Anastomotic complications after Ivor Lewis esophagectomy in patients treated with neoadjuvant chemoradiation are related to radiation dose to the gastric fundus.

PURPOSE: Neoadjuvant chemoradiation (CRT) is increasingly used in locally advanced esophageal cancer. Some studies have suggested that CRT results in increased surgical morbidity. We assessed the influence of CRT on anastomotic complications in a cohort of patients who underwent CRT followed by Ivor Lewis esophagectomy. PATIENTS AND METHODS: Clinical and pathologic data were collected from all patients treated with neoadjuvant CRT (36 Gy combined with 5-fluorouracil and cisplatin) followed by Ivor Lewis esophagectomy. On the radiotherapy (RT) planning computed tomography scans, normal tissue volumes were drawn encompassing the proximal esophageal region and the gastric fundus. Within these volumes, dose-volume histograms were analyzed to generate the total dose to 50% of the volume (D(50)). We studied the ability of the D(50) to predict anastomotic complications (leakage, ischemia, or stenosis). Dose limits were derived using receiver operating characteristics analysis. RESULTS: Fifty-four patients were available for analysis. RT resulted in either T or N downstaging in 51% of patients; complete pathologic response was achieved in 11%. In-hospital mortality was 5.4%, and major morbidity occurred in 36% of patients. Anastomotic complications (AC) developed in 7 patients (13%). No significant influence of the D(50) on the proximal esophagus was noted on the anastomotic complication rate. The median D(50) on the gastric fundus, however, was 33 Gy in patients with AC and 18 Gy in patients without AC (p = 0.024). Using receiver operating characteristics analysis, the D(50) limit on the gastric fundus was defined as 29 Gy. CONCLUSIONS: In patients undergoing neoadjuvant CRT followed by Ivor Lewis esophagectomy, the incidence of AC is related to the RT dose on the gastric fundus but not to the dose received by the proximal esophagus. When planning preoperative RT, efforts should be made to limit the median dose on the gastric fundus to 29 Gy with a V(30) below 40%.

The location of photodegradable nitric oxide store in the mouse stomach fundus.

The aim of this study was to investigate the location of photodegradable nitric oxide (NO) store using a pharmacological approach in mouse gastric fundus. The ultraviolet light irradiation (UV; 360 nm, 60 s), electrical field stimulation (EFS; 4 Hz, 25 V, 1 ms, 15s-train), exogenous nitric oxide (NO; 10 microM), nitroglycerin (100 microM) and isoproterenol (5 nM) induced relaxation in mouse gastric fundus preparations in the absence or presence of an intact mucosa. The NO scavenger, haemoglobin (20 microM), significantly inhibited the relaxation of intact and denuded mucosa stomach fundus to UV light irradiation, EFS and NO, but not to nitroglycerin and isoproterenol. The superoxide anion generator, pyrogallol (50 microM), inhibited relaxation of intact and denuded mucosa stomach fundus induced by UV light irradiation, EFS, NO, but not to nitroglycerin and isoproterenol. The inhibition observed with pyrogallol was prevented by exogenous Cu/Zn superoxide dismutase (SOD; 100 U/ml), a membrane impermeable antioxidant. The Cu/Zn SOD inhibitor, diethyldithiocarbamic acid (DETCA; 8 mM), inhibited the relaxation of intact and denuded mucosa stomach fundus to UV light irradiation, EFS, NO and nitroglycerin but not those to isoproterenol. Exogenous SOD (100 U/ml) partially prevented the inhibitory effect of DETCA on relaxation to UV light irradiation, EFS, NO but not to nitroglycerin. DETCA-induced inhibition of the nitroglycerin-induced relaxation was partially prevented by the cell-permeable polyethylene-glycol-superoxide dismutase (100 U/ml). These results indicate that photodegradable NO store is, at least in part, unlikely to be within smooth muscle cells, and furthermore, that UV light-induced relaxation is not dependent on gastric mucosal layer.

Selective modifiers of glutathione prevent restoration of photorelaxations in mouse gastric fundus.

