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Pyriform sinus cancer remains one of the most lethal of human diseases. Regardless of approach attempted significant enhancement of survival has not been realized. In this study a retrospective single institutional review of all patients diagnosed with pyriform sinus cancer during the 1980s was conducted. The results in 93 patients show an overall determinant 5-year survival of 14.3%. Of patients undergoing surgery, median determinant survival was 37 months and 5-year survival was 34.6%. In resectable patients treated with radiation with or without chemotherapy, median determinant survival was 13 months with 5-year survival of 7.1% (P < .01). Surgical salvage was attempted in 8 patients without success. In conclusion, due to the apparent survival advantage for surgical patients, the low rate of surgical salvage, and the relatively low rate of organ preservation in prospective trials, pyriform sinus cancer is a poor site for organ preservation. Surgery followed by radiation therapy should remain the standard of care for pyriform sinus cancer.

Background: Fever associated with sinus disease in the immunocompromised bone marrow transplant recipient requires prompt evaluation and therapy. Very little is known about the incidence, risk factors, and sequelae of nonsurgically treated sinus disease in this population., Methods: A retrospective review of 107 consecutive allogeneic and autologous bone marrow transplant recipients from August 1987 to July 1989 was performed to determine (1) the overall incidence of sinus disease; (2) factors that influence the development of sinus disease; and (3) the sequelae of sinus disease treated nonsurgically., Results: Overall 33 (31%) of 107 bone marrow transplant recipients had sinus disease defined as a radiographic abnormality with clinical symptoms. Eleven (10%) of 107 recipients had preexisting sinus disease. Sinus disease developed in 22 (21%) of 107 recipients after bone marrow transplantation. Sinus abnormalities were significantly higher among allografted bone marrow transplant recipients than among autografted recipients (p = 0.027). The diagnosis, stage of disease, cytoreductive regimen, or graft-vs.-host disease were not different between recipients in whom sinus disease did and did not develop. There were no deaths as a result of sinus complications., Conclusions: Sinus disease developed in 21% of the studied population after bone marrow transplantation. Allogeneic recipients had a higher incidence of sinus disease than autologous recipients. There were no deaths attributed to sinus complications. All sinus disease in this bone marrow transplant population was treated medically. No patient required surgical intervention either before or after bone marrow transplantation.

Background: The context-sensitive half-time, rather than the terminal elimination half-life, has been proposed as a more clinically relevant measure of decreasing drug concentration after a constant infusion of a given duration. The context-sensitive half-time is derived from computer modelling using known pharmacokinetic parameters. The modelled context-sensitive half-time for a 3-h infusion of alfentanil is 50-55 min and is 3 min for remifentanil. The terminal elimination half-life is 111 min for alfentanil and 12-30 min for remifentanil. It has not been tested whether the modelled context-sensitive half-time reflects the true time for a 50% decrease in drug concentration or drug effect., Methods: Thirty volunteers received a 3-h infusion of remifentanil or alfentanil at equieffective concentrations. Depression of minute ventilation to 7.5% ETCO2 was used as a measure of drug effect. Minute ventilation response was measured, and blood samples for drug concentration were taken during and after drug infusion. The recovery of minute ventilation (drug effect) and decrease in blood drug concentration was plotted, and the time for a 50% change was determined., Results: The measured pharmacokinetic context-sensitive half-time for remifentanil after a 3-h infusion was 3.2 +/- 0.9 min, and its pharmacodynamic offset was 5.4 +/- 1.8 min. Alfentanil's measured pharmacokinetic context-sensitive half-time was 47.3 +/- 12 min, and its pharmacodynamic offset was 54.0 +/- 48 min. The terminal elimination half-life modelled from the volunteers was 11.8 +/- 5.1 min for remifentanil and 76.5 +/- 12.6 min for alfentanil., Conclusions: The measured context-sensitive half-times were in close agreement with the context-sensitive half-times previously modelled for these drugs. The results of this study confirm the value of the context-sensitive half-time in describing drug offset compared to the terminal elimination half-life.

Ameloblastic carcinoma is an unusual tumour. There have been a total of 34 cases of ameloblastic carcinoma in the English literature to date. Of these only 11 cases have occurred in the maxilla. The authors report the 12th such case. The histological classification for odontogenic carcinoma has been debated for many years and recently revised, thus differentiating between malignant ameloblastoma and ameloblastic carcinoma. The authors review the current literature regarding diagnosis and treatment of this unusual lesion, and support the use of the term malignant ameloblastoma for the tumours that metastasize in spite of their benign histological appearance, whereas, the ameloblastic carcinoma is referred to as the primary tumour with malignant transformation, regardless of its metastatic potential.

Cell death in the Drosophila embryonic central nervous system (CNS) proceeds by apoptosis, which is revealed ultrastructurally by nuclear condensation, shrinkage of cytoplasmic volume, and preservation of intracellular organelles. Apoptotic cells do not accumulate in the CNS but are continuously removed and engulfed by phagocytic haemocytes. To determine whether embryonic glia can function as phagocytes, we studied serial electronic microscopic sections of the Drosophila CNS. Apoptotic cells in the nervous system are engulfed by a variety of glia including midline glia, interface (or longitudinal tract) glia, and nerve root glia. However, the majority of apoptotic cells in the CNS are engulfed by subperineurial glia in a fashion similar to the microglia of the vertebrate CNS. A close proximity between macrophages and subperineurial glia suggests that glia may transfer apoptotic profiles to the macrophages. Embryos affected by the maternal-effect mutation Bicaudal-D have no macrophages. In the absence of macrophages, most apoptotic cells are retained at the outer surfaces of the CNS, and subperineurial glia contain an abundance of apoptotic cells. Some apoptotic cells are expelled from the CNS, which suggests that the removal of apoptotic cells can occur in the absence of macrophages. The number of subperineurial glia is unaffected by changes in the rate of neuronal apoptosis.

