Survival in patients with hypoechoic muscularis propria lesions suggestive of gastrointestinal stromal tumors in gastric wall.

BACKGROUND: Subepithelial lesions (SEL) on upper gastrointestinal endoscopy are frequently encountered and referred to endoscopic ultrasound (EUS). Management of small gastric hypoechoic SELs of muscularis propria (MP) is controversial since EUS-assisted fine needle aspiration may be inconclusive, and surgical excision may be too invasive. We aimed to analyze our gastric MP-SELs in terms of survival and confounding factors. METHODS: Data from gastric hypoechoic MP-SELs suggestive of gastrointestinal stromal tumor (GIST) by EUS were retrospectively reviewed. Surgically resected GISTs were stratified according to the current pathological risk criteria. RESULTS: Sixty-one patients were identified. The mean age was 55.5 ± 13.2 years and 45.6% were male. Mean follow-up duration was 53.4 ± 26.7 (12-110) months. Twenty-eight (45.9%) patients were managed conservatively (diameter 15.3 ± 10.1 mm). There were no metastasis- or tumor-related deaths and no significant size changes (≥ 5 mm) in this group during follow-up. Thirty-three (54.1%) patients underwent complete resection (diameter 34.2 ± 14.1 mm) among which 25 (75.8%) had the final diagnosis of GIST; 2 (8.0%), 14 (56%) and 6 (24%) patients were classified in no-risk, very-low-risk, low-risk categories respectively, while 2 (8.0%) were in moderate-risk and only 1 (4.0%) was in high-risk category. CONCLUSIONS: The excellent survival of patients with small hypoechoic gastric MP-SELs with conservative management represents indolent course of those lesions. We suggest re- consideration of the recommendations in the current guidelines towards extending the follow-up intervals for small MP-SELs.

Preliminary evidence of an association between the functional c-kit rs6554199 polymorphism and achalasia in a Turkish population.

BACKGROUND: C-kit-positive interstitial cells of Cajal (ICC) of the lower esophageal sphincter are reduced in achalasia. Two functional gene polymorphisms (rs2237025 and rs6554199) within the c-kit gene may affect its transcriptional activity. In this pilot study, we hypothesized that these polymorphisms would be associated with achalasia. METHODS: Genomic DNA was extracted and real-time PCR reactions were used to determine the rs2237025 and rs6554199 c-kit polymorphisms in 88 Turkish patients with achalasia and 101 healthy controls. KEY RESULTS: The frequency of the T allele of rs6554199 was significantly higher in patients with achalasia [odds ratio (OR): 1.55; 95% confidence interval (CI), 1.03-2.34; P = 0.038] compared with the G allele. Under a dominant model of inheritance, the carriage of at least one T allele was significantly more frequent in patients with achalasia (80.7%) than in controls (65.3%; OR: 2.21; 95% CI, 1.13-4.33; P = 0.022). No association of the c-kit rs2237025 polymorphism with achalasia was detected. CONCLUSIONS & INFERENCES: Despite the small sample size and the possibility of a false positive finding, our preliminary data support the hypothesis that the T allele of the c-kit rs6554199 polymorphism may be associated with achalasia in the Turkish population. These findings need to be replicated in other racial-ethnically diverse populations.

Adrenomedullin in cirrhotic and non-cirrhotic portal hypertension.

AIM: Adrenomedullin (ADM) is a potent vasodilator peptide. ADM and nitric oxide (NO) are produced in vascular endothelial cells. Increased ADM level has been linked to hyperdynamic circulation and arterial vasodilatation in cirrhotic portal hypertension (CPH). The role of ADM in non-cirrhotic portal hypertension (NCPH) is unknown. plasma ADM levels were studied in patients with NCPH, compensated and decompensated cirrhosis in order to determine its contribution to portal hypertension (PH) in these groups. METHODS: There were 4 groups of subjects. Group 1 consisted of 27 patients (F/M: 12/15) with NCPH due to portal and/or splenic vein thrombosis (mean age: 41+/-12 years), group 2 consisted of 14 patients (F/M: 6/8) with compensated (Child-Pugh A) cirrhosis (mean age: 46+/-4), group 3 consisted of 16 patients (F/M: 6/10) with decompensated (Child-Pugh C) cirrhosis (mean age: 47+/-12). Fourteen healthy subjects (F/M: 6/8) (mean age: 44+/-8) were used as controls in Group 4. ADM level was measured by ELISA. NO was determined as nitrite/nitrate level by chemoluminescence. RESULTS: ADM level in Group 1 (236+/-61.4 pg/mL) was significantly higher than that in group 2 (108.4+/-28.3 pg/mL) and group 4 (84.1+/-31.5 pg/mL) (both P<0.0001) but was lower than that in Group 3 (324+/-93.7 pg/mL) (P=0.002). NO level in group 1 (27+/-1.4 micromol/L) was significantly higher than that in group 2 (19.8+/-2.8 micromol/L) and group 4 (16.9+/-1.6 micromol/L) but was lower than that in Group 3 (39+/-3.6 micromol/L) (for all three P<0.0001). A strong correlation was observed between ADM and NO levels (r=0.827, P<0.0001). CONCLUSION: Adrenomedullin and NO levels were high in both non-cirrhotic and cirrhotic portal hypertension and were closely correlated, Adrenomedullin and NO levels increased proportionally with the severity of cirrhosis, and were significantly higher than those in patients with NCPH. Portal hypertension plays an important role in the increase of ADM and NO. Parenchymal damage in cirrhosis may contribute to the increase in these parameters.

Clinical efficacy and toxicity of standard dose adriamycin in hyperbilirubinaemic patients with hepatocellular carcinoma: relation to liver tests and pharmacokinetic parameters.

