Carditis in patients with gastro-oesophageal reflux disease: results of a controlled study based on both endoscopy and 24-h oesophageal pH monitoring.

BACKGROUND: There are conflicting reports on the role of gastro-oesophageal reflux disease (GERD) and Helicobacter pylori infection in the aetiology of carditis. AIM: The role of reflux and H. pylori infection in causing carditis was assessed in 113 consecutive patients with GERD and in 25 controls. METHODS: All subjects underwent endoscopy and pH test and carditis was diagnosed on biopsies taken across the squamocolumnar junction. Helicobacter pylori was assessed by histology and rapid urease test. GERD was diagnosed by endoscopic oesophagitis or abnormal pH test. RESULTS: Carditis was detected in 53 of 71 GERD patients and in 15 of 20 controls. Among patients, 18 showed absent, 39 mild and 14 marked cardia inflammation and their H. pylori infection rates were 17, 23 and 57%, respectively (P < 0.025). Most patients with carditis (68%) lacked H. pylori infection. pH-metry was abnormal in 15 of 18 patients with normal cardia, 33 of 39 with mild carditis and 12 of 14 with marked inflammation. CONCLUSIONS: Carditis is a frequent finding in GERD and controls. Mild, non-active carditis is frequent in GERD patients. Marked inflammation is associated with both H. pylori and abnormal pH testing. Thus, both GERD and H. pylori infection may play a role in inducing carditis.

Helicobacter pylori infection is not involved in the pathogenesis of either erosive or non-erosive gastro-oesophageal reflux disease.

BACKGROUND: The majority of reflux patients have non-erosive reflux disease. AIM: To evaluate the influence of Helicobacter pylori on oesophageal acid exposure in patients with both non-erosive and erosive reflux disease and in a group of controls. The pattern and distribution of chronic gastritis were also assessed. METHODS: One hundred and twelve consecutive patients with symptoms of gastro-oesophageal reflux disease agreed to undergo both upper gastrointestinal endoscopy and 24-h oesophageal pH-metry. Patients were grouped as H. pylori-positive or H. pylori-negative on the basis of both CLO-test and histology, and as cases with or without oesophagitis on the basis of endoscopy. The controls consisted of 19 subjects without reflux symptoms and with normal endoscopy and oesophageal pH-metry. RESULTS: H. pylori was positive in 35 patients (31%) and in six controls (31%); oesophagitis was found in 44 patients (39%) and non-erosive reflux disease in 68 (61%). The prevalence of chronic gastritis in the antrum and corpus was higher in H. pylori-positive than in H. pylori-negative patients (P < 0.001), but was more frequently mild (P < 0.001) than moderate or severe. The percentage total time the oesophageal pH < 4.0 was higher in patients than in controls (P < 0.008-0.001), but there was no difference between H. pylori-positive and H. pylori-negative patients (12.3% vs. 12%, P = 0.43) or H. pylori-positive and H. pylori-negative controls (1.07% vs. 1.47%, P = 0.19). CONCLUSIONS: H. pylori infection had the same prevalence in reflux patients and in controls. It did not affect oesophageal acid exposure, as there was no difference between H. pylori-positive and H. pylori-negative individuals. The high prevalence of mild body gastritis in H. pylori-positive patients suggests that H. pylori eradication is unlikely to lead to gastric functional recovery, which might precipitate or worsen symptoms and lesions in patients with gastro-oesophageal reflux disease.

Stool antigen assay (HpSA) is less reliable than urea breath test for post-treatment diagnosis of Helicobacter pylori infection.

BACKGROUND: The diagnostic yield of the stool antigen test (HpSA) in evaluating the results of Helicobacter pylori eradication therapy is controversial, but many studies have used only the 13C-urea breath test (13C-UBT) as a gold standard which has greatly reduced their relevance. AIM: To compare the reliability of HpSA and 13C-UBT in patients post-treatment using biopsy-based methods as reference tests. METHODS: A total of 100 consecutive dyspeptic patients (42 male and 58 female; mean age, 56 +/- 18 years) were enrolled in our study. All patients were H. pylori positive on the basis of at least two biopsy-based methods, and underwent 1 week of treatment with various triple therapies. They were again endoscoped 4 weeks after completing therapy and six biopsy specimens were taken from the gastric antrum and corpus for rapid urease test, histology and culture. HpSA and 13C-UBT were also performed within 3 days of the second endoscopy. RESULTS: On the basis of biopsy-based tests, infection was eradicated in 77 patients but continued in 23. Three false negatives were observed with HpSA and two with 13C-UBT. In contrast, the number of false positives was significantly higher (P < 0.01) with HpSA than with 13C-UBT (nine vs. one), confirming the lower specificity of the former test. The overall accuracy of HpSA was 88% vs. 97% for 13C-UBT (P < 0.02). CONCLUSIONS: HpSA has lower diagnostic value than 13C-UBT in the evaluation of the outcome of anti-H. pylori therapy. 13C-UBT remains the first-line diagnostic method to monitor eradication results. The use of HpSA should be reserved for those settings in which 13C-UBT is not available.