Increasing numbers of patients have had tracheostomies for prolonged periods of time and when subsequently decannulated have developed persistent tracheocutaneous fistula. A substantial percentage of these patients have undergone successful combined modality therapy excluding surgery for advanced head and neck cancer with resulting healing deficits of the remaining tissues. Although these patients may be deemed suitable for decannulation at this particular point, the potential still exists that access to the trachea will be required sometime in the future. This situation requires a method of closure that is reasonably reliable and yet, at the same time, relatively easily reversible. The surgical technique presented appears to meet these demands. After primary inversion of the edges of the tracheocutaneous fistula, a bipedicle flap is developed and positioned over the tracheostomy site. The inferior edge of the flap is left open for temporary air escape to decompress the suture line. This line subsequently heals by secondary intention over the succeeding weeks. Although there has not been, to date, the need to reverse the closure, the relative thinness of the tissue as opposed to alternative techniques suggests that it should not be difficult.

The central compartment of an n-compartment mammillary model was concatenated with a gradient compartment (i.e., venous sampling compartment) and with a conventional effect compartment to model arterial-venous drug concentration gradients and the arterial drug concentration vs effect relationship, respectively. To model drug metabolism during transit between the peripheral arterial and peripheral venous circulations, the gradient compartment included a first-order elimination path. Simulations of the model were employed to demonstrate the impact of sampling site (e.g., arterial vs peripheral venous) on analyses of the concentration vs effect relationship.

A selection of lectins was used to characterise changes in the distribution of glycoconjugates during the embryonic development of Drosophila melanogaster. The blastoderm of pre-gastrulation embryos bound low levels of the lectins LPA, UEA-I and PNA. The germ line progenitors (pole cells) bound ConA, PNA and LPA. The yolk granules, the trachea, and the gut bound GSA-I. All lectins had detectable labeling of the ectoderm. The somata of the nervous system bound ConA and LPA. Electron microscopic analysis of PNA labeling of the nervous system revealed exclusive binding to the axon tracts and ensheathing glia. Hyaluronate lyase digestion of oligosaccharides revealed gut and nervous system binding with WGA and UEA-I. This study revealed useful biochemical probes of gut, epidermal and nervous system development that identify the distribution of likely ligands for as yet uncharacterised endogenous lectins.

The effect of aging on the pharmacodynamics of midazolam was investigated in a double-blinded study involving 39 consenting patients ranging in age from 39 to 77 yr. Midazolam was infused intravenously (i.v.) using a pharmacokinetic model-driven drug infusion device to achieve a plasma midazolam concentration that was held constant for the 10-min duration of the study. Blood samples were obtained from the radial artery at 5 and 10 min for subsequent measurement of the plasma midazolam concentrations. With the 10-min sample, the patients were also assessed for the presence or absence of responsiveness to verbal command. To ensure that the pharmacodynamic end-point was assessed under the condition of a relative steady-state effect-site midazolam concentration, only those patients (n = 33) in whom the plasma midazolam concentration at 10 min was within 30% of the measured concentration at 5 min were included in the subsequent data analyses. Logistic regression was used to fit the verbal command response/no response data to a mathematical model that included patient age and the plasma midazolam concentration measured at 10 min. Cp50, the steady-state plasma midazolam concentration at which 50% of patients would be expected not to respond to a specific stimulus (e.g., verbal command), was calculated as a function of age from the parameterized logistic model. The midazolam Cp50 for response to verbal command decreased significantly (P = 0.034) with increasing patient age, demonstrating that aging increases pharmacodynamic sensitivity to the hypnotic effects of midazolam independent of pharmacokinetic factors.

The growth, behavior, and protein status of 59 healthy preterm (mean gestational age 30 wk) infants fed either human milk or one of three infant formulas were studied post-discharge from the hospital. Formula-fed infants received either a standard term formula, a standard preterm formula, or an experimental preterm formula from discharge to 8 wk of age. From 8 to 16 wk, all formula-fed infants received the standard term formula. At 2, 8, and 16 wk, anthropometric, dietary intake, blood biochemistry, amino acid, and Brazelton Neonatal Behavioral Assessment measurements were evaluated. Weights, lengths, and head circumferences were similar for all feeding groups at discharge. After discharge all formula-fed infants were heavier than human milk-fed infants. Length and head circumference values and plasma urea nitrogen and retinol-binding protein concentrations were not different among dietary groups. Formula-fed infants had higher plasma concentrations of numerous amino acids compared with those of human milk-fed infants during the first 8 wk but not at 16 wk. There were no differences among the feeding groups in the Brazelton assessment. This study found little effect on the growth or behavioral or protein status of preterm infants discharged from the hospital who were fed either human milk or formulas designed for term or preterm infants.

Precise reporting of surgical staging and operative data in multi-institutional protocol studies could provide a number of benefits: 1) fewer cases would be discarded because of inadequate data, 2) staff review time would be reduced, 3) there would be assurance that participating surgeons were performing similar operations on similar tumors, 4) the resulting precision in stratification should improve the likelihood of achieving accurate comparison of the treatment options under study, and 5) by comparing the surgical parameters with local-regional control of disease, the specific factors that have a statistically significant correlation with outcome could be identified. This paper presents a computer-based, anatomically oriented reporting instrument that should improve the reliability of surgical data available to multi-institutional protocols.

The indications, consequences, and value of resection of the carotid artery as part of an extended neck dissection has been discussed for many years. Many of the earlier reports have focused on the sequelae of carotid artery ligation and tests to predict patient tolerance for the procedure. Efforts to reconstruct the carotid artery have been limited primarily to vein grafts. The authors report on 11 cases of reconstruction of the carotid artery using the patient's superficial femoral artery. The femoral artery itself is reconstructed using a Gore-Tex graft. Free autografts of the superficial femoral artery in the carotid location have been found to be an excellent size match, mechanically stronger than a vein graft, and tolerant of bacterial contamination. Arteriography in 1 case with 14 months' follow-up demonstrates long-term patency.

Patient compliance with the increasingly complex adjuvant therapy protocols has always been of concern, particularly in the head and neck cancer population. The Head and Neck Intergroup recently concluded a phase III prospective randomized trial testing the addition of three courses of cisplatinum containing combination chemotherapy to standard treatment defined as surgery and postoperative radiotherapy for advanced stage III and IV squamous cell carcinoma. The chemotherapy was administered following the surgery prior to the postoperative radiotherapy. Variation from protocol is ranked retrospectively as minor acceptable, major acceptable, and major unacceptable. The incidence of major unacceptable variation from the protocol for radiotherapy immediately following the surgery was 15% vs. 19% in the population that completed all three courses of the chemotherapy (P < 0.10). However, for those patients that completed less than the three courses of chemotherapy, the incidence of major unacceptable variation in radiotherapy was 33% (P < 0.001). This observation was controlled for site, stage, performance status, age, sex, surgical margins and experience of participating institution. We conclude that compliance with a multicourse adjuvant chemotherapy regimen is predictive of subsequent compliance to radiotherapy in the head and neck cancer population.

