The short- and long-term efficacy of empirical esophageal dilation in patients with nonobstructive dysphagia: a prospective, randomized study.

OBJECTIVE: The efficacy of empirical esophageal dilation for nonobstructive dysphagia (NOD) is unknown. Our aim was to assess the efficacy and safety of empirical dilation with a large bougie in patients with NOD. METHODS: Patients with NOD (normal barium swallow, free passage of a 13-mm barium pill, and normal esophagogastroduodenoscopy) were randomized to dilation with either a 50-Fr (Group A) or 26-Fr (Group B) Maloney dilator. Before dilation, the dysphagia (DyspSC) and diet (DietSc) scores were recorded and an esophageal manometry performed. Both scores were reassessed at 1, 3, 7, and 14 days after dilation. Success was defined at day 14 as an improvement in the DietSc of at least 25% from baseline, or a DyspSc of < or =3. Nonresponders were crossed-over to the alternate dilator and restudied. RESULTS: Twenty-three patients (58.7+/-1.9 yr) were enrolled: 13 in Group A and 10 in Group B. Both groups were matched for age, baseline DyspSc (4.2+/-0.6 vs 3.8+/-0.5), baseline DietSc (13.3+/-1.7 vs 12.0+/-1.9), and manometric findings. A nonspecific motility disorder was seen in 43.4% patients. Group A had an initial response rate significantly greater (84.6%) than Group B (40%) (p = 0.03; odds ratio [OR] = 8.25). The DyspSc and DietSc were better than baseline with both dilators, but only the DietSc improved significantly in patients dilated with the 50-Fr dilator (5.3+/-1.9 vs 12.3+/-1.4; p = 0.004). At 2 yr, 80% of the patients responding to the 50-Fr Maloney had a sustained response. CONCLUSION: Empirical dilation with a large (50-Fr) bougie is safe, effective, and long-lasting in improving nonobstructive dysphagia.

Formation of stable DNA adducts and apurinic sites upon metabolic activation of bay and fjord region polycyclic aromatic hydrocarbons in human cell cultures.

Carcinogenic polycyclic aromatic hydrocarbons (PAH), such as benzo[a]pyrene (B[a]P), 7,12-dimethylbenz[a]anthracene (DMBA), and dibenzo[a,l]pyrene (DB[a,l]P), are metabolically activated to electrophilically reactive bay or fjord region diol epoxides that bind to the exocyclic amino groups of purine bases in DNA to form stable adducts. In addition, it has been reported that these PAH can be enzymatically oxidized to yield radical cations that form apurinic (AP) sites in DNA via depurinating adducts. The formation of stable adducts and AP sites in DNA of human cells exposed to PAH was examined in cytochrome P450 (P450)-expressing mammary carcinoma MCF-7 cells and in leukemia HL-60 cells, which display a high peroxidase but no P450-mediated activity, after exposure to these PAH. Stable DNA adducts were assessed by (33)P-postlabeling/HPLC analysis, and the induction of AP sites in DNA was analyzed by an aldehyde reactive probe (ARP) and a slot blot method. After exposure for 4 h, the levels of stable DNA adducts were comparable in MCF-7 cells treated with B[a]P and DMBA, but significantly lower than those observed in MCF-7 cells treated with the stronger carcinogen DB[a,l]P. While the levels of stable adducts increased more than 10-fold (B[a]P and DMBA) or 100-fold (DB[a,l]P) after exposure for 24 h, the levels of AP sites remained low after both treatment periods. Thus, the levels of stable adducts were approximately 5-fold higher than the levels of AP sites after treatment with B[a]P or DMBA and more than 100-fold higher in cells exposed to DB[a,l]P for 24 h. None of these carcinogenic PAH formed detectable levels of stable DNA adducts or AP sites in HL-60 cells. The results demonstrate that metabolic activation of B[a]P, DMBA, and DB[a,l]P is catalyzed by P450 enzymes leading to diol epoxides that form predominantly stable DNA adducts but only low levels of AP sites.

Cancer initiation by polycyclic aromatic hydrocarbons results from formation of stable DNA adducts rather than apurinic sites.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants with high carcinogenic potencies that have been linked to the etiology of human cancers through their presence in cigarette smoke and environmental mixtures. They are metabolically activated in cells by cytochrome P450 enzymes and/or peroxidases to reactive intermediates that damage DNA. One pathway of activation forms dihydrodiol epoxides that covalently bind to exocyclic amino groups of purines in DNA to form stable adducts. Another pathway involves formation of radical cations that bind to the N7 or C8 of purines to form unstable adducts that depurinate to leave apurinic (AP) sites in DNA. In the present study the proportions of stable DNA adducts and AP sites formed by the carcinogenic PAHs dibenzo[a,l]-pyrene (DB[a,l]P), 7,12-dimethylbenz[a]anthracene (DMBA), and benzo[a]pyrene (B[a]P) have been investigated in a target tissue for carcinogenesis, mouse epidermis. After topical application of the PAHs on the skin of female SENCAR mice epidermal DNA was isolated and the formation of stable DNA adducts was measured by (33)P-postlabeling and HPLC analysis. AP sites in DNA were measured with an aldehyde reactive probe in a slot-blot assay. At both 4 and 24 h after exposure, DB[a,l]P formed significantly higher amounts of stable DNA adducts than DMBA, and B[a]P exhibited the lowest level of binding. In contrast, the number of AP sites present in mice treated with these PAHs was in the order: DMBA > B[a]P >> DB[a,l]P. The level of AP sites was significantly lower than the level of stable adducts for each PAH. The most potent carcinogen, DB[a,l]P, induced the highest level of stable adducts and the lowest level of AP sites in epidermal DNA. These results indicate that stable DNA adducts rather than AP sites are responsible for tumor initiation by carcinogenic PAHs.