Comparison of the main oesophageal pathophysiological characteristics between short- and long-segment Barrett's oesophagus.

AIM: To assess the oesophageal manometric characteristics and 24-h pH profiles of patients with both short-segment and long-segment Barrett's oesophagus and compare them with those of patients with reflux oesophagitis and controls. METHODS: Seventy-nine patients who had undergone upper digestive endoscopy were recruited: 16 had short-segment Barrett's oesophagus, 13 had long-segment Barrett's oesophagus, 25 had grade III oesophagitis according to the Savary-Miller classification and 25 were used as controls. The diagnosis of Barrett's oesophagus was based on the histological detection of specialized intestinal metaplasia, which extended < 3 cm into the oesophagus in patients with short-segment disease and > 3 cm in patients with long-segment disease. All subjects underwent oesophageal manometry and basal 24-h oesophageal pH monitoring. RESULTS: The lower oesophageal sphincter pressure was significantly lower in patients with reflux oesophagitis and short-segment and long-segment Barrett's oesophagus than in controls (P=0.0004-0.0001), but there was no difference among the three reflux groups. The peristaltic wave amplitude of patients with long-segment Barrett's oesophagus was significantly lower than that of controls (P=0.002) and patients with short-segment Barrett's oesophagus (P=0.02), but was no different from that of patients with reflux oesophagitis. The percentage of non-propagated wet swallows was significantly higher in patients with reflux oesophagitis and short-segment and long-segment Barrett's oesophagus when compared with that of controls (P=0.0004-0.0001). The total percentage of time the oesophagus was exposed to pH < 4.0 was significantly higher in patients with reflux oesophagitis and short-segment and long-segment Barrett's oesophagus (P=0.0001) than in controls, and was higher in patients with long-segment disease than in those with short-segment disease (P=0.01). CONCLUSIONS: Long-segment Barrett's oesophagus is characterized by a greater impairment of peristaltic wave amplitude and a higher oesophageal acid exposure than is short-segment Barrett's oesophagus. However, both forms are linked to increased acid reflux.

Effect of Helicobacter pylori eradication on 24-hour gastric pH and duodenal gastric metaplasia.

Published data on the regression of the extent of duodenal gastric metaplasia (DGM) after the eradication of Helicobacter pylori infection and the normalization of the organism-induced alterations in gastric physiology are scanty and controversial. Therefore, we decided to assess the circadian pattern of gastric acidity and the degree of DGM before and one year after H. pylori eradication in a group of duodenal ulcer patients. Fifteen consecutive H. pylori-positive patients with endoscopically proven duodenal ulcer were recruited for this study. The diagnosis of H. pylori infection was based on CLO-test and histology, and DGM was assessed on four bulb biopsies taken before and one year after H. pylori eradication. At the same time, gastric pH was measured by 24-hr continuous intraluminal recording. H. pylori eradication was ascertained by means of concomitant negative CLO-test and histology performed both four weeks after the end of the eradicating treatment and at the one-year endoscopic control. After successful cure, all patients discontinued any antiulcer medication. The mean 24-hr gastric pH was 1.7 +/- 0.4 before and 1.6 +/- 0.4 after one year of H. pylori eradication (P = 0.75). DGM improved in three cases, worsened in four cases, and was unchanged in eight cases at the one-year control (P = 0.87). No correlation was found between 24-hr gastric pH and DGM (P = NS) both at baseline and one year after eradication. Our results show that neither circadian gastric acidity nor DGM change significantly one year after H. pylori eradication in duodenal ulcer patients. Thus, the disappearance of H. pylori infection does not determine any increase in gastric pH and any reversal of gastric-type epithelium in the duodenum.

