Overexpressed eIF4E is functionally active in surgical margins of head and neck cancer patients via activation of the Akt/mammalian target of rapamycin pathway.

PURPOSE: Overexpression of eIF4E in surgical margins of head and neck cancer patients is an independent risk factor for recurrence. We hypothesize that overexpressed eIF4E is functionally active in tumor margins through activation of the Akt/mammalian target of rapamycin (mTOR) pathway EXPERIMENTAL DESIGN: Western blots and/or immunohistochemistry were performed to determine whether phosphorylation of mTOR and activation of its downstream molecules eIF4E-binding protein-1 (4E-BP1) and p70 S6 kinase and the upstream modulator of mTOR, Akt, were expressed in margins overexpressing eIF4E. RESULTS: There was a significant association between phospho-4E-BP1 and eIF4E expression of a margin or a significant difference in phospho-4E-BP1 expression between the eIF4E-positive and -negative margins (P < 0.01). A significant association between eIF4E and phospho-p70 S6 kinase as well as eIF4E and phospho-mTOR was also noted (P < 0.05). Western blot analysis indicated a highly significant difference in the phosphorylation status of 4E-BP1 between tumors and resection margins. A total of 89% of the 4E-BP1-expressing margins expressed more of the phosphorylated (beta, gamma, and delta) isoforms, whereas 81% of the 4E-BP1-expressing tumors expressed more of the unphosphorylated alpha isoform. A similar difference in Akt activation was noted between eIF4E-positive margins and tumors (P < 0.05). CONCLUSIONS: Overexpression of eIF4E is functionally active in tumor margins through activation of the Akt/mTOR signaling pathway. The greater degree of expression of downstream targets and upstream regulators of mTOR in margins compared with the tumors indicates preferential activation of the Akt/mTOR signaling pathway in margins overexpressing eIF4E. Rapamycin analogs can potentially be used as adjuvant therapy for patients with eIF4E-positive margins.     

Prognostic factors for patients with chronic myeloid leukaemia in chronic phase treated with imatinib mesylate after failure of interferon alfa.

We assessed clinical results in 145 patients with chronic myeloid leukaemia in chronic phase who satisfied criteria for interferon-alpha failure and were thus eligible for treatment with imatinib at the Hammersmith Hospital. We used univariate and multivariate analyses to develop a risk score based on features defined after treatment for 3 months. We identified a low neutrophil count and poor cytogenetic response (<35% Ph-negative marrow metaphases) at 3 months as principal independent predictive factors and incorporated them into a three-tier prognostic scoring system for individual patients. For patients in the low-, intermediate- and high-risk groups, the probabilities of survival at 24 months were 100, 82 and 40% (P<0.0001) and progression-free survival 100, 66 and 15% (P<0.0001), respectively. This Hammersmith prognostic scoring system was validated with an independent cohort of patients treated at another UK centre.     

Non-compliance with lens care and maintenance in diabetic contact lens wearers

We hypothesize that diabetic contact lens wearers may represent a special group displaying higher levels of compliance with their lens care regimens as a result of learned behaviour relating to maintenance of their diabetic condition. To test this hypothesis, a prospective, single centre, controlled, masked study was performed whereby 29 diabetic contact lens patients and 29 non-diabetic control subjects were issued with disposable hydrogel contact lenses and a multipurpose lens care regimen. All participants were given identical instruction on lens care and maintenance. Compliance levels were assessed at a 12-month aftercare appointment by demonstration and questionnaire. Twenty-four different aspects of compliance were scored, 12 by observation and 12 by questionnaire report, of which only two showed a significant difference between the diabetic and control groups. Although the combined population of contact lens wearers was generally compliant, there were examples of non-compliance in both groups. Neither the duration of diabetes nor the degree of metabolic control appeared to have a significant effect on compliance. The results suggest that eye care practitioners cannot assume that diabetic patients will be more compliant with contact lens care and maintenance than non-diabetic patients.     

Controversies in the management of children with bronchiolitis

In this review, we present and summarize data from recently conducted research regarding controversial aspects of the management of children with bronchiolitis. These data suggest that chronic medical history, gestational age at birth, postnatal age, and physiological variables can identify those children at higher risk for a more severe course of bronchiolitis. Large prospective studies also suggest that the likelihood of significant bacterial illness in febrile infants with bronchiolitis may be lower than in children without bronchiolitis. Nevertheless, urinary tract infections remain relatively common in young febrile children with bronchiolitis. Lastly and unfortunately, the data note a relative lack of effective therapies for children with bronchiolitis, although certain therapies such as systemic corticosteroids show potential efficacy and are in need of further study. The remaining uncertainty surrounding many issues pertaining to bronchiolitis highlight the need for more research aimed to: (1) develop prognostic models to identify patients at risk for a more severe clinical course, (2) develop generalizable diagnostic models to identify febrile infants with bronchiolitis at high and very low risk of significant bacterial illness, and (3) evaluate the effectiveness of promising therapies.     

A benign congenital myopathy in an inbred Samaritan family.

We describe a novel form of myopathy in a mother and her two daughters from an inbred Samaritan family. The patients displayed severe neonatal hypotonia, lethargy and dysmorphic features. Motor milestones were delayed; however, the hypotonia and muscle weakness gradually improved during the first 2 years of life and independent walking was achieved by 18 months. The mother at the age of 23 years shows myopathic facies and minimal proximal weakness. Her intelligence is normal. Her muscle biopsy revealed central nuclei and disruption of the intermyofibrillary network with moth eaten and spiral fibers. Mutations in SMN, MTM1 and the myotonic dystrophy genes were excluded. We suggest this is a new benign form of congenital myopathy. Inheritance is probably autosomal recessive.