High-dose-rate brachytherapy for primary carcinomas of the oral cavity and oropharynx.

OBJECTIVE: Local control for patients treated with primary radiation therapy for tumors of the oral cavity is improved using low-dose-rate brachytherapy. Oropharyngeal carcinomas have also been treated with brachytherapy. The few reports in the literature regarding high-dose-rate brachytherapy (HDRBT) for head and neck cancer involve small numbers of patients and often contain a mix of palliative and curative cases. The purpose of this study is to evaluate the feasibility of HDRBT in the largest reported cohort of primary head and neck cancer patients treated with primary radiation therapy. STUDY DESIGN: This is a prospective nonrandomized study. METHODS: Fifty-five patients with primary untreated squamous cell carcinomas of the oral cavity and oropharynx were analyzed. There were 16 patients with T1, 26 with T2, 8 with T3, and 5 with T4 tumors. All patients received external-beam radiotherapy (EBRT) followed by HDRBT. Thirty-eight patients received hyperfractionated (twice daily) EBRT followed by HDRBT two or three times daily. Patients with cervical adenopathy also received hyperthermia and an electron boost to the site(s) of positive nodes. Median follow-up was 2.7 years. Toxicity and local control were analyzed. Data were analyzed by the Kaplan-Meier life-table method with statistical significance determined by the X2 and log-rank tests. RESULTS: High-dose-rate brachytherapy was extremely well tolerated. Only 9 patients (16%) developed a complication. Four patients developed osteoradionecrosis, and five developed soft tissue necrosis, all of which healed with conservative medical management. No complication required surgical intervention or hospitalization. Actuarial 2-year local control for the entire cohort was 79%. Local control was 87% for patients with T1 (15/16) and T2 (22/26) tumors versus 47% for T3 (5/8) and T4 (2/5) tumors (P < .01). CONCLUSIONS: High-dose-rate brachytherapy is feasible as a boost for patients with primary squamous cell carcinomas of the oral cavity and oropharynx. Patients with T1 and T2 tumors fared exceptionally well; those with advanced tumors may require more aggressive treatment, such as higher radiation doses, surgical resection, or systemic chemotherapy. The use of HDRBT both shortens the overall treatment time and limits the volume of tissue exposed to high doses of radiation therapy. In the future, as more patients treated with HDRBT are evaluable, we hope to identify potential factors that predict for local control so that we may select patients optimally for this treatment.

Leukotriene B4 activates the NADPH oxidase in eosinophils by a pertussis toxin-sensitive mechanism that is largely independent of arachidonic acid mobilization.

Experiments were designed to investigate whether leukotriene (LTB4) receptors can couple directly to phospholipase A2 (PLA2) in guinea pig eosinophils and the role of endogenous arachidonic acid (AA) in LTB4-induced activation of the NADPH oxidase. LTB4 (EC50 approximately 16 nM) and AA (EC50 approximately 6 microM) generated hydrogen peroxide (H2O2) in a concentration-dependent manner and at an equivalent maximum rate (5-6 nmol/min/10(6) cells). LTB4 stimulated PLA2 over a similar concentration range that activated the NADPH oxidase, although kinetic studies revealed that the release of [3H]AA (t1/2 approximately 2 s) preceded H2O2 generation (t1/2 > 30 s). Pretreatment of eosinophils with pertussis toxin abolished the increase in inositol(1,4,5)trisphosphate mass, [Ca2+]c, [3H]AA release, and H2O2 generation evoked by LTB4. Qualitatively identical results were obtained in eosinophils in which phospholipase C (PLC) was desensitized by 4beta-phorbol 12,13-dibutyrate with the exception that [3H]AA release was largely unaffected. Additional studies performed with the protein kinase C inhibitor, Ro 31-8220, and under conditions in which Ca2+ mobilization was abolished, provided further evidence that LTB4 released [3H]AA independently of signal molecules derived from the hydrolysis of phosphatidylinositol(4,5)bisphosphate by PLC. Pretreatment of eosinophils with the PLA2 inhibitor, mepacrine, abolished LTB4-induced [3H]AA release at a concentration that inhibited H2O2 by only 36%. Collectively, the results of this study indicate that agonism of LTB4 receptors on guinea pig eosinophils mobilizes AA by a mechanism that does not involve the activation of PLC. In addition, although LTB4 effectively stimulated PLA2, a central role for AA in the activation of the NADPH oxidase was excluded.

Early signalling events implicated in leukotriene B4-induced activation of the NADPH oxidase in eosinophils: role of Ca2+, protein kinase C and phospholipases C and D.

