mTOR as a target of everolimus in refractory/relapsed Hodgkin lymphoma

Despite impressive treatment advances, few options for refractory or relapsed Hodgkin Lymphoma (HL) are available and there is a need for new compounds development. A number of promising agents with multiple mechanisms of action are under investigation. Microenvironment and neoangiogenesis are acquiring a rising relevance in the pathophysiology and progression of HL. Everolimus (RAD001) is an oral antineoplastic agent derived from rapamycin, a macrocyclic lactone antibiotic, targeting the mammalian target of rapamycin (mTOR). Although the importance of mTOR signaling in the deregulated cell growth of human neoplastic cells has been recognized, this pathway is also emerging as a key regulator of the tumor response to hypoxia, as well as endothelial and stromal cells function, thereby regulating neoangiogenesis. Furthermore, mTOR plays an important role in anticancer drug resistance. The actions of everolimus within the mTOR pathway in HL result in decreased protein synthesis and cell cycle arrest, as well as in decreased angiogenesis. Everolimus has shown preliminary evidence of efficacy as a single-agent in heavily pretreated relapsed/refractory HL, with an overall fair safety profile. The purpose of this review is to discuss the employment of everolimus as an antiproliferative and antiangiogenic agent in HL and to report the critical role of the mTOR pathway and angiogenesis in this malignancy.     

Oral cyclophosphamide improves pulmonary function in scleroderma patients with fibrosing alveolitis: experience in one centre

Lung involvement constitutes nowadays the major cause of morbidity and mortality in scleroderma patients. Pulmonary fibrosis in systemic sclerosis (SSc) is thought to be the consequence of interstitial inflammation. Early diagnosis and treatment of active alveolitis is essential to prevent the deterioration of pulmonary function, improving outcome in SSc patients. The aim of the study was to investigate the effect of 1-year treatment with oral cyclophosphamide (CYC) on the evolution of interstitial lung disease in scleroderma patients with a diagnosis of active alveolitis. An open-label one-arm monocenteric study was conducted on 33 scleroderma patients with active alveolitis—defined as the presence of areas of ‘ground-glass attenuation’ on high-resolution computed tomography and a recent deterioration in lung function—treated with oral CYC 2 mg kg⁻¹ day⁻¹ for 1 year and medium-low dose steroids (prednisone 25 mg for 3 months and then tapered to 5 mg/day). Results showed that diffusing capacity for carbon monoxide (DLco) values remained stable after 6 months of treatment and significantly increased after 12 months (2.06±1.38, 2.21±1.62 and 2.39±1.64 mmol/min/kPa, at baseline/6/12 months, respectively; p<0.001 12th month vs baseline) vital capacity (VC) values slightly increased (i.e. stabilised) in the same time frame (2.46±0.71, 2.41±0.76 and 2.56±0.75 l). Accordingly, the vast majority of our patients (n=29, 87.9%) presented a DLco and/or a VC improvement or stabilisation with respect to baseline. Favourable results were more likely to be observed in patients with a lower Wells’ radiological grade (grade I). In 25 patients followed up for further 12 months after the interruption of therapy, VC and DLco remained stable. Thus, long-term therapy with oral CYC is effective in ameliorating and/or stabilising lung function in scleroderma patients with active alveolitis, with beneficial effects lasting up to 1 year after interruption. The higher efficacy in those patients with an early pulmonary disease stage and a lower radiological grade underlies the importance of an early diagnosis and intervention.     

Urine erythrocyte morphology in patients with microscopic haematuria caused by a glomerulopathy

The evaluation of urinary erythrocyte morphology (UEM) has been proposed for patients with isolated microscopic haematuria (IMH) to early orientate the diagnosis towards a glomerular or a nonglomerular disease. However, to date, the role of this test in patients with IMH has very rarely been investigated. Sixteen patients (ten children, six adults) with persistent IMH classified as glomerular on the basis of repeated UEM evaluations (55 urine samples, two to eight per patient) were submitted to renal biopsy. This showed a glomerular disease in 14/16 patients (87.5%) (nine thin basement membrane disease; three Alport syndrome; two other), whereas in two patients, no abnormalities were found. Of four microscopic criteria investigated to define a IMH as glomerular, >80% dysmorphic erythrocytes were not found in any sample, >or=40% dysmorphic erythrocytes alone were seen in seven samples (12.7%), >or=5% acanthocytes alone in 15 samples (27.3%) and erythrocytic casts in six samples (10.9%). There was >or=40% dysmorphic erythrocytes associated with >or=5% acanthocytes in 25 samples (45.5%). Sensitivity and positive predictive values in diagnosing a glomerular haematuria were 59.2% and 90.6%, respectively, for >or=40% dysmorphic erythrocytes, 69.4% and 85% for >or=5% acanthocytes/G1 cells and 12.2% and 100% for erythrocytic casts. Our findings demonstrate that the evaluation of UEM is useful to identify patients with an IMH of glomerular origin.     

Endogenous substrates of the semicarbazide-sensitive amine oxidase increased nitric oxide production in rat white adipocytes

Inflammation Research -     

Regression of a congenital mesoblastic nephroma

Histologically, the cellular variant of congenital mesoblastic nephroma (CMN) is very similar to another rare tumor of infancy, infantile fibrosarcoma (IFS). In addition to the histologic similarities, these tumor types share cytogenetic abnormalities including translocation t(12;15)(p13;q25). We describe herein the case of a child who did not have immediate surgical resection of a CMN and whose tumor was untreated for 8 months. During that time, the tumor demonstrated a significant degree of regression. The shared translocation with IFS, a tumor with well‐documented potential for spontaneous regression, suggests that this genetic abnormality may have contributed to the favorable clinical course. Pediatr Blood Cancer. 2010;55:364–368. © 2010 Wiley–Liss, Inc.     

Asthma, cardiac arrhythmias, and albuterol aerosol

Twenty asthmatic patients clinically free of heart disease were studied for the possible arrhythmogenic action of albuterol (salbutamol). Two puffs of either albuterol or placebo were inhaled four times per day on two consecutive days and continuous ECG recordings obtained during each 24-hour period. Sixteen patients had atrial extrasystoles, four with albuterol, one with placebo, and 11 with both drugs. The extrasystoles/hour were 6.55 (23.75 SD) with albuterol and 8.37 (33.82) with placebo, a nonsignificant difference. Ventricular extrasystoles were shown in 11 patients, two with albuterol, two with placebo, and seven during both treatments. The extrasystoles/hour were 2.57 (6.36) and 3.10 (7.61) with albuterol and placebo, respectively. This difference was not significant. These findings suggest that therapeutic doses of albuterol aerosol in asthmatic patients without evidence of heart disease and severe hypoxemia should not be considered a cause of cardiac arrhythmias.     

T-cell acute lymphoblastic leukemia with t(11;14) in children.

We review and update our examination of the clinical and biologic findings in 19 cases of acute lymphoblastic leukemia (ALL) with the t(11;14) and discuss the literature relevant to the clinical, biologic, and molecular aspects of these translocations. In nine consecutively diagnosed cases at St. Jude Children's Research Hospital and 10 cases reported by other institutions, clinical features did not differ among T-cell ALL patients with and without the t(11;14), although leukemic cells with this translocation were more likely to coexpress CD4 and CD8 antigens. The t(11;14)(p13;q11) appears to occur exclusively in T-cell malignancies of intermediate- or late-stage thymocyte differentiation; further studies will be needed to determine whether it has prognostic significance.