Rebecca M. Thomas

Hypersensitivity and idiosyncratic reactions to oxaliplatin.

Oxaliplatin is a third‐generation platinum analog that is used to treat a variety of solid tumors, particularly colorectal carcinoma. Patients may develop hypersensitivity reactions, although this complication occurs infrequently.

Acute experimental colitis decreases colonic circular smooth muscle contractility in rats

Distal colitis decreases the contractility of the underlying circular smooth muscle. We examined how time after injury and lesion severity contribute to the decreased contractility and how colitis alters the calcium-handling properties of the affected muscle. Distal colitis was induced in rats by intrarectal administration of 4% acetic acid. Contractile responses to acetylcholine, increased extracellular potassium, and the G protein activator NaF were determined for circular muscle strips from sham control and colitic rats at days 1, 2, 3, 7, and 14 postenemas. Acetylcholine stimulation of tissues from day 3colitic rats was performed in a zero calcium buffer, in the presence of nifedipine, and after depletion of intracellular stores of calcium. The colitis was graded macroscopically as mild, moderate, or severe. Regardless of agonist, maximal decrease in force developed 2 to 3 days posttreatment, followed by a gradual return to control by day 14. The inhibitory effect of colitis on contractility increased with increasing severity of inflammation. Limiting extracellular calcium influx had a greater inhibitory effect on tissues from colitic rats; intracellular calcium depletion had a greater inhibitory effect on tissues from control animals. The data suggest that both lesion severity and time after injury affect the contractile response of circular smooth muscle from the inflamed distal colon. Impaired utilization of intracellular calcium may contribute to the decreased contractility.Distal colitis decreases the contractility of the underlying circular smooth muscle. We examined how time after injury and lesion severity contribute to the decreased contractility and how colitis alters the calcium-handling properties of the affected muscle. Distal colitis was induced in rats by intrarectal administration of 4% acetic acid. Contractile responses to acetylcholine, increased extracellular potassium, and the G protein activator NaF were determined for circular muscle strips from sham control and colitic rats at days 1, 2, 3, 7, and 14 postenemas. Acetylcholine stimulation of tissues from day 3 colitic rats was performed in a zero calcium buffer, in the presence of nifedipine, and after depletion of intracellular stores of calcium. The colitis was graded macroscopically as mild, moderate, or severe. Regardless of agonist, maximal decrease in force developed 2 to 3 days posttreatment, followed by a gradual return to control by day 14. The inhibitory effect of colitis on contractility increased with increasing severity of inflammation. Limiting extracellular calcium influx had a greater inhibitory effect on tissues from colitic rats; intracellular calcium depletion had a greater inhibitory effect on tissues from control animals. The data suggest that both lesion severity and time after injury affect the contractile response of circular smooth muscle from the inflamed distal colon. Impaired utilization of intracellular calcium may contribute to the decreased contractility.

Detection of JC virus DNA sequences and expression of viral T antigen and agnoprotein in esophageal carcinoma.

The human polyomavirus JC virus (JCV) causes progressive multifocal leukoencephalopathy. Subclinical infection with JCV occurs in 85–90% of the population worldwide. The virus usually remains latent but can reactivate under immunosuppressive conditions, resulting in progressive multifocal leukoencephalopathy. JCV is oncogenic in experimental animals and is associated with human brain tumors. JCV is found in normal mucosa of the gastrointestinal tract, and some colon carcinomas express the oncogenic JCV T‐antigen protein. The objective of this study was to examine the presence of JCV DNA sequences and JCV protein expression in normal and malignant human esophageal tissues.

Results of steroid-based therapy for the hepatitis C-autoimmune hepatitis overlap syndrome.

OBJECTIVE:Overlap syndromes in which persons manifest clinical, histological, or immunological features of both hepatitis C infection and autoimmune hepatitis are well described. The discordant forms of treatment for hepatitis C and autoimmune hepatitis have made medical management of these patients difficult. We report our experience in using corticosteroids as first line therapy for the hepatitis C–autoimmune hepatitis overlap syndrome.METHODS:Seven patients with this overlap syndrome (diagnosis based on the presence of serum hepatitis C antibody by RIBA and serum hepatitis C RNA by polymerase chain reaction, and serum hypergammaglobulinemia, elevated ANA or ASMA titers, or histological findings consistent with autoimmune hepatitis) were treated with prednisone with or without azathioprine or cyclosporine, and followed for a median duration of 44.5 months.RESULTS:Five patients (71%) showed improvement of median serum ALT level from 162 U/L to 38 U/L (p = 0.04) and median serum γ-globulin from 2.1 g/dl to 1.4 g/dl (p = 0.04) by 6 months of therapy. The mean modified histological activity index score also decreased from 11.4 ± 2.5 to 6.6 ± 2.6 (p = 0.04) by at least 1 yr of therapy. One patient discontinued prednisone while taking azathioprine and experienced a rebound elevation of serum ALT that did not respond to retreatment with prednisone. Antiviral therapy was subsequently administered and resulted in biochemical and virologic response. Hepatitis C virus RNA remained detectable in all other patients.CONCLUSION:Corticosteroids are beneficial as a first line therapy for some patients with the hepatitis C–autoimmune overlap syndrome, resulting in appreciable biochemical and histological response but without viral eradication.

