Serum cytokines in follicular lymphoma. Correlation of TGF-ß and VEGF with survival.

The prognosis of follicular lymphoma could vary with the tumor immune microenvironment. We evaluated the prognostic value of serum levels of ten cytokines. Our study cohort included 60 follicular lymphoma patients and 20 controls. Serum was available at diagnosis in 31 patients, at first relapse in 18, and complete remission in 11. Bioplex technology was used for determination of nine cytokines [interleukin (IL)-1Ra, IL-6, IL-7, IL-10, IL-13, tumor necrosis factor alpha (TNF-α), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and basic fibroblast growth factor (b-FGF)]. Transforming growth factor beta (TGF-ß) was measured by sandwich enzyme-linked immunosorbent assay. IL-1Ra, IL-6, IL-7, IL-10, IL-13, TNF-α, VEGF, and PDGF levels were found increased in follicular lymphoma patients compared to controls. Multivariate analysis identified early stage and high TGF-ß levels as independent predictors of overall survival associated with improved outcome. High lactate dehydrogenase and VEGF levels were independently associated with poorer progression-free survival. These results show the prognostic value of TGF-ß and VEGF in follicular lymphoma and suggest their contribution to tumor microenvironment alterations.

Is surgical biopsy mandatory in case of atypical ductal hyperplasia on 11-gauge core needle biopsy? A retrospective study of 300 patients.

BACKGROUND: Atypical ductal hyperplasia (ADH) is diagnosed in 4% to 10% of directional vacuum-assisted stereotactic biopsies (DVABs) performed for microcalcifications. Since the underestimation rate varies from 7% to 36%, surgical excision is still recommended, although some authors have tried to identify a subset of patients who can be spared surgery. METHODS AND RESULTS: In this study, we analyzed a retrospective series of 300 patients with ADH on 11-gauge DVAB. The only 4 events that occurred (3%) in 135 of 184 patients (61%) who were followed may not be due to underestimation. Comparing the diagnoses on DVAB and surgical excisions for 116 patients (39%), we identified 3 subsets of patients: no underestimation (size <6 mm and complete removal), low rate of 4% (< or =2 foci ADH in microcalcifications either <6 mm with incomplete removal or > or =6 mm and <21 mm), and high rate of 36% to 38% (>2 foci ADH in microcalcifications either <6 mm with incomplete removal or > or =6 mm and <21 mm, lesion size > or =21 mm). CONCLUSIONS: Our results suggest that strict follow-up can be a safe option for the first 2 groups of patients, but that surgical excision is mandatory for patients from the third group.

Combination of rituximab with chemotherapy in diffuse large B-cell lymphoma. Evaluation in daily practice before and after approval of rituximab in this indication.

Randomized trials have demonstrated improved outcome from adding rituximab to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) for patients with diffuse large B-cell lymphoma (DLBCL). This retrospective study compared the outcomes of 224 patients with DLBCL treated in our institution before (Period 1, 1996-2002) and after (Period 2, 2002-2005) approval of rituximab in this indication to evaluate the impact of the drug in daily practice in unselected patients receiving different types of chemotherapy. We treated 131 patients in Period 1 versus 93 in Period 2 (median follow-up, 75 and 29 months, respectively) with no difference in patient characteristics between the two periods. Event-free and overall survivals (EFS and OS) were significantly improved in Period 2 for elderly patients and a significant shift in the selection of regimens was observed at the time when rituximab became available. More patients received the CHOP regimen in Period 2 than in Period 1 (82 vs. 57%, p < 0.007) with CHOP being substituted for epirubicin-based regimens. In younger patients treated mostly with the ACVBP regimen (doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone) these differences were not observed, suggesting that combination of rituximab with dose-dense chemotherapy may deserve further evaluation in this age group.

Angioimmunoblastic T-cell lymphoma: clinical and laboratory features at diagnosis in 77 patients.

