease extending intracranially and should be in doses of 3,600 cGy or larger.

Oral lichen planus and its association with squamous cell carcinoma: an update on pathogenesis and treatment implications.

Lichen planus of the oral mucosa (OLP) is characterized by lymphocytic mucositis, basal cell lysis, and lymphocyte transmigration into the epithelial compartment. Some reports have suggested a high incidence of oral squamous cell carcinoma (OSCCA) in OLP patients and have implicated OLP as a premalignant lesion. We describe five cases of OSCCA arising in patients with preexisting OLP. At our institution, the incidence of OSCCA in patients with OLP approximates that reported in other series. The immunopathologic basis for OLP, its potential association with malignancy, and the variable clinical picture of OSCCA in patients with OLP are reviewed. Specific recommendations are given for treatment and follow-up of lesions, including the role of future testing with viral and oncogene markers.

Transcutaneous Teflon injection of the paralyzed vocal cord: a new technique.

Because of anatomical deformity, trismus, or for other reasons, it may on occasion be impossible to visualize a larynx by the usual laryngoscopy methods. Such difficulties in patients who have paralytic dysphonia may also make it impossible to effect improved vocal cord closure by the usual techniques of Teflon injection. We have applied a new technique, detailed in this report, to these problem cases. Following topical anesthesia of the nose, nasopharynx, and larynx, 1% Xylocaine is injected over the cricothyroid membrane. A flexible or telescopic laryngoscope connected to a television camera is introduced through the nose or oral cavity, respectively. A 16-gauge spinal needle is introduced into the subglottic tracheal lumen via the cricothyroid membrane and directed into the undersurface of the paralyzed vocal cord under indirect visual control. Teflon is then injected, monitored via the television image. Our early experience with this simple technique indicates that voice improvement is comparable to that expected using conventional transoral laryngoscopic techniques.

Surgical trauma to the lateral semicircular canal with preservation of hearing.

Surgical trauma to the lateral semicircular canal (LSC) is a rare complication which does not always result in cochlear damage. The authors present six such cases, discuss the histopathological findings of one case, and review 12 previous reports. Transient cochlear depression with normalization of function within 6 weeks of trauma occurred in most instances. Vestibular symptoms were pronounced and, although compensation was not delayed, positional dizziness and instability usually persisted for several months and occasionally for a year or more. Histopathological findings (two specimens) were significant for obliterative scarring of the LSC at the site of injury and for the structural integrity of the labyrinth and cochlea. The mechanism of cochlear protection in these cases remains obscure; however, clean injuries away from the ampullary end of the canal occurring in patients without preexisting inner ear disease appear to have a better prognosis. Intraoperative closure of the defect, postoperative bed rest, and antibiotics are the basic elements of management.

Rhinocerebral mucormycosis: evolution of the disease and treatment options.

Rhinocerebral mucormycosis is recognized as a potentially aggressive and commonly fatal fungal infection. The classic presentation is involvement of nasal mucosa with invasion of the paranasal sinuses and orbit. Mucormycosis is most commonly seen in association with diabetic ketoacidosis, but disease demographics have changed with the onset of AIDS and the advent of powerful immunosuppressive drugs. Treatment includes aggressive debridement, systemic antifungal therapy, and control of underlying comorbid factors. Although surgical intervention remains essential, advances in medical therapy have permitted a more limited surgical approach to minimize functional loss without compromising survival. We present the UCLA experience with rhinocerebral mucormycosis from 1955 to 1995, with emphasis on the evolution of disease presentation and alternative treatment options.

Positron emission tomography: a new, precise imaging modality for detection of primary head and neck tumors and assessment of cervical adenopathy.