Comparison of cytochrome P450- and peroxidase-dependent metabolic activation of the potent carcinogen dibenzo[a,l]pyrene in human cell lines: formation of stable DNA adducts and absence of a detectable increase in apurinic sites.

The potent carcinogen dibenzo[a,l]pyrene (DB[a,l]P) has been reported to form both stable and depurinating DNA adducts upon activation by cytochrome P450 enzymes and/or cellular peroxidases. Only stable DB[a,l]P-DNA adducts were detected in DNA after reaction of DB[a,I]P-11,12-diol-13,14-epoxides in solution or cells in culture. To determine whether DB[a,l]P can be activated to metabolites that form depurinating adducts in cells with either high peroxidase (human leukemia HL-60 cell line) or cytochrome P450 activity (human mammary carcinoma MCF-7 cell line), cultures were treated with DB[a,l]P for 4 h, and the levels of stable adducts and apurinic (AP) sites in the DNA were determined. DNA samples from DB[a,l]P-treated HL-60 cells contained no detectable levels of either stable adducts or AP sites. MCF-7 cells exposed to 2 microM DB[a,l]P for 4 h contained 4 stable adducts per 10(6) nucleotides, but no detectable increase in AP sites. The results indicate that metabolic activation of DB[a,l]P by cytochrome P450 enzymes to diol epoxides that form stable DNA adducts, rather than one-electron oxidation catalyzed either by cytochrome P450 enzymes or peroxidases to form AP sites, is responsible for the high carcinogenic activity of DB[a,l]P.

Formation of stable adducts and absence of depurinating DNA adducts in cells and DNA treated with the potent carcinogen dibenzo[a,l]pyrene or its diol epoxides.

Polycyclic aromatic hydrocarbons (PAH) are widespread environmental contaminants, and some are potent carcinogens in rodents. Carcinogenic PAH are activated in cells to metabolites that react with DNA to form stable covalent DNA adducts. It has been proposed [Cavalieri, E. L. & Roger, E. G. (1995) Xenobiotica 25, 677-688] that unstable DNA adducts are also formed and that apurinic sites in the DNA resulting from unstable PAH adducts play a key role in the initiation of cancer. The potent carcinogen dibenzo[a,l]pyrene (DB[a, l]P) is activated in cells to (+)-syn- and (-)-anti-DB[a,l]P-11, 12-diol-13,14-epoxide (DB[a,l]PDE), which have been shown to form stable adducts with DNA. To evaluate the importance of unstable PAH adducts, we compared stable adduct formation to apurinic site formation. Stable DB[a,l]PDE adducts were determined by 33P-postlabeling and HPLC. To measure apurinic sites they were converted to strand breaks, and these were monitored by examining the integrity of a particular restriction fragment of the dihydrofolate reductase gene. The method easily detected apurinic sites resulting from methylation by treatment of cells or DNA with dimethyl sulfate or from reaction of DNA with DB[a,l]P in the presence of horseradish peroxidase. We estimate the method could detect 0.1 apurinic site in the 14-kb fragment examined. However, apurinic sites were below our limit of detection in DNA treated directly with (+)-syn- or (-)-anti-DB[a,l]PDE or in DNA from Chinese hamster ovary B11 cells so treated, although in these samples the frequency of stable adducts ranged from 3 to 10 per 14 kb. We also treated the human mammary carcinoma cell line MCF-7 with DB[a,l]P and again could not detect significant amounts of unstable adducts. These results indicate that the proportion of stable adducts formed by DB[a,l]P activated in cells and its diol epoxides is greater than 99% and suggest a predominant role for stable DNA adducts in the carcinogenic activity of DB[a,l]P.

A study at 10 medical centers of the safety and efficacy of 48 flexible sigmoidoscopies and 8 colonoscopies during pregnancy with follow-up of fetal outcome and with comparison to control groups.

