Observations on use of montelukast in pediatric eosinophilic esophagitis: insights for the future.

Eosinophilic esophagitis is characterized by dense infiltration of the esophageal epithelium with eosinophils, typically accompanied by dysphagia. Effective therapies include the use of topical and systemic steroids as well as elimination diets. No previous reports have described the use of montelukast in the management of pediatric eosinophilic esophagitis. We retrospectively reviewed the charts of all patients with eosinophilic esophagitis followed in our pediatric center between 2000 and 2009. Those treated with montelukast were studied in detail. Study outcome was clinical response rate, defined by symptom (not histologic) improvement. Twenty-one patients with eosinophilic esophagitis were identified. Eight patients were maintained on montelukast (range 4-10 mg daily) after confirming the diagnosis of eosinophilic esophagitis histologically and failing to respond to a trial of proton pump inhibitor therapy. Three of eight patients had a clinical response (one had complete response and two with partial response) that could be attributed to montelukast. Four other patients responded clinically, but other therapies were concomitantly implemented. No side effects were reported with montelukast treatment with a mean follow-up duration of 32 months. Five patients had remained on montelukast therapy at the time of the final follow-up. Montelukast has minimal risk of adverse reactions compared with steroid therapy and may offer clinical relief in a small subset of children with eosinophilic esophagitis. Histologic response could not be verified in this study. Prospective studies, using higher montelukast doses, may potentially play a role and should be considered for future investigation.

The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations.

BACKGROUND: Juvenile polyposis (JP) is an autosomal dominant syndrome predisposing to colorectal and gastric cancer. We have identified mutations in two genes causing JP, MADH4 and bone morphogenetic protein receptor 1A (BMPR1A): both are involved in bone morphogenetic protein (BMP) mediated signalling and are members of the TGF-beta superfamily. This study determined the prevalence of mutations in MADH4 and BMPR1A, as well as three other BMP/activin pathway candidate genes in a large number of JP patients. METHODS: DNA was extracted from the blood of JP patients and used for PCR amplification of each exon of these five genes, using primers flanking each intron-exon boundary. Mutations were determined by comparison to wild type sequences using sequence analysis software. A total of 77 JP cases were sequenced for mutations in the MADH4, BMPR1A, BMPR1B, BMPR2, and/or ACVR1 (activin A receptor) genes. The latter three genes were analysed when MADH4 and BMPR1A sequencing found no mutations. RESULTS: Germline MADH4 mutations were found in 14 cases (18.2%) and BMPR1A mutations in 16 cases (20.8%). No mutations were found in BMPR1B, BMPR2, or ACVR1 in 32 MADH4 and BMPR1A mutation negative cases. DISCUSSION: In the largest series of JP patients reported to date, the prevalence of germline MADH4 and BMPR1A mutations is approximately 20% for each gene. Since mutations were not found in more than half the JP patients, either additional genes predisposing to JP remain to be discovered, or alternate means of inactivation of the two known genes are responsible for these JP cases.

Germline SMAD4 or BMPR1A mutations and phenotype of juvenile polyposis.

BACKGROUND: Juvenile polyposis (JP) is an inherited condition predisposing to upper gastrointestinal (UGI) polyps and colorectal cancer. Two genes are known to predispose to JP, SMAD4 and bone morphogenetic protein receptor type 1A (BMPR1A). The object of this study was to determine the differences in phenotype of patients with SMAD4 or BMPR1A mutations (MUT+) compared with those without (MUT-). METHODS: DNA was extracted from 54 JP probands and used for polymerase chain reaction of all exons of SMAD4 and BMPR1A. Products were then sequenced and analyzed for mutations. Medical record data were used to create a JP database, and statistical analysis was performed using Fisher's exact and unpaired t-tests. RESULTS: Nine of 54 patients had germline SMAD4 mutations, 13 had BMPR1A mutations, and 32 had neither. There were no significant differences between SMAD4+ and BMPR1A+ cases in terms of clinical factors examined, except for a family history of UGI involvement (P <.01). There was a higher prevalence of familial cases in MUT+ patients (P =.09), >10 lower gastrointestinal polyps (P =.06), and frequency of family history of gastrointestinal cancer compared with MUT- patients (P =.01). CONCLUSIONS: Patients with germline SMAD4 or BMPR1A mutations have a more prominent JP phenotype than those without, and SMAD4 mutations predispose to UGI polyposis.