Purpose: The purpose of this study was to determine whether or not for patients with squamous cell carcinomas of the head and neck, a surgical resection leaving positive margins followed by postoperative adjuvant therapy improves the outcome compared to a matched group of patients treated with definitive radiotherapy alone., Methods and Materials: From January 1985 through January 1990 a consortium of national cooperative groups (Radiation Therapy Oncology Group, Cancer and Leukemia Group B, Eastern Cooperative Oncology Group, Northern California Oncology Group, Southeast Group, and Southwest Oncology Group) conducted a phase III clinical trial testing the efficacy of adjuvant chemotherapy for patients with resectable, squamous cell carcinomas of the head and neck. One hundred and nine patients were excluded from this study due to positive surgical margins. These patients have been followed prospectively with regards to local/regional tumor control, development of distant metastases, and survival. The postoperative treatment of these patients was not specified by the protocol but the majority of patients received postoperative radiotherapy +/- chemotherapy. These patients were compared with a matched group of patients from the Radiation Therapy Oncology Group head and neck database of patients treated with definitive radiotherapy alone using a standard fractionation schema. Matching parameters included primary tumor site, T-stage, N-stage, Karnofsky performance status, and age., Results: Actuarial curves are presented for local/regional control and survival. At 4 years the local/regional control rate is 44% for the positive margin patients compared to 24% for the patients from the data base (p = 0.007). However, there is no significant difference between the survival curves (p = 0.76) with respective median survivals being 18.1 months vs. 17.9 months and 4-year survivals being 29% vs. 25%., Conclusion: While an incomplete excision followed by postoperative therapy does not seem to improve survival compared to treatment with radiotherapy alone, it appears to yield significantly better local/regional control. This would argue for its applicability in selected palliative settings. A follow-up, Phase III trial for patients with advanced tumors may be warranted to test traditional resectability criteria.

In most computer-controlled pharmacokinetic model-driven drug infusion pumps, simulation of a linear compartmental pharmacokinetic model is used to compute the rate of intravenous drug infusion required to achieve setpoint central compartment (plasma) drug concentrations. For many drugs, it has been suggested that it is the drug concentration in a hypothetical "effect" compartment, rather than in the plasma, that should be manipulated to achieve maximum control over pharmacologic action. Controlling the effect compartment drug concentration is algorithmically more difficult than controlling the central compartment drug concentration because of the time delay between administration of drug into the central compartment and its subsequent appearance in the effect compartment. Presented in this paper is a model-based dosing algorithm for use in pharmacokinetic model-driven drug infusion devices that target the theoretical effect compartment drug concentration.

The effect of 3 plasma concentrations of alfentanil on the minimum alveolar concentration (MAC) of halothane in horses was evaluated. Five healthy geldings were anesthetized on 3 occasions, using halothane in oxygen administered through a mask. After induction of anesthesia, horses were instrumented for measurement of blood pressure, airway pressure, and end-tidal halothane concentrations. Blood samples, for measurement of pH and blood gas tensions, were taken from the facial artery. Positive pressure ventilation was begun, maintaining PaCO2 at 49.1 +/- 3.3 mm of Hg and airway pressure at 20 +/- 2 cm of H2O. The MAC was determined in triplicate, using a supramaximal electrical stimulus of the oral mucous membranes. Alfentanil infusion was then begun, using a computer-driven infusion pump to achieve and maintain 1 of 3 plasma concentrations of alfentanil. Starting at 30 minutes after the beginning of the infusion, MAC was redetermined in duplicate. Mean +/- SD measured plasma alfentanil concentration during the infusions were 94.8 +/- 29.0, 170.7 +/- 29.2 and 390.9 +/- 107.4 ng/ml. Significant changes in MAC were not observed for any concentration of alfentanil. Blood pressure was increased by infusion of alfentanil and was dose-related, but heart rate did not change. Pharmacokinetic variables of alfentanil were determined after its infusion and were not significantly different among the 3 doses.

Continuous infusion of intravenous anesthetics can be achieved either by a manually controlled infusion (MCI) pump, or by a computer-assisted continuous infusion (CACI) pharmacokinetic model-driven infusion system. Randomized double-blind comparisons of the two infusion systems for general anesthesia were performed in 24 patients undergoing coronary artery bypass grafting. Patients were allocated to receive continuous infusions of midazolam and fentanyl by either a MCI device or CACI. Midazolam and fentanyl infusions were independently titrated to maintain hemodynamic stability, defined as mean arterial pressure (MAP) and heart rate (HR) within 20% of baseline values. As directed by the study design, comparable hemodynamic control was achieved in both groups. Mean plasma fentanyl concentrations measured at specific timepoints were similar between groups. The plasma midazolam level for induction was 196 +/- 139 ng/mL in the CACI group and 300 +/- 128 ng/mL in the MCI group, and the fentanyl level was similar in both groups, 6.7 +/- 1.9 ng/mL in CACI and 6.3 +/- 4.6 ng/mL in the MCI group. The drug levels were lower (P < or = .05) for midazolam during maintenance of anesthesia and similar for fentanyl during the maintenance of anesthesia. In the MCI group, the average duration of anesthesia was 246.5 +/- 35.0 minutes, with a mean total fentanyl dose of 30.27 +/- 11.14 micrograms/kg. In the CACI group, the average duration of anesthesia was 230.8 +/- 44.1 minutes, with a mean total fentanyl dose of 34.61 +/- 5.40 micrograms/kg (P > 0.05 for comparisons between groups for duration of anesthesia and total fentanyl dose).(ABSTRACT TRUNCATED AT 250 WORDS)