Histological and functional recovery in patients with multifocal atrophic gastritis after eradication of Helicobacter pylori infection.

BACKGROUND/AIMS: To assess the effect of Helicobacter pylori eradication on gastric histology and physiology in patients with multifocal atrophic gastritis over 1-year period. PATIENTS: Fourteen consecutive patients with histological evidence of chronic gastritis and Helicobacter pylori infection diagnosed by histology and serology entered this study. Patients with pernicious anaemia, gastric ulcer or carcinoma, duodenal ulcer, reflux oesophagitis and regular intake of nonsteroidal anti-inflammatory drugs were excluded. METHODS: Patients underwent triple anti-Helicobacter treatment for one week, which resulted successful in all subjects on the basis of negative CLO test and histology as well as 50% decrease in IgG antibodies after 4 weeks and 6 months of treatment, respectively. Histological and functional investigations were performed at baseline, 6 and 12 months after Helicobacter pylori eradication. Histological assessment of inflammatory cell infiltrates was performed on multiple biopsy specimens of the corpus and fundus. Functional tests were 24-hour continuous gastric pH-metry, fasting serum gastrin assay and pepsinogen I levels. RESULTS: There was a progressive significant improvement (p < 0.01-0.001) in acute and chronic inflammatory cell infiltrates in the gastric mucosa throughout the 12-month period. Functional recovery with increase in gastric acidity (p < 0.01) and decrease in gastrin and pepsinogen I levels (p < 0.001) was more evident at the 6-month than at the 12-month checkpoint after Helicobacter pylori eradication (p = NS for gastric pH and p < 0.02 for the other two variables) between 6 and 12 months. CONCLUSIONS: Eradication of Helicobacter pylori infection significantly improves the inflammatory status of oxyntic mucosa and this promotes an almost complete functional recovery. However, the non-parallel behaviour of gastric acidity, which was maximal at 6-month checkpoint, and histological parameters which continued to improve throughout the entire 12-month observation period, seems to indicate that removal of acid-inhibitory substances induced by Helicobacter pylori infection was also responsible for the more rapid recovery of gastric secretory function.

Risk of inflammatory bowel disease attributable to smoking, oral contraception and breastfeeding in Italy: a nationwide case-control study. Cooperative Investigators of the Italian Group for the Study of the Colon and the Rectum (GISC).

BACKGROUND: Using data from a case-control study carried out in Italy 1989-1992, we estimated the odds ratios (OR) and the population attributable risks (AR) for inflammatory bowel diseases (IBD) in relation to smoking, oral contraception and breastfeeding in infancy. METHODS: The study focused on 819 cases of IBD (594 ulcerative colitis: UC; 225 Crohn's disease: CD) originating from populations resident in 10 Italian areas, and age-sex matched paired controls. RESULTS: Compared with non-smokers, former smokers were at increased risk of UC (OR = 3.0; 95% confidence interval [CI]: 2.1-4.3), whereas current smokers were at increased risk of CD (OR = 1.7; 95% CI: 1.1-2.6). Females who reported use of oral contraceptives for at least one month before onset of symptoms had a higher risk of CD (OR = 3.4; 95% CI: 1.0-11.9), whereas no significant risk was observed for UC. Lack of breastfeeding was associated with an increased risk of UC (OR = 1.5; 95% CI: 1.1-2.1) and CD (OR = 1.9; 95% CI: 1.1-3.3). Being a 'former smoker' was the factor with the highest attributable risk of UC both in males (AR = 28%; 95% CI: 20-35 %) and in females (AR = 12%; 95% CI: 5-18%). Smoking was the factor with the highest attributable risk for CD in males (AR = 31%; 95% CI: 11-50%). Lack of breastfeeding accounted for the highest proportion of CD in females (AR = 11%; 95% CI: 1-22%). Oral contraceptive use accounted for 7% of cases of UC and for 11% of cases of CD. CONCLUSIONS: Taken together, the considered factors were responsible for a proportion of IBD ranging from 26% (CD females) to 36% (CD males). It is concluded that other environmental and genetic factors may be involved in the aetiology of IBD.

24-hour gastric pH and extent of duodenal gastric metaplasia in Helicobacter pylori-positive patients.