Suprahepatic venacavaplasty (cavaplasty) with retrohepatic cava extension in liver transplantation: experience with first 115 cases.

BACKGROUND: We first introduced the orthotopic liver transplantation utilizing cavaplasty technique in 1994. This paper describes the surgical technique and assesses the outcome of the cavaplasty OLT. METHODS: The cavaplasty procedure was used in 115 consecutive orthotopic liver transplantations, including six left lateral and two right lobe transplantations, between November 1994 and September 2000. Fifty-three (66.3%) transplantations required femoro-axillary veno-venous bypass in the initial 4 years, whereas only eight (22.9%) needed VB in the subsequent 2 years. Conversion to piggyback or standard technique was not necessary in any patient. RESULTS: Median results are as follows: operative time 4.5 hr, warm ischemia time 25 min, and blood transfused (packed red blood cells) 6 units. These findings did not differ between first transplantation and retransplantation. There were no perioperative deaths related to the cavaplasty technique. No hepatic venous outflow obstruction was observed, including living-related OLTs. No patient required postoperative hemodialysis for acute renal failure. The median intensive care and hospital stays were 2 days and 10 days, respectively. CONCLUSIONS: The cavaplasty technique requires no retrocaval, hepatic vein, or short hepatic vein dissection, and the inferior vena cava can be preserved, which provides advantages for hepatectomy and easy hemostasis, especially during retransplantation. The wide-open triangular caval anastomosis is easy to perform, allowing short implantation time and size matching and avoiding outflow obstruction. The short implantation time reduces the need for veno-venous bypass. Our experience indicates that the cavaplasty technique can be applied to all patients and is justified by minimal technical complications.

Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis.

Juvenile polyposis (JP; OMIM 174900) is an autosomal dominant gastrointestinal hamartomatous polyposis syndrome in which patients are at risk for developing gastrointestinal cancers. Previous studies have demonstrated a locus for JP mapping to 18q21.1 (ref. 3) and germline mutations in the homolog of the gene for mothers against decapentaplegic, Drosophila, (MADH4, also known as SMAD4) in several JP families. However, mutations in MADH4 are only present in a subset of JP cases, and although mutations in the gene for phosphatase and tensin homolog (PTEN) have been described in a few families, undefined genetic heterogeneity remains. Using a genome-wide screen in four JP kindreds without germline mutations in MADH4 or PTEN, we identified linkage with markers from chromosome 10q22-23 (maximum lod score of 4.74, straight theta=0.00). We found no recombinants using markers developed from the vicinity of the gene for bone morphogenetic protein receptor 1A (BMPR1A), a serine-threonine kinase type I receptor involved in bone morphogenetic protein (BMP) signaling. Genomic sequencing of BMPR1A in each of these JP kindreds disclosed germline nonsense mutations in all affected kindred members but not in normal control individuals. These findings indicate involvement of an additional gene in the transforming growth factor-beta (TGF-beta) superfamily in the genesis of JP, and document an unanticipated function for BMP in colonic epithelial growth control.

Serologic testing for celiac disease in the United States: results of a multilaboratory comparison study.

The aim of this study was to compare the efficiencies of six reference laboratories for serologic testing for celiac disease. Serum from 20 patients with untreated celiac disease and from 20 controls was thawed, divided, and distributed to each participating laboratory, which performed endomysial antibody tests. Five laboratories also performed antigliadin antibody tests. Sensitivity for endomysial antibody immunoglobulin A (IgA) varied from 57 to 90%. In all laboratories, the specificity for celiac disease was 100%. The sensitivity and specificity for both IgA and IgG antigliadin antibody varied significantly. When results from all three tests were combined in each laboratory, sensitivity was 90 to 100%. The specificity for endomysial antibody was 100% in the laboratories. Sensitivity was less than reported previously. Standardization of these tests is needed in the United States.