Barrett's esophagus and achalasia.

Two unusual cases of achalasia with endoscopic and histologic documentation of Barretts esophagus are presented. One patient had Barretts esophagus at the time of initial endoscopy for achalasia, before any treatment. The other patient developed specialized columnar epithelia in the esophagus after treatment with pneumatic dilation. Each patient had evidence of low-grade dysplasia. Including these two patients, 30 cases of Barretts esophagus in patients with achalasia have been reported in the literature. In 73% (22 of 30) of the cases, Barretts esophagus was detected after esophagomyotomy. In 20% (6 of 30) of the cases of achalasia and Barretts esophagus, adenocarcinoma developed. The current two cases are unusual because Barretts esophagus in achalasia generally develops from gastroesophageal reflux after esophagomyotomy. No other patients have been reported to develop Barretts esophagus after pneumatic dilation alone. Patients with achalasia and Barretts esophagus may be at a particularly high risk for developing dysplasia and adenocarcinoma.

Esophageal Bacteria and Barrett's Esophagus: A Preliminary Report

The objective of this study was to investigate if esophageal bacteria are associated with Barretts esophagus (BE). This study was comprised of a retrospective (Part 1) and a subsequent prospective (Part 2) study. In Part 1, Gram stains were performed on esophageal biopsy specimens obtained in 47 patients. Bacteria were quantitated from 0 to 4. In Part II, Gram stains and cultured bacterial counts of esophageal biopsies were obtained in 18 GERD patients (9 with BE and 9 without BE). Part 1 results were as follows. Bacteria were found in 37 of 47 esophageal biopsies. Quantitative bacterial stain scores for BE (2.5±0.2) were higher than for non-BE (1.5±0.3; P = 0.02). The quantitative bacterial stain scores correlated with increasing severity of dysplasia (r = 0.37, P = 0.028). In Part 2, bacteria were found in 8 of 18 esophageal biopsies by Gram stain (6 of 9 patients with BE vs. 2 of 9 non-BE). The distal esophageal bacterial stain scores in BE patients (1.6±0.5) were higher than in those without BE (0.4±0.3; P = 0.07). Patients on proton pump inhibitors tended to have higher bacterial stain scores (1.2±0.4) than patients who were not (0.7±0.3; P = 0.45). Bacterial colony counts were similar in patients with BE compared to those without BE. In conclusion, bacteria in esophageal biopsies were detected more often in BE than non-BE. Increasing bacterial stain scores were associated with metaplasia and increasing dysplasia. Esophageal bacteria, possibly related to stasis or gastric acid suppression therapy, may play a role in the pathogenesis of BE and dysplasia.

Predictors of recurrent specialized intestinal metaplasia after complete laser ablation

OBJECTIVES:The aim of this study was to determine whether specialized intestinal metaplasia recurs after complete laser ablation and to evaluate the persistence of colon epithelial protein in esophageal mucosa after laser ablation as a predictor of recurrence.METHODS:A total of 31 patients with specialized intestinal metaplasia (Barretts esophagus) underwent laser photoablation. Investigators without knowledge of treatment status evaluated serial hematoxylin and eosin–stained slides, Alcian blue–stained slides, and immunohistochemistry for the detection of colon epithelial protein (mAb Das-1).RESULTS:Endoscopic ablation of specialized intestinal epithelium was accomplished in 21 patients after 6.5 ± 1.2 laser sessions. Complications included one perforation, one UGI bleed and one stricture. Of eight post-laser recurrences, seven were successfully re-ablated; one developed adenocarcinoma requiring esophageal resection. Cardia-type mucosa was present by biopsy at the time of complete ablation in all eight recurrent cases despite a normal endoscopic appearance. Colon epithelial protein was detected in all 31 patients before ablation, six of 21 completely ablated patients before they recurred and all eight recurrences. Only two of 15 patients, colon epithelial protein negative at the time of complete ablation, developed recurrent Barretts esophagus. Thus, cardia-type mucosa and persistent colon epithelial protein staining after complete ablation of specialized intestinal epithelium were predictors of future recurrence (p < 0.001).CONCLUSION:Specialized intestinal epithelium was ablated by neodymium:yttrium-aluminum-garnet laser but recurred in eight of 21 (38%) of patients. Colon epithelial protein was present in all primary (31 of 31) and all recurrent (eight of eight) Barretts esophagus. Recurrent specialized intestinal metaplasia may be deep to squamous epithelium. Replacement of specialized intestinal mucosa by cardia-type mucosa and persistence of colonic epithelial protein are predictors of recurrent specialized intestinal mucosa before its endoscopic or histological detection. Laser ablation of Barretts epithelium is an investigational intervention that should be restricted to research protocols.

