Biomedical subjects

D Beauchamp

Publications and source records attributed to D Beauchamp.

At least 19 recordsLinked to original sources

PubMed2002

Dietary composition alters gentamicin-induced nephrotoxicity in rats.

Previous studies have shown temporal variations in gentamicin-induced renal toxicity characterized by a peak when administered during the resting period and a trough during the active period. This time-dependent toxicity was also altered according to the macronutrient composition of dietary regimens offered to female rats. In the present study, adult female Sprague-Dawley rats were adapted to semipurified isocaloric diets containing 20% casein or soy-protein (10% fat each) or to a standard chow diet (18.1% mixed proteins; 4.5% fat). The animals were then chronically treated for 10 days with a nephrotoxic dose of gentamicin sulfate (40 mg/kg/day ip) or a saline solution administered in the middle of their resting period (1200 h) or in the middle of their activity period (0000 h). Body weights of rats injected in the middle of their resting period decreased over the last 6 days of gentamicin treatment. Total 12-h light and 12-h dark food intakes were decreased in gentamicin-treated rats. Rats fed the standard chow diet had significantly lower corticocellular regeneration, serum creatinine and blood urea nitrogen compared to those fed the casein- and soy-containing diets. The present study demonstrates that chronic gentamicin-induced renal toxicity varies temporally according to the time of administration and that a mixed protein diet containing a lower fat level can protect against gentamicin-induced nephrotoxicity.

Acetylglucosaminidase↗

PubMed2001

The effect of fosfomycin on glycopeptide antibiotic-induced nephrotoxicity in rats.

The effect of coadministration of fosfomycin (FOM) on glycopeptide antibiotic-induced nephrotoxicity for 3 days was investigated in rats. To induce nephrotoxicity in a short time, gentamicin (GM) was also coadministered. In the present study, FOM decreased glycopeptide antibiotic-induced nephrotoxicity as shown by reduced urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG) as well as fewer histopathological signs of nephrotoxicity in the groups treated with the combination of glycopeptide and FOM as compared with a glycopeptide alone. In addition, the higher the dose of FOM, the more it decreased urinary NAG levels, suggesting that the role of FOM in alleviating nephrotoxicity is dose dependent. The accumulation of teicoplanin and vancomycin was significantly lower in the renal cortex of rats treated with the combination of glycopeptide antibiotics and FOM as compared with glycopeptide antibiotics alone (P < 0.05). In conclusion, the concomitant administration of FOM and glycopeptide antibiotics may help to achieve a chemotherapeutic strategy that reduces the nephrotoxic effects of glycopeptide antibiotics.

Acetylglucosaminidase↗

PubMed2001

Aminoglycoside nephrotoxicity: do time and frequency of administration matter?

Aminoglycosides remains the mainstay in the treatment of gram-negative infections despite their potential oto-and nephrotoxicity although alternatives with equal or better efficacy are available. Several approaches were investigated to decrease aminoglycosides nephrotoxicity. Among them, only the once-daily dosing of aminoglycosides has been brought to the clinic and physicians are now increasingly adopting this approach to reduce the toxicity of these agents. The incidence of aminoglycoside nephrotoxicity can be further reduced in view of the recent data on the circadian variations of their nephrotoxicity. In fact, it has been clearly demonstrated in both experimental animals and humans that the toxicity is maximal when the drug is injected during the rest period compared with the activity period. Thus, injecting aminoglycosides once-daily at the time of the lowest toxicity is actually the most interesting and clinically applicable approach to reduce aminoglycosides toxicity.

Aminoglycosides↗

PubMed2001

Pulmonary and systemic host response to Streptococcus pneumoniae and Klebsiella pneumoniae bacteremia in normal and immunosuppressed mice.