To analyze the risks versus benefits of flexible sigmoidoscopy and colonoscopy to the pregnant female and fetus, we conducted a multiyear, retrospective study at 10 hospitals of 46 patients undergoing 48 sigmoidoscopies and 8 patients undergoing 8 colonoscopies during pregnancy. Sigmoidoscopy controls included two study control groups and the average American pregnancy outcomes. Sigmoidoscopy indications included hematochezia in 28, diarrhea in 10, abdominal pain in 4, and other in 3. Thirteen patients were in the first trimester of pregnancy, 18 were in the second trimester, and 15 were in the third trimester. Twenty-seven patients had a lesion diagnosed by sigmoidoscopy, including reactivated or newly diagnosed inflammatory bowel disease, bleeding internal hemorrhoids, and other colitidies. Twenty-two of 29 patients with rectal bleeding had a significant lesion identified by sigmoidoscopy. Sigmoidoscopy was significantly more frequently diagnostic for hematochezia than for other indications (p < 0.03, chi2). No endoscopic complications occurred to the pregnant patients. Excluding 4 voluntary abortions and 1 unknown pregnancy outcome, 38 (93%) of 41 pregnant females delivered healthy babies (study control rate = 93%; NS, Fisher's exact test). Mean live-born infant Apgar scores were 8.2+/-1.5 (SD) at 1 min and 9.0+/-0.2 at 5 min (control mean Apgar scores: 8.1+/-1.7 at 1 min and 8.8+/-1.0 at 5 min; NS, Student's t test). Three high-risk pregnancies ended with fetal demise at 8, 9, or 12 weeks after sigmoidoscopy, from causes unrelated to sigmoidoscopy. No fetal cardiac abnormalities were detected by fetal cardiac monitoring during two sigmoidoscopies. Eight pregnant females underwent colonoscopy, without complications. Pregnancy outcomes included six healthy babies delivered at full term, one voluntary abortion, and one fetal demise in a high-risk pregnancy 4 months after colonoscopy from causes unrelated to colonoscopy. This study suggests that sigmoidoscopy does not induce labor or result in congenital malformations, that sigmoidoscopy is not contraindicated during pregnancy, and that sigmoidoscopy may be beneficial in pregnant patients with significant lower gastrointestinal bleeding. Colonoscopy during pregnancy should be considered for life-threatening lower gastrointestinal bleeding or when the only alternative is surgery.

A study of eight medical centers of the safety and clinical efficacy of esophagogastroduodenoscopy in 83 pregnant females with follow-up of fetal outcome with comparison control groups.

OBJECTIVES: To analyze risks versus benefits of esophagogastroduodenoscopy (EGD) during pregnancy to the fetus and pregnant female. METHODS: Retrospective study of 83 consecutive pregnant patients who underwent EGD admitted to eight university teaching hospitals during a study period of up to 14 yr, with follow-up of fetal outcome. Controls included: 48 pregnant females matched for EGD indications who did not undergo EGD (pregnant controls), 83 nonpregnant females undergoing EGD matched for age and EGD indication (EGD controls), and national pregnancy outcome rates (national controls). RESULTS: EGD indications included acute GI bleeding in 37, vomiting and abdominal pain in 17, vomiting in 14, abdominal pain in 11, and other in four. The mean week of gestation was 19.8 +/ 8.9 EGD was diagnostic in 65 patients. The diagnostic yield of EGD was 95% for acute GI bleeding and ranged from 50 to 82% for the other indications (significantly different rates, odds ratio = 9.3, p < 0.001, odds ratio confidence interval = 2.22-45.5). Esophagitis was found in 62+ of patients with a diagnostic EGD. No significant endoscopic complications occurred. EGD did not induce labor. Excluding six voluntary abortions and three unknown pregnancy outcomes, 70 (95%) of 74 patients delivered healthy babies (pregnant control rate = 94%, national control rate = 98.4%, all not significant, Fisher's exact test). Moreover, the four poor outcomes (three stillbirths and one involuntary abortion) occurred in high risk pregnancies and were unrelated to EGD temporally or etiologically. No other infant had a congenital malformation noted in the neonatal nursery. Nine (12.7%) of the live born infants had a low birth weight (pregnant control rate = 8.5%, national control rate = 7.0%, all not significant, kappa 2). Mean Apgar scores of live born infants were 7.7 +/ 1.6 at 1 min and 9.0 +/ 0.6 at 5 min (pregnant control scores = 7.6 +/ 2.0 at 1 min and 8.5 +/ 1.1 at 5 min; national control mean scores = 8.0 +/ 1.4 at 1 min and 9.0 +/ 0.9 at 5 min; all not significant, Student's t test). In three cases with fetal cardiac monitoring, EGD did not induce abnormal fetal heart rates (preendoscopy rate = 143.3 +/ 5.8 beats/min, postendoscopy rate = 148.0 +/ 10.6 beats/min). CONCLUSIONS: In this study, EGD did not induce labor or result in congenital malformations. EGD is not contraindicated during pregnancy. EGD is beneficial in pregnant patients with upper GI bleeding.