Effect of endotoxin on opossum gallbladder motility: a model of acalculous cholecystitis.

OBJECTIVE: To determine whether endotoxin causes histologic changes in the gallbladder consistent with acalculous cholecystitis, and to determine the effects of endotoxin on gallbladder motility. SUMMARY BACKGROUND DATA: Acute acalculous cholecystitis is frequently seen in critically ill, septic patients, after prolonged fasting and gallbladder stasis. The pathogenesis of acalculous cholecystitis is unknown; however, previous studies have suggested that ischemia may play a role. METHODS: Adult opossums received Escherichia coli lipopolysaccharide. The gallbladder was removed for histologic examination or for physiologic studies 4 hours to 2 weeks later. For histologic examination, gallbladder strips underwent standard hematoxylin-and-eosin processing. For physiologic studies, they were mounted in a tissue bath to determine responses to cholecystokinin octapeptide or electrical field stimulation. RESULTS: Intravenous endotoxin at a dose of 0.005 mg/kg resulted in disrupted mucosal surfaces and areas of hemorrhage; higher doses of endotoxin resulted in coagulation necrosis, hemorrhage, areas of fibrin deposition, and extensive mucosal loss, consistent with an acute ischemic insult. Endotoxin abolished the contractile response to cholecystokinin octapeptide in gallbladder strips 4 hours after endotoxin administration. The 0.005-mg/kg dose of endotoxin decreased the contractile response to cholecystokinin octapeptide for up to 96 hours after endotoxin administration and decreased the contractile response to electrical field stimulation for 48 hours after administration. Inhibition of nitric oxide synthase reversed the decreased contractile response to cholecystokinin octapeptide. CONCLUSIONS: Endotoxin causes an ischemic insult to the gallbladder similar to that seen in acalculous cholecystitis. Also, endotoxin may lead to gallbladder stasis by decreasing gallbladder contractile responses to hormonal and neural stimuli.

Hepatitis C virus (HCV) infection and cryoglobulinemia: analysis of whole blood and plasma HCV-RNA concentrations and correlation with liver histology.

The influence of cryoprecipitate (CP) on liver histology and peripheral titers of hepatitis C virus (HCV) RNA was evaluated for 115 patients with chronic hepatitis. Fifty-four patients had measurable CP levels whereas 61 did not. Assessment of liver biopsies for grade of fibrosis revealed that patients with CP had increased fibrosis (P <.001) and incidence of cirrhosis (P =.001) compared with those without CP. In contrast, there was not a significant difference in the inflammatory activity score between the 2 groups. HCV RNA in whole blood (WB) and plasma (Pl) was evaluated in patients with or without CP by end-point-limiting dilution titer. Among patients with CP, WB titers were significantly higher than Pl titers (P <.001); however, there was no difference in WB or Pl titers in patients without CP (P =.068). Histological activity and fibrosis scores of patients from either group were compared with peripheral viral titers of WB and Pl, percentage of CP, rheumatoid factor (RF) titer, and serum alanine transaminase (ALT). There were significant correlations between the amount of fibrosis and the percentage of CP and rheumatoid factor titer, yet neither of the latter parameters was correlated with inflammatory activity. These data suggest that patients with CP and chronic hepatitis owing to HCV are more likely to have progressive disease than patients without CP. Furthermore, the presence of CP in patients infected with HCV appears to influence the amount of virus detected in patient Pl, suggesting that WB assays may be more reliable for HCV-RNA quantitation in patients with CP.

The risk of gastrointestinal carcinoma in familial juvenile polyposis.