Mortality related to bacteremic pneumonia remains high, and the role of sepsis in inflammation, pulmonary injury, and death remains unclear, mostly in leukopenic states. In the present study, the microbiology, histopathology, and host response to Streptococcus pneumoniae and Klebsiella pneumoniae infection were determined in an experimental model of bacteremia in immunocompetent and leukopenic mice. Leukocyte depletion by cyclophosphamide did not impair the early clearance of pneumococci from blood but facilitated growth in lungs. By contrast, klebsiellae rapidly grew in blood of leukopenic mice. These observations suggest that tissue-based phagocytes and circulating leukocytes, respectively, play prominent roles in S. pneumoniae and K. pneumoniae eradication. The kinetics of leukocyte recruitment in lungs during S. pneumoniae bacteremia suggested early strong inflammation in immunocompetent mice that is associated with tumor necrosis factor alpha release and histological disorders, including cell debris and surfactant in alveolar spaces. Leukocyte depletion further stimulated pulmonary capillary leakage both in S. pneumoniae and K. pneumoniae bacteremia, which seemed attributable to bacterial virulence factors. Nitric oxide production did not differ significantly among groups. Leukopenia and low platelet counts characterized the late stage of bacteremia for both strains, but only K. pneumoniae altered renal function. Understanding the pathogenesis of bacteremia will help establish beneficial therapies for both sepsis and pneumonia.

Animals↗

PubMed2000

Modulation of cytokines and chemokines, limited pulmonary vascular bed permeability, and prevention of septicemia and death with ceftriaxone and interleukin-10 in pneumococcal pneumonia.

Interleukin (IL)-10 is a biologically active anti-inflammatory and immunomodulatory cytokine. The respective effects or combined effect of ceftriaxone (Ctri) and IL-10 on host response was studied in a mouse model of lethal pneumococcal pneumonia. A once daily intraperitoneal (ip) injection of IL-10 (1 microg/mouse) for 2 days did not affect inflammation but accelerated bacterial dissemination to the bloodstream. Of mice treated with 1 ip 20 mg/kg Ctri injection, 40% developed septicemia, and only 52% survived. However, the addition of IL-10 to Ctri enhanced bacterial clearance, prevented septicemia, and yielded a 95% survival rate (P<.001). This approach also significantly (P<.05) decreased IL-1beta, IL-6, macrophage inflammatory protein-2, and myeloperoxidase levels in lungs and the production of nitric oxide in bronchoalveolar lavage fluid. Furthermore, Ctri plus IL-10 significantly (P<.05) reduced pulmonary vascular leakage and the appearance of red blood cells in alveoli. These data indicate a beneficial role for IL-10 as an adjunctive therapy to antibiotics against pneumococcal pneumonia.

Animals↗

PubMed2000

[Amyotrophic lateral sclerosis manifesting as cognitive disorders. Value of brain perfusion scintigraphic tomography in intensive care].

BACKGROUND: Cognitive disorders have been described in amyotrophic lateral sclerosis, but usually after the diagnosis has ben established. CASE REPORT: A 57-year-old man was intubated for acute respiratory distress subsequent to pneumonia and diaphragm palsy. He had a 2-year history of drug-resistant depression and deterioration of cognitive functions. A pyramidal syndrome associated with biopsy-proven chronic neurogenic atrophy led to the diagnosis of amyotrophic lateral sclerosis. The electromyogram did not contribute to diagnosis. Brain MRI only evidenced moderate bilateral frontal-temporal atrophy. Brain SPECT demonstrated major perfusion defects in the frontal lobes. DISCUSSION: This patient had amyotrophic lateral sclerosis and frontal-temporal dementia with an unusually late onset clinical presentation: cognitive disorder was the inaugural sign. Brain SPECT and muscle biopsy enabled us to identify the cortical and peripheral motor neurone involvement in this uncooperative intensive care patient totally dependent on mechanical ventilation.

Biopsy↗

PubMed2000

Temporal modulation of nephrotoxicity, feeding, and drinking in gentamicin-treated rats.