The longitudinal glia (LG), progeny of a single glioblast, form a scaffold that presages the formation of longitudinal tracts in the ventral nerve cord (VNC) of the Drosophila embryo. The LG are used as a substrate during the extension of the first axons of the longitudinal tract. I have examined the differentiation of the LG in six mutations in which the longitudinal tracts were absent, displaced, or interrupted to determine whether the axon tract malformations may be attributable to disruptions in the LG scaffold. Embryos mutant for the gene prospero had no longitudinal tracts, and glial differentiation remained arrested at a preaxonogenic state. Two mutants of the Polycomb group also lacked longitudinal tracts; here the glia failed to form an oriented scaffold, but cytological differentiation of the LG was unperturbed. The longitudinal tracts in embryos mutant for slit fused at the VNC midline and scaffold formation was normal, except that it was medially displaced. Longitudinal tracts had intersegmental interruptions in embryos mutant for hindsight and midline. In hindsight, there were intersegmental gaps in the glial scaffold. In midline, the glial scaffold retracted after initial extension. LG morphogenesis during axonogenesis was abnormal in midline. Commitment to glial identity and glial differentiation also occurred before scaffold formation. In all mutants examined, the early distribution of the glycoprotein neuroglian was perturbed. This was indicative of early alterations in VNC pattern present before LG scaffold formation began. Therefore, some changes in scaffold formation may have reflected changes in the placement and differentiation of other cells of the VNC. In all mutants, alterations in scaffold formation preceded longitudinal axon tract formation.

Background: The Cp50 (minimal steady state plasma concentration of an intravenous analgesic/anesthetic required to prevent a somatic response in 50% of patients following skin incision) and the Cp50-BAR (minimal plasma concentration of an analgesic/anesthetic required to prevent either a somatic, hemodynamic, or autonomic response in 50% of patients following skin incision) have been recently proposed as a measure, like minimum alveolar concentration (MAC; and MAC-BAR), to establish the relative potency of intravenous analgesics. This study was conducted to establish the Cp50 for fentanyl., Methods: Unpremedicated patients were administered fentanyl (in the presence of 70% N2O) via computer-assisted continuous infusion, a pharmacokinetic model-driven infusion device. After induction of anesthesia with fentanyl, the randomized target fentanyl concentration was entered into computer-assisted continuous infusion. This target fentanyl concentration was maintained until skin incision. Before induction, prior to skin incision, and immediately after skin incision, arterial blood samples were obtained for measurement of fentanyl and norepinephrine concentrations. At skin incision, patients were observed for a somatic, hemodynamic, or autonomic response. Only patients in whom the pre- and postincision fentanyl concentrations were within +/- 30% were included in the calculation of the Cp50. The Cp50 was calculated using logistic regression., Results: The Cp50 for fentanyl was 3.26 ng/ml, and the Cp50-BAR was 4.17 ng/ml., Conclusions: Comparing these results with the previously published Cp50 of alfentanil, the potency of fentanyl relative to alfentanil is 1:58. Establishing the Cp50, once effect site equilibration has occurred, will allow pharmacodynamic comparisons between the opioids at equipotent concentrations.

Esmolol hydrochloride was administered by constant-rate continuous infusion to 10 patients undergoing hypothermic cardiopulmonary bypass for coronary artery revascularization surgery. After a suitable loading dose, the esmolol infusion was started approximately 30 minutes before bypass and was stopped 10 minutes after termination of bypass. Esmolol concentrations were measured in arterial and venous blood samples collected before and after bypass and in samples taken from the inflow and outflow ports of the membrane oxygenator during bypass. Blood esmolol concentrations increased during hypothermia in a manner that correlated significantly and inversely with temperature. All patients were separated from the extracorporeal circulation without difficulty, and the average arterial esmolol concentration was slightly below the prebypass concentration within minutes of discontinuing bypass. Esmolol disappeared from the blood rapidly on terminating the infusion. There was no difference between esmolol concentrations measured simultaneously from the inflow and outflow ports of the membrane oxygenator during bypass, but radial arterial esmolol concentrations before and after bypass were on average about sevenfold higher than forearm venous esmolol concentrations during the esmolol infusion. The results of this study lead to two important conclusions: (1) in vivo clearance of esmolol demonstrates acute temperature dependence and (2) esmolol is removed irreversibly as it passes through the microcirculation of the hand, making measurement of peripheral esmolol concentrations markedly dependent on sampling site (arterial versus venous).

The recently concluded Head and Neck Intergroup trial tested the addition of three courses of cis-platinum containing chemotherapy to standard treatment of surgery and postoperative radiotherapy for patients with advanced operable squamous cell carcinoma of the head and neck. Only patients with negative surgical margins were eligible for the trial. One hundred twelve patients with positive surgical margins were dropped from the trial but continued to be followed. These patients received a variety of treatments. Positive surgical margins were most often seen in nonglottic primaries and with increasing frequency as the N stage increased. Patients with positive margins who achieved a complete clinical response to subsequent treatment had a median survival of 33.8 months vs. 9.1 months for those with less than a complete clinical response. The addition of chemotherapy did not significantly alter the median survival of the positive margin patients.

Thiopental and fentanyl are commonly combined for induction of anesthesia. The effect of an analgesic concentration of fentanyl on the plasma concentration of thiopental to induce sleep was studied in 46 unpremedicated patients. As a measure of drug effect, sleep (the lack of response to open eyes to a verbal command) was used. Forty-six patients were randomized to receive thiopental infused to one of several predetermined plasma concentrations. Twenty-two of these patients also received a fentanyl infusion to a desired analgesic concentration of 1 ng/mL. Thiopental and fentanyl were infused by means of a pharmacokinetic model-driven infusion device (computer-assisted continuous infusion, CACI). Venous blood samples were taken from the contralateral antecubital fossa at 5 and 10 min after the start of the infusion. At 10 min, the patients' names were firmly spoken, and they were instructed to open their eyes. If they did not respond to this command, they were considered to be asleep. Only patients in whom the 5- and 10-min measured plasma concentrations of thiopental and fentanyl, respectively, were within +/- 30% of each other were used for the determination of the Cp50(asleep), the plasma concentration at which 50% of the patients were asleep. The Cp50(asleep) with and without fentanyl was calculated by logistic regression. The Cp50(asleep) for patients in whom concentrations were maintained within +/- 30% for thiopental alone (n = 17) was 7.32 micrograms/mL (95% confidence interval, 5.53-10.95); for thiopental in the presence of fentanyl (n = 18 with a measured fentanyl concentration of 1.27 +/- 0.5 ng/mL), this was 7.22 micrograms/mL (95% confidence interval, 4.83-10.15).(ABSTRACT TRUNCATED AT 250 WORDS)

