TGFβ signalling is required for normal cardiac development. To investigate which cell types are involved, we used mice carrying a floxed Type II TGFβ receptor (Tgfbr2fl) allele and Cre‐lox genetics to deplete this receptor in different regions of the heart. The three target tissues and corresponding Cre transgenic lines were atrioventricular myocardium (using cGata6‐Cre), ventricular myocardium (using Mlc2v‐Cre), and vascular endothelium (using tamoxifen‐activated Cdh5(PAC)‐CreERT2). Spatio‐temporal Cre activity in each case was tracked via lacZ activation from the Rosa26R locus. Atrioventricular‐myocardial‐specific Tgfbr2 knockout (KO) embryos had short septal leaflets of the tricuspid valve, whereas ventricular myocardial‐specific KO embryos mainly exhibited a normal cardiac phenotype. Inactivation of Tgfbr2 in endothelial cells from E11.5 resulted in deficient ventricular septation, accompanied by haemorrhage from cerebral blood vessels. We conclude that TGFβ signalling through the Tgfbr2 receptor, in endothelial cells, plays an important role in cardiac development, and is essential for cerebral vascular integrity. Developmental Dynamics 239:2435–2442, 2010. © 2010 Wiley‐Liss, Inc.

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Patients (pts) with CLL have diverse clinical features, including time to first treatment (Rx), response to Rx, remission duration, and outcomes with salvage Rx. We identified serum beta-2 microglobulin (B2M) of 4 mg/L or greater as a high-risk feature, predicting for lower complete remission (CR) rate and shorter progression-free survival (PFS), with frontline chemoimmunotherapy. For pts <70 years old and B2M≥4 treated with the fludarabine (F), cyclophosphamide (C), rituximab (R)-based combination, the CR rate and estimated median PFS were 59% and 60 mo, compared to 81% CR and 80 mo PFS for similar aged pts with B2M<4. We combined FCR with alemtuzumab (A) in the CFAR regimen that was well-tolerated and had activity in treating relapsed/refractory pts. The CFAR regimen is being evaluated in higher-risk pts with an NCI indication for frontline therapy. Frontline CFAR consists of C-200mg/m2 d3–5; F-20mg/m2 d3–5; A-30mg IV d1,3,5, and R-375–500mg/m2 d2, each 28 days for 6 intended courses. Tumor lysis prophylaxis was allopurinol 300 mg/d for 7d, course 1 only. Neulasta 6mg d6 was routine. Antibiotic prophylaxis was TMP-SMZ DS twice daily 2–3 d/wk and valacyclovir (VA) or valgancyclovir (VG) during and for at least 2 months after completion of treatment. CMV antigen in blood was monitored before each course. There currently are 40 pts registered on this trial. The median age for the 21 pts currently evaluable for response was 63 yrs (43–69), B2M was 5.1mg/L (4–9.8), ALC was 72 K/μL (6–355), HGB was 10.9gm/dL (7.9–13.5), and PLT was 158 K/μL (65–390); 13 were Rai high-risk. The median time from diagnosis to Rx was 35 (2–117) mo. The median number of cycles administered was 4 (3–6). Reasons for not completing 6 courses included delayed recovery of counts (6), pt choice (3), AIHA (2), infection (1), and Rx failure (1). CR was achieved in 71%, nPR in 5%, PR in 19%, and 1 pt of 21 did not respond. All pts in CR and nPR and 3 of 4 in PR were free of disease in the bone marrow by 3-color flow cytometry. There was no significant correlation between CR or OR and Rai stage, IgVH mutation status, FISH status, or ZAP70 or CD38 expression. Grade 3 or 4 neutropenia and thrombocytopenia were seen in 27% and 7% of courses, respectively. Major and minor infections were seen in 2% and 8% of courses and FUO in 34% of courses. These FUO included A-infusion related fevers. CMV reactivation occurred in 2/8 pts who received VA and none of 13 pts who received VG prophylaxis during treatment. Two pts developed CMV reactivation 3–6 months after they switched from VG to VA after completing CFAR. In conclusion, CFAR is an active and promising frontline regimen in higher-risk pts with CLL. Accrual and treatment continue on this clinical trial.

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