Gentamicin-induced nephrotoxicity varies temporally, with a peak being observed when this antibiotic is administered during the resting period and a trough when given during the activity period of rats. These nychthemeral variations are modified by fasting and by restricted feeding schedules. In this study, food and water intakes of adult female Sprague-Dawley rats were measured during pretreatment (Days 1 to 5) and during treatment (Days 6 to 10) with gentamicin (80 mg/kg/day, i.p.) injected at 1300 or 0100h. A significantly higher level of serum creatinine was observed when gentamicin was administered at 1300 h compared to 0100 h, and a significantly lower creatinine clearance was found in rats treated with gentamicin at 1300 h compared to those treated with saline at the same time. Gentamicin treatment at 1300 or 0100 h resulted in a decrease in the 24-h food intake. In addition, in the gentamicin-treated group at 0100 h, the maximal food intake observed at late dark during the pretreatment period decreased during treatment, and early dark rather than late dark maximal intake occurred. Our data demonstrate that gentamicin induces a nephrotoxicity that varies temporally, and that gentamicin treatment inhibits food intake and alters its nocturnal variations.

Animals↗

PubMed2000

In vivo activity and pharmacokinetics of ziracin (SCH27899), a new long-acting everninomicin antibiotic, in a murine model of penicillin-susceptible or penicillin-resistant pneumococcal pneumonia.

The effectiveness of ziracin (SCH27899), a novel everninomicin, was at first investigated against lethal pneumonia caused by a penicillin-susceptible Streptococcus pneumoniae strain. A single intravenous injection of ziracin at a dose of 60 mg/kg of body weight given at 18 h postinfection protected 100% mice and led to the complete clearance of bacteria from their lungs. The activity of ziracin was observed to be the same as that of ceftriaxone: the 50% protective doses (PD(50)s) of ziracin and ceftriaxone were 24.8 and 24.6 mg/kg, respectively. Evaluation of this therapy with leukopenic mice showed that a single injection of ziracin protected 75% of these mice. A delay in therapy with ziracin, which was initiated at 48 h postinfection with 30 mg/kg given once daily for 3 days, resulted in an 83% survival rate of immunocompetent mice. The efficacy of ziracin was further compared to that of vancomycin against lethal pneumonia caused by a penicillin-resistant S. pneumoniae strain in leukopenic mice. The PD(50)s of ziracin and vancomycin were 40.5 and 44.2 mg/kg, respectively. Treatment with ziracin at 30 mg/kg once daily for 2 days (initiated 18 h postinfection) yielded an 83% survival rate and achieved complete eradication of the bacteria. The results were the same as those obtained with vancomycin administered at 15 mg/kg twice daily for 2 days. It is notable that the high survival rates for mice treated with ziracin were associated with effective eradication of the bacteria and rapid recovery of pulmonary tissues from pneumonia. The pharmacokinetic properties of ziracin, ceftriaxone, and vancomycin were estimated following intravenous administration of a single dose of 30 mg/kg to immunocompetent mice. The half-life of ziracin was observed to be longer than those of ceftriaxone and vancomycin (2.3 h versus 1.0 and 0.36 h in the bloodstream and 3 h versus 1.9 and 0. 45 h in lung tissues). The areas under the concentration-time curves (AUCs) in lung tissue for ziracin versus those for ceftriaxone and vancomycin were 36 microg. h/g versus 20 and 9.5 microg. h/g. The prolonged half-life and high AUC for ziracin in tissue contributed to its excellent in vivo activities.

Aminoglycosides↗

PubMed2000

A pilot study of neoadjuvant paclitaxel and radiation with correlative molecular studies in stage II/III breast cancer.