S-nitrosoglutathione (GSNO) has previously been shown to have a role in ultraviolet (UV) light-elicited relaxations and proposed to account for the photosensitive store in the mouse gastric fundus. Furthermore, the depletion of this photosensitive store and its replenishment via long-term electrical field stimulation were demonstrated in the same tissue. In relation to these results, the aim of the present study was to investigate the putative role of S-nitrosothiols in the restorative effect of long-term electrical field stimulation on the reduced photosensitive store. Two series of UV light-elicited relaxations (photorelaxations) were obtained, and the magnitudes of the responses were 53 +/- 6 and 26 +/- 3%, respectively. The second series of photorelaxations attenuated statistically when compared with those in the first series. Ethacrynic acid (1 microm), diamide (1 microm) and glutathione (1 microm) had no effect on the photorelaxations occurred in the second series of responses. Electrical field stimulation (4 Hz, 25 V, 1 ms, 60 min), applied between two series of photorelaxations, revealed a complete recovery of the attenuated photorelaxations appeared in the second series. N(G)-monomethyl-L-arginine (100 microm), ethacrynic acid (1 microm) and diamide (1 microm) extensively prevented the restorative effect of electrical field stimulation on photorelaxations. In addition, glutathione (1 microm) reversed the prevention achieved by ethacrynic acid and diamide. The conclusion is that the restoration accomplished by electrical field stimulation is because of the activation of nitric oxide synthase, which in turn brings about the regeneration of GSNO proposed to be the photodegradable material store.

Neocuproine inhibits the decomposition of endogenous S-nitrosothiol by ultraviolet irradiation in the mouse gastric fundus.

In the present study, we investigated whether copper ions are involved in the decomposition of endogenous S-nitrosothiols by ultraviolet (UV) light irradiation in the mouse gastric fundus. The effects of copper ions and chelators of copper(I) and copper(II), neocuproine and cuprozine, respectively, were studied on relaxations in response to S-nitrosoglutathione, UV irradiation, exogenous nitric oxide (NO), added as acidified NaNO(2), and isoproterenol. UV irradiation of smooth muscle strips induced fast and transient relaxations which were mimicked by exogenous NO. S-Nitrosoglutathione induced concentration-dependent relaxations, which were more sustained than those elicited by UV irradiation or NO. CuCl(2) did not affect relaxations elicited by UV irradiation, exogenous NO and isoproterenol but enhanced those elicited by S-nitrosoglutathione. CuSO(4) but not FeSO(4) mimicked the effect of CuCl(2) on relaxations elicited by S-nitrosoglutathione. Neocuproine, the copper(I)-specific chelator, inhibited both photorelaxation and S-nitrosoglutathione-induced relaxation, and this inhibition was prevented by CuCl(2). In contrast, neocuproine significantly enhanced the relaxations in response to exogenous NO, without affecting the relaxations elicited by isoproterenol. Cuprizone, a specific copper(II) chelator, did not affect relaxations in response to S-nitrosoglutathione, UV irradiation, exogenous NO and isoproterenol. These results suggest that copper(I) and not copper(II) may play a role in the NO release evoked by the light-induced decomposition of endogenous S-nitrosothiols in mouse gastric fundus. Also, results with the selective copper(I) chelator, neocuproine, confirmed our recent findings that the endogenous "store" of S-nitrosoglutathione, rather than NO, acts as an intermediate in photorelaxation of the mouse gastric fundus, and that photorelaxation may be a suitable model to elucidate the nature of endogenous S-nitrosothiols.

A putative role for S-nitrosoglutathione as the source of nitric oxide in photorelaxation of the mouse gastric fundus.

Mouse gastric fundus strips were relaxed by ultraviolet light (UV) irradiation, exogenous nitric oxide (NO), isoproterenol, S-nitrosoglutathione, S-nitroso-L-cysteine and S-nitroso-N-acetyl-penicillamine. Glutathione did not affect relaxations in response to UV irradiation, exogenous NO and isoproterenol while inhibiting that with S-nitrosoglutathione. L-Cysteine inhibited responses to UV irradiation and exogenous NO, but not in the presence of exogenous Cu(2+)/Zn(2+) superoxide dismutase. However, L-cysteine alone or in combination with Cu(2+)/Zn(2+) superoxide dismutase did not affect the relaxations in response to S-nitroso-L-cysteine. Ethacrynic acid and diamide inhibited photorelaxations but not the relaxations with exogenous NO and isoproterenol. This inhibition was prevented by glutathione, but not by L-cysteine. S-nitrosoglutathione-induced relaxations were abolished by diamide and ethacrynic acid, whereas responses to S-nitroso-L-cysteine and S-nitroso-N-acetyl-penicillamine were only inhibited by ethacrynic acid. These results suggest that S-nitrosoglutathione may, at least in part, be the putative S-nitrosothiol, which is converted to NO in response to UV irradiation in mouse gastric fundus strips.