BACKGROUND: Familial juvenile polyposis (JP) is an autosomal dominant condition in which affected individuals develop upper or lower gastrointestinal (GI) juvenile polyps, or both, and have a predisposition to cancer of the gastrointestinal tract. The risk of GI cancer has not been well defined because of the small number of these families and the lack of follow-up. The objective of this study was to determine the prevalence and age at diagnosis of GI polyposis and cancer in a large JP kindred. METHODS: Medical records were reviewed, patients were interviewed, and histories were taken. Pathology reports and slides were reviewed by our pathologists. A database was created for analysis of clinical and pathologic factors. RESULTS: This kindred contains 117 members, 29 of whom have had upper or lower GI polyps or cancer, or both. All those affected have had colonic juvenile polyps or cancer, except for two who died of advanced gastric cancer and never had colonic evaluation. Nine individuals have had both upper and lower GI polyps or cancer. Sixteen of 29 (55%) affected patients have developed gastrointestinal cancer. Eleven (38%) have had colon cancer, and six (21%) have had upper GI cancers. CONCLUSIONS: The risk of gastrointestinal malignancy in affected members of this JP kindred exceeds 50%. The high risk of GI cancer warrants frequent endoscopic screening of both affected and at-risk family members. Screening will soon be facilitated by presymptomatic genetic testing for the identification of gene carriers.

Mutations in the SMAD4/DPC4 gene in juvenile polyposis.

Familial juvenile polyposis is an autosomal dominant disease characterized by a predisposition to hamartomatous polyps and gastrointestinal cancer. Here it is shown that a subset of juvenile polyposis families carry germ line mutations in the gene SMAD4 (also known as DPC4), located on chromosome 18q21.1, that encodes a critical cytoplasmic mediator in the transforming growth factor-beta signaling pathway. The mutant SMAD4 proteins are predicted to be truncated at the carboxyl-terminus and lack sequences required for normal function. These results confirm an important role for SMAD4 in the development of gastrointestinal tumors.

A gene for familial juvenile polyposis maps to chromosome 18q21.1.

Familial juvenile polyposis (FJP) is a hamartomatouspolyposis syndrome in which affected family members develop upper and lower gastrointestinal juvenile polyps and are at increased risk for gastrointestinal cancer. A genetic locus for FJP has not yet been identified by linkage; therefore, the objective of this study was to perform a focused genome screen in a large family segregating FJP. No evidence for linkage was found with markers near MSH2, MLH1, MCC, APC, HMPS, CDKN2A, JP1, PTEN, KRAS2, TP53, or LKB1. Linkage to FJP was established with several markers from chromosome 18q21.1. The maximum LOD score was 5.00, with marker D18S1099 (recombination fraction of .001). Analysis of critical recombinants places the FJP gene in an 11.9-cM interval bounded by D18S1118 and D18S487, a region that also contains the tumor-suppressor genes DCC and DPC4. These data demonstrate localization of a gene for FJP to chromosome 18q21.1 by linkage, and they raise the possibility that either DCC or DPC4 could be responsible for FJP.

Surreptitious hepatitis C virus (HCV) infection detected in the majority of patients with cryptogenic chronic hepatitis and negative HCV antibody tests.

Reverse transcription-polymerase chain reaction was used to identify hepatitis C virus (HCV) RNA in peripheral whole blood (WB) and plasma samples from 15 patients with chronic, unexplained hepatitis. These patients were serologically negative for hepatitis A, B, and C and were classified as having chronic non-A, non-B, non-C hepatitis (NANBNC). HCV RNA was repeatedly detected in WB samples from 10 (67%). In contrast, plasma samples from only 5 were intermittently positive. Statistically, HCV RNA detection in WB was significantly more sensitive than in plasma. Nucleic acid hybridization and HCV genotypic analysis confirmed the specificity of the HCV RNA assay. Liver biopsies from these patients suggested histopathologic differences between HCV RNA-positive and -negative groups. These data demonstrate that HCV infection is present in patients with unexplained chronic hepatitis more frequently than previously believed. Additionally, WB HCV RNA detection is more sensitive than plasma assays in identifying antibody-negative HCV infection.

Intrahepatic arterial chemoembolization for hepatocellular carcinoma and metastatic neuroendocrine tumors in the era of liver transplantation.

