Christine Silvain

Sclerotherapy with or without Octreotide for Acute Variceal Bleeding

BACKGROUND Sclerotherapy is considered the most effective way to stop bleeding from esophageal varices, but acute variceal bleeding is still associated with a high risk of rebleeding and death. We compared sclerotherapy alone with sclerotherapy and octreotide to control acute variceal bleeding and prevent early rebleeding in patients with cirrhosis. METHODS In a double-blind, prospective trial, 199 patients with cirrhosis and acute variceal bleeding who underwent emergency sclerotherapy were randomly assigned to receive a continuous infusion of octreotide (25 micrograms per hour) or placebo for five days. The primary outcome measure was survival without rebleeding five days after sclerotherapy. RESULTS After five days, the proportion of patients who had survived without rebleeding was higher in the octreotide group (85 of 98 patients, or 87 percent) than in the placebo group (72 of 101, or 71 percent; 95 percent confidence interval for the difference, 4 to 27 percent; P = 0.009). The mean number of units of blood transfused within the first 24 hours after sclerotherapy was lower in the octreotide group (1.2 units; range, 0 to 7) than in the placebo group (2.0 units; range, 0 to 10; P = 0.006). A logistic-regression analysis showed that the treatment assignment (P = 0.003) and the number of blood units transfused before any other treatment was undertaken (P = 0.002) were the only two variables independently associated with survival without rebleeding. After adjustment for base-line differences between the two groups, the odds ratio for treatment failure in the placebo group, as compared with the octreotide group, was 3.3 (95 percent confidence interval, 1.5 to 7.3). The mean (+/- SD) 15-day cumulative survival rate (estimated by the Kaplan-Meier method) was 88 +/- 12 percent in both groups. Side effects were minor, and their incidence was similar in the two groups. CONCLUSIONS In patients with cirrhosis, the combination of sclerotherapy and octreotide is more effective than sclerotherapy alone in controlling acute variceal bleeding, but there is no difference between the overall mortality rates associated with the two approaches to treatment.

Diagnosis of choledocholithiasis: EUS or magnetic resonance cholangiography? A prospective controlled study

BACKGROUND Endoscopic ultrasonography (EUS) appears to be the best imaging method for the diagnosis of choledocholithiasis. The aim of this preliminary, prospective, controlled study was to assess the accuracy of EUS and magnetic resonance cholangiopancreatography (MRCP) in the diagnosis of common bile duct stones. METHODS From December 1995 through April 1997, all patients referred because of suspicion of the presence of common bile duct stones were included in the study. EUS and MRCP were performed. Each examination was performed by a different operator unaware of the result of the other procedure. The definitive diagnosis was established by means of endoscopic retrograde cholangiography with sphincterotomy or a surgical procedure. RESULTS Forty-three patients (18 men, 25 women) with a mean age of 60.9 +/- 14.5 years (range 25 to 81 years) were included in the study. Eleven patients were excluded because of unavailability of magnetic resonance imaging(n = 5) or EUS (n = 6). Ten patients (31.2%) had choledocholithiasis. For this diagnosis, the sensitivity of EUS was 100%, the specificity was 95.4%, the positive predictive value was 90.9%, and the negative predictive value was 100%. The corresponding values for MRCP were 100%, 72.7%, 62.5%, and 100%, not significantly different from EUS results. The accuracy of EUS was 96.9%, and that of MRCP was 82.2%. CONCLUSION This preliminary study confirmed EUS as an accurate and noninvasive procedure for the diagnosis of common bile duct stones. MRCP, which had a high sensitivity and high negative predictive value, might be an accurate technique for patients with a contraindication to EUS.