A commonly used approach to the management of locally advanced breast cancer currently involves neoadjuvant chemotherapy, followed by surgery and radiation. Earlier neoadjuvant regimens had utilized doxorubicin, making concurrent treatment with radiation less desirable given dose-limiting normal tissue toxicities. With the development of paclitaxel, we can now reconsider the use of concurrent chemoradiation in the treatment of breast cancer. Although paclitaxel is a known radiation sensitizer, its precise mechanism of action is still unclear. One of its proposed mechanisms is that it binds tubulin and induces an M-phase arrest. As cells in M-phase are very sensitive to radiation, it thereby increases radiation sensitivity. The ability to predict tumor response for individual patients would allow us to tailor subsequent therapy for the individual patient. This study is designed to evaluate if paclitaxel's effects on the cell cycle of an individual patient can predict the responsiveness of that patient's tumor to paclitaxel and radiation. Patients will be treated with 3 cycles of paclitaxel followed by concurrent paclitaxel and radiation prior to definitive surgery.

Antineoplastic Agents, Phytogenic↗

PubMed2000

Nephrotoxicity of teicoplanin in rats.

Teicoplanin, a glycopeptide antibiotic, is marketed in a number of European countries and has recently been put on the market in Japan. The spectrum of antibacterial activity of teicoplanin is equivalent or superior to that of vancomycin. The aim of the present study is to examine the nephrotoxicity of teicoplanin compared with vancomycin in rats. Wistar male rats, housed in a light-controlled room at room temperature for 1 week, were used. They were injected with either 15 or 50 mg/kg/day of teicoplanin or 50 or 200 mg/kg/day of vancomycin at 13:00 daily for 14 days. The rats were randomly assigned to groups of five rats each and were housed individually in metabolic cages to collect urine. Urine samples were collected 24 hours prior to the drug treatment and every 24 hours thereafter for 14 days. N-Acetyl-beta-D-glucosaminidase (NAG) activity was determined in the supernatant and expressed in international units per total urine collected for 24 hours. The group which was given vancomycin 200 mg/kg/day had significantly elevated urinary NAG levels compared with the other groups (p < 0.05). No significant differences were observed in the NAG levels in urine among the remaining three groups. These results suggest that the nephrotoxicity of teicoplanin may be only one-fourth that of vancomycin in rats. It appears that by extrapolating the dose amount required for the treatment in humans to rats, the high dose of teicoplanin was set at 50 mg/kg/day and that of vancomycin, 200 mg/kg/day. The recommended dose for teicoplanin will probably be 200 mg/day compared to 2 g/day of vancomycin. If the teicoplanin dose is only one-tenth that of the vancomycin dose, then teicoplanin should be better tolerated than vancomycin in terms of nephrotoxicity.

Acetylglucosaminidase↗

PubMed1999

Pharmacologic Basis for the Treatment of Pyelonephritis.

Urinary tract infections (UTIs) are among the most common bacterial infections in humans. Even though physicians have been treating UTIs for 60 years, there has been no standardized approach regarding the rational choice of antimicrobial agents and optimal treatment duration for these infections. This review discusses the pharmacologic basis for the treatment of UTIs. Although most antibiotics concentrate well in the urine and can eradicate most of the sensitive uropathogens that cause lower UTI, antibiotics given for the treatment of pyelonephritis must concentrate and kill bacteria embedded within the renal parenchyma. Investigators once believed that antibiotics must concentrate in sufficient amounts in the urine of infected patients to be effective in treating pyelonephritis. In fact, the efficacy of an antibiotic in the treatment of pyelonephritis is proportional to its capacity to converge in high concentration not only in urine but also in the renal parenchyma because serum and urine levels of antibiotics are poor predictors of the intrarenal levels. Other factors should also be taken into consideration in the management of UTIs, such as the time of day antibiotics are given because significant time-dependent differences have been observed in the pharmacokinetics and rate of excretion in urine of several antibiotics. Finally, the authors review the recent development in the inflammatory response in the urinary tract that may explain the clinical features of UTI and may be useful in the diagnosis as well as better management of UTI.

Journal Article↗

PubMed1999

Reducing chorioretinal viral counts with intravitreal foscarnet injections in a rabbit model of Herpes simplex virus type-1 retinitis.