The early signalling events that may ultimately contribute to the assembly and subsequent activation of the NADPH oxidase in guinea-pig peritoneal eosinophils were investigated in response to leukotriene B4 (LTB4). LTB4 promoted a rapid, transient and receptor-mediated increase in the rate of H2O2 generation that was potentiated by R 59 022, a diradylglycerol (DRG) kinase inhibitor, implicating protein kinase C (PKC) in the genesis of this response. This conclusion was supported by the finding that the PKC inhibitor, Ro 31-8220, attenuated (by about 30%) the peak rate of LTB4-induced H2O2 generation under conditions where the same response evoked by 4 beta-phorbol 12,13-dibutyrate (PDBu) was inhibited by more than 90%. Paradoxically, Ro 31-8220 doubled the amount of H2O2 produced by LTB4 which may relate to the ability of PKC to inhibit cell signalling through phospholipase C (PLC). Indeed, Ro 31-8220 significantly enhanced LTB4-induced Ins(1,4,5)P3 accumulation and the duration of the Ca2+ transient in eosinophils. Experiments designed to assess the relative importance of DRG-mobilizing phospholipases in LTB4-induced oxidase activation indicated that phospholipase D (PLD) did not play a major role. Thus, although H2O2 generation was abolished by butan-1-ol, this was apparently unrelated to the inhibition of PLD, as LTB4 failed to stimulate the formation of Ptd[3H]BuOH in [3H]butan-1-ol-treated eosinophils. Rather, the inhibition was probably due to the ability of butan-1-ol to increase the eosinophil cyclic AMP content. In contrast, Ca(2+)- and PLC-driven mechanisms were implicated in H2O2 generation, as LTB4 elevated the Ins(1,4,5)P3 content and intracellular free Ca2+ concentration in intact cells, and cochelation of extracellular and intracellular Ca2+ significantly attenuated LTB4-induced H2O2 generation. Pretreatment of eosinophils with wortmannin did not affect LTB4-induced H2O2 production at concentrations at which it abolished the respiratory burst evoked by formylmethionyl-leucylphenylalanine in human neutrophils. Collectively, these data suggest that LTB4 activates the NADPH oxidase in eosinophils by PLD- and PtdIns 3-kinase-independent mechanisms that involve Ca2+, PLC and PKC. Furthermore, the activation of additional pathways that do not require Ca2+ is also suggested by the finding that LTB4 evoked a significant respiratory burst in Ca(2+)-depleted cells.

Inhibitory effects of sulfonated shale oil fractions on the oxidative burst and Ca++ mobilization in stimulated macrophages.

The effect of sulfonated shale oil fractions on the oxidative burst and the mobilization of intracellular calcium in purified guinea pig peritoneal macrophages was investigated in vitro. Three sulfonated shale oil fractions of varying boiling range, No. 1 = R = 1269 (powder, sodium salt of sulfonated shale oil dark), No. 2 = R 3269 (watery solution, sodium salt of sulfonated shale oil pale, Ichthyol hell), No. 3 = R 2069 (watery solution, ammonium salt of sulfonated shale oil dark, Ichthyol) were investigated. Two of three compounds dose-dependently inhibited leukotriene (LT) B4-induced Ca++ mobilization with complete inhibition at 10 mumol/l. The phorbol ester-stimulated generation of superoxide anion was dose-dependently inhibited by all three compounds with an optimal concentration of 1 to 10 mumol/l and maximal inhibition of 34.7, 39 and 38%. High concentrations of the compounds promoted the release of superoxide anion into the buffer medium. The LTB4-stimulated generation of hydrogen peroxide was also dose-dependently inhibited by all three compounds with maximal inhibition of 34, 40 and 32% with an optimal concentration of 100 mumol/l. Our observations support the hypothesis that sulfonated shale oil fractions are capable of modulating inflammatory responses through inhibition of inflammatory cell functions.

Salmeterol is a competitive antagonist at beta-adrenoceptors mediating inhibition of respiratory burst in guinea-pig eosinophils.

The ability of the long-acting beta-adrenoceptor agonists eformoterol and salmeterol to inhibit leukotriene (LT) B4 (100 nM; approximately EC70)-induced hydrogen peroxide (H2O2) generation by guinea-pig peritoneal eosinophils was investigated and compared with salbutamol. Eformoterol and salbutamol produced a concentration-dependent inhibition of LTB4-induced H2O2 generation with pIC50 values of 6.22 and > 5.0 respectively. The inhibitory effect eformoterol was mediated through an interaction with beta-adrenoceptors for it was antagonised by propranolol with an affinity (7.21) that was independent of antagonist concentration (100 nM and 1 microM). In contrast, salmeterol (1 nM to 10 microM) failed to inhibit H2O2 generation at any concentration examined irrespective of the pre-incubation time (0, 0.25, 0.5, 1, 2, 15 or 30 min). Salmeterol did, however, competitively antagonise (slope of Schild plot = 0.91) the inhibition of H2O2 generation induced by eformoterol with a pA2 of 5.9. Possible explanations for the lack of inhibitory effect of salmeterol on LTB4-induced respiratory burst are advanced and critically discussed.

The effect of anion transport inhibitors and extracellular Cl- concentration on eosinophil respiratory burst activity.