Surgical resection has been the standard approach for primary and metastatic liver tumors. Long-term survival, however, is limited because of recurrence or hepatic decompensation. Failure of chemotherapeutic regimens or liver transplantation (OLT) to prevent recurrence has resulted in the need for multimodality therapies. We report our experience with preoperative hepatic arterial chemoembolization (CET) followed by OLT in highly select patients. Over a 33-month period, 23 of 41 patients (56%) referred with primary (n = 16) or metastatic neuroendocrine (n = 7) liver tumors met eligibility requirements. Despite mild, self-limited chemical hepatitis, CET was well tolerated in all but three elderly patients who succumbed to liver failure. Four of five patients ultimately received OLT. Three are alive and free of disease at a mean followup of 17 months, one died of recurrent hepatocellular carcinoma, and one (NET) remains well at 33 months with elevated glucagon levels but no measurable disease. All NET patients are alive with resolution of hormonal symptoms. Four of five noncirrhotic patients died of disease, and one has progressive tumor growth. Although OLT following CET achieves superior survival, its application is limited to a minority of patients with such tumors. Careful pretreatment staging and patient selection combined with caution in the use of CET in elderly cirrhotic patients is critical to the success of such therapies.

Practice guideline development task force of the College of American Pathologists. Hereditary hemochromatosis.

Hereditary hemochromatosis is an autosomal recessive disorder, the gene for which occurs in approximately 10% of Americans, most of whom are unaffected heterozygotes. Approximately 5/1000 white Americans are homozygous and at risk of developing severe and potentially lethal hemochromatosis. The disorder affects numerous organ systems, but the most common symptoms are fatigue, palpitations, joint pains, and impotence; the most common signs are those that relate to hypothalamic, cardiac, hepatic or pancreatic dysfunction, including poor cold tolerance, impotence in males, amenorrhea in females, cardiac arrhythmias, dyspnea, edema, hepatosplenomegaly, spider telangiectases, ascites, deformity, swelling or limitation of motion of joints, weight loss, hyperpigmentation. Characteristic abnormalities of laboratory tests include elevated serum iron concentration, high transferrin saturation, elevated serum ferritin concentration, elevated serum transaminases, hyperglycemia and low values for thyroid-stimulating hormone (TSH) and gonadotropins. Death may be the result of cardiac arrhythmia, congestive heart failure, liver failure or liver cancer. Since many of these complications cannot be reversed once they have developed, early diagnosis and treatment are essential. In view of the high prevalence in the American population (prevalence varies with ethnic background), the low cost of diagnosis and treatment, the efficacy of treatment if begun early, and, on the other hand, high costs and low success rate of late diagnosis and treatment, systematic screening for hemochromatosis is warranted for all persons over the age of 20 years. The initial screening should be by measurement of serum iron concentration and transferrin saturation. The practice guideline provides a diagnostic algorithm for cases in which the serum transferrin saturation is 60% or greater. It also provides guidelines for clinical management.

Polyps: the pathologist's perspective.

Adenomas of the colon and rectum are perhaps the most commonly encountered of human benign epithelial neoplasms. Evidence of their relationship to the development of colorectal carcinoma has mounted over the years. They represent a phase present for significant duration in many fated to develop colon cancer. Because of this, and because of the technical advances in endoscopy, a great deal of effort has been expended on identifying and removing these lesions. Subsequent care of the patient is heavily dependent on the pathologic analysis of these lesions. they must be properly classified; the presence of cancer must be carefully sought. If present, the character and location of the cancer arising in the polyp must be carefully described. Communication between clinician and pathologist if of paramount importance. Attention must be paid to the precise meaning of such terms as dysplasia, carcinoma, and invasion. The pathologist's report needs to detail parameters important in determining prognosis and further therapy.

Heat stress does not sensitize rats to the toxic effects of bacterial lipopolysaccharide.