Effect of low-frequency KRAS mutations on the response to anti-EGFR therapy in metastatic colorectal cancer

BACKGROUND Only patients with wild-type (WT) KRAS tumors benefit from anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (Mabs) in metastatic colorectal cancer (mCRC). Pyrosequencing is now widely used for the determination of KRAS mutation burden and a conservative cut-off point of 10% has been defined. Up until now, the impact of low-frequency KRAS mutations (<10%) on the response to anti-EGFR Mabs has yet to be evaluated. PATIENTS AND METHODS Tumors from patients receiving anti-EGFR Mabs based on a WT genotype for KRAS, as determined using direct sequencing, have been retrospectively analyzed by pyrosequencing. Patients were categorized as WT (no KRAS mutation) or low-frequency mutation when KRAS mutation was <10% (KRAS low MT). RESULTS A total of 168 patients treated by anti-EGFR Mabs for mCRC were analyzed. According to pyrosequencing, 138 tumors remained KRAS WT, while 30 tumors were KRAS low MT. In the KRAS low MT and KRAS WT groups, the response rates were 6.7% and 37.0%, respectively, while stabilization amounted to 23.3% versus 32.6% and progression to 70% versus 29% (P < 0.01). Progression-free survival (PFS) was 2.7 ± 0.5 months for KRAS low MT and was 6.0 ± 0.3 months for KRAS WT (P < 0.01). CONCLUSIONS These results appear to validate consideration of low-frequency KRAS mutation tumors as positive, and justify a large-scale prospective study.

Quadruplex Real-Time PCR Assay Using Allele-Specific Scorpion Primers for Detection of Mutations Conferring Clarithromycin Resistance to Helicobacter pylori

ABSTRACT We developed a single-vessel multiplex real-time PCR assay that detects Helicobacter pylori infection and identified the four existing alleles of the 23S rRNA genes of H. pylori—the wild-type sequence and the three mutations conferring clarithromycin resistance—using allele-specific Scorpion primers directly on biopsy specimens. The Scorpion primers combine a primer and a probe in a single molecule and are able to distinguish single-nucleotide polymorphism. Fluorescent signals, produced when the probes are annealed, are read in four channels by a SmartCycler thermocycler. The assay was first applied successfully on 4 reference and 61 clinical strains. MICs of clarithromycin were determined by the Etest method. A perfect concordance was obtained between Etest and Scorpion PCR. Mixed populations were better detected by Scorpion PCR. We examined 259 biopsies from 229 patients by culture, PCR-restriction fragment length polymorphism (RFLP), and Scorpion PCR. One biopsy, positive for culture, exhibited inhibitors for both PCR-RFLP and Scorpion PCR. Twelve biopsies were positive for PCR-RFLP and Scorpion PCR but negative for culture with concordant determination of mutations in the 23S rRNA genes by the two PCR assays. Three biopsies were positive for Scorpion PCR only. Compared to culture, the sensitivity of Scorpion PCR was 98.3% and the specificity was 92.5%. The Scorpion PCR assay provides a highly accurate, rapid, and precise method for the detection and determination of mutations conferring clarithromycin resistance to H. pylori.

Cirrhosis and bleeding: the need for very early management.

BACKGROUND/AIMS Retrospective studies suggest that the prognosis of patients with cirrhosis and variceal hemorrhage has improved in more recent decades. In a prospective cohort study in which the choice of prophylactic therapy was left to each practitioner, we followed cirrhotic patients with medium/large varices to determine factors predictive of bleeding and death. METHODS Three hundred fourteen patients with grades 2 or 3 esophageal varices (Child A and B/C: 218 and 96) were enrolled. One hundred seventy-three patients had no previous history of variceal bleeding. Only 245 patients (100% of patients with prior variceal hemorrhage, 61% of patients without prior hemorrhage) were receiving some form of prophylactic therapy. The median follow-up was 18 months. RESULTS There were 76 bleeding events and 14 related deaths (18%); nine of these deaths occurred within 24 h of bleeding onset (two at home, two during hospital transfer, and five in hospital, a mean of 2.5 h after onset; six involved Child C patients). Twenty-five deaths were not due to bleeding but were closely related to cirrhosis. In a Cox model, the presence of tense ascites (relative risk 3.4, 95% confidence interval, CI 2.5-5.9) and a prior history of hemorrhage (relative risk 4.4, 95% CI 2.6-7.5) were independent predictors of variceal hemorrhage. In patients without a prior history of bleeding, bleeding risk was higher with more prolonged prothrombin time and lower when patients were receiving propranolol. CONCLUSIONS Despite the advent of effective drugs and endoscopic therapy for variceal bleeding, about a quarter of deaths occur very early after bleeding onset, confirming the need for rapid specific management.