The efficacy of intravitreal foscarnet injections was evaluated in a rabbit model of Herpes simplex virus type-1 (HSV-1) retinitis. In untreated infected animals, viral titration revealed that the optic chiasm, vitreous and chorioretina were positive for HSV-1. On the other hand, foscarnet treatment significantly decreased the viral count in the chorioretina when compared to the untreated group. Immunolocalization of HSV in untreated infected animals clearly showed infected cells in the outer and inner layers of the retina and also in the ciliary body of the eye. Clinical examination by indirect ophthalmoscopy indicated an absence of optic nerve congestion and a lower level of vitritis in foscarnet treated animals compared to the untreated group. It is concluded that intravitreal injections of foscarnet reduced the viral titer in the chorioretina in a rabbit model of HSV-1 retinitis. This route of administration might be valuable for the treatment of CMV retinitis in AIDS patients with sight threatening lesions or intolerance to intravenous anti-CMV drugs.

Administration, Topical↗

PubMed1999

Protective effect of a thermoreversible gel against the toxicity of nonoxynol-9.

BACKGROUND AND OBJECTIVES: One major problem associated with the use of nonoxynol-9 is that it can induce local inflammation and ulceration of the vaginal and cervical mucosa that might favor the entry of pathogens. With the aim of developing a gel formulation that could be effective in preventing sexually transmitted infections, the authors have evaluated the capacity of a polyoxypropylene/polyoxyethylene polymer to reduce or eliminate the toxicity of nonoxynol-9. STUDY DESIGN: The cytotoxicity of nonoxynol-9 alone or incorporated into the gel was investigated in human cervical and colon epithelial cells and after daily intravaginal application for 2 weeks in rabbits. RESULTS: In vitro experiments showed that nonoxynol-9 was highly toxic to human cervical and colon epithelial cells in a dose-dependent manner. However, the incorporation of the spermicide into the gel markedly reduced its toxicity under the same experimental conditions. In vivo studies showed that in animals treated with nonoxynol-9, the spermicide was very toxic to the vaginal and cervical mucosa as evidenced by the presence of bleeding, irritation, epithelial disruption, necrosis, the accumulation of leukocytes in the submucosa, and the loss of integrity of the epithelial cells. Of prime importance, the incorporation of nonoxynol-9 into the gel markedly reduced the toxicity of this potent spermicide/microbicide. CONCLUSION: The gel formulation could be used as an interesting approach to eliminate the toxicity of potent spermicides/microbicides such as nonoxynol-9.

Animals↗

PubMed1999

Effect of fasting on temporal variation in the nephrotoxicity of amphotericin B in rats.

Evidence for temporal variation in the nephrotoxicity of amphotericin B was recently reported in experimental animals. The role of food in these variations was determined by studying the effect of a short fasting period on the temporal variation in the renal toxicity of amphotericin B. Twenty-eight normally fed and 28 fasted female Sprague-Dawley rats were used. Food was available ad libitum to the fed rats, while the fasted animals were fasted 12 h before and 24 h after amphotericin B injection to minimize stress for the animals. Water was available ad libitum to both groups of rats, which were maintained on a 14-h light, 10-h dark regimen (light on at 0600 h). Renal toxicity was determined by comparing the levels of excretion of renal enzyme and the serum creatinine and blood urea nitrogen (BUN) levels at the time of the maximal (0700 h) or the minimal (1900 h) nephrotoxicity after the intraperitoneal administration of a single dose of dextrose (5%; control group) or amphotericin B (50 mg/kg of body weight; treated group) to the rats. The nephrotoxicities obtained after amphotericin B administration at both times of day were compared to the nephrotoxicities observed for time-matched controls. In fed animals, the 24-h urinary excretion of N-acetyl-beta-D-glucosaminidase and beta-galactosidase was significantly higher when amphotericin B was injected at 0700 and 1900 h. The excretion of these two enzymes was reduced significantly (P < 0.05) in fasting rats, and this effect was larger at 0700 h (P < 0.05) than at 1900 h. The serum creatinine level was also significantly higher (P < 0.05) in fed animals treated at 0700 h than in fed animals treated at 1900 h. Fasting reduced significantly (P < 0.05) the increase in the serum creatinine level, and this effect was larger in the animals treated at 0700 h. Similar data were obtained for BUN levels. Amphotericin B accumulation was significantly higher (P < 0.05) in the renal cortexes of fed rats than in those of fasted animals, but there was no difference according to the time of injection. These results demonstrated that fasting reduces the nephrotoxicity of amphotericin B and that food availability is of crucial importance in the temporal variation in the renal toxicity of amphotericin B in rats.