BACKGROUND & AIMS: Gastric metaplasia (GM) is essential to explain duodenal colonization by Helicobacter pylori. It seems to be acid induced but also occurs in H. pylori-positive patients with nonulcer dyspepsia (NUD), who are not acid hypersecretors. The aim of this study was to assess the circadian gastric acidity of 47 patients with duodenal ulcers (DUs) and 32 patients with NUD, both H. pylori positive, and its correlation to duodenal GM extent. METHODS: H. pylori was detected by histology and CLOtest, and GM was diagnosed and graded on four bulb biopsy specimens. Each patient underwent 24-hour gastric pH-metry, and the relation between gastric pH and GM extent was assessed by factorial analysis. RESULTS: Gastric pH was greater in patients with NUD than in patients with DU during 24 hours, night and daytime (P < 0.03-0.005). Gastric pH differed significantly (P < 0.0002) in relation to GM extent between the two populations, whereas no difference was found among the pH values of GM degrees. A significant increase in 24-hour gastric pH was associated with greater GM in patients with DU, whereas the opposite occurred in patients with NUD (P < 0.007). CONCLUSIONS: The lower gastric acidity in patients with NUD than in patients with DU and the lack of correlation between gastric pH and the various GM degrees in the two H. pylori-positive populations suggest that gastric hyperacidity is not associated with duodenal GM.

Circadian gastric acidity in Helicobacter pylori positive ulcer patients with and without gastric metaplasia in the duodenum.

BACKGROUND: The presence of gastric metaplasia allows helicobacter pylori to colonise the duodenum and this condition is thought to be acquired as a response to acid hypersecretion. This functional disorder, however, is present only in a subgroup of duodenal ulcer patients and, in addition, surface gastric metaplasia has been frequently found in the proximal duodenum of normal subjects and patients with non-ulcer dyspepsia, who cannot be certainly considered as acid hypersecretors. AIMS: To clarify the role of acid in inducing gastric type epithelium in the duodenum. This study aimed at assessing whether the pattern of circadian gastric acidity differs between H pylori positive duodenal ulcer patients with and without duodenal gastric metaplasia. PATIENTS: Seventy one patients with duodenal ulcer confirmed by endoscopy and who were found to be positive for H pylori infection by histology on antrum biopsy specimens were enrolled into this study. METHODS: Gastric type epithelium in the duodenum was found in 49 of 71 ulcer patients (69%). Continuous 24 hour gastric pH metry was performed in 50 healthy subjects and in the two subgroups of duodenal ulcer patients with and without gastric metaplasia in the duodenum. Gastric acidity was calculated for 24 hours (1700-1659), night (2000-0759) and day-time (0800-1959). RESULTS: Ulcer patients without gastric metaplasia showed a significantly higher gastric acidity (p < 0.001) than controls for every time interval considered, while the ulcer subgroup with gastric metaplasia was more acid than healthy subjects (p < 0.001) during the whole 24 hour period and the daytime. There was no difference between the two subgroups of duodenal ulcer patients with and without gastric metaplasia during the various time segments analysed. CONCLUSION: The findings confirm that the circadian gastric acidity of duodenal ulcer patients is higher than that of controls. As there is no difference in gastric pH between duodenal ulcer patients with and without gastric metaplasia, gastric hyperacidity is not specific to patients with duodenal gastric metaplasia. It is probable that this histological change is a non-specific response to mucosal injury resulting from various factors and not exclusively to acid.

Time pattern of gastric acidity in Barrett's esophagus.

Increased gastroesophageal acid reflux is frequently found in patients with Barrett's esophagus, and it has been hypothesized that gastric acid hypersecretion could be an important factor aggravating the exposure of esophageal mucosa to acid and then contributing to the development of this disorder. The aim of the present study was to assess whether the circadian pattern of gastric acidity differs between refluxer patients with and without Barrett's esophagus and normal subjects. Continuous 24-hr gastric pH monitoring was performed in 119 healthy volunteers, 20 patients with Barrett's esophagus, 37 patients with moderate and 10 patients with severe reflux esophagitis without Barrett's esophagus. In all these diseases the final diagnosis was ascertained by means of endoscopy plus biopsy. There was no difference in the 24-hr and daytime patterns of gastric pH between healthy subjects and patients with Barrett's esophagus, while nocturnal acidity was significantly lower (P < 0.05) in the latter population. Gastric acidity, in contrast, was higher (P < 0.05) in controls than in patients with both moderate and severe reflux esophagitis without Barrett's esophagus during the whole 24-hr period. There was no difference between refluxer patients with and without Barrett's esophagus in any of the three time intervals we analyzed. Because normal subjects had lower gastric pH than patients with Barrett's esophagus during the night and than patients with reflux esophagitis during the whole 24-hr period, gastric hyperacidity is not a relevant factor in the development of both metaplastic columnar epithelium and inflammatory changes in the distal esophagus, and other pathophysiological mechanisms are involved in these histological alterations.

