Epidermal growth factor receptor and caveolin-1 coexpression identifies adult supratentorial ependymomas with rapid unfavorable outcomes

Supratentorial ependymomas account for a minority of intracranial ependymomas, which still have uncertain prognostic markers. Among them, epidermal growth factor receptor (EGFR) overexpression correlates with a poor prognosis. In glioblastoma cells, EGFR function has been reported to be regulated by its migration from cell membrane infoldings called caveolae and by its colocalization with the caveolae-associated protein caveolin-1 (cav-1). Therefore, we decided to investigate cav-1 expression and coexpression with EGFR in a series of adult intracranial ependymomas. We analyzed 22 adult supratentorial ependymomas and compared tumor grades as determined by the WHO classification and patient survival rates with the expression of EGFR, cav-1, and p53 and the values of the proliferation marker Ki-67, all tested by immunohistochemistry; in addition, we investigated the mutational profile of cav-1. The results demonstrate that the tumor grade is directly correlated with EGFR, Ki-67, and cav-1 expression only, whereas (by univariate analysis) the expression of all the studied markers, as well as the tumor histological grade, significantly correlated with the patient's overall survival (OS). By multivariate analysis using the Cox proportional hazards model, among all variables considered, cav-1 was the only independent prognostic marker related to OS (relative risk = 13.92; P = .013). Among grade II ependymomas, only cav-1 correlated with poor OS (P = .011), distinguishing 2 distinct subgroups of tumors with different outcomes despite sharing identical grading. All the patients studied carried wild-type cav-1 sequences, demonstrating that cav-1 overexpression is not driven by activating mutations, as previously reported in other tumor types. Interestingly, after stratifying all cases into 4 distinct groups according to cav-1 and EGFR expression (cav-1+/EGFR+, cav-1-/EGFR-, cav-1+/EGFR-, and cav-1-/EGFR+), the coexpression of cav-1 and EGFR identified a subset of patients with definitively poor prognoses. Further studies are needed to support this evidence on a larger scale and to clarify how cav-1 and EGFR interaction can influence tumor aggressiveness.     

Clinical features of community-acquired <Emphasis Type="Italic">Pseudomonas aeruginosa</Emphasis> urinary tract infections in children

This retrospective chart review sought to determine clinical, radiological, and gender-associated characteristics of community-acquired Pseudomonas aeruginosa (PA) urinary tract infections (UTIs) among children admitted to two medical centers. The records of 73 children with community-acquired PA UTIs were compared with records of 109 children with community-acquired UTIs caused by other pathogens. The mean age of both groups was similar. The PA UTI group included more boys. Features significantly more common in the PA UTI group were the number of patients who had undergone urinary tract surgery, patients with skeletal and/or neurological malformation, patients with >1 previous episode of UTI, patients on prophylactic antibiotic treatment on admission, and patients with pathological renal ultrasound and voiding cystourethrography (VCUG) findings. Multivariate logistic regression analysis revealed the following to be associated with PA UTI: >1 episode of UTI in the past [odds ratio (OR) = 35.5; 95% confidence interval (CI) 11.6–108.7], previous urinary tract surgery (OR = 34.1; 95% CI 7.00–166.2), and pathological VCUG results (OR = 2.62; 95% CI 0.96–7.15). In conclusion, PA UTI is associated with >1 previous UTI, urinary tract abnormalities, and past urinary tract surgery. We recommend that when UTI is suspected in children with these risk factors, a thorough radiologic investigation, including a VCUG, should be considered. Drs. Goldman and Rosenfeld-Yehoshua contributed equally to this work.     

Stress hyperglycemia: a sign of familial diabetes in children

Stress hyperglycemia in children is considered a benign condition that usually does not mandate further investigation. In some clinical settings it might be the first sign of diabetes mellitus (DM). Two unrelated boys, one aged 2 years 7 months and the other aged 5 days, were evaluated in the emergency department for a febrile infection and found to have elevated blood glucose levels (238 and 150 mg/dL [preprandial], respectively). In both cases the elevated hemoglobin A1c levels (6.5% and 6.6%, respectively) combined with a history of gestational DM in the mother and positive family history for DM suggested maturity-onset diabetes of the young. Genetic analysis revealed 2 known heterozygote mutations in the glucokinase gene: c.697T→C p.C233R in the first case and c.616A→C p.T206P in the second case. Our findings suggest that stress hyperglycemia during early childhood in association with a positive family history of DM might be a sign of monogenic diabetes.     

Cathepsin B inhibition limits bone metastasis in breast cancer

Metastasis to bone is a major cause of morbidity in breast cancer patients, emphasizing the importance of identifying molecular drivers of bone metastasis for new therapeutic targets. The endogenous cysteine cathepsin inhibitor stefin A is a suppressor of breast cancer metastasis to bone that is coexpressed with cathepsin B in bone metastases. In this study, we used the immunocompetent 4T1.2 model of breast cancer which exhibits spontaneous bone metastasis to evaluate the function and therapeutic targeting potential of cathepsin B in this setting of advanced disease. Cathepsin B abundancy in the model mimicked human disease, both at the level of primary tumors and matched spinal metastases. RNA interference-mediated knockdown of cathepsin B in tumor cells reduced collagen I degradation in vitro and bone metastasis in vivo. Similarly, intraperitoneal administration of the highly selective cathepsin B inhibitor CA-074 reduced metastasis in tumor-bearing animals, a reduction that was not reproduced by the broad spectrum cysteine cathepsin inhibitor JPM-OEt. Notably, metastasis suppression by CA-074 was maintained in a late treatment setting, pointing to a role in metastatic outgrowth. Together, our findings established a prometastatic role for cathepsin B in distant metastasis and illustrated the therapeutic benefits of its selective inhibition in vivo.     

Bleeding, Obstruction, and Perforation in a Series of Patients With Aggressive Gastric Lymphoma Treated With Primary Chemotherapy

Background The management of patients with gastric lymphoma has evolved, with a shift toward nonsurgical treatment. The rates of surgical complications in patients receiving chemotherapy have been insufficiently studied. The objective of this study was to assess the frequency of bleeding, perforation, and gastric outlet obstruction in patients who received chemotherapy as primary treatment for gastric diffuse large B cell lymphoma (DLBCL).Methods We reviewed files of all patients with gastric DLBCL who were diagnosed and treated primarily with chemotherapy in our hospital between 1990 and 2005.Results Eighteen (25%) of 73 patients experienced surgical complications, of whom 6 (8%) underwent surgery. Eight patients (11%), six with active lymphoma, experienced gastric bleeding; one required gastrectomy. Eight patients (11%) developed gastric outlet obstruction, of whom three were treated conservatively, three required surgery, one stopped treatment, and one received further chemotherapy. Six of the eight patients had no evidence of active lymphoma at the time of obstruction. Two additional patients underwent gastrectomy due to resistant or relapsed disease. Gastric perforation was not observed. Median survival was 90 months for the entire series, 94 months for patients with gastric outlet obstruction, and 11.5 months for patients with gastric bleeding.Conclusions Given the rate of surgical complications, especially gastric bleeding and gastric outlet obstruction, there is still an important role for the surgical consultant in the treatment of patients with gastric DLBCL receiving chemotherapy. Gastric perforation, although frequently cited as a complication, is in fact rarely observed.     

Epidemiology of Crohn's disease in Israel: a survey of Israeli kibbutz settlements

OBJECTIVE: The prevalence of Crohn's disease ranges from 10 to 70 cases per 100,000 population, and is 3-8 times more common among Jews. However, this excess risk is not evident in the Jewish population of Israel. Recently we have described a significant increase in the prevalence and incidence of Crohn's disease in the south of Israel. The aim of this study was to confirm this trend in a stable population found in communal (kibbutz) settlements. METHODS: We repeated a community-based survey in 124,400 kibbutz residents, 10 yr after our first study. This population represents 5% of the Jewish population of Israel. All Crohn's disease patients were located by contacting the kibbutz clinics of the 269 kibbutz settlements (100% compliance). Data was updated to December 31st, 1997, which was designated the point prevalence date, and included information on gender, age, origin, education, profession, extent of the inflammatory process, clinical spectrum of the disease, therapy, complications of the disease, and treatment. The average annual incidence for the 10 yr was calculated from the prevalence data. Only cases with a definite diagnosis of Crohn's disease made in a recognized gastroenterology unit were accepted into the study. RESULTS: There were 81 confirmed cases of Crohn's disease and the prevalence rate rose from 25.5/100,000 in 1987 to 65.1/100,000 in 1997 (p < 0.001). The mean annual incidence rate for this period (1987-1997) is 5.0/100,000/yr. Prevalence rates were higher in women than men, and in those born in Israel or Europe/America than in Asia/Africa. The mean age at presentation of the disease was lower in 1997 than in 1987, 37.4 +/- 17.0 and 45.0 +/- 17.0 yr, respectively (p = 0.041). Prevalence was highest in men with > 16 yr of education, and in women with 11-12 yr education, 119.7 and 100.3/100,000, respectively. CONCLUSIONS: During the decade 1987-1997, the prevalence of Crohn's disease has increased in Israel and is approaching the rates in Europe and America.     

An in vivo role for Trypanosoma cruzi calreticulin in antiangiogenesis

Angiogenesis leads to neovascularization from existing blood vessels. It is associated with tumor growth and metastasis and is regulated by pro- and antiangiogenic molecules, some of them currently under clinical trials for cancer treatment. During the last few years we have cloned, sequenced and expressed a Trypanosoma cruzi calreticulin gene (TcCRT). Its product, TcCRT, a 45 kDa protein, is more than 50% identical to human CRT (HuCRT). TcCRT, present on the surface of trypomastigotes, binds both C1q and mannan binding lectin and inhibits the classical activation pathway of human complement. Since TcCRT is highly homologous to a functional antiangiogenic fragment from HuCRT (aa 120–180), recombinant (r) and native (n) TcCRT were tested in their antiangiogenic effects, in the chick embryonic chorioallantoid membrane (CAM) assay. Both proteins mediated highly significant antiangiogenic effects in the in vivo CAM assay. This effect was further substantiated in experiments showing that the plasmid construct pSecTag/TcCRT also displayed significant antiangiogenic properties, as compared to the empty vector. Most likely, the fact that antiangiogenic substances act preferentially on growing neoplasic tissues, but not on already established tumors, is due to their effects on emerging blood vessels. The results shown here indicate that TcCRT, like its human counterpart, has antiangiogenic properties. These properties may explain, at least partly, the reported antineoplasic effect of experimental T. cruzi infection.     

Prevalence and characteristics of heteroresistant vancomycin-intermediate Staphylococcus aureus bacteremia in a tertiary care center

Infections with S. aureus with heterogeneous intermediate resistance to vancomycin (hVISA) are occurring more frequently. The detection of these infections, their prevalence, clinical characteristics, and significance are controversial. During 2003 and 2004, all blood culture isolates of methicillin-resistant Staphylococcus aureus (264 patients) at the Sheba Medical Center, Tel Hashomer, Israel, were assessed for hVISA by using the Etest macromethod. A total of 16 patients (6%) were positive for hVISA. Resistance to teicoplanin alone and to vancomycin alone using the Etest macromethod was found in 14 and 10 patients, respectively. Standard MICs to vancomycin were between 1 to 4 mg/ml. Most of these isolates (12 of 16 [75%]) would have been missed without specific testing. The median number of bacteremic days was 4. Seven patients had positive blood cultures for more than 5 days. Twelve patients died, and for eight of these the deaths were directly related to hVISA sepsis. We found that hVISA bacteremia was prevalent in our institution, and we suggest seeking hVISA in patients with persistent S. aureus bacteremia.     

Extracellular phosphorylation converts pigment epithelium-derived factor from a neurotrophic to an antiangiogenic factor

The pigment epithelium-derived factor (PEDF) belongs to the superfamily of serine protease inhibitors (serpin). There have been 2 distinct functions attributed to this factor, which can act either as a neurotrophic or as an antiangiogenic factor. Besides its localization in the eye, PEDF was recently reported to be present also in human plasma. We found that PEDF purified from plasma is a phosphoprotein, which is extracellularly phosphorylated by protein kinase CK2 (CK2) and to a lesser degree, intracellularly, by protein kinase A (PKA). CK2 phosphorylates PEDF on 2 main residues, Ser24 and Ser114, and PKA phosphorylates PEDF on one residue only, Ser227. The physiologic relevance of these phosphorylations was determined using phosphorylation site mutants. We found that both CK2 and PKA phosphorylations of PEDF markedly affect its physiologic function. The fully CK2 phosphorylation site mutant S24, 114E abolished PEDF neurotrophic activity but enhanced its antiangiogenic activity, while the PKA phosphorylation site mutant S227E reduced PEDF antiangiogenic activity. This is a novel role of extracellular phosphorylation that is shown here to completely change the nature of PEDF from a neutrophic to an antiangiogenic factor.