Acetylglucosaminidase↗

PubMed1999

Effectiveness and toxicity of gentamicin in an experimental model of pyelonephritis: effect of the time of administration.

Temporal variations in the renal toxicity of aminoglycosides have been reported for experimental animals as well as for humans. In fact, maximal renal toxicity of aminoglycosides was observed when the drug was given during the rest period, while a lower toxicity was observed when the drug was injected during the activity period. The aim of the present study was to evaluate temporal variations in the effectiveness and renal toxicity of gentamicin in an experimental model of pyelonephritis in rats. The experiments were carried out with female Sprague-Dawley rats (185 to 250 g). They had free access to food and water throughout the study and were maintained on a 14-h light-10-h dark cycle. Animals were divided into four groups corresponding to the respective time of induction of pyelonephritis and treatment: 0700, 1300, 1900, and 0100 h. Pyelonephritis was induced by a direct inoculation of Escherichia coli (10(7) to 10(8) CFU) in the left kidney. Animals were treated for 3 and 7 days with a single daily dose of gentamicin (20 and 40 mg/kg of body weight, respectively) or saline (NaCl, 0.9%) at either 0700, 1300, 1900, or 0100 h. Animals treated at 0100 h for 3 days with gentamicin (20 mg/kg) showed a significantly lower number of bacteria in their kidneys than did all other groups (P < 0.01). After 7 days of treatment, the efficacy, evaluated by the log CFU per gram of tissue and by the percentage of sterilized kidneys, was also higher when gentamicin was administered at 0100 h. The beta-galactosidase and the N-acetyl-beta-D-glucosaminidase activities were significantly higher in urine of rats given gentamicin at 1300 h than in urine of rats treated at another time of day (P < 0.05). Gentamicin injected at 1300 h induced a significantly greater increase of [3H]thymidine incorporation into DNA of renal cortex (P < 0.01), a significantly greater inhibition of sphingomyelinase activity (P < 0.05), and significantly more histopathological lesions than the same dose injected at another time of the day. Creatinine and blood urea nitrogen levels in serum were significantly higher (P < 0.05) and the creatinine clearance was significantly lower (P < 0.05) when gentamicin was injected at 1300 h than when it was injected at another time of day. Our data suggest temporal variations in both the toxicity and the effectiveness of gentamicin, the drug being more effective and less toxic when injected during the activity period of the animals.

Animals↗

PubMed1998

Epstein-Barr virus infects and induces apoptosis in human neutrophils.

The role of neutrophils during Epstein-Barr virus (EBV) infection is not known. Disruption of the initial and nonspecific immune response may favor the spread of EBV infection. We have previously shown that EBV interacts with human neutrophils and modulates protein expression. In this study we have investigated the ability of EBV to infect neutrophils. Electron microscopy studies showed penetration of virus and its subsequent localization to the nucleus. The presence of viral genomes in isolated nuclei from neutrophils was also shown by polymerase chain reaction (PCR). Expression of viral transcripts like EBNA-2 (Epstein-Barr nuclear antigen-2) and ZEBRA (BamHI Z EBV replication activator) was not detected by reverse transcriptase (RT)-PCR, suggesting that EBV does not seem to establish a latent or a lytic infection in neutrophils. However, at 20 hours post-EBV infection, 77% of cells were apoptotic as compared to 22% in uninfected cell cultures, as evaluated by flow cytometry. This EBV-induced apoptosis was prevented by the addition of granulocyte-macrophage colony-stimulating factor to the cell cultures. Apoptotic cell death seems to implicate the Fas/Fas ligand (L) pathway, as reflected by an increase of Fas/Fas L expression on neutrophils treated with EBV and an increase of soluble Fas L, which may function in an autocrine/paracrine pathway to mediate cell death. Lastly, EBV genome was detected from neutrophils of infectious mononucleosis (IM) patients in contrast to neutrophils obtained from healthy EBV-seropositive donors. Our findings on the interactions of EBV with neutrophils will then provide new insights on the immunosuppressive effects associated with EBV infection.