Furosemide has been shown recently to protect asthmatic patients against certain bronchoconstrictor challenges. We investigated the effect of furosemide on eosinophil function. Since furosemide may be exerting its inhibitory effect on the eosinophil by inhibiting anion transport, we also assessed the effects of the anion transport inhibitors 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB) and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS). Furosemide, NPPB and DIDS inhibited the eosinophil respiratory burst in response to leukotriene B4 (LTB4) and, to a smaller extent, inhibited the response to opsonized zymosan (OZ). To assess whether the anion transport inhibitors were achieving their inhibitory effect by inhibiting an influx of Cl- ions into the eosinophil, the effect of removing extracellular Cl- on eosinophil function was determined. OZ-induced H2O2 production was inhibited by removing extracellular Cl- whereas the LTB4 response was not affected by the concentration of extracellular Cl-.

A new look at postoperative instructions following cataract extraction.

We sought to determine whether, given the decreasing rate of complications associated with cataract surgery and IOL implantation, postoperative restrictions placed on patients undergoing these procedures could be significantly and safely relaxed. We reviewed the charts of 216 patients who had undergone capsulorhexis or "can-opener" capsulotomy, phacoemulsification, and insertion of an oval IOL over a 3-year period, noting any operative or postoperative complications. All of these patients had been examined the day after surgery and, if no complications were noted, had been instructed only to refrain from activities that produced pain. No shield was required, and no instructions were given to restrict showering, hair washing, or any other normal physical activity. We found no complications related to any postoperative activity. These results suggest that current postoperative instructions typically restricting such patients' activities should be reevaluated.

Evaluation of the bronchodilator properties of Ro 31-6930, a novel potassium channel opener, in the guinea-pig.

1. Ro 31-6930 (0.001-0.3 microM), cromakalim (0.03-3.0 microM), salbutamol (0.001-0.3 microM) and theophylline (0.3-100 microM) evoked dose-related reductions in guinea-pig spontaneous tracheal tone with IC50 values of 0.044, 0.20, 0.021 and 21.0 microM respectively. All four agents also relaxed tone supported by betahistine, carbachol, 5-hydroxytryptamine (5-HT), leukotriene D4 (LTD4), U46619 and prostaglandin D2 (PGD2). The order of potency of tracheal relaxants was always salbutamol greater than Ro 31-6930 greater than cromakalim greater than theophylline. 2. All four agents evoked dose-related reductions in 5-HT- and histamine-induced bronchoconstriction in pithed vagotomised guinea-pigs. The dose of Ro 31-6930 producing 50% inhibition of a 5-HT bronchoconstriction was 11.6 micrograms kg-1 and the dose producing 50% inhibition of a histamine bronchoconstriction was 4.4 micrograms kg-1. Salbutamol was approximately 4-5 times more potent than Ro 31-6930 whilst cromakalim was approximately 10 times less potent than Ro 31-6930 as a bronchodilator. Theophylline was markedly less potent than any of the other agents. 3. Ro 31-6930, cromakalim, salbutamol and theophylline each protected conscious guinea-pigs from histamine-induced respiratory distress. Ro 31-6930 and salbutamol were each effective at oral doses of 1.0 and 3.0 mg kg-1 whilst cromakalim was effective at oral doses of 3.0 and 10.0 mg kg-1. Theophylline showed activity only at 300 mg kg-1 p.o. 4. Ro 31-6930 is a novel potassium channel opener which is a potent relaxant of guinea-pig tracheal smooth muscle in vitro and a bronchodilator in vivo.

Preclinical pharmacology of Ro 31-6930, a new potassium channel opener.

The present study compares the effects of Ro 31-6930, a novel potassium channel opener, with those of cromakalim and nitrendipine on blood pressure and other haemodynamic parameters. In conscious, spontaneously hypertensive rats (SHR) the oral dose of Ro 31-6930 for lowering blood pressure was 10 times lower than that of cromakalim and some 100 times lower than that of nitrendipine. In addition, the duration of antihypertensive activity of Ro 31-6930 was longer than that of cromakalim or nitrendipine. The tachycardia evoked by Ro 31-6930 and cromakalim was of shorter duration than the antihypertensive effect of either agent. In a repeat, once daily dosing experiment no tolerance was observed to the antihypertensive effect of Ro 31-6930 over a 22-day period. In conscious normotensive cats Ro 31-6930 was 10 times more potent than cromakalim and 1,000 times more potent than nitrendipine in reducing blood pressure. The duration of hypotensive activity was in excess of 5 h for each agent. In anaesthetised dogs all three agents reduced mean arterial pressure (MAP) and total peripheral resistance (TPR), while increasing cardiac output (CO) via a rise in stroke volume (SV). Both Ro 31-6930 and cromakalim significantly reduced femoral (FVR) and mesenteric vascular resistances (MVR), while only cromakalim reduced renal vascular resistance (RVR). Ro 31-6930 is a potent new antihypertensive agent that compares favourably with cromakalim and nitrendipine.