Hepatitis C virus impairs TLR3 signaling and inhibits IFN-λ 1 expression in human hepatoma cell line

Toll-like receptor 3 (TLR3) activation plays an important role in the innate immune responses to viral infections. We show here that the activation of TLR3 signaling pathway by poly I:C, a synthetic mimic of dsRNA, could induce high-level expression of interferon (IFN)-λ1 in a hepatoma cell line. The induced IFN-λ1 contributed to poly I:C-mediated inhibition of hepatitis C virus (HCV) Japanese fulminant hepatitis-1 (JFH-1) replication in Huh7 cells. This inhibitory effect of poly I:C on HCV replication, however, was compromised by HCV infection of Huh7 cells. Investigation of the mechanisms showed that HCV infection suppressed the expression of poly I:C-induced IFN-λ1 and IFN-stimulated genes [IFN-stimulated gene 56 (ISG-56), myxovirus resistance A (MxA) and 2′-5′-oligoadenylate synthetase 1 (OAS-1))], the key antiviral elements in IFN signaling pathway. Among the HCV nonstructural (NS) proteins tested, NS3/4A, NS5A and NS5B had the ability to inhibit poly I:C-induced IFN-λ1 expression in Huh7 cells. These observations provide the experimental evidence that HCV and its proteins impair TLR3 signaling and inhibit intracellular IFN-λ1/ISG expression in a hepatoma cell line, which may account for HCV persistence in the liver.

Acute amiodarone hepatotoxicity after liver transplantation.

after LDLT (P 0.012; Table 1). It is important to clarify when patients with HCC should be listed as candidates for LDLT. Actually, 47 of 68 patients underwent more than two pretransplant treatments. The times of pretransplant treatment, the interval between the first treatment and LDLT, and the interval between the last pretransplant treatment and LDLT did not affect the outcome. We could not find a correlation between the kind of pretransplant treatment and the outcome, because most patients in this study had undergone more than two kinds of pretransplant treatment before LDLT to treat primary and recurrent HCC. Moreover, there was no evidence concerning how prior hepatic resection, especially major resection, might affect the outcome of LDLT in this study, probably due to the relatively small number of cases. On the basis of the results, we propose that HCC can be treated with any treatment modality as long as the patients’ liver can tolerate it (7). Especially, HCC patients with hepatitis C might not be good candidates for LDLT at initial diagnosis because of high recurrence rate of hepatitis C after LDLT. The up-to-seven criteria might be able to predict patient survival even after LDLT (4). However, the absence of microscopic vascular invasion was crucial to use as a criterion, and surrogate markers to predict microscopic vascular invasion are necessary. DCP more than 300 mAU/mL was an independent risk factor for tumor recurrence after LDLT. DCP level is significantly correlated with pathologic vascular invasion (8) or intrahepatic metastasis, or both (5). In conclusion, the kind, times, and interval of pretransplant treatment did not affect the outcome of LDLT, but its indications should be carefully considered for patients with HCC who have had pretransplant treatment associated with DCP more than 300 mAU/mL to prevent tumor recurrence.

Unusually large extraintestinal GIST presenting as an abdomino-pelvic tumor

BackgroundGastrointestinal stromal tumor (GIST) is a rare visceral tumor that may mimic ovarian tumor.CaseA 56-year-old woman presented with a large abdomino-pelvic mass and moderately elevated CA-125. A large tumor occupying the whole abdominal cavity and pelvis was noted on laparotomy. In addition, multiple tumor nodules were seen from the ligament of Treitz to the terminal ileum involving only the surface intestine. The ovaries appeared normal. The tumor demonstrated spindle and epithelioid components and was found to be morphologically and immunohistochemically consistent with GIST.ConclusionGynecologists need to be cognizant of extra-ovarian pathology in the atypical presentation of a pelvic mass. Correct diagnosis is essential for proper management since GISTs specifically respond to the c-kit selective tyrosine kinase inhibitor, Imatinib mesylate.