Are clinical patterns of dyspepsia a valid guideline for appropriate use of endoscopy? A report on 2253 dyspeptic patients.

We studied 2253 consecutive dyspeptic patients, without clinical evidence of organic disease, who were referred to our open access endoscopy service. The aim was to assess whether the various clinical patterns of dyspepsia can be considered a valid guideline for the appropriate use of endoscopy. According to the symptomatological patterns, our patients were defined as sufferers from 1) ulcer-like (973 patients), 2) reflux-like (857), and 3) dysmotility-like dyspepsia (423). In our patient population, which reflects the general population of our city, the dysmotility-like type of dyspepsia was the least frequent (19%), whereas the ulcer-like (43%) and the reflux-like (38%) dyspepsia were almost equivalent. A negative endoscopy (35.7%) occurred significantly (p < 5 x 10(-4)) more often in dysmotility-like than in ulcer-like (26.3%) and reflux-like dyspepsia (25.7%). Furthermore, in dysmotility-like dyspepsia, we observed no malignancies in patients less than 60 yr old, and no gastric ulcers in patients less than 50 yr old. In the latter subgroup of patients (under 50 yr), duodenal ulcers and esophagitis were rare (occurring in only one and five, respectively, out of 145 patients). In ulcer-like and reflux-like dyspepsia, abnormal endoscopic findings occurred frequently (in 73.5% and 74.1%, respectively), and no relationship with patients' age was observed. Our data indicate that patients under 50 yr old with dysmotility-like dyspepsia can be considered a kind of population for which endoscopy is inappropriate. However, because the prevalence of dysmotility-like dyspepsia was 19% (423/2253) in our patient sample, and only 7.15% of them were under 50 yr old (161/2253), we can obtain only a small percentage of reduction in endoscopic service load if the guideline of age < 50 yr is adopted.

Hormonal therapy of pancreatic carcinoma. Rationale and perspectives.

Exocrine pancreas carcinoma is still diagnosed at a relatively late stage, so that only a few cases can be cured by surgery. Therefore, it is desirable that an effective medical therapy be found first to stall the development of the disease and second to improve the life conditions of patients. On the basis of recent discoveries, a new therapeutic approach seems to derive from hormone manipulation. The growth of pancreatic carcinoma appears to be stimulated by various factors, such as Epidermal Growth Factor (EGF) and Insulin-like Growth Factor I (IGF-I), and by various hormones, such as androgens and cholecystokinin. Several studies performed on cell lines and on animal models of pancreatic carcinoma demonstrated an antitumoral effect of certain antihormones and of somatostatin. Taking such studies as a premise, the first clinical studies were finally started in patients suffering from nonoperable pancreatic cancer. Results are still partial and contradictory, but such research is certainly worthy of further study along the lines already taken.

Open access endoscopy: a large-scale analysis of its use in dyspeptic patients.

We examined 2,253 consecutive dyspeptic patients referred to our endoscopy service by general practitioners ("open" group) and hospital clinicians ("clinic" group) to study the prevalence of the various endoscopic findings according to patient age and the route of endoscopic referral. The results obtained are representative of that specific population. Normal endoscopic findings progressively lessened as patients' age increased, and the overall rate was as low as 26.5% in the open and 30.3% in the clinic groups. Erosive prepyloric changes and duodenitis were the most frequently noted abnormalities in patients < 40 years of age (16.9% and 20.1%, respectively, in the open and 11.6% and 14.2% in the clinic groups). Chronic gastritis was prevalent in patients > 60 years of age. Duodenal ulcer decreased from 9.7% (open) and 18% (clinic) in patients < 40 to 2% and 1.1% in patients > 60. No malignancy was found in patients < 40, while only approximately 1% of those < 60 had neoplasms. All our endoscopic findings, both in the open and the clinic groups, were not significantly different. No significant differences in symptoms were observed among patients with different endoscopic findings. We conclude that (a) endoscopy is really useful only in a small group of patients < 40 years of age; (b) individual symptoms alone have a poorly discriminant diagnostic power; and (c) restriction of open access endoscopy is not justified.