A standard dose of Adriamycin (60 mg m-2) was administered to 30 patients with inoperable hepatocellular carcinoma, 16 of whom were hyperbilirubinaemic (18-37 mumol l-1). The hyperbilirubinaemic patients experienced marked myelosuppression, but only minor symptomatic side-effects. The degree of neutropenia was directly related to the serum bilirubin concentration, but not to any other standard liver test, presence or absence of cirrhosis, or any pharmacokinetic parameter studied including the area under the Adriamycin or adriamycinol concentration-time curve to 48 h or infinity, or the terminal half-life of Adriamycin. The area under the log concentration-time curve was significantly greater for both Adriamycin and adriamycinol in patients who were hyperbilirubinaemic compared to those with normal bilirubin. Whilst hyperbilirubinaemic patients may tolerate a full dose of Adriamycin, we found no evidence that this was associated with a better response rate, which was disappointingly low at only 18%.

Pharmacokinetics and toxicity of intraarterial adriamycin for hepatocellular carcinoma: effect of coadministration of lipiodol.

To determine the effect of coadministration of lipiodol on the pharmacokinetics and systemic toxicity of intraarterial Adriamycin in patients with hepatocellular carcinoma, nine patients were studied in detail. Each received two courses of a bolus injection of Adriamycin (60 mg/m2), in one of which the Adriamycin was mixed with 10 ml of lipiodol. Analysis of the paired data, and additional 'non-paired' data from a further seven patients, showed that there was no significant difference in the area under the concentration-time curve for Adriamycin or adriamycinol or, in the case of Adriamycin, the terminal half-life. Likewise the fall in haemoglobin concentration, white cell count and platelet count following treatment, and the degree of nausea and vomiting were not significantly different. Comparison with a series of 12 patients receiving intravenous Adriamycin, in the same dose schedule, revealed no difference in terms of pharmacokinetic parameters or toxicity with intraarterial administration of Adriamycin, with or without lipiodol.

Effect of diltiazem on renal function in patients with liver cirrhosis.

Calcium channel blockers have strong vasodilator, natriuretic and diuretic actions in normal and hypertensive subjects. The aim of this study was to evaluate the effect of diltiazem on renal function, renin-angiotensin-aldosterone axis (RAA) and atrial natriuretic factor (ANF) in patients with liver cirrhosis. Seven patients (3 females and 4 males) with a mean age of 56.3 +/- 11.1 years (36-68) entered the trial. All of the patients had HBV (6 cases) or HCV (1 case) related Child A (3 cases) or Child B (4 cases) liver cirrhosis proven by liver biopsy. Patients were given placebo for 15 days followed by p.o. diltiazem 30 mg t.i.d. for 15 days. Urinary volume, natriuresis, creatinine clearance, plasma renin activity (PRA), ANF and aldosterone (ALD) levels were determined after the washout period and during the first and second weeks of drug treatment. Urinary volume increased by 25-170% in 5 cases but this difference did not reach statistical significance. Slight increases in natriuresis occurred in some cases on the 3rd day of the trial but the overall results were not statistically significant (191.50 +/- 26.85 vs 204.07 +/- 39.83 mmol/l). Diltiazem induced no significant changes in PRA, ALD and ANF levels or creatinine clearance during the first or second weeks of the trial. There was a significant drop in the pulse rate on the first or second weeks of the treatment (p less than 0.01 and p less than 0.05, respectively). No significant changes were noted on mean arterial pressure (MAP).(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatitis B virus related hepatocellular carcinoma in the non-cirrhotic liver.

To complement investigations of hepatitis B virus infection in hepatocellular carcinoma associated with cirrhosis, we studied hepatitis B virus infection in 137 hepatoma patients without cirrhosis. Ninety-five were from the U.K. (where the prevalence of hepatitis B virus markers is very low) and 42 were from overseas. Of these 137 patients, seven (5%) were hepatitis B surface antigen seropositive. None of the hepatitis B surface antigen positive patients had any recognisable risk factors other than birth in an area of high hepatitis B virus prevalence in four of the patients. Of the 95 U.K. patients three (3%) were hepatitis B surface antigen positive as compared to a carriage rate of less than 0.1% in the normal population. The frequency of antibodies to hepatitis B surface and core antigens alone (both 7.5%) was also higher than that seen in the normal U.K. population (2.4%). Histological examination of the non-tumorous liver showed fine fibrous septa in three patients, more extensive subcapsular scars in one, chronic persistent hepatitis in two and non-specific inflammation in one. On immunohistochemical examination five patients had hepatitis B surface antigen (but not core antigen) detectable in the non-tumorous liver tissue. Hepatitis B virus infection appears to be a small, but significant, risk factor for the development of hepatoma in the non-cirrhotic group.

Intraarterial adriamycin and lipiodol for inoperable hepatocellular carcinoma: a comparison with intravenous adriamycin.

The technique of 'targeting' cytotoxic drugs by mixing them with the contrast medium lipiodol is now widely used in Japan and the Far East where it has been reported to enhance response rates in patients with hepatocellular carcinoma. In the present study 19 patients with this tumour were treated with intra-(hepatic) arterial adriamycin (60 mg/m2), at least one course of which was combined with lipiodol (10-20 ml). Two patients (11%) had a remission as indicated by a significant fall in serum alphafetoprotein and there was a reduction of tumour size in one of these. The median survival period was 3 months (range 1-18) with the two responding patients surviving 8 and 12 months. This response rate was no better than the figure of 14% seen in 31 consecutive patients treated with intravenous adriamycin at the same dose, and the survival curves of the two groups of patients were not significantly different. Lipiodol in combination with adriamycin is not superior to intravenous adriamycin administered alone.