Carcinoma-in-situ of the glottic larynx: results of treatment with radiation therapy.

PURPOSE: Carcinoma-in-situ (CIS) of the vocal cords frequently progresses to invasive disease if untreated. Treatment approaches include vocal cord stripping, radiation therapy (RT), and laser excision. The purpose of this analysis was to assess the efficacy and safety of a standard RT regimen in the treatment of this condition. METHODS AND MATERIALS: Between January 1980 and December 1994, 67 patients (52 men, 15 women; median age, 65 years) with glottic CIS were treated with RT. The standard RT regimen was 51 Gy in 20 fractions given over 4 weeks (99% of patients). Prior to receiving RT, 21 patients (31%) had undergone 1 or 2 vocal cord stripping procedures, and 1 had been treated with laser. RESULTS: With a median follow-up of 6.5 years, 1 patient developed invasive glottic cancer, giving a 5-year actuarial local control rate of 98%. This patient recurred 14 months after treatment and was salvaged with laryngectomy. He is currently free of disease 2 years after surgery. There were no serious acute or late treatment complications. Sixteen patients (24%) developed subsequent malignancies, 8 of these being in the upper aerodigestive tract, although none were in the radiation field. CONCLUSIONS: Moderate-dose radiation therapy is an effective treatment for glottic CIS. It is well tolerated, produces no serious acute or long-term side effects, with an excellent cure rate.

Studies of the kallikrein-kinin system and prostaglandins in epithelial ion transport.

Tissue kallikrein of colon mucosa is synthesized rapidly, and this synthetic process can now be examined in relation to hormonal or dietary manipulations or pathological circumstances that affect intestinal ion transport. Although the identical renal tissue enzyme is known to be enriched in membranes of distal convoluted tubular epithelial cells, the precise localization of the intestinal enzyme is uncertain. An understanding of the intestinal cellular locale of kallikrein will help in defining its local role. That tissue kallikreins can be inhibited by monovalent cations and some drugs (e.g., amiloride) and that kallikrein inhibitors affect cation transport across epithelial surfaces containing such enzymes must be reconciled with the new observations of kinin-induced chloride secretion. Extracellular calcium, eicosanoid synthesis, and cyclic nucleotide production are involved in the secretory response to kinins, although an absolute requirement for intact eicosanoid synthesis may not exist.

Mediators of the secretory response to kinins.

The output of immunoreactive (i) 6 keto prostaglandin F1 alpha (i6ketoPGF1 alpha), iPGE2 and ithromboxane B2 (iTXB2) from isolated colonic epithelium of the rat into the apical and basolateral bathing solution has been measured. In some instances tissues were also voltage clamped at 0 mV to measure short circuit current (SCC). Kallidin (lysylbradykinin) stimulated the output of all three eicosanoids, specifically from the basolateral face of the tissue. The output was similar whether or not the tissues were short circuited. Both the SCC response and eicosanoid output were dependent upon the concentration of kallidin, but not in a strictly proportional manner, there being relatively more eicosanoid output at submaximal kinin concentrations. Indomethacin, 5 microM, abolished the eicosanoid output, in response to kinin, while some part of the SCC response remained. Calcium removal from the basolateral bathing fluid severely attenuated the SCC response, reduced the output of i6ketoPGF1 alpha to half, but left the output of iPGE2 unchanged. In the presence or absence of calcium it is probable that sufficient PGE material is released to cause part of the SCC changes seen with kinin. Kinin and PGE1 increased the cyclic AMP content of intact epithelia, provided a phosphodiesterase inhibitor was added at the same time. It is proposed that kinin causes an increase in calcium influx at the basolateral pole of the tissue. This calcium is necessary for the production of some eicosanoids and the subsequent generation of cyclic AMP, which then increases apical chloride permeability. In addition, calcium may facilitate entry of chloride through the basolateral face of the cells by activating a cotransport mechanism.

Role of calcium ions in kinin-induced chloride secretion.