Patterns of dyspepsia in patients with no clinical evidence of organic diseases.

We studied 2000 dyspeptic patients with no obvious signs of organic disease at their first examination, in order to (1) verify how many diagnoses of idiopathic dyspepsia had really been made after exhaustive diagnostic procedures and (2) evaluate the diagnostic power of the symptoms in distinguishing organic from idiopathic dyspepsia. This latter was considered only when no structural abnormalities were found. In all the other cases, a distinction was made between "related" and "associated" organic dyspepsia according to whether or not there was a certain relationship between the abnormalities and the dyspeptic symptoms. The patients were referred to us as follows: (1) spontaneously, (2) sent by physicians collaborating with us, (3) referred to our open access endoscopic service. The results show the frequency of idiopathic dyspepsia was 26%, whereas associated structural abnormalities were present in 45.4%. Obvious organic causes of dyspepsia were seen in 28.6% (24% benign and 4.6% malignant diseases). When considered separately, no symptom alone allows a correct diagnosis. The simultaneous evaluation of the symptoms with linear discriminant analysis distinguishes between idiopathic and organic dyspeptic patients in about 70% of the cases. A higher discrimination percentage in about 70% of the cases. A higher discrimination percentage could probably be obtained using a wider range of clinical parameters and/or a more complex statistical analysis of the interrelationships which exist between the clinical symptoms and the final diagnosis.

Fine-needle aspiration cytodiagnosis: a simple and safe procedure for cancer of the pancreas.

One hundred fine-needle aspirations (45 percutaneous ultrasonically-guided and 55 intraoperative) were performed in 82 patients suspected of having pancreatic cancer, in order to evaluate the contribution of cytologic data to definitive diagnosis of this tumor. The overall success rate of both cytologic methods was 90.6 p. 100 in our 64 patients who were histologically proved to have pancreatic cancer. Sensitivity was 77.4 p. 100 with percutaneous and 75.5 p. 100 with intraoperative aspirations. In all 18 cases with the final diagnosis of chronic pancreatitis results of both techniques were negative. Neither relevant morbidity nor mortality were recorded in any of the 82 patients. These cytologic studies are at present reliable, rapid, highly cost-effective (especially percutaneous aspiration) and most important, safer than histologic examinations. We believe that fine-needle aspiration cytology has gained a primary role in the diagnostic process of pancreatic carcinoma. Therefore the old view of considering examination of cytologic material only as a screening procedure should be abandoned.

Comparative study of percutaneous and peroperative fine-needle aspirations in the diagnosis of pancreatic cancer.

A consecutive series of 51 patients with suspected pancreatic cancer were studied in order to evaluate the contribution of cytologic data in establishing a definitive diagnosis of the tumor. A percutaneous ultrasonically-guided, and a peroperative fine-needle, aspiration were performed in 26 and 29 patients, respectively; 4 cases underwent both methods. Final histologic diagnosis in surgical or autopsy specimens showed cancer of the pancreas in 41 cases and chronic pancreatitis in 10. Cytology was successful in 33/41 cancer patients (80.5%): percutaneous aspiration was positive in 15/20 (75%) cases, and peroperative aspiration in 18/25 (72%). The difference between the two methods was not significant. Neither technique gave false positives in chronic pancreatitis. In none of the 51 patients was relevant morbidity reported. These cytological studies are at present accurate and mostly safer than histologic examinations. In particular ultrasound-guided percutaneous aspiration should be given precedence, since it provides preoperative confirmation of the tumor, thus obviating the need for exploratory laparotomy.

Leucovorin rescue of enteric lesions induced by high-dose methotrexate: a time-related study in mice.

In this study, different groups of mice were treated with a single high-dose of methotrexate or with a leucovorin-methotrexate association, and the changes in structure and cell types of the small intestine were studied histologically. The results suggested that leucovorin rescue diminished the degree of mitotic abatement induced by methotrexate in the first days after treatment, with better preservation of enteric structures and the cell type ratio.

Pulmonary toxicity in mice after high-dose methotrexate administration with and without leucovorin rescue.

Interstitial lung lesions were induced in mice by high-dose methotrexate with high frequency. They appeared early after treatment; their onset, evolution and recovery parallelled those of lesions to the hemopoietic tissues and the intestine. The pathogenesis of methotrexate lung toxicity in mice is discussed. Leucovorin rescue was ineffective in preventing the lung lesions induced by high-dose methotrexate.