Long-term outcome of severe radiation enteritis treated by total parenteral nutrition.

The outcome of 31 patients with severe radiation enteritis treated by total parenteral nutrition (TPN) was analyzed. Before initiation of parenteral nutrition, 18 of the patients had not had abdominal surgery, while 13 had either a resection or an intestinal bypass for radiation enteritis. Median follow-up was 21/2 years (range: 1 month to 12 years) from the time of initiation of parenteral nutrition. Surgery was required in 15 cases because parenteral alimentation could not be continued. Only eight of these 15 were able to resume a normal oral intake. Total parenteral nutrition allowed oral feeding to be resumed in 11 (36%) after a median follow-up of 40 months (range: 6–142 months). In general, total parenteral nutrition was well tolerated and was associated with low morbidity. Eighteen patients died, 13 of complications due to radiation therapy, four of cancer recurrence, and one of an unrelated cause. Survival probability was 58% at one year and 36% at five years. When possible, prognostic factors present either before or at initiation of total parenteral nutrition were analyzed. Age, predisposing vascular factors (hypertension, diabetés mellitus, or vascular disease), and enteric fistula and/or perforation were found to have prognostic value. The probability of clinical radiation enteritis recurrence was 34% at one year and 47% at two years. A clinical recurrence of symptoms was more frequent but not significantly so after parenteral nutrition as compared to surgical therapy of radiation enteritis. Although TPN corrected denutrition and allowed deferred surgery in some patients, severe radiation enteritis remains a poorly predictable progressive disease with numerous relapses.

Treatment and long-term outcome of chronic radiation esophagitis after radiation therapy for head and neck tumors. A report of 13 cases.

The natural history of chronic radiation esophagitis occuring in previously normal esophagus is still unknown. We describe here the long-term outcome of chronic esophagitis arising after neck irradiation for oropharynx and larynx carcinomas in 13 consecutive adult patients. The first clinical signs of radiation esophagitis were dysphagia or impossibility of oral intake, which appeared within 26 months (range 2–120 months) after the end of radiation for pyriform fossae carcinoma (N=5), tonsil carcinomaN=2), larynx carcinoma (N=2), pharynx carcinoma (N=2), base of the tongue (N=1), and thyroid carcinomas (N=1). During upper endoscopy, an esophageal stenosis was found in 11 cases and was associated with ulceration in three cases. An isolated esophageal ulceration was present in only two cases. Chronic radiation esophagitis diagnosis was confirmed by histology and durgery in seven cases. In the last six cases, diagnosis was supported by the absence of first cancer relapses within a median follow-up of two years (16 months to nine years) and by endoscopic findings. Seven patients received parenteral or enteral nutrition. Ten patients were treated by peroral dilatation. These treatments allowed nearly normal oral diet in 11/13 patient. Only one patient was lost of follow-up after 20 months. Four patients died from chronic radiation esophagitis. One of these patients died from massive hemorrhage after peroral dilatation. Four patients died of a second carcinoma with no first cancer recurrence. Four patients were alive after dix months to nine years of follow-up. Moderate dysphagia was still present, allowing nearly normal oral feeding. In conclusion, chronic radiation esophagitis is a severe disease with an underestimated frequency. In our study, peroral dilatations appeared to be necessary and were not associated with an increased morbidity.