Electrogenic ion transport across the epithelium lining the descending colon of male Sprague-Dawley rats has been measured under short-circuit conditions. Responses to kallidin (lysylbradykinin) were inhibited by 70% if calcium was removed from the solution bathing the basolateral aspect of the tissue. Under identical conditions responses to prostaglandin E1 and dibutyryl cyclic adenosine monophosphate were not changed. Forskolin, which directly activates the catalytic subunit of adenylate cyclase, was inhibited by 35% by calcium removal, whereas responses to the phosphodiesterase inhibitor isobutylmethylxanthine were inhibited by 45% by the same procedure. In the absence of calcium, strontium could substitute in promoting the chloride secretory events triggered by kallidin. Magnesium ions antagonized the effects of the kinin in the presence of calcium ions in the bathing solution. The effects of kallidin were partially antagonized by verapamil and trifluoperazine and were potentiated by isobutylmethylxanthine. These results, together with earlier evidence, suggest that kinin elicits a chloride secretory response in this epithelium by stimulating the formation of prostaglandins which then activate adenylate cyclase. Extracellular calcium ions appear to have an important role in the proximal part of this cascade for prostaglandin generation. However, biochemical correlates of these biophysical responses presented in the following paper indicate a more complex role for calcium in the genesis of the kinin response.

Conversion of sodium channels to a form sensitive to cyclic AMP by component(s) from red cells.

Sodium transport has been measured in the isolated epithelium from colons of male Sprague-Dawley rats. Sodium transport in colons was induced by pretreating the animals with dexamethasone (6 mg kg-1) which caused the appearance of an amiloride-sensitive short circuit current within a few hours. Forskolin, a diterpene, which activates adenylate cyclase, was found to increase the cyclic adenosine monophosphate (cyclic AMP) content of rat colons and also to increase short circuit current at the same time. However, measurements of chloride and sodium fluxes across the epithelium indicated that forskolin activates chloride secretion but has no effect on sodium transport. In confirmation of (3) it was found that the amiloride-sensitive short circuit current was unchanged after the short circuit current had been increased by forskolin under a variety of conditions. The behaviour of the mammalian colon as indicated in (3) and (4) is unlike that of amphibian sodium transporting epithelia. It is shown that in toad urinary bladder forskolin increases amiloride-sensitive short circuit current. Procedures were investigated which might make sodium transport in the mammalian colon sensitive to cyclic AMP. Exposing the apical surface to sonicated suspensions of nucleated red cells (frog, toad and duck), followed by washing, gave preparations with amiloride-sensitive short circuit currents which were increased by forskolin or dibutyryl cyclic AMP. It would appear that the sodium channel in the mammalian colon, unlike that of amphibian tissues, has lost the ability to have its properties modified by cyclic AMP. Incubation of colons with sonicated suspensions of nucleated red cells apparently modifies the tissues such that sodium transport across the tissue becomes sensitive to the nucleotide.

Stimulation of sodium and of chloride transport in epithelia by forskolin.

The diterpene, forskolin, is shown to produce a concentration-dependent, increase in short circuit current in two epithelial preparations, amphibian skin and rat colon. In the amphibian tissue the increase is sensitive to amiloride and due to an increase in electrogenic transepithelial sodium transport towards the serosal side. In the rat colon piretanide attenuated the forskolin effect, suggesting the terpene increases electrogenic transepithelial chloride transport towards the mucosal side. Half-maximal activation of both processes was achieved with concentration of 1-3 microM, similar to those required to activate half-maximally the catalytic subunit of adenylate cyclase.

The inflammatory effects of hydroperoxy and hydroxy acid products of arachidonate lipoxygenase in rabbit skin.

1. The inflammatory effects of hydroperoxy (HPETE) and hydroxy (HETE) acids, synthesized by arachidonic acid lipoxygenases, have been investigated in rabbit skin. 2. High doses (10-20 micrograms) of 5-, 12- or 15-HPETE or the 5,12-di-hydroxy acid, leukotriene B4 (0.1-1 micrograms), caused small but significant increases in plasma exudation following intra-dermal injection. 3. Leukotriene B4 was equipotent with prostaglandin E2 and prostacyclin in potentiating bradykinin-induced plasma exudation, and was 100 times more active in this property than any other lipoxygenase product tested. 4. Leukotriene B4-induced plasma exudation was enhanced by prostaglandin E2. 5. The mono-HETEs were relatively inactive in causing or enhancing plasma exudation. 6. Leukotriene B4 (0.1 microgram) or prostaglandin E1 (1.0 micrograms) significantly elevated leukocyte accumulation in rabbit skin, whereas PGE2, 5-HPETE, 5-HETE, 12-HPETE or 12-HETE were inactive at doses up to 1 microgram.