Possible stimulation of Na+-K+-ATPase by NO produced from sodium nitrite by ultraviolet light in mouse gastric fundal strip.

1. In the present study, we investigated the roles of Na+-K+-ATPase and extracellular Na+ or Ca2+ ions in ultraviolet (UV) light-induced photorelaxation of methacholine-contracted mouse isolated gastric fundus in the presence of NaNO2 (50 microM). 2. Ouabain (1-500 microM), sodium vanadate (10 microM to 3 mM) and amiloride (1-100 microM) completely inhibited the photorelaxation in a concentration-dependent manner. 3. Metabolic inhibitors, sodium azide (10-100 microM), 2,4-dinitrophenol (100 microM to 1 mM) and sodium fluoride (100 microM to 1 mM) significantly reduced photorelaxation. 4. Substitution of sucrose, lithium or KCl with extracellular Na+ completely abolished the photorelaxant responses. 5. Replacement of all extracellular CaCl2 with BaCl2 also completely inhibited UV-induced relaxation. 6. Verapamil (1-10 microM) decreased UV-induced relaxation significantly. 7. These results suggest that nitric oxide produced from NaNO2 by UV-light in mouse gastric fundus probably stimulates Na+-K+-ATPase activity, and photorelaxation of gastric smooth muscle is dependent on extracellular Na+ and Ca2+ ions.

Sensitization of rat gastrointestinal tract to acetylcholine and histamine produced by X-radiation.

Abdominal x-radiation produces both acute and chronic disturbances of gastrointestinal motility. Anaesthetized Albino-Oxford rats received one-session x-radiation (absorbed dose 10 Gy) of whole abdomen. Two hours after irradiation the rats were sacrificed and segments of their gastrointestinal tract (gastric fundus, jejunum, ileum and ascending colon, were mounted in isolated organ bath. Acetylcholine and 5-hydroxytryptamine produced tonic contractions of all gut segments, while histamine did so only with gastric fundus. While contractile effect of 5-hydroxytryptamine was not affected by x-radiation, the responses of all gut segments on acetylcholine were potentiated and shifted towards lower concentrations. After x-radiation histamine produced concentration-dependent tonic contraction of previously unresponsive jejunum and ascending colon. The results of our study suggest that x-radiation produces acute sensitization of rat gastrointestinal tract to acetylcholine and histamine.

[Effect of copper vapor laser on the microrelief and ultrastructure of gastric mucosal glandulocytes]. / Vliianie lazera na parakh medi na mikrorel'ef i ul'trastrukturu glandulotsitov slizistoi obolochki zheludka.

It was investigated the influence of low intensive irradiation by the copper++ vapor laser (lambda-510.6 nm) on the glandulocytes of gastric mucosa of 28 white rats. The doses of endogastric irradiation were 6.78, 20.34 and 33.90 J/cm2. It has been shown that after irradiation of gastric mucosa with the copper++ vapor laser the microrelief and ultrastructure of glandulocytes changes testified to stimulation of specific secret function. This changes took place under irradiation doses from 6.78 to 20.34 J/cm2. The doses exceeded 20.34 J/cm2 caused the alterations of the epitheliocytes. Thus it is necessary to take into account that during laser therapy of the ulcers with copper++ vapor laser, doses of 20.34 J/cm2 caused the alterative effect on the epitheliocytes.

Induction of intestinal metaplasia in the rat gastric mucosa by local X-irradiation.

Attempts were made to learn about an optimal condition for the induction of intestinal metaplasia in the gastric mucosa. The gastric region of 5-week-old female Wistar rats was irradiated with 500 rad of X-ray daily for 6 times (Group I) or with 1,000 rad of X-ray every two days for 3 times (Group III). In addition, the effect of immunization by allogeneic stomach antigen on the intestinalization was studied in rats irradiated with 500 rad of X-ray daily for 6 times (Group II). In a group of rats (Group II) injected with allogeneic stomach antigen and X-irradiated the process of intestinalization was more accelerated as compared to that in rats treated with X-ray (Group I). The similar results were obtained in rats irradiated with 1,000 rad of X-ray 3 times (Group II). Intestinal metaplasia developed more later in the fundic gland mucosa which became usually atrophic due to the loss of parietal cell mass. There was an intimate association among the parietal cell loss in the fundic gland, a rise in pH value and the development of intestinal metaplasia. In all groups, no case of gastric adenocarcinoma was detected during observation period up to 52nd week.