We retrospectively analyzed 77 patients with pathologically diagnosed angioimmunoblastic T-cell lymphoma from a single city. There were 43 men and 34 women; the median age was 64.5 years (range, 30-91 yr). Average time between first symptoms of the disease and diagnosis was 3.6 months. At diagnosis, peripheral nodes were present in all but 1 patient, and were generalized in 90% of cases. Constitutional symptoms were reported in 77% of cases and spleen enlargement in 51%. A cutaneous eruption--morbilliform, urticarial, or more polymorphic--was present in 45% of patients; in one-third of them, the eruption occurred after drug administration. Other clinical manifestations included pleuritis (22%); arthralgia or arthritis (17%); ear, nose, and throat involvement (14%); central or peripheral neurologic manifestations (10%); and ascites (5%). Most patients presented with advanced disease at diagnosis (bone marrow involvement in 60% of cases). The main laboratory abnormalities were elevated lactate dehydrogenase levels (71%), inflammatory syndrome (67%), hypergammaglobulinemia (50%), anemia (51%), and lymphopenia (52%). Auto- or disimmune manifestations were reported in one-third of patients: autoimmune hemolytic anemia was present at diagnosis in 19% of patients and thrombocytopenic purpura in 7%. Documented vasculitis was described in 12% of cases. Clonality was analyzed in lymph nodes in 47 patients: T-cell and B-cell clones were found in 45 (96%) and 20 (45%) patients, respectively. Chromosomal abnormalities were identified in 62% of cases: trisomies 3, 5, 18, 19, additional X chromosome, and deletion of chromosome 7 were the most common abnormalities. The current study underlines the diversity of presenting manifestations of angioimmunoblastic T-cell lymphoma.

ANG II type 1 receptor antagonist irbesartan inhibits coronary angiogenesis stimulated by chronic intermittent hypoxia in neonatal rats.

Chronic hypoxia has been shown to stimulate myocardial microvascular growth and improve cardiac ischemic tolerance in young and adult rats. The aim of this study was to determine whether the ANG II type 1 receptor (AT(1)) pathway was involved in these processes. Newborn Wistar rats, exposed to chronic intermittent hypoxia (8 h/day) for 10 days, were simultaneously treated with AT(1) receptor blocker irbesartan and compared with untreated animals. The major finding is that chronic hypoxia increased the capillary supply of myocardial tissue, which was even more pronounced in hypertrophied right ventricle, whereas increased arteriolar supply was found only in the left ventricle. This angiogenic response was completely prevented by irbesartan. Moreover, chronic hypoxia improved the postischemic recovery of cardiac contractile function during reperfusion, and this protective effect was also completely abolished by irbesartan. Chronic hypoxia increased the myocardial density of AT(1) but not of ANG II type 2 receptor subtypes, whereas the effect of irbesartan was not significant. The expression of caveolin-1alpha markedly increased in response to chronic hypoxia, and irbesartan prevented this effect. Neither hypoxia nor irbesartan treatment altered the expression of nitric oxide synthase 3, heat shock protein 90, and VEGF. It is concluded that the AT(1) receptor pathway plays an important role in coronary angiogenesis and improved cardiac ischemic tolerance induced in neonatal rats by chronic hypoxia.

Second autologous transplantation after failure of a first autologous transplant in 18 patients with non-Hodgkin's lymphoma.

High-dose chemotherapy and autologous marrow or peripheral stem cell support offers the best chance of cure in some subgroups of patients with non-Hodgkin's lymphoma (NHL). Less is known about the role of a second course of myeloablative chemotherapy in patients who relapse after a first autologous transplant. The aim of this retrospective study was to evaluate the disease outcome, morbidity and mortality associated with second autologous transplantation in patients with NHL. Between 1985 and 2001, 225 patients who had received autologous transplantation for NHL in two institutions in Lyon relapsed. Of these 225 patients 18 underwent a second autologous transplantation. The median age at second transplant was 41 years. There were six indolent lymphomas and 12 aggressive lymphomas. The median follow-up from the second transplant was 42 months. The OS rate at 2 and 5 years were 58 and 27%, respectively. The PFS rate at 2 and 5 years was 36%. Five patients are alive without disease 20 to 100 months after the second transplant. Seven patients died of disease recurrence. Four (22%) toxic deaths occurred: one of pulmonary fibrosis, one of fungal infection and cardiac failure and two of acute leukaemia. A minority of patients with NHL recurrence after a first transplant can be cured by a second course of myeloablative chemotherapy at the cost however of high-risk toxic death.