Positron emission tomography (PET) has been shown to be effective in detecting intracranial malignancies based on cerebral glucose metabolism. To evaluate the ability of PET to detect extracranial head and neck neoplasms and cervical metastases, 16 patients with primary squamous cell carcinomas were examined. All patients received preoperative computerized tomography (CT) and magnetic resonance imaging (MRI) scans and underwent PET evaluation using intravenous 18F-2-fluoro-2-deoxy-D-glucose (FDG). Histopathologic analysis compared tumor invasion and positive lymph nodes with findings on MRI, CT, and PET images. All primary tumors were delineated by PET, while MRI and CT failed to detect one superficial tumor involving the anterior tongue. Ten nodes were detected by CT and MRI versus 12 nodes demonstrated by PET. PET is highly effective in detecting head and neck carcinomas as well as metastatic cervical lymph nodes. In addition, PET may be useful in evaluating postsurgery and postradiotherapy patients for recurrent and new primary tumors.

The use of positron emission tomography for early detection of recurrent head and neck squamous cell carcinoma in postradiotherapy patients.

Positron emission tomography (PET) has recently proved to be highly sensitive in detecting known extracranial head and neck squamous cell carcinomas when compared to computed tomography and magnetic resonance imaging (MRI). The ability of PET to detect early subclinical recurrent squamous cell malignancies in patients who received primary radiotherapy was evaluated. A new PET-MRI coregistration technique was used to determine precise anatomic tumor location, enabling directed biopsies to confirm the presence of malignancy, and to plan additional therapeutic strategies. Ten patients underwent PET evaluation with intravenous [18F]-fluorodeoxyglucose and received postradiotherapy MRI scans. In all cases, PET accurately detected the presence of recurrent disease despite negative or equivocal MRI scans and indeterminate clinical examinations. PET appears to be highly effective in detecting early recurrent head and neck squamous cell malignancies in postirradiated patients.

Teratomas of the head and neck in childhood.

Teratomas are tumors consisting of tissue arising from all three embryonic germ layers. Their occurrence in the head and neck region is rare. Three patients with this lesion are presented. Although exhibiting progressive uncoordinated growth, histologic evidence of malignancy in the head and neck form of this tumor is distinctly uncommon. Mortality associated with teratomas is most often secondary to respiratory compromise. Complete surgical extirpation is the treatment of choice to lower mortality and recurrences. The use of fine needle aspiration in the management of neck masses in children is discussed.

Magnetic resonance imaging--guided fine-needle aspiration biopsies of retropharyngeal lesions.

OBJECTIVE: The retropharyngeal space is a deep neck space susceptible to a host of disease processes. Surgical access to this space is technically difficult and associated with potential morbidity. An image-guided fine-needle aspiration (FNA) biopsy, if proven accurate and safe, would be of great benefit as an alternative diagnostic approach to this space. This study reports on the use of magnetic resonance imaging (MRI)--guided FNA for diagnostic evaluation of retropharyngeal lesions. Technical details of needle systems, approach to this space, and reliability of this method are described. STUDY DESIGN: This is a prospective study of 14 patients with retropharyngeal lesions who underwent MRI-guided FNA biopsy at the University of California at Los Angeles Center for the Health Sciences between October 1989 and October 1998. METHODS: A 0.2-tesla open magnet was used to obtain magnetic resonance images of each retropharyngeal lesion. After standard skin preparation a coaxial needle system was used to reach and sample the lesion. In most instances, the specimen was immediately stained and examined by a cytopathologist for adequacy before removing the patient from the scanner. RESULTS: Eleven of 14 (78%) patients had diagnostic aspirations; only 2 of these 11 patients required additional surgical biopsy for more specific histological characterization of their lesions before definitive treatment recommendations were given. All aspiration procedures were well tolerated and without any complications. CONCLUSION: We have demonstrated that MRI-guided approach to the retropharynx is feasible, safe, and sensitive enough to obviate the need for open biopsies in a large percentage of patients.

CT-directed fine needle aspiration biopsies of masses in the head and neck.

Fine needle aspiration (FNA) biopsy is a safe, reliable, and cost-effective technique available for the evaluation of head and neck masses. Its utility is enhanced by the use of CT-directed aspiration. Candidates for CT-directed FNA include patients with: 1. deep-seated lesions; 2. distorted anatomy as a result of surgery or irradiation; 3. medical problems which contraindicate general anesthesia. The initial UCLA experience with this modality is reviewed. In certain clinical settings, CT-directed FNA can be a highly productive source of clinical information.