Little consensus or systematic research exists regarding the symptoms that constitute depersonalization and its association with affective and perceptual dysfunctions. A scale was constructed to measure depersonalization experiences reported in the literature and four items representing psychotic symptoms. Five factors representing different types of depersonalization emerged: Inauthenticity, Self-Negation, Self-Objectification, Derealization, and Body Detachment. Based on the factors, scales were constructed; these scales have internal consistency ranging from .78 to .84. Each of these factor scales was factorially distinguishable from psychosis and correlated between .48 and .58 with the Jackson and Messick (1972) Feelings of Unreality Scale, suggesting divergent and convergent validity. Inauthenticity, the most frequent and pervasive form of depersonalization experience, was best predicted by a cognitive style featuring intense, critical examination of self and others. In contrast, Self-Objectification was best predicted by thought disorganization and perceptual distortion and was experienced somewhat infrequently by relatively few subjects. All forms of depersonalization were associated with depression, except Inauthenticity.

Prototype systems implementing algorithms for automated drug infusions are typically constructed by coupling a microcomputer to a drug infusion pump through a serial communications interface. Infusion rates demanded of the infusion pump in many computed-controlled drug delivery applications are made to change at intervals much shorter than those encountered under routine clinical use. Because the ability of infusion pumps to maintain accurate flow rates during high frequency rate changes has not been documented, the purpose of this study was to validate the volumetric accuracy of three commercially available infusion pumps operating in a demanding computer-controlled application. In independent 2-h evaluations, the infusion rate demanded of each pump changed as often as every 5, 10, or 15 s using an algorithm for computer-controlled pharmacokinetic model-driven intravenous infusion. Accuracy of the infusion devices was determined gravimetrically. At all measurement times, each of the infusion pumps was accurate to within approximately +/- 5% of the expected volumetric output under each of the infusion rate intervals tested. Flow rate accuracy of +/- 5% is equal to the nominal expected accuracy of these infusion pumps in conventional clinical use.

Reconstruction of tracheal defects may be necessary following trauma or oncologic surgery. Defects up to 8 cm can often be repaired using end-to-end anastomosis. Use of a tracheal prosthesis for larger defects has been complicated by recurrent stenosis and infection. Recent animal studies, utilizing a Dacron polyurethane prosthesis suggest that problems with anastomotic stenosis and infection can be controlled. Problems with a central stenosis within the prosthesis persist when used for defects greater than 6 cm. Establishment of a confluent lining of respiratory epithelium is believed to be necessary for successful prosthetic tracheal reconstruction. Using cell culture techniques, we report the first successful seeding and growth of human respiratory epithelium onto a Dacron polyurethane tracheal prosthesis.

Elimination half-life is the pharmacokinetic parameter used most commonly to describe duration of pharmacologic action, including that expected of intravenous anesthetic drugs administered by continuous infusion. Little consideration has been given, however, to the relevance of elimination half-life in describing plasma (central compartment) drug concentrations in the context of relevant infusion durations. Therefore, simulations were performed with multicompartment pharmacokinetic models for six intravenous anesthetic drugs. These models had elimination half-lives ranging from 111 to 577 min. The input in each simulation was an infusion regimen designed to maintain a constant plasma drug concentration for durations ranging from 1 min to 8 h and until steady state. The time required for the plasma drug concentration to decline by 50% after terminating each infusion in each of the models was determined and was designated the "context-sensitive half-time," where "context" refers to infusion duration. The context-sensitive half-times were markedly different from their respective elimination half-lives and ranged from 1 to 306 min. The half-times were explained by posing each pharmacokinetic model in the form of a hydraulic model. These simulations demonstrate that elimination half-life is of no value in characterizing disposition of intravenous anesthetic drugs during dosing periods relevant to anesthesia. We propose that context-sensitive half-times are a useful descriptor of postinfusion central compartment kinetics.

Regional metastases are a major determinant in the treatment outcome of patients with squamous cell carcinoma of the head and neck. Metastases do not respond as well to cytotoxic therapy as do primary tumors. DNA diploid tumors or tumor components also respond poorly to intermittent cytotoxic therapy. In our series of 497 patients with squamous cell carcinoma of the head and neck, the percentage of pure DNA diploid tumors and the mean DNA indexes in 497 primary tumors and 82 regional metastases were 34% and 1.54 and 50% and 1.34, respectively. Paired comparisons were performed in 61 patients and revealed a statistically significant increase in the frequency of DNA diploid tumors (27.4% to 41.2%) in associated lymph node metastases. The clinical observation that patients with squamous cell carcinoma of the head and neck and regional lymph node metastases have a poorer prognosis and a poorer response to cytotoxic therapy may in part be explained by the increased incidence of DNA diploid tumors in their regional lymph nodes, and the poorer response of such tumors to cytotoxic therapy.

Patients with advanced head and neck carcinomas often suffer from impaired deglutition and require prolonged enteral feedings during therapy. This retrospective study analyzed 75 patients managed with three different gastrostomy techniques. Thirty patients received a percutaneous endoscopic gastrostomy; 28 patients had an open tube gastrostomy using a Foley or Malecot catheter through a purse-string stay suture; and 17 patients received an open-tube gastrostomy with a 1-cm Dacron-cuffed Silastic catheter enclosed in a 3-cm Witzel tunnel with the cuff buried in the subperitoneal pocket. The complication rate for 100 days of tube use was 0.21 for cuffed Silastic gastrostomy, 0.35 for open tube gastrostomy, and 1.41 for the percutaneous endoscopic gastrostomy group. We conclude that the cuffed Silastic gastrostomy technique is superior in this patient population.