Expression of angiotensin type II receptor downregulates Cdk4 synthesis and inhibits cell-cycle progression.

Accumulating evidence suggests that angiotensin II type II (AT(2)) receptor subtype negatively regulates cell proliferation in pathophysiological conditions associated with tissue remodeling. However, the mechanisms through which AT(2) receptor achieves this effect remain poorly understood. In this study, we demonstrate that expression of AT(2) receptor inhibits the proliferation of rat fibroblasts in a ligand-independent manner. The antiproliferative action of AT(2) is dependent on the density of surface receptors. We show that AT(2) receptor expression negatively regulates G1 phase progression in both cycling cells and G0-arrested cells stimulated to re-enter the cell cycle, but has no detectable effect on apoptosis. The delay in cell-cycle progression of AT(2)-expressing cells is associated with downregulation of cyclin E expression, decreased assembly of cyclin E-Cdk2 complexes, and the resulting attenuation of Cdk2 activation. The induction of Cdk4 expression and activity is also markedly attenuated, which likely contributes to the inhibition of cyclin E expression. Ectopic expression of Cdk4 alleviates the proliferation defect of AT(2)-expressing cells. These findings suggest that the growth-inhibitory effects of the AT(2) receptor are attributable in part to its spontaneous inhibitory action on the cell cycle machinery.

Cardiac modulations of ANG II receptor expression in rats with hypoxic pulmonary hypertension.

Right ventricular myocardial hypertrophy during hypoxic pulmonary hypertension is associated with local renin-angiotensin system activation. The expression of angiotensin II type 1 (AT(1)) and type 2 (AT(2)) receptors in this setting has never been investigated. We have therefore examined the chronic hypoxia pattern of AT(1) and AT(2) expression in the right and left cardiac ventricles, using in situ binding and RT-PCR assays. Hypoxia produced right, but not left, ventricular hypertrophy after 7, 14, and 21 days, respectively. Hypoxia for 2 days was associated in each ventricle with a simultaneous and transient increase (P < 0.05) in AT(1) binding and AT(1) mRNA levels in the absence of any significant change in AT(2) expression level. Only after 14 days of hypoxia, AT(2) binding increased (P < 0.05) in the two ventricles, concomitantly with a right ventricular decrease (P < 0.05) in AT(2) mRNA. Along these data, AT(1) and AT(2) binding remained unchanged in both the left and hypertrophied right ventricles from rats treated with monocrotaline for 30 days. These results indicate that chronic hypoxia induces modulations of AT(1) and AT(2) receptors in both cardiac ventricles probably through direct and indirect mechanisms, respectively, which modulations may participate in myogenic (at the level of smooth or striated myocytes) rather than in the growth response of the heart to hypoxia.

Angiotensin II AT(2) receptor inhibits smooth muscle cell migration via fibronectin cell production and binding.

To explore the vascular function of the angiotensin II (ANG II) AT(2) receptor subtype (AT(2)R), we generated a vascular smooth muscle cell (SMC) line expressing the AT(2)R (SMC-vAT(2)). The involvement of AT(2)R in the motility response of SMCs was examined in SMC-vAT(2) cells and their controls (SMC-v) cultured on either laminin or fibronectin matrix proteins with the agarose drop technique. All experiments were conducted in the presence of a saturating concentration of losartan to inactivate the AT(1)R subtype. Under basal conditions, both cell lines migrated outside drops, but on laminin only. Treatment with ANG II significantly inhibited the migration of SMC-vAT(2) but not SMC-v cells, and this effect was prevented by the AT(2)R antagonist CGP-42112A. The decreased migration of SMC-vAT(2) was not associated with changes in cell growth, cytoskeleton stiffness, or smooth muscle actin, desmin, and tenascin expression. However, it was correlated with increased synthesis and binding of fibronectin. Both responses were prevented by incubation with selective AT(2)R antagonists. Addition of GRGDTP peptide, which prevents cell attachment of fibronectin, reversed the AT(2)R inhibitory effect on SMC-vAT(2) migration. These results suggest that activated ANG II AT(2)R inhibits SMC migration via cellular fibronectin synthesis and associated cell binding.