Characterization of melatonin binding sites in chicken and human intestines

The radioligand 2-[125I]iodomelatonin was used to study melatonin binding sites in chicken and human intestines. In the chicken duodenum, 2-[125I]iodomelatonin binding sites were enriched in the musculosa layer (Bmax approximately 1 fmol/mg protein) as compared to the mucosa/submucosa layer (Bmax approximately 0.2 fmol/mg protein). 2-[125I]iodomelatonin bound with a Kd of 68 +/- 18 pM (mean +/- S.E.M., n = 13) and was displaced by melatonin with a Ki of 0.3 nM. The Kd value for 2-[125I]iodomelatonin was increased 2- to 4-fold by a GTP analog, suggesting that the binding sites might be coupled to a G-protein. The affinity order of nine melatonin analogs at the enteric binding sites was in agreement with the pharmacological profile of melatonin receptors described in other tissues. In the human jejunum, 2-[125I]iodomelatonin binding could be observed in the mucosa/submucosa layer (Kd = 150-200 pM, Bmax = 0.7 fmol/mg protein). The radioligand was efficiently displaced by melatonin (Ki = 0.6 nM) but only marginally by N-acetyltryptamine (Ki = 22 microM) and serotonin (Ki = 14 microM).

Atherosclerosis risk in HIV-infected patients: The influence of hepatitis C virus co-infection

BACKGROUND The influence of hepatitis C virus (HCV) infection on atherosclerosis risk in HIV-infected patients has not been adequately evaluated in real-life situations. OBJECTIVES AND METHODS We compared indexes of early atherosclerosis evaluated by echo-Doppler ultrasound (presence of plaque in carotid or femoral arteries) in 18 HCV-HIV co-infected patients versus 22 HIV mono-infected patients. RESULTS Prevalence of subclinical carotid plaque was significantly higher in HCV-HIV co-infected patients (p=0.04), despite of the fact LDL-cholesterol and blood pressure (BP) were lower in the co-infected patients (p=0.003). HCV chronic infection (OR=10; IC: 1.5-72; p=0.02) was an independent risk factor. CONCLUSION This cross sectional study suggests that HCV infection might be an independent cardiovascular risk factor in HCV-HIV co-infected patients. HCV infection might be considered as not only a liver infection but also as a metabolic disease in HIV patients, justifying regular cardiovascular surveillance.

Specific increase in caspase-1 activity and secretion of IL-1 family cytokines: a putative link between mevalonate kinase deficiency and inflammation

The mevalonate kinase deficiency (MKD), including hyperimmunoglobulinemia D periodic fever syndrome (HIDS) and the more severe mevalonic aciduria are rare, autosomal recessive, autoinflammatory diseases belonging to the hereditary periodic fever (HPF) family. Other members include: familial mediterranean fever (FMF), the cryopyrin-associated periodic syndromes (CAPS) and TNFR-associated periodic syndromes (TRAPS). MKD is caused by mutations in the gene encoding mevalonate kinase (MK), an enzyme of the cholesterol pathway, leading to its inactivation. The molecular mechanisms linking MKD and abnormalities of isoprenoid biosynthesis to cytokine production and inflammation have yet to be fully elucidated. Statins, which are extensively prescribed for lowering cholesterol, are potent inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase, the enzyme directly upstream of MK. In this review, we discuss recent reports demonstrating that in vitro inhibition of the mevalonate pathway by statins specifically increases the production, by activated monocytes, of cytokines of the IL-1 family, by enhancing caspase-1 activity, the enzyme responsible for IL-1beta and IL-18 maturation. The molecular mechanisms involve geranylgeranylation and the enhancement of the activity of G proteins such as Rac-1. Interestingly, activated fibroblasts from MKD patients secrete more IL-1beta than fibroblasts from healthy donors. Taken together, these data highlight the specific enhancement of the IL-1 family of cytokines, the maturation of which is caspase-1-dependent in MKD. Finally, the spectacular decrease in febrile attacks in patients with severe HIDS under IL-1 receptor antagonist (anakinra) treatment, reinforces this hypothesis. Deregulated caspase-1 activation could be responsible for the inflammatory component of MKD, thereby mechanistically linking MKD to FMF and CAPS through cytokines of the IL-1 family.