To test the efficacy of sequential chemotherapy as an adjuvant to surgery and postoperative radiotherapy for patients with locally-advanced but operable squamous cell cancers of the head and neck region, a randomized clinical trial was conducted under the auspices of the Head and Neck Intergroup (Radiation Therapy Oncology Group, Southwest Oncology Group, Eastern Oncology Group, Cancer and Leukemia Group B, Northern California Oncology Group, and Southeast Group). Eligible patients had completely resected tumors of the oral cavity, oropharynx, hypopharynx, or larynx. They were then randomized to receive either three cycles of cis-platinum and 5-FU chemotherapy followed by postoperative radiotherapy (CT/RT) or postoperative radiotherapy alone (RT). Patients were categorized as having either "low-risk" or "high-risk" treatment volumes depending on whether the surgical margin was greater than or equal to 5 mm, there was extracapsular nodal extension, and/or there was carcinoma-in-situ at the surgical margins. Radiation doses of 50-54 Gy were given to "low-risk" volumes and 60 Gy were given to "high-risk" volumes. A total of 442 analyzable patients were entered into this study with the mean-time-at-risk being 45.7 months at the time of the present analysis. The 4-year actuarial survival rate was 44% on the RT arm and 48% on the CT/RT arm (p = n.s.). Disease-free survival at 4 years was 38% on the RT arm compared to 46% on the CT/RT arm (p = n.s.). At 4 years the local/regional failure rate was 29% vs. 26% for the RT and CT/RT arms, respectively (p = n.s.). The incidence of first failure in the neck nodes was 10% on the RT arm compared to 5% on the CT/RT arm (p = 0.03 without adjusting for multiple testing) and the overall incidence of distant metastases was 23% on the RT arm compared to 15% on the CT/RT arm (p = 0.03). Treatment related toxicity is discussed in detail, but, in general, the chemotherapy was satisfactorily tolerated and did not affect the ability to deliver the subsequent radiotherapy. Implications for future clinical trials are discussed.

We evaluated the efficacy of a computer-assisted continuous infusion device (CACI) using a two-drug infusion of midazolam and sufentanil as an anesthetic technique during pediatric cardiac surgery. Seventeen pediatric patients were anesthetized with CACI using age-appropriate pharmacokinetic models for administering sufentanil and midazolam. Predicted CACI plasma concentrations were correlated with assayed plasma drug concentrations at eight predefined intervals. The accuracy was assessed using median absolute prediction error. We found that plasma levels predicted by CACI provided a reasonable approximation of measured plasma concentrations for both drugs. The median absolute prediction error for sufentanil during cardiopulmonary bypass was compared with measurements made off of cardiopulmonary bypass (both pre and post cardiopulmonary bypass) and were 49% and 32%, respectively, and for midazolam 44% and 32%, respectively. We conclude that (a) current kinetic models provide a reasonable estimate of plasma drug concentrations, and (b) the ease of administration and targeted plasma level provided by the CACI system is an alternative to inhalation anesthesia using calibrated vaporizers.

As part of the developmental process for the Head and Neck Intergroup trial of adjuvant chemotherapy for advanced resectable head and neck carcinoma, in 1981 the Radiation Therapy Oncology Group, Philadelphia, Pa, conducted two nonrandomized pilot studies using chemotherapy consisting of three courses of cisplatin and fluorouracil infusion. Chemotherapy was administered prior to surgery in 42 patients (induction) and after surgery in an additional 29 patients (sequential). The populations were roughly comparable with respect to tumor site and stage. Twelve of the 42 patients in the induction group and seven of the 29 in the sequential group are alive and with no evidence of disease at the last reported follow-up. The median survival was 31 months in the sequential group vs 20 months in the induction group. Only two of the 26 patients with less than a complete clinical response following induction chemotherapy are still alive. Twenty-seven of the 42 patients who received induction chemotherapy did not undergo surgery as initially planned. Despite the lack of surgery, at 5 years the survival between the two groups was not significantly different (27% for the induction group vs 23% for the sequential group).

A row of mesectodermal cells separates the two lateral neurogenic regions in the Drosophila embryo and generates a discrete set of glia and neurons. Most CNS growth cones initially head straight toward the midline, suggesting that these midline cells play a key role in the formation of the axon commissures. We have used antibodies that stain the first axons, beta-galactosidase enhancer trap lines that selectively stain the different midline cells, and electron microscopic studies to elucidate the cells and interactions that mediate the normal formation of the two major commissures in each segment. This analysis has led to a model that proposes a series of sequential cell interactions controlling the development of the axon commissures. A genetic test of this model has utilized a number of mutations that, by either eliminating or altering the differentiation of various midline cells, perturb the development of the axon commissures in a predictable fashion.

One of the current national prospective clinical trials of the Head and Neck Intergroup explores the usage of chemotherapy in advanced operable head and neck cancer patients. The experimental arm consists of the addition of 3 courses of cisplatin-containing chemotherapy to standard treatment defined as surgery followed by postoperative radiotherapy. In the design of the study it is necessary to define not only the extent of the surgery performed for each eligible lesion, but also to insure uniformity of surgery performed between surgeons and institutions. This will hopefully insure that any variation between the 2 arms of the study represent the effect of the chemotherapy. The procedure to obtain and confirm uniformity of surgery is multifaceted. It is, however, fundamentally based upon the current TNM staging system and therefore has intrinsic limitations.

This is a report of a 10-year median follow-up of a randomized, prospective study investigating the optimal sequencing of radiation therapy (RT) in relation to surgery for operable advanced head and neck cancer. In May 1973, the Radiation Therapy Oncology Group (RTOG) began a Phase III study of preoperative radiation therapy (50.0 Gy) versus postoperative radiation therapy (60.0 Gy) for supraglottic larynx and hypopharynx primaries. Of 277 evaluable patients, duration of follow-up is 9-15 years, with 7.6% patients lost to follow-up before 7 years. Loco-regional control was significantly better for 141 postoperative radiation therapy patients than for 136 preoperative radiation therapy patients (p = 0.04), but absolute survival was not affected (p = 0.15). When the analysis was restricted to supraglottic larynx primaries (60 postoperative radiation therapy patients versus 58 preoperative radiation therapy patients), the difference for loco-regional control was highly significant (p = .007), but not for survival (p = 0.18). In considering only supraglottic larynx, 78% of loco-regional failures occurred in the first 2 years. Thirty-one percent (18/58) of preoperative patients failed locally within 2 years versus 18% (11/60) of postoperative patients. After 2 years, distant metastases and second primaries became the predominant failure pattern, especially in postoperative radiation therapy patients. This shift in the late failure pattern along with the increased number of unrelated deaths negated any advantage in absolute survival for postoperative radiation therapy patients. The rates of severe surgical and radiation therapy complications were similar between the two arms. Because of an increased incidence of late distant metastases and secondary primaries, additional therapeutic intervention is required beyond surgery and postoperative irradiation to impact significantly upon survival.