To determine whether heat stress sensitizes rats to lipopolysaccharide (LPS), four groups were examined: saline, LPS, heat stressed+saline, and heat stressed+LPS treated rats. Saline or LPS (Escherichia coli, 5 mg.kg-1 body weight, i.v.) was given after exposure to heat and at the same time of day for nonheated rats. Survival was monitored for 24 or 48 h; samples of liver and small intestine were obtained at 24 h for histological analysis. Thermal responses were similar (P > 0.05) for the heat stressed saline and LPS treated rats: mean values for maximum colon temperature were 43.0 +/- 0.1 and 42.9 +/- 0.1 degrees C, respectively. Mortality was similar for rats exposed to heat stress+saline (11%, 2/19) and heat stress+LPS (32%, 6/19). No lethality was observed in nonheated rats given saline or LPS. Tissue damage was similar in heat stress+saline and heat stress+LPS treated rats. Liver showed mild to severe degrees of coagulative necrosis while duodenum exhibited damage to the villous tips. These findings show that severe heat stress does not markedly sensitize the rat to the lethal activity of LPS.

CT findings of plexiform neurofibromatosis involving the ileum and its mesentery.

We present a case of plexiform neurofibromatosis involving the ileum and its mesentery. Computed tomography (CT) scans showed a cluster of small soft-tissue density nodules, which represented a cross-sectional image of the enlarged peripheral nerves and wall thickening of the distal ileum. Trapped fat tissue was demonstrated between these enlarged nerves. Histopathologic studies of the resected specimen correlated well with CT findings.

Acute gastritis associated with spiral organisms from cats.

Numerous studies implicated Helicobacter pylori as one causative agent producing gastritis and dyspepsia. Recent reports focus on another bacterium, Gastrospirillum hominis, as a possible pathogen producing gastritis. We report a 30-year-old researcher who became acutely ill with epigastric pain indicative of esophagitis or peptic ulcer disease. Gastritis and a gastric ulcer were observed endoscopically. Histological examination of the gastric mucosa revealed an acute gastritis and large spiral-shaped organisms. The spiral forms were present in large quantities in the gastric mucosa of experimental animals (cats) handled by the patient in his research. Electron microscopy confirmed that the organisms from the cat and patient were morphologically identical. The patient was successfully treated with bismuth subsalicylate. His symptoms resolved and the organisms were cleared from his stomach. This study provides evidence that another bacterium, a Gastrospirillum, may cause gastritis in man and may be transmitted from animal to man.

Morphology and pathology of radiation-induced esophagitis. Double-blind study of naproxen vs placebo for prevention of radiation injury.

Radiation-induced esophagitis can cause substantial morbidity. Experiments in lab animals have shown that pretreatment with indomethacin protects the esophagus from radiation damage. We conducted a prospective, double-blind, randomized trial of naproxen vs placebo in patients undergoing thoracic radiation therapy for lung cancer. Twenty-eight patients were enrolled, of which 26 completed the study. Sixteen patients were given a short course of radiation (30 Gy/10 fractions/2 weeks), and 10 patients were given a longer course and a larger dose (40-50 Gy/25 fractions/5 weeks). Half of the irradiated patients were treated with naproxen, 375 mg, taken orally twice a day, and half were given an identical placebo. All patients were given ranitidine 300 mg, taken orally once a day. Study drugs were taken throughout the course of radiation. Endoscopy with esophageal biopsies and brushings was performed before and on the last day of treatment. Patients kept a daily diary for symptom scoring. Symptoms such as chest pain, dysphagia, odynophagia, and/or heartburn were reported in 15 patients from both subgroups, resulting in diet restriction to liquids only in eight patients and requiring temporary discontinuation of radiation therapy in one of them. Approximately half the patients in each subgroup developed esophagitis, usually mild and usually limited to the proximal esophagus. Severity of symptoms was not proportional to the severity of esophagitis. Candidiasis was documented in eight patients, but only four had symptoms that were severe in one. We conclude that acute radiation injury to the esophagus is observed in approximately half the patients receiving radiation therapy and can result in substantial morbidity.(ABSTRACT TRUNCATED AT 250 WORDS)