Apoptosis↗

PubMed1998

Protective effect of ceftriaxone against the nephrotoxicity of isepamicin administered once daily in rats.

The protective effect of ceftriaxone on isepamicin-induced nephrotoxicity was investigated. For 14 d, Wistar rats were administered either ceftriaxone 100 mg/kg intraperitoneally, isepamicin 300 mg/kg subcutaneously, or ceftriaxone isepamicin in combination. The animals given 300 mg/kg of isepamicin showed a significant increase in urine NAG (N-acetyl-beta-D-glucosaminidase) levels as compared with the control animals which received saline (p<0.01). However, the increase in NAG level was markedly less when isepamicin was administered in combination with ceftriaxone (p<0.01). Ceftriaxone alone had no effect on urine NAG activity. Serum creatinine levels were significantly higher in animals treated with isepamicin alone than in control animals (p<0.01) or animals receiving the isepamicin ceftriaxone combination (p<0.01). After 14 d of treatment, ceftriaxone had not accumulated in renal tissue, but it did reduce the renal intracortical accumulation of isepamicin (p<0.01). Histopathologically, ceftriaxone induced very few cellular alterations and considerably reduced the manifestation of typical signs of isepamicin nephrotoxicity. This investigation demonstrates that ceftriaxone protects animals against isepamicin-induced nephrotoxicity.

Animals↗

PubMed1998

Expression of beta-catenin, alpha-catenin, and E-cadherin in Barrett's esophagus and esophageal adenocarcinomas.

Loss of expression and function of the E-cadherin/catenin membrane complex can result in loss of cell adhesion and contribute to invasive or metastatic potential in carcinomas. The aim of this study was to examine the expression of alpha- and beta-catenin and E-cadherin in Barrett's esophagus with and without dysplasia and in esophageal adenocarcinomas and to identify any relationship with tumor growth pattern and clinical outcome. Immunoperoxidase staining for alpha- and beta-catenin and E-cadherin was performed on specimens of Barrett's esophagus with and without dysplasia and on 54 esophageal adenocarcinoma specimens. Membranous staining for all of the components was seen in normal gastric and esophageal mucosa. Abnormal expression of beta-catenin, alpha-catenin, and E-cadherin was significantly associated with higher degrees of dysplasia in Barrett's esophagus. Fourteen of 16 cases of high grade dysplasia and 7 of 7 cases of intramucosal carcinoma showed abnormal expression of beta-catenin, compared with 3 of 6 cases indefinite for dysplasia and 11 of 17 cases with low grade dysplasia (P = 0.022). Similar results were seen for expression of alpha-catenin (P < .01) and E-cadherin (P = .049). In esophageal adenocarcinomas, preserved expression of these proteins occurred more frequently in well-differentiated tumors; abnormal expression was more common in diffusely infiltrative poorly differentiated tumors that did not form glands. Focal nuclear staining for beta-catenin was present in two high-grade dysplasias, two intramucosal carcinomas, and five adenocarcinomas. No survival advantage was demonstrated for patients whose tumors retained expression of these cell adhesion components. In conclusion, abnormal expression of the E-cadherin/catenin membrane complex is common in esophageal adenocarcinoma and occurs early in the dysplasia/carcinoma sequence in Barrett's esophagus, indicating that disturbances in this cell adhesion complex might be important in tumorigenesis and tumor progression in this disorder.

Adenocarcinoma↗