Computer-assisted continuous infusion (CACI) is a pharmacokinetic model-driven infusion device that enables physicians to administer intravenous (iv) drugs in a quantitative fashion, specifying a theoretical blood or plasma concentration. This study evaluated the accuracy of CACI administration of fentanyl using a newly developed CACI device programmed with a well-known set of pharmacokinetic parameters for fentanyl. Patients received diazepam 1 or 2 h before surgery. Anesthesia was induced by a combination of 70% N2O and fentanyl administered by CACI to a predicted concentration of 15-25 ng.ml-1. After neuromuscular blockade and tracheal intubation, the desired plasma fentanyl concentration (setpoint) entered into CACI was 3-6 ng.ml-1, and then the setpoint fentanyl concentration was titrated according to strict criteria of adequate or inadequate anesthesia. Plasma samples for subsequent assay of fentanyl concentration then were taken: at predefined stimuli, when inadequate anesthesia occurred, or 5 min before an anticipated decrease in the fentanyl setpoint. The predictive accuracy of CACI was assessed by calculating for each patient the tenth, 50th, and 90th percentile of the performance error and absolute performance error from each measured and predicted plasma sample pair. Cumulative probability functions for each of these were then plotted. Precision was defined as the dispersion of the tenth to 90th percentile of the median percent performance error for the population and was found to be -31-26%. The median population performance error was -4%, and the median population absolute performance error was 21%.(ABSTRACT TRUNCATED AT 250 WORDS)

Radiation-induced carotid artery disease following high-dose (greater than 50-Gy) radiotherapy for head and neck cancer may become more common as improved treatment results in longer survival. Duplex ultrasound scans were obtained in 91 consecutive patients to determine whether increased incidence and severity of extracranial carotid disease correlate with prior radiotherapy. Fifty-three patients who underwent radiotherapy an average of 28 months previously and 38 patients who received no radiotherapy were studied. Thirty percent of the irradiated group had lesions of the carotid arteries that were either moderate or severe vs only 6% of the control patients. Five patients were symptomatic; all had undergone radiotherapy. Long-term follow-up with sequential duplex ultrasound examinations is indicated in patients receiving high-dose radiotherapy for head and neck tumors, to detect radiation-induced carotid artery disease and prevent late sequelae.

Esmolol, administered as a bolus followed by continuous infusion, was used to treat the occurrence of transient tachycardia and hypertension or tachycardia alone before cardiopulmonary bypass in 45 patients. The study was conducted in two phases. Phase I (15 patients) was a dose-finding study and phase II (30 patients) was a randomized, double-blind, placebo-controlled efficacy study. All patients received the last dose of their usual beta-adrenergic blocker the night before the operation and were anesthetized with midazolam, vecuronium, and enflurane in oxygen. Treatment criteria were either a systolic blood pressure greater than 140 mm Hg and a heart rate greater than 70 or a heart rate greater than 80 beats/min. In phase I, graduated doses of esmolol were given to successive patients. A dose of 80 mg followed by a 12 mg/min infusion was declared effective. Phase II patients were randomized to receive esmolol (n = 16) or placebo (n = 14). Hemodynamic data were collected at baseline and 1, 3, 5, and 10 minutes after the administration of esmolol. Plasma norepinephrine was measured at baseline, 1, and 10 minutes. Esmolol significantly (p less than 0.05) reduced heart rate at 1, 3, 5, and 10 minutes but did not change blood pressure, pulmonary artery diastolic pressure, right atrial pressure, cardiac output, or systemic vascular resistance. Our results show that a bolus loading dose of esmolol is safe and effective in the treatment of tachycardia in patients with ischemic heart disease and that esmolol rapidly blocks the beta-adrenergic effects of norepinephrine associated with surgical stress.

In pharmacokinetic modeling it is common to use compartmental structures to describe the disposition of a drug in the blood or plasma. Typically, a linear multicompartment mammillary model is equated with the multiexponential equation derived from observing the decay of the plasma drug concentration following an intravascular injection. Classically, the mammillary models are constructed so that the concentrations in each of the compartments are equal at steady state, the apparent volume of distribution at steady state is equal to the sum of the individual compartment volumes, and the apparent volume of each peripheral compartment is equal to the ratio of its intercompartmental rate constants times the central compartment volume. On the basis of what can be measured in the plasma, however, it is equally valid to assume that the sizes of the peripheral compartment volumes are equal to the central compartment volume and that the steady-state concentration in each peripheral compartment is equal to the ratio of its intercompartmental rate constants times the concentration in the central compartment. In fact, these are but two of an infinite number of interpretations of the peripheral compartment volumes.

Tumors of the nerve sheaths are very unusual. They occur with the highest frequency in the head and neck region, yet only 4% have been found to occur within the paranasal sinuses. Only 40 cases of nerve sheath tumors with direct involvement of the paranasal sinuses have been reported in the world's literature to date. Three new cases of neurofibroma not associated with Recklinghausen's disease and one case of a schwannoma of the frontoethmoid and maxillary sinuses are presented. The clinical, radiographic, and histopathologic features of these lesions will be discussed with emphasis on electron microscopy and immunohistochemical differentiation of these rare and often confusing lesions.

The ability to interpret conversational utterances was assessed in a group of 12 male patients with unilateral right hemisphere brain damage (RHD) and 12 non-brain-damaged, age-matched male control subjects. Subjects listened to short vignettes which described both the affective tone of the relationship between a speaker and an actor, and the actor's performance on a task. Each vignette concluded with the speaker characterizing the actor's performance. In half of the items, the speaker's utterance was literally true; in the other half, the utterance was literally false and invited a nonliteral interpretation. Results showed no appreciable differences in the performance of control subjects and RHD patients when interpreting literally true utterances. In contrast, the two groups differed reliably when interpreting the pragmatic intent of nonliteral utterances: Control subjects used information about both the actor's performance and the speaker-actor relationship, while RHD patients demonstrated difficulty in using the information about the speaker-actor relationship. Results have implications for patients' understanding of essential elements of conversations, such as characters' internal states and their intentions in employing different forms of literal and nonliteral language.

Computerized pharmacokinetic model-driven administration of intravenous anesthetic agents has been implemented using a variety of algorithms to control the drug infusion regimen. All such algorithms are similar to the extent that they use a linear pharmacokinetic model of the drug being administered to determine drug infusion rates to theoretically achieve and maintain plasma drug concentrations (setpoints) specified by the physician. Since the behavior of the pharmacokinetic model can be computed for any input, it should be possible to achieve regulation of the drug infusion rates that is flexible (i.e., the physician can interactively adjust the setpoint), practical, and analytically optimized; these objectives are realized by the algorithm described in this communication.

Three classes of glial cells are present early in embryogenesis and appear to play a major role in axon pathway formation in the Drosophila CNS. Six longitudinal glial (LG) cells are present over the longitudinal connective on each side of each segment. Six midline glia (MG) cells surround the anterior and posterior commissures of each segment. Finally, the intersegmental nerve root is covered by a glial cell: the segment boundary cell (SBC). All 3 classes of glial cells are present in their final position before axon outgrowth and their pattern prefigures the first axon pathways. The pioneer growth cones that establish the first axon pathways in the longitudinal connective and intersegmental nerve extend along the elongate surface of the LG and SBC glial cells; the pioneer growth cones for the anterior and posterior commissures extend toward and make close contact with the end feet of the MG glial cells. Later, all 3 classes of glial cells enwrap the axon tracts in much the same way as vertebrate oligodendrocytes. The results suggest that these early glial cells provide guidance cues for the first growth cones in the Drosophila CNS. More than simply providing a permissive substrate, the differential extension of specific early growth cones towards either the MG cells or along the LG cells suggests an active role for these glia in growth cone guidance.

From a group of 765 patients treated primarily at Barnes Hospital (St Louis) for epidermoid carcinoma of the larynx and the hypopharynx, 199 cases of recurrent disease were identified. To define this group of recurrent carcinoma, the following study parameters were selected: initial site of lesion, initial pathologic condition, initial therapy, complications of therapy, site of recurrence, secondary treatment, and end results. Cause of death is detailed as a result of primary cancer (local, neck, distant, and mixed), complications of treatment, secondary cancer, or intercurrent disease. An attempt is made to correlate the data to understand this anomaly and its responses to therapy better.

Cisplatin (cis-platinum, 100 mg/m2) and fluorouracil (1000 mg/m2/d), for 120 hours' infusion every three weeks for three courses, produced a 93% overall response rate and a 54% complete clinical response at the single-institution level. The same combination was tested in the Radiation Therapy Oncology Group to evaluate the effectiveness and feasibility of this combination. An overall response rate of 86% was obtained, with a 38% complete clinical response. Only 27 of 42 patients completed planned surgery. Compliance with chemotherapy and radiation therapy was substantially better. No additional morbidity after surgical resection or postoperative radiation therapy was identified as secondary to the induction chemotherapy. We conclude that the combination of cisplatin and fluorouracil infusion is effective, with high complete clinical response rate in patients with advanced, previously untreated head and neck carcinoma.

Acutely ill patients with myocardial infarction may require immediate cardiac catheterization and coronary angioplasty to achieve myocardial reperfusion. To determine the feasibility of using general anesthesia under these circumstances, a randomized clinical trial was performed. Of 50 patients, 25 received anesthesia and 25 receive intravenous sedation. There were transient increases in heart rate and blood pressure after tracheal intubation in the anesthetized patients, followed by significant and sustained decreases below baseline values once steady state anesthesia was attained. Arterial oxygenation was significantly improved in anesthetized patients. There were no serious complications due to anesthesia, but the small sample size limited the power of the study to detect differences in morbidity or mortality. Patients strongly preferred anesthesia. These results show that general anesthesia is feasible in patients undergoing interventional cardiac catheterization during acute myocardial infarction, when pain, anxiety or agitation do not respond adequately to conventional measures.

Previous studies described three different classes of glial cells in the developing CNS of the early Drosophila embryo that prefigure and ensheath the major CNS axon tracts. Among these are 6 longitudinal glial cells on each side of each segment that overlie the longitudinal axon tracts. Here we use transformant lines carrying a P element containing a 130 bp sequence from the fushi tarazu gene in front of the lacZ reporter gene to direct beta-galactosidase expression in the longitudinal glia. Using this molecular lineage marker, we show that 1 of the "neuroblasts" in each hemisegment is actually a glioblast, which divides once symmetrically, in contrast to the typical asymmetric neuroblast divisions, producing 2 glial cells, which migrate medially and divide to generate the 6 longitudinal glial cells. As with neuroblasts, mutations in Notch and other neurogenic genes lead to supernumerary glioblasts. The results indicate that the glioblast is similar to other neuroblasts; however, the positionally specified fate of this blast cell is to generate a specific lineage of glia rather than a specific family of neurons.

We have identified the neurons that pioneer the major CNS axon tracts in the Drosophila embryo and determined their trajectory and fasciculation choices using serial section electron microscopy. Although Drosophila pioneer neurons make choices similar to those of their grasshopper homologs, there are interesting differences that reflect the much smaller nervous system size and the much faster rate of development characteristic of Drosophila. For example, where 2 longitudinal tracts are pioneered independently in grasshopper, only one is formed in Drosophila. This change is due to a change in fasciculation affinity of the pCC growth cone. Additionally, the intersegmental (IS) nerve is pioneered by a different neuron in Drosophila (aCC) than in the grasshopper (U1) because the smaller Drosophila CNS places the IS nerve within filopodial reach of the aCC soma, while in the grasshopper it is not. Drosophila growth cones explore a much more confined neuropil volume than do grasshopper growth cones but can also sample a larger fraction of the CNS as well. For this reason, some cell-cell recognition events critical to pathfinding in the grasshopper embryo may not be as essential in Drosophila. Nevertheless, many specific cellular affinities have been retained through the evolutionary divergence of these 2 species.