Characteristic mTOR activity in Hodgkin-lymphomas offers a potential therapeutic target in high risk disease – a combined tissue microarray, in vitro and in vivo study

BACKGROUND: Targeting signaling pathways is an attractive approach in many malignancies. The PI3K/Akt/mTOR pathway is activated in a number of human neoplasms, accompanied by lower overall and/or disease free survival. mTOR kinase inhibitors have been introduced in the therapy of renal cell carcinoma and mantle cell lymphoma, and several trials are currently underway. However, the pathological characterization of mTOR activity in lymphomas is still incomplete. METHODS: mTOR activity and the elements of mTOR complexes were investigated by immunohistochemistry on tissue microarrays representing different human non-Hodgkin-lymphomas (81 cases) and Hodgkin-lymphomas (87 cases). The expression of phospho-mTOR, phospho-4EBP1, phospho-p70S6K, phospho-S6, Rictor, Raptor and Bcl-2, Bcl-xL, Survivin and NF-kappaB-p50 were evaluated, and mTOR activity was statistically analyzed along with 5-year survival data. The in vitro and in vivo effect of the mTOR inhibitor rapamycin was also examined in human Hodgkin-lymphoma cell lines. RESULTS: The majority (>50%) of mantle cell lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, anaplastic large-cell lymphoma and Hodgkin-lymphoma cases showed higher mTOR activity compared to normal lymphoid tissues. Hodgkin-lymphoma was characterized by high mTOR activity in 93% of the cases, and Bcl-xL and NF-kappaB expression correlated with this mTOR activity. High mTOR activity was observed in the case of both favorable and unfavorable clinical response. Low mTOR activity was accompanied by complete remission and at least 5-year disease free survival in Hodgkin-lymphoma patients. However, statistical analysis did not identify correlation beetween mTOR activity and different clinical data of HL patients, such as survival. We also found that Rictor (mTORC2) was not overexpressed in Hodgkin-lymphoma biopsies and cell lines. Rapamycin inhibited proliferation and induced apoptosis in Hodgkin-lymphoma cells both in vitro and in vivo, moreover, it increased the apoptotic effect of chemotherapeutic agents. CONCLUSIONS: Targeting mTOR activity may be a potential therapeutic tool in lymphomas. The presence of mTOR activity probably indicates that the inclusion of mTOR inhibition in the therapy of Hodgkin-lymphomas may be feasible and beneficial, especially when standard protocols are ineffective, and it may also allow dose reduction in order to decrease late treatment toxicity. Most likely, the combination of mTOR inhibitors with other agents will offer the highest efficiency for achieving the best clinical response

Bulimic eating disorders in primary care : hidden morbidity still?

The current study examined the features of women with bulimic-type eating disorders ( n = 24) attending primary care in two smaller urban regions of the USA. The assessment included measures of eating disorder psychopathology, medical comorbidity, impairment in role functioning, potential barriers to treatment and actual use of health services. Eating disorders, primarily variants of bulimia nervosa and binge eating disorder not meeting formal diagnostic criteria, were associated with marked impairment in psychosocial functioning. Although two-thirds of participants recognized a problem with their eating, less than 40% had ever sought treatment from a health professional for an eating or weight problem and only one in ten had sought such treatment from a mental health specialist. Only one-third had ever been asked about problems with eating by a primary care practitioner or other health professional. However, more than 80% had sought treatment from a health professional for symptoms of anxiety or depression. Most reported some degree of discomfort in discussing eating problems with others, and half reported that they would not be truthful about such problems if asked. Having an eating disorder was associated with several chronic medical conditions, including joint pain, gastrointestinal problems and fatigue. Although the small sample size limits any firm conclusions, the findings suggest that the health burden of bulimic-type eating disorders is substantial but remains largely hidden. Efforts may be needed to improve the eating disorders “mental health literacy” of both patients and primary care practitioners in order to